applied pharmacology and toxicology a. genetic and ... online lecture notes... · fpgop lecture...
TRANSCRIPT
Pharmacists Council of Nigeria
1 FPGOP Lecture Note on Applied Pharmacology and Toxicology
APPLIED PHARMACOLOGY AND TOXICOLOGY
A. GENETIC AND NUTRITIONAL FACTORS IN DRUG ACTION
Course outline
(1). Nutritional factors in drug action
(i). Malnutrition
(ii). Some features of protein-energy malnutrition and drug action
(iii). Miscellaneous dietary factors and drug action
(iv). Food-derived intoxicants
(2). Pharmacogenetics
Learning Objectives
At the end of the course participants should
(a). Explain how malnutrition, particularly protein-energy malnutrition, can influence drug
absorption, distribution, metabolism, excretion, and therapeutic effect.
(b). Mention poisons/intoxicants from food.
(c). State some constituents of our diet that may affect drug action, and how?
(d). Mention genetic factors involved in drug action, and the mechanisms involved.
(e). Understand the roles of pharmacogenetics, including its possible applications.
(f). Mention some drugs whose actions are affected by genetic polymorphisms, and the
mechanism(s) involved.
(g). Mention drugs and other substances to be avoided by G6PD deficient individuals.
A1. NUTRITIONAL FACTORS IN DRUG ACTION
Human nutrition deals with the provision of essential nutrients in food, that are necessary to
support life and health. Nutrition as a science, involves the interaction of nutrients and other
substances in food relative to maintenance, growth, reproduction, health and disease of
humans. It encompasses food intake, absorption, catabolism and excretion. Nutrition is
dependent on the diet. A good nutrition provides essential nutrients needed for good health and
sustenance, while poor nutrition or malnutrition results in morbidity and mortality.
(i). Malnutrition
Pharmacists Council of Nigeria
2 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Malnutrition is one of the major public health problems of the Third World and several million
people are underfed and suffer from deficiencies of essential nutrients.
Definition of Malnutrition
Malnutrition is a condition due to consumption of diet in which one or more nutrients are either
inadequate or in excess, resulting in ill health. Lack of adequate nutrients is called
undernutrition or undernourishment while too much is called overnutrition. Overnutrition may
result in being overweight, obesity and other disorders. Undernutrition may lead to starvation,
physical and mental underdevelopment, infections, and other diseases.
Generally, malnutrition is often used to specifically refer to undernutrition where an individual is
not getting enough calories, protein, or micronutrients. There are two main types of
undernutrition; protein-energy malnutrition and dietary deficiencies.
Protein-energy malnutrition (PEM) results when the body is lacking the calories it needs from
protein, carbohydrates and fats. In addition to macronutrient deficiency, there is clinical and/or
subclinical deficiency of micronutrients. Three forms of PEM are marasmus, kwashiorkor and
marasmic-kwashiorkor.
Kwashiokor
Kwashiorkor, also called protein malnutrition, is due to severe protein deficiency. Kwashiokor
was first described in children in 1932. The term kwashiorkor is derived from the Ga language
of coastal Ghana, translated as ‘the sickness the baby gets when the new baby comes’ or ‘the
disease of the deposed child’; this refers to the development of the disorder in an older child
who has been weaned from the breast when a younger sibling comes. In another dialect, it
connotes ‘red boy’, referring to the reddish orange discoloration of the hair that is characteristic
of the disease.
Kwashiorkor occurs in areas of famine or poor food supply, e.g. during the Nigerian civil war. It
is most often encountered in areas where the diet is high in starch and low in proteins, cases
are rare in the developed countries. In at-risk populations, kwashiorkor may develop after a
mother weans her child from breast milk (contains proteins and amino acids vital to a child's
growth), replacing it with a diet high in carbohydrates and low in proteins. It is common in
young children weaned to a diet consisting mainly of cereal grains, cassava, yam, sweet potato
or other foods high in carbohydrates. Ignorance of nutrition could also be a cause of
Pharmacists Council of Nigeria
3 FPGOP Lecture Note on Applied Pharmacology and Toxicology
kwashiorkor. In addition to protein-deficient diet, other causes of kwashiorkor include poor
intestinal absorption, chronic alcoholism, kidney disease, infection, and burns or other trauma
resulting in the abnormal loss of body protein.
Symptoms of kwashiorkor include distended abdomen with ascites, edema (including pitting
edema), thinning of hair reddish orange discoloration of the hair, dry skin, skin rash, skin
depigmentation, dermatitis, wide spread dermatosis, shock due to bacterial infection, weakness,
nervous irritability, anemia, digestive disturbances such as diarrhea, anorexia, enlarged liver
with fatty infiltrates, and delayed growth. Generally, the disease can be treated by adding
protein to the diet; however, it can have a long-term impact on a child's physical and mental
development, and in severe cases may lead to death.
Marasmus
Marasmus is a form of severe malnutrition characterized by energy deficiency. It can be
distinguished from kwashiorkor in that kwashiorkor is protein deficiency with adequate energy
intake whereas marasmus is inadequate energy intake in all forms, including protein (some
body protein is metabolized to supply the body’s energy needs, in cases of inadequate
carbohydrate intake).
It can occur in anyone with severe malnutrition but usually occurs in children. The incidence of
marasmus increases prior to 1 year of age, whereas kwashiorkor increases after 18 months. A
child with marasmus looks emaciated, body weight is reduced to less than 62% of the normal
(expected) body weight for the age. Protein wasting in kwashiorkor generally leads to edema
and ascites, while muscule wasting and loss of subcutaneous fat are the main clinical signs of
marasmus.
Precise separation of marasmus and kwashiorkor is however not always clinically evident and a
mixed clinical picture, called marasmic-kwashiorkor occurs.
(ii). Some features of protein-energy malnutrition and drug action
Nutritional status is one of the major factors that modify the pharmacological effect of drugs.
Macro- and micro-nutrient deficiencies cause pathological changes that interfere with
pharmacokinetic and pharmacodynamic processes in the body, resulting in altered drug
response. Studies in laboratory animals and in malnourished human subjects indicate that
dietary factors and nutritional status considerably influence absorption, distribution, plasma
Pharmacists Council of Nigeria
4 FPGOP Lecture Note on Applied Pharmacology and Toxicology
protein binding, metabolism and excretion of drugs; hence therapeutic response and toxicity are
likely to be altered.
In malnutrition, changes in nutrient transport, morphology of body tissues (e.g mucosal and
villous atrophy), permeability of the intestinal mucosa and activity of enzymes could contribute
to modifications in drug absorption. Drug distribution could be altered by changes in body
composition (such as changes in fat/lean body mass ratio secondary to malnutrition), and
decreased protein-binding capacity. Numerous studies have demonstrated that drug metabolism
may be affected by acute starvation, undernutrition, and deficiencies of macro- and
micronutrients. Liver dysfunction in malnutrition contributes to the altered metabolism of
drugs; also impaired renal function, especially in dehydration, significantly influences drug
excretion.
Definitely, kwashiorkor, marasmus, and other types of malnutrition may lead to many
pathophysiological changes which may subsequently influence pharmacokinetics and
pharmacodynamics of drugs. For instance, infections such as measles, malaria, acute
respiratory tract infection, intestinal parasitosis, tuberculosis and HIV/AIDS may complicate PEM
with two or more infections co-existing. Thus, numerous drugs may be required to treat the
patients. The treatment of malnourished patients is very difficult; and impaired nutritional status
may contribute to ineffective treatment of patients, especially those with severe concomitant
diseases. A good knowledge of pathophysiology of PEM and pharmacology of drugs frequently
used is essential for safe and rational treatment. The following features and pathophysiological
changes in PEM may affect drug disposition:
(a). Body fluid distribution: The total body water (TBW) is increased in proportion to the
degree of malnutrition. The increased TBW is associated with a proportional rise in extracellular
fliud, particularly in malnourished children with edema. Children with marasmus have the
highest TBW, while there is a significant reduction in adipose mass as well as lean body mass in
marasmus and marasmic- kwashiorkor which can alter the apparent volume of distribution of
drugs. The distribution of lipid soluble drugs into adipose tissues is reduced in PEM;
consequently, the concentration of a lipid soluble drug would increase at the target tissues,
prolonging the actions with possible increased toxicity.
Children with severe PEM may have edema, wide spread dermatosis and shock due to bacterial
infection. Infection is a major complication of PEM and may occur without the classical signs
Pharmacists Council of Nigeria
5 FPGOP Lecture Note on Applied Pharmacology and Toxicology
and symptoms. Consequently, the WHO has recommended that all children admitted with PEM
should routinely receive parenteral antibiotics. The clinical efficacy and toxicity potentials of
antibiotics are determined by their volume of distribution, penetration into superficial and deep
tissues, and other pharmacokinetic parameters. The volume of distribution of some drugs,
including antibiotics may be affected by the edematous state, and other pathophysiologic
features of PEM with consequent modification of drug action.
(b). Plasma protein concentration: Plasma protein concentration is low in edema, especially
in children. Hypoproteinemia is a common feature of PEM. Plasma albumin and fractions of the
glycoproteins responsible for binding drugs are decreased, leading to decreased protein binding.
This decreased protein binding may theoretically lead to an increase in the plasma free-drug
fractions of highly protein-bound drugs, variations in response to the drug, and risk of increased
drug toxicity. However, in clinical practice, decreased plasma protein has not been reported to
signficantly increase plasma free-drug fractions in PEM patients.
(c). Changes in the gastrointestinal system: Symptoms of PEM include diarrhea and
vomiting. With diarrhea and vomiting, orally administered drugs may not be retained;
nevertheless if retained, the intestinal transit time may be decreased. PEM is associated with
various degrees of intestinal malabsorption, e.g. villous atrophy of the jejunal mucosa resulting
in impaired drug absorption. The oral absorption of chloroquine, chloramphenicol, sulfadiazine
and carbamazepine have been demonstrated to decrease significantly, attributable to the
morphological changes in the jejunum, in children with PEM compared with healthy normal
children.
(d). Changes in hepatic function: Hepatic drug metabolism may be impaired in PEM,
leading to decreased clearance of some drugs.
(e). Changes in renal function: There may be renal dysfunction in PEM, as shown by
decreased glomerular filtration rate and renal blood flow in children with PEM, particularly in the
presence of dehydration. Also the edema observed in kwashiorkor and marasmic-kwashiokor
has been attributed to the inability of the kidneys to adequately excrete excess fluid and
sodium, as well as the presence of hypoproteinaemia and aflatoxins. The renal clearance of
penicillin, cefoxitin, gentamicin, ethambutol, and other drugs were shown to be decreased in
children with PEM. In malnourished patients, adjustment of doses of drugs primarily excreted
Pharmacists Council of Nigeria
6 FPGOP Lecture Note on Applied Pharmacology and Toxicology
by the kidneys using their relative weight and other specific features such as glomerular
filtration rate may be necessary.
(f). Deficiency in immune system: Malnutrition is one of the causes of secondary
immunodeficiency. Lack of proteins and immune mediators causes deficiency in humoral and
cellular immunity, with consequent increased infections in individuals with PEM.
(g). Changes in cardiovascular system: Heart failure occurs in severe PEM; also children
with severe PEM have a smaller and thinner heart, and a lower stroke volume. The inability of
the kidneys to adequately excrete excess fluid and sodium in kwashiorkor and marasmic-
kwashiokor, and the resultant edema adversely affects the heart. Consequently, there is volume
overload in the circulation, increased permeability of the cardiac cell membranes, and
ultimately, reduced cardiac contractility, pumping efficiency and stroke volume. Circulatory
insufficiency, as occurs in PEM, is associated with a prolonged circulation time and ineffective
transport of substances in the circulation; consequently there is inadequate absorption and
distribution of drugs and nutrients.
Furthermore, fluid retention would cause expansion of the extracellular fluid (ECF) volume and
may increase the volume of distribution of water soluble drugs.
(h). Changes in endocrine function: Insulin levels are decreased while growth hormone is
elevated in children with PEM. Serum triiodothyronine (T3) was found to be decreased with
normal thyroxine (T4) level in children with PEM, possibly due to a reversible defect in extra-
thyroidal conversion of T4 to T3. Though thyroid hormones are associated with the action of
some drugs, the implications of these findings in PEM are yet to be explored.
(iii). Miscellaneous dietary factors and drug action
An individual’s nutrition is dependent on the diet, which is what one eats as determined by the
availability and palatability of foods.
A healthy diet ensures balanced availability of nutrients in the food, and consists of micro- and
macronutrients needed for well-being, good health and sustenance. It also encompasses the
care and preparation of food, storage methods that prevent deterioration of nutrients and
reduce the risk of foodborne illness. Diet contributes to individual variations in drug response.
Pharmacists Council of Nigeria
7 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(a). Diet may affect the metabolism of drugs: Grapefruit and grapefruit juice inhibit
CYP3A4, and hence interact with several drugs; e.g. grapefruit juice inhibits the metabolism of
co-administered drugs such as halofantrine, erythromycin, quinine, alprazolam, cisapride,
cyclosporine, midazolam and triazolam atorvastatin, lovastatin, simvastatin nifedipine, etc.
Cruciferous vegetables (e.g. cabbage, broccoli, cauliflower) induce CYP1A2; consequently,
consumption of cruciferous vegetables may decrease bioavailability and half-life of some drugs
metabolized by CYP1A2 such as haloperidol and theophylline.
(b). Diet counteracts the effect of some drugs: Nutrient or food ingredient may oppose
the desired action of a drug. High fat diet counteracts the effect of antihyperlipidemic drugs
such as lovastatin or gemfibrozil. Vitamin K aids the production of clotting factors in direct
opposition to the action of warfarin. Caffeine (present in coffee, some teas) is a stimulant which
may counteract the effect of central nervous system depressants.
(c). Diet may enhance the effects or toxicity of drug: Foods or additives that have effects
similar to those of a drug, may enhance its effects or toxicity. High caffeine intake may increase
the central nervous system stimulant and other adverse effects of theophylline (such as
nervousness, tremor and insomnia). Tyramine (in e.g., strong or aged cheese, yeast extracts,
tofu and some red wines), dopamine or other vasoconstrictors in food enhance the toxic effects
of monoamine oxidase inhibitors, such as tranylcypromine; this effect may cause a hypertensive
crisis, which can be fatal. Diet rich in fat increases the absorption, bioavailability and toxicity of
halofantrine.
(iv). Food-derived intoxicants
Food-derived intoxicant is a toxin arising from food; it could be due to consumption of
contaminated food or improperly processed food. The intake of food derived intoxicants gives
rise to foodborne illness.
Foodborne illness (foodborne disease, food poisoning) results from consumption of food
contaminated with chemicals (from e.g. pesticides, storage cans, etc); pathogenic bacteria,
viruses, or parasites; and toxins (e.g. poisonous mushrooms). Foodborne illness may also result
from consumption of spoiled food, improperly processed food such as inadequately processed
cassava, and improperly cooked food e.g meat, beans, etc. The contamination of food may
occur at any stage in the process from food production to consumption (‘farm to fork’).
Pharmacists Council of Nigeria
8 FPGOP Lecture Note on Applied Pharmacology and Toxicology
The process of monitoring food to prevent foodborne illness is known as food safety. Good
safety and hygienic practices before, during, and after food preparation can reduce the chances
of introducing toxins to food. Regular hand-washing is one of the most effective ways to
prevent food contamination and spread of foodborne illness.
Sources of food-derived intoxicants
Food-derived intoxicants could arise from improper handling, preparation, or storage (e.g.
botulinum toxin) of food. Food-derived intoxicants could be from a large variety of
environmental toxins, pesticides, other chemicals (used during cultivation, preservation of
produce or ready-to-eat food), and natural toxic substances such as poisonous mushrooms,
plants or animals.
Toxins that may contaminate food include:
(a). Bacteria – For example, Staphyloccocus, Campylobacter jejuni, Salmonella, Escherichia
coli, Clostridium botulinum, Clostridium perfringens, Bacillus cereus, etc. Botulism occurs when
the anaerobic bacterium Clostridium botulinum grows in improperly canned low-acid foods and
produces botulinum toxin a neurotoxic protein, which causes flaccid paralysis. Tetrodotoxin, a
lethal toxin, is produced by Pseudoalteromonas tetraodonis, certain species of Pseudomonas
and Vibrio, and some other bacteria.
(b). Enterotoxins – In addition to disease caused by direct bacterial infection, some
foodborne illnesses are caused by enterotoxins (i.e. bacterial exotoxins targeting the intestines).
Enterotoxins are chromosomally encoded or plasmid encoded exotoxins that are produced and
secreted from several bacteria. Enterotoxins can produce illness even when the microbes that
produced them have been killed. Examples are staphylococcal enterotoxins A and B which occur
mainly in cooked and processed foods.
(c). Mycotoxins - Mycotoxins are produced by fungi that readily colonize crops. Mycotoxins
include aflatoxins (found in groundnuts, maize, etc.) and ochratoxins (found in dried fruit,
maize, wheat, oats and other cereals, etc.).
(d). Viruses – e.g. enteroviruses, hepatitis A
(e). Parasites – Parasites such as nematodes, platyhelminthes, and other helminths; protozoa
(e.g. Entamoeba histolytica, Giardia lamblia) also contaminate food and cause foodborne illness.
Pharmacists Council of Nigeria
9 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(f). Natural toxins - Some animals and plants used as food naturally contain toxins: e.g.
cyanide in cassava, phytohaemaagglutinin in red kidney beans; toxins in some fish, tetrodotoxin
is also found in moon snails, certain species of fish and octopus.
A2. PHARMACOGENETICS
Pharmacogenetics is the study of the genetic basis for individual variation in drug response.
Although individual differences in drug response can result from the effects of age, sex,
disease, or drug interactions, genetic factors also influence both the efficacy of a drug and the
likelihood of an adverse reaction. The potential of pharmacogenetics lies in identification of the
right drug and dose for each patient.
The term pharmacogenomics is often used interchangeably with pharmacogenetics.
Pharmacogenomics (pharmaco- + genomics; reflects combination of pharmacology and
genomics) is the study of the role of the genome in drug response. Although both terms relate
to drug response based on genetic influences, pharmacogenetics focuses on single drug-gene
interactions, while pharmacogenomics encompasses a more genome-wide approach,
incorporating genomics and epigenetics while dealing with the effects of multiple genes on drug
response.
(i). Genetic factors affecting drug action
Genetic Polymorphisms
Genetic polymorphisms are naturally occurring variations (or variants) in the DNA sequence
(gene structure) that occur in more than 1 percent of the population, i.e. it is present at an
allele frequency of 1% or greater in a population. A true genetic polymorphism is defined as the
occurrence of a variant allele of a gene at a population frequency of ≥ 1%, resulting in altered
expression or functional activity of the gene product, or both.
Genetic polymorphisms (genetic variations, genetic alterations) may influence a drug's action by
changing its pharmacokinetics or its pharmacodynamics.
Types of polymorphisms
Pharmacists Council of Nigeria
10 FPGOP Lecture Note on Applied Pharmacology and Toxicology
The most common type of polymorphism involves variation at a single base pair, however
polymorphisms may be much larger in size and involve long stretches of DNA. Types of genetic
variations include single nucleotide polymorphism (SNP), insertion deletion mutations (indel)
and copy number variations. Single nucleotide polymorphism and indel are majorly associated
with variations in human phenotype.
There are over 1 million SNPs in the human genome that occur at a frequency of 1% or greater
in the general population. A SNP is a variation/change in a single (1) nucleotide or base-pair
within a codon in the DNA. Depending on its location, a SNP may alter how a gene is
transcribed or the amino acid sequence for the protein being made, ultimately causing a change
in activity of that protein. SNPs can occur with many proteins involved in drug transport,
metabolism and receptors that ultimately influence both the pharmacokinetic and
pharmacodynamic properties of drugs. The SNP is one of the most common and studied genetic
polymorphisms increasingly being recognized in clinical practice.
Genetic polymorphisms for many drug-metabolizing enzymes and drug targets (e.g., receptors)
have been identified, thereby making it increasingly important in drug development, and routine
drug prescription and dosing. Pharmacogenetic testing may enable physicians to understand
why patients react differently to various drugs and to make better decisions about therapy.
Currently, some drugs (e.g. clopidogrel and mercaptopurine) contain labels stating that
genotyping before prescription is recommended or mandatory. Ultimately, application of
pharmacogenetics may provide highly individualized, safer and more effective therapeutic
regimens.
Pharmacogenetic Phenotypes
Genes known to exhibit polymorphisms, with consequent modification of therapeutic and other
actions of a drug, can be divided into three categories: pharmacokinetics, drug target, and
disease-modifying genes polymorphisms.
(a). Pharmacokinetics genes
Pharmacokinetics is the study of the nature, rate and extent of drug absorption, distribution,
metabolism and excretion. These processes determine the fate of a drug in the body.
Furthermore, multiple enzymes and transporters may be involved in the pharmacokinetics of a
single drug. Polymorphism in genes that encode determinants of the pharmacokinetics of a
Pharmacists Council of Nigeria
11 FPGOP Lecture Note on Applied Pharmacology and Toxicology
drug, particularly metabolizing enzymes and transporters, affect drug concentrations, and are
therefore major determinants of therapeutic efficacy and adverse drug reactions (ADRs);
oftentimes dosage adjustment may be necessary.
The toxicity of some drugs can be predicted by the occurrence of particular genes encoding
drug‐metabolising enzymes. A retrospective study, showed that 49% of ADRs were associated
with drugs that are substrates for polymorphic drug metabolizing enzymes, a proportion larger
than estimated for all drugs (22%) or for top-selling drugs (7%). Consequently, prospective
genotype determinations may result in the ability to prevent adverse drug reactions. Well-
defined and clinically relevant genetic polymorphisms in both phase I and phase II drug-
metabolizing enzymes exist, consequently distinct population phenotypes of individuals who
have metabolism capabilities ranging from poor (deficient) to extremely fast have been
identified. The major phenotypes with respect to drug metabolism are grouped into poor
metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs) and ultra-
rapid metabolizers (UMs). In another parlance there may be slow and fast metabolizers
(e.g.slow vs. fast acetylators of isoniazid) or poor and extensive metabolizers (e.g. poor vs.
extensive metabolizers of debrisoquine or sparteine).
Examples of polymorphisms in genes that determine the pharmacokinetics of drugs are:
(i). Irinotecan and mercaptopurine toxicity are affected by UDP glucuronosyl transferase 1
family polypeptide A1 (UGT1A1) and thiopurine S-methyltransferase (TPMT) polymorphisms,
respectively.
TPMT is partly responsible for the inactivation of 6-mercaptopurine, in a reaction that prevents
further conversion of mercaptopurine into active, cytotoxic thioguanine nucleotide metabolites.
Polymorphisms in TPMT that result in decreased or absent TPMT activity lead to increased risk
of severe myelosuppression. In some countries approved drug label for mercaptopurine
recommends testing for TPMT activity to identify individuals at risk for myelotoxicity; this is one
of the few examples of pharmacogenetics being translated into and applied in routine clinical
care.
(ii). Polymorphism in dihydropyrimidine dehydrogenase (DPD), associated with deficiency of the
enzyme results in increased toxicity of fluorouracil. The DPD metabolizes fluorouracil and
endogenous pyrimidines.
Pharmacists Council of Nigeria
12 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(iii). Majority of drug metabolism is carried out by cytochrome P450 (CYP450) enzymes. The
polymorphic CYP450 enzymes account for 40% of the phase I drug metabolism. The respective
effective dose of clopidogrel, warfarin, tricyclic antidepressants, tamoxifen, some antipsychotics,
and some other drugs is determined by CYP450 polymorphism. A few examples are:
CYP2C9: CYP2C9 is involved in the metabolism of many commonly used drugs such as
glipizide, tolbutamide, losartan, phenytoin, clopidogrel and warfarin. The CYP2C9*2 and
CYP2C9*3 phenotypes are the two most common variants and are associated with reduced
enzymatic activity. CYP2C9 is the principal enzyme responsible for the metabolism of S-
warfarin. Persons who are CYP2C9 poor metabolizers have reduced S-warfarin clearance,
require lower doses of warfarin and are at an increased risk of excessive anticoagulation.
CYP2C19: CYP2C19 metabolizes many drugs, including proton pump inhibitors, zafirlukast,
citalopram, diazepam, and imipramine. More than 17 variations of CYP2C19, associated with
deficient, reduced, normal, or increased activity, have been identified. Genotyping for
CYP2C19*2 and CYP2C19*3 identifies most CYP2C19 poor metabolizers. The CYP2C19*17
variant is associated with ultra-rapid metabolizers. Omeprazole is primarily metabolized by
CYP2C19 to its inactive metabolite, 5-hydroxyomeprazole. Poor metabolizers of CYP2C19 may
have five-fold higher blood concentrations of omeprazole and experience superior acid
suppression and higher cure rates than the rest of the population. Conversely, blood
concentrations of omeprazole are predicted to be 40% lower in ultra-rapid metabolizers than in
the rest of the population, thus putting CYP2C19 ultra-rapid metabolizers at risk of therapeutic
failure.
CYP2D6: CYP2D6 is involved in the metabolism of an estimated 25% of all drugs. More than
75 allelic variants have been identified, with enzyme activities ranging from deficient to ultra-
rapid. The most common variants associated with poor metabolizer phenotype are CYP2D6*3,
CYP2D6*4, CYP2D6*5, and CYP2D6*6 in whites and CYP2D6*17 in blacks. Codeine is
metabolized by CYP2D6 to its active metabolite, morphine. Clinical studies have shown that
CYP2D6 poor metabolizers have poor analgesic response as a result of the reduced conversion
of codeine to morphine. Conversely, CYP2D6 ultra-rapid metabolizers quickly convert codeine to
morphine and have enhanced analgesic response. Other consequences of the deficient CYP2D6
phenotype include increased risk of toxicity of some antidepressants or antipsychotics
catabolized by the enzyme, and lack of activation of tamoxifen leading to a greater risk of
Pharmacists Council of Nigeria
13 FPGOP Lecture Note on Applied Pharmacology and Toxicology
relapse or recurrence in breast cancer. Conversely, the ultra-rapid metabolizers have extremely
rapid clearance and thus inefficacy of antidepressants.
(b). Drug targets genes
Many drug target (e.g. receptors, enzymes) polymorphisms have been shown to predict
responsiveness to drugs. Some examples are:
(i).β-adrenergic receptor polymorphisms have been linked to asthma responsiveness (degree of
change in forced expiratory volume in 1 second (FEV1) after use of a β agonist).
Several studies have shown that some patients benefit from use of short-acting β2 agonists
while others do not. This variation in response is partly explained by the alteration in the amino
acid sequence or altered transcription of the β2 receptor. Patients with the β2 receptor arginine
genotype experience poor asthma control with frequent symptoms and a decrease in scores on
FEV1 compared with patients who have the glycine genotype. Studies show that 17% of whites
and 20% of blacks carry the arginine genotype.
(ii). Also, variation in the genes involved in the biologic action of inhaled corticosteroids may
explain the variability in response and adverse effects to inhaled corticosteroids. Polymorphisms
in corticotropin-releasing hormone receptor-1 (CRHR1 gene) is associated with enhanced
response to inhaled corticosteroids in asthma patients.
(iii). Polymorphisms in 5-LOX and LTC4 synthase pathways have been identified, and may
determine and predict how a person reacts to therapy with 5-LOX inhibitors and leukotriene
receptor antagonists.
(iv). Serotonin receptor polymorphisms determine and predict not only the responsiveness to
antidepressants, but also the overall risk of depression.
(v). Renal function following therapy with angiotensin-converting enzyme inhibitors.
(vi). Polymorphisms in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been
linked to the degree of lipid lowering by statins (HMG-CoA reductase inhibitors).
(vii). Ion channel polymorphisms have been linked to a risk of cardiac arrhythmias in the
presence and absence of drug triggers.
(viii). Warfarin exerts its anticoagulant effects by inhibiting hepatic vitamin K epoxide reductase,
an enzyme involved in the synthesis of various clotting factors. Polymorphisms in the vitamin K
epoxide reductase complex subunit 1 (VKORC1) gene have been identified and are believed to
contribute to the variability in response to warfarin therapy.
Pharmacists Council of Nigeria
14 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(ix). Black hypertensive patients require a high dosage of angiotensin-converting enzyme
inhibitors or combined therapy with low-dose diuretics to reduce blood pressure effectively.
(x). Breast cancer patients with expression of the Her2 antigen (i.e HER2 receptor positive ) are
more likely to benefit from the monoclonal antibody trastuzumab than are those who are
negative for Her2 expression.
(c). Disease-modifying genes
Some genes do not directly interact with the drug, but are associated with an underlying
disease being treated. Polymorphisms in such genes may predispose to drug-induced events
and other diseases; such knowledge may be useful to understand and predict possible disease-
predisposing risk factors.
(i). The risk of a drug-induced thrombosis is dependent not only on the use of prothrombotic
drugs, but on environmental and genetic predisposition to thrombosis, which may be affected
by germline polymorphisms in methylene tetrahydrofolate reductase (MTHFR), factor V, and
prothrombin. These polymorphisms do not directly act on the pharmacokinetics or
pharmacodynamics of prothrombotic drugs, such as glucocorticoids, estrogens, and
asparaginase, but may modify the risk of the phenotypic event (thrombosis) in the presence of
the drug.
The methylene tetrahydrofolate reductase gene (MTHFR) polymorphism is associated with
homocysteinemia, which is a possible risk factor for development of coronary artery disease.
Methylene tetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle,
and it is encoded by the MTHFR gene. Methylene tetrahydrofolate reductase catalyzes the
conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for
homocysteine re-methylation to methionine. Natural variation in this gene is common in healthy
people. Some mutations in MTHFR gene are associated with MTHFR deficiency, resulting in
accumulation of homocysteine, homocysteinemia, homocystinuria. Elevated blood levels of
homocysteine leads to intellectual disability, severe mental retardation, psychosis, weakness,
ataxia, spasticity, cardiovascular disease and other disorders.
(ii). Polymorphisms in ion channels (e.g., HERG, KvLQT1, Mink, and MiRP1) may affect the
overall risk of cardiac dysrhythmias, which may be accentuated in the presence of a drug that
can prolong the QT interval in some circumstances (e.g., macrolide antibiotics, antihistamines).
Pharmacists Council of Nigeria
15 FPGOP Lecture Note on Applied Pharmacology and Toxicology
These disease-modifier polymorphisms may impact on the risk of disease phenotypes even in
the absence of drug challenges.
(ii). The importance of pharmacogenetics in the tropics
The importance of study and application of pharmacogenetics in populations in the tropics, and
Nigeria in particular cannot be over-emphasized. Pharmacogenetics will likely impact drug
development and regulatory considerations in Nigeria in several ways, especially considering the
fact that more than 90% of all the drugs used in Nigeria are developed and produced outside
the country.
Unfortunately not much research has focused on identifying the potential role of genetics in the
pathophysiology and management of diseases prevalent in Nigeria. The importance of
pharmacogenetics in the tropics, and particularly in Nigeria, include:
(a). Pharmacogenetics may identify subsets of patients with very high or very low likelihood of
responding to a drug. This will permit testing of the drug in a selected population that is more
likely to respond (e.g, germline variations in 5-lipoxygenase (5-LOX) determine which asthma
patients are likely to respond to 5-LOX inhibitors); thereby allow for optimal definition of
parameters of response in the subset more likely to benefit, and minimize/avoid the possibility
of adverse events in patients who derive no benefit. This role of pharmacogenetics is especially
important in Nigeria, where drugs used were developed using traits and responses from non-
Nigerians outside Nigeria.
(b). Another related role for pharmacogenetics in drug development is to identify which genetic
subset of patients is at highest risk for a serious adverse drug effect, and to avoid use of the
drug in that subset of patients. For example, the identification of human leukocyte antigen
(HLA) subtypes associated with hypersensitivity to the HIV-1 reverse transcriptase inhibitor
abacavir identifies a subset of patients who should receive alternative antiretroviral therapy, and
this has been shown to decrease the frequency of abacavir-induced hypersensitivity reactions.
Hypersensitivity to abacavir is strongly associated with HLA-B*5701, whose prevalence is
reported to be about 0% in Yoruba (Nigeria), 1% in African Americans, 3.3% in Luhya (Kenya),
and 13.6% in Masai (Kenya).
(c). Pharmacogenetic testing may also help to identify patients who require altered dosages,
but not exclusion from use of some drugs.
Pharmacists Council of Nigeria
16 FPGOP Lecture Note on Applied Pharmacology and Toxicology
In summary, application of pharmacogenetics in the tropics could serve to:
Improve drug safety, and reduce adverse drug reactions;
Tailor treatments to meet patients' unique genetic pre-disposition, including
identification and administration of optimal dosing;
Improve drug discovery and development targeted towards diseases encountered in the
region; and
Improve proof of principle/proof of concept in clinical trials.
(iii). Drugs whose response or metabolism are affected by hereditary (genetic)
factors
The response or metabolism of several drugs are affected by genetic polymorphisms (Table1).
Some of such drugs are:
(1). Isoniazid: Human populations show genetic heterogeneity in the rate of acetylation of
isoniazid. There is a bimodal distribution of slow and rapid acetylators due to differences in the
activity of N-acetyltransferase.
Fast acetylation, i.e. high acetyltransferase activity is inherited as an autosomal dominant trait,
while the slow acetylator phenotype is inherited as an autosomal recessive trait. The average
concentration of active isoniazid in the circulation of rapid acetylators is about 30 – 50% of that
in slow acetylators. The mean t1/2 of isoniazid is approximately 70 minutes in fast acetylators,
and 2-5 hours in slow acetylators. More rapid clearance of isoniazid by rapid acetylators is
usually of no therapeutic consequence when appropriate doses are administered daily, but sub-
therapeutic concentrations may occur if drug is administered as a once-weekly dose or if there
is malabsorption. The slow acetylator phenotype is associated with a higher incidence of
isoniazid-induced peripheral neuritis, drug-induced autoimmune disorders, and bicyclic aromatic
amine-induced bladder cancer.
(2). Mercaptopurine: Thiopurine methyltransferase (TPMT), encoded by the TPMT gene,
methylates thiopurines such as mercaptopurine (an anti-leukemic drug that is also the product
of azathioprine metabolism). One in 300 individuals (0.33%) is homozygous deficient, 10% are
heterozygotes (with low enzyme activity), and approximately 90% are homozygous (with
normal enzyme activity) for the wild-type alleles for TPMT. Defects in TPMT gene lead to
decreased methylation and decreased inactivation of 6-mercaptopurine, leading to enhanced
Pharmacists Council of Nigeria
17 FPGOP Lecture Note on Applied Pharmacology and Toxicology
bone marrow toxicity which may cause myelosuppression, anemia, bleeding tendency,
leukopenia and infection. Mercaptopurine has a narrow therapeutic range, and dosing by trial
and error can place patients at higher risk of toxicity; thus, adjustment of thiopurine doses
based on TPMT genotype is recommended. Measurement of TPMT activity is encouraged prior
to commencement of treatment with thiopurine drugs such as azathiopurine, 6-mercaptopurine
and 6-thioguanine.
(3). Warfarin: Warfarin dosing can be challenging because of its narrow therapeutic index and
the serious risk of bleeding with overdosage. Both pharmacokinetic and pharmacodynamic
polymorphisms affect warfarin dosing.
Warfarin exerts its anticoagulant effects by inhibiting hepatic vitamin K epoxide reductase, an
enzyme involved in the synthesis of various clotting factors. Polymorphisms in the vitamin K
epoxide reductase complex subunit 1 gene (VKORC1) have been identified and are believed to
contribute to the variability in responses to warfarin therapy.
Warfarin is metabolized by CYP2C9; CYP2C9 poor metabolizers are associated with lower
warfarin clearance, a higher risk of bleeding complications, and lower dose requirements.
(4). Abacavir: There is genetic polymorphism in hypersentivity reactions to abacavir. In some
countries, drug label for abacavir recommends pre-therapy screening for the HLA-B*5701 allele
and the use of alternative therapy in patients with the allele.
(5). Clopidogrel: Clopidogrel requires biotransformation to active metabolite by CYP450
enzymes. On treatment with clopidogrel, carriers of reduced-function CYP2C19 alleles (CYP2C19
– poor metabolizers) have significantly lower levels of active metabolite, diminished platelet
inhibition, and higher rates of treatment failure and cardiovascular events events such as
stroke, heart attack and death.
(6). Zafirlukast: Zafirlukast, a cysteinyl leukotriene receptor antagonist used in the treatment
of asthma, is extensively metabolized by hepatic CYP2C9. Genetic polymorphisms in LTC4
synthase and CYP2C9 may predict how an individual reacts to treatment with zafirlukast.
Table 1: Clinical consequences of metabolizer phenotypes on drug response
Drug type Metabolizer phenotype
Effect on drug metabolism
Potential consequence
Prodrug, needs to be metabolized to active
Poor to intermediate
Slow -Poor drug efficacy, patient at risk of therapeutic failure
Pharmacists Council of Nigeria
18 FPGOP Lecture Note on Applied Pharmacology and Toxicology
substance (e.g. codeine, clopidogrel)
-Accumulation of prodrug, patient at increased risk of drug-induced adverse effects
Ultrarapid Fast -Good drug efficacy, rapid effect
Active drug metabolized to inactive compound (e.g. omeprazole metabolized to 5-hydroxyomeprazole)
Poor to intermediate
Slow -Good drug efficacy -Accmulation of active drug, patient at increased risk of drug-induced adverse effects - lower dosage may be required
Ultrarapid Fast -Poor dug efficacy, patient at risk of therapeutic failure - higher dosage may be required
Poor metabolizers have markedly reduced or absent enzyme activity; intermediate metabolizers
have reduced enzyme activity; and ultrarapid metabolizers have high enzyme activity.
Table 2: Some drugs whose actions are influenced by genetic polymorphisms
Drug Gene product (gene)
Phenotype Clinical consequencesa
Drug Transport
Metformin Organic cation transporter (SLC22A1, OCT1)
- Affects pharmacological effect and pharmacokinetics
Metformin Organic cation transporter (SLC22A1, OCT2)
- Renal clearance of metformin is affected
Statins Organic anion transporter (SLC01B1)
- Increase in statin plasma levels, and myopathy
Methotrexate - Increase in methotrexate plasma levels and mucositis
Gabapentin Novel organic cation transporter (SLC22A4, OCTN1)
Affects renal clearance
Drug metabolism
Acetaminophen GST PM Impaired GSH conjugation due to gene deletion Busulphan PM
Isoniazid NAT2 (NAT2)
Slow and rapid acetylators
Peripheral neuropathy in slow acetylators
Hydralazine Hydralazine-induced lupus erythematosus-like syndrome in PM
Sulfonamides Hypersensitivity in PM
Procainamide Increase in the antiarrhythmic metabolite, N-acetylprocainamide in rapid acetylators
Mercaptopurine Thiopurine PM Increase in thiopurine toxicity, e.g.
Pharmacists Council of Nigeria
19 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Thioguanine methyltransferase (TPMT)
myelosuppression, risk of second cancers. Dose adjustment may be required
Azathioprine
Fluorouracil Dihydropyrimidine dehydrogenase; DPD (DPYD)
PM Increased toxicity of fluoropyrimidines in DPD deficient individuals Capecitabine
Morphine UGT2B7 - Morphine plasma levels affected by increased or decreased enzyme activity
Levodopa COMT (COMT) PM Lower enzyme activity results in enhanced drug effect
Irinotecan UGT1A1 PM Reduced clearance in poor metabolizers, leading to toxicity such as immunosuppression, GIT dysfunction; dose adjustment may be required.
Succinylcholine BCHE PM Prolonged apnea
Mivacurium PM Prolonged muscle paralysis
Cocaine PM Increased blood pressure, tachycardia, ventricular arrhythmias
Cyclophosphamide CYP2B6 PM Reduced clearance, increased risk of ADRs Ifosfamide
Efavirenz
Repaglinide CYP2C8 PM Reduced clearance, increased risk of ADRs Paclitaxel
Amodiaquine
Chloroquine
Amiodarone
Celecoxib CYP2C9
PM Reduced clearance, increased risk of ADRs Diclofenac
Warfarin PM Highly clinically relevant. Enhanced risk of bleeding, dose adjustment required
Tolbutamide PM Cardiotoxicity
Phenytoin PM Nystagmus, diplopia, ataxia
Omeprazole CYP2C19
PM Increased therapeutic efficacy
Omeprazole EM Reduced therapeutic efficacy
Amitriptyline, clomipramine
PM Reduced clearance, increased risk of ADRs. Dose adjustment required
Citalopram PM Increased risk of gastrointestinal side effects
Clopidogrel PM Reduced activation and reduced therapeutic efficacy
Escitalopram EM Reduced therapeutic efficacy
Tamoxifen EM Increased metabolic activation, increased therapeutic efficacy; reduced risk of relapse. Dose adjustment required
Pharmacists Council of Nigeria
20 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Chlorproguanil EM Increased metabolic activation, increased therapeutic efficacy. Dose adjustment required.
Clopidogrel EM Increased metabolic activation, increased therapeutic efficacy. Dose adjustment required.
Nortriptyline CYP2D6 PM Reduced clearance, increased risk of ADRs
Nortriptyline UM Reduced therapeutic efficacy due to increased clearance
Tamoxifen PM Reduced metabolic activation to endoxifen, and thus reduced therapeutic efficacy
Tramadol PM Increased risk of seizures
Tramadol UM Reduced therapeutic efficacy due to increased clearance
Dextromethophan PM Reduced clearance, increased risk of ADRs
Codeine PM Reduced metabolic activation to morphine, hence reduced analgesia
Codeine UM Increased metabolic activation o morphine, with increased risk of respiratory depression
Drugs metabolized by these enzymes, e.g. macrolides, calcium channel blockers, midazolam, tamoxifen, saquinavir
CYP3A4/3A5/3A7 PM Reduced clearance
Ethanol Aldehyde dehydrogenase 2 (ALDH2*2)
PM Increased acetaldehyde resulting In facial flushing, hypotension, tachycardia, nausea, vomiting (‘hangover’ symptoms)
Drug target (receptors, enzymes, etc) genes
ACE inhibitors (e.g., enalapril)
Angiotensin converting enzyme (ACE)
- Renoprotective effects, hypotension, reduced left ventricular mass, cough. Patients with ACE DD phenotype are resistant to renoprotection by ACEIs.
5-fluorouracil Thymidylate synthase
- Affects response in colorectal cancer chemotherapy
β2 adrenergic receptor agonists, e.g. salbutamol,
β2 adrenergic receptor
- Affects response to agonist therapy (e.g. bronchodilation in asthma). Susceptibility to agonist-induced
Pharmacists Council of Nigeria
21 FPGOP Lecture Note on Applied Pharmacology and Toxicology
terbutaline desensitization, cardiovascular effects (e.g., increased heart rate, cardiac index, peripheral vasodilation)
Leukotriene receptor antagonists
5-lipoxygenase - Altered response to therapy.
Pravastatin HMG-CoA reductase
- Affects degree of lipid lowering
Warfarin Vitamin K epoxide reductase (VKORCI)
- Reduced susceptibility of enzyme to warfarin or increased sensitivity, leading to altered anticoagulant effect and risk of bleeding
Glucocorticoids Corticotropin releasing hormone receptor
Enhanced response (e.g. bronchodilation) to inhaled corticosteroids in asthmatics, osteopenia
Estrogen hormone replacement therapy
Estrogen receptors α and β
- Altered responses, e.g., changes in high density liopoprotein. E.g., some postmenopausal women with ERα IVSI-401 C/C genotype, with coronary disease show augmented response of HDL to hormone replacement therapy
Disease-modifier genes
Dapsone G6PD G6PD deficiency
Methemoglobinemia
Erythromycin, cisapride, clarithromycin, quinidine
Ion channels (HERG, KvLQTI, Mink, MiRPI)
- Increased risk of drug-induced arrhythmias, e.g. torsades de pointes, increased QT interval etc
Statins (e.g. simvastatin)
Apolipoprotein E - Lipid lowering; clinical improvement in Alzheimer’s disease
Estrogens Estrogen receptor β (ER β)
- Associated with breast cancer in women and gynaecomastia in men.
Abacavir, carbamazepine, phenytoin
Human leukocyte antigen
- Hypersensitivity reactions
a Observed or predictable; ADR = adverse drug reaction; PM = poor metabolizer; EM = extensive metabolizer; UM = ultra-rapid metabolizer
(iv). Interactions involving genetic factors: Glucose-6-phosphate dehydrogenase
deficiency
(a). Glucose-6-phosphate dehydrogenase deficiency
Pharmacists Council of Nigeria
22 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common X-linked recessive
hereditary genetic defect caused by mutations in the G6PD gene, resulting in variants with
different levels of enzyme activity that are associated with a wide range of biochemical and
clinical phenotypes. G6PD is X-linked, and so deficient variants are expressed more commonly
in males than in females.
Glucose-6-phosphate dehydrogenase deficiency (G6PDD) affects about 400 million people
worldwide, with a high prevalence in persons of African, Asian, and Mediterranean descent. The
prevalence of G6PDD in Nigeria ranges from 4 – 26%, with the male population having about
20 – 26%. The following prevalence was reported for Nigerian children Yoruba (16.9%), Igede
(10.5%), Igbo (10.1%) and Tiv (5.0%). Prevalence rate varies from one community to another;
however, there is paucity of documented studies on the pattern of distribution of G6PD activity
in Nigerian population.
G6PD generates NADPH which is a primary defense against oxidative stress in red blood cells
(RBCs). Mutations in the G6PD gene can destabilize the enzyme and reduce its level of activity,
leaving RBCs vulnerable to damage from exogenous triggers, including certain foods, infections
and drugs that may lead to lysis and acute hemolytic anemia.
(b). Variants of Glucose-6-phosphate dehydrogenase gene
Over 300 allelic variants of G6PD gene are currently characterized, some of which express
different levels of enzyme activity ranging from low – normal – high. Some well-known and
described variants are G6PD B, G6PDA+, G6PDA-, G6PD Ijebu-ode, G6PD Mediterranean, G6PD
Canton, G6PD Ibadan-Austin, G6PD Chatham, G6PD Cosenza, G6PD Mahidol, G6PD Orissa,
G6PD Asahi, amongst others. The G6PD A− and G6PD Mediterranean variants are the most
common in human populations. G6PD A− has an occurrence of 10% of Africans and African-
Americans while G6PD Mediterranean is prevalent in the Middle East. In tropical Africa,
including Nigeria, the G6PD-A variant is thought to account for 90% of G6PDD. G6PD-
Mediterranean is associated with low enzyme activity (about <1% of normal), and predisposes
individuals to favism and acute hemolytic anaemia following e.g. primaquine therapy.
Few studies have investigated the variants of known G6PD genes from the African region. In
sub- Saharan Africa, well known and studied G6PD variants with polymorphic gene frequencies
include G6PD B, G6PD A+ and G6PD A-. G6PD B is the wild type and most common in Africa
Pharmacists Council of Nigeria
23 FPGOP Lecture Note on Applied Pharmacology and Toxicology
and worldwide, it has normal enzyme activity. G6PD A+ is next in frequency; it has slightly
reduced enzyme activity, about 80 - 100% of normal enzyme activity and is also not associated
with hemolysis. The third variant is G6PD A- with about 8 -20% of the wild type enzyme
(normal) activity; it is associated with relatively mild enzyme deficiency, and hemolysis may
occur especially after exposure to certain substances like camphor, menthol or drugs like
primaquine, dapsone, sulfadimidine, nitrofurantoin, etc. Primaquine toxicity reported for G6PD
A- was relatively mild and self-limiting. Currently, SNPs of G6PD A- variants in Nigerian and
West African populations have been documented, such as G6PD A-968, G6PD A-202, and others.
These may partly explain the observation of severe reactions requiring transfusions, and
hemolysis induced by fava beans in this populations thought to be associated with ‘mild’ variant
of G6PDD.
The World Health Organization (WHO) classifies G6PD genetic variants into five according to the
level of enzyme activity in RBCs and the clinical manifestations. Class I includes severely
deficient variants that are associated with a chronic non-spherocytic hemolytic anaemia
(CNSHA). Class II variants have less than 10% of residual enzyme activity but without CNSHA
and include the common Mediterranean and common severe oriental variants. Class III variants
are moderately deficient (10-60% residual enzyme activity) and include the common African (A)
form. Class IV variants have normal enzyme activity, and in class V the enzyme activity is
increased. The first three are deficiency states.
Class I: Severe deficiency with chronic non-spherocytic hemolytic anemia (CNSHA)
Class II: Severe deficiency (<10% activity), e.g. G6PD Mediterranean
Class III: Moderate deficiency (10-60% activity), e.g. the common African form, G6PD A
Class IV: Non-deficient variant, no clinical sequelae
Class V: Increased enzyme activity, no clinical sequelae
In practice, clinical manifestations are confined to variants associated with enzyme deficiency,
and the common pathological variants are all in classes II and III. From the public health point
of view, the importance of a variant depends on its clinical implications and its prevalence;
usually, a variant is considered common, or polymorphic, if it occurs with a frequency of 1% or
more among males in a particular population.
Variants of Glucose-6-phosphate dehydrogenase gene in Nigeria
Pharmacists Council of Nigeria
24 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Few studies have been done to determine the variants found in Nigerians. Nevertheless, a study
of a homogenous population in Nigeria, showed that there is a high frequency of G6PD A-
variant in the population. Currently, SNPs of G6PD A- variants in Nigerian and West African
populations have been documented, such as G6PD A-968, G6PD A-202, and others.
Table4: Glucose-6 phosphate dehydrogenase gene variants found in Nigeria
G6PD variant RBC enzyme activity (% of
normal)
Population origin
Population frequency
Class
G6PD B 100 Various Usual - (wild type, normal)
G6PD A+ 80 – 100 African descent Common IV
G6PD A- 8 – 20 African descent Common III
G6PD Ijebu-ode 100 African descent Rare IV
G6PD Ibadan-Austin 72 African descent Rare IV
Adapted from Yoshida et al., 1971
(c). Pathophysiology and clinical manifestations of glucose-6-phosphate
dehydrogenase deficiency
Pathophysiology
Glucose-6-phosphate dehydrogenase (G6PD) is a cytosolic enzyme that is distributed widely in
all cells. It catalyses the first step in pentose phosphate pathway (PPP) (hexose monophosphate
shunt pathway), producing reduced nicotinamide adenosine dinucleotide phosphate (NADPH).
This co-enzyme (NADPH) is required as hydrogen donor for numerous reductive processes of
various biochemical pathways as well as for the stability of catalase and the preservation and
regeneration of reduced glutathione. Catalase and glutathione are both essential for the
detoxification of hydrogen peroxide and free radicals generated during the normal cellular
metabolic processes. The defence of cells against hydrogen peroxide, free radicals and other
forms of oxidative stress, therefore, depends on G6PD for the generation of NADPH.
Since red blood cells (RBCs) do not contain mitochondria, the PPP is their only source of
NADPH; therefore, defence against oxidative damage in RBCs is essentially dependent on G6PD.
The red cells are particularly sensitive to oxidative damage in the absence or reduced activity of
G6PD as they lack other NADPH-producing enzymes.
Pharmacists Council of Nigeria
25 FPGOP Lecture Note on Applied Pharmacology and Toxicology
In individuals with deficiency of G6PD there is low level of reduced glutathione; on exposure to
specific triggers (oxidative stress), when all the remaining reduced glutathione is consumed,
enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants,
leading to cross-bonding and protein deposition in the RBC membrane. Damaged RBCs are
phagocytosed and sequestered in the spleen. The hemoglobin is metabolized to bilirubin,
accumulation of which causes hyperbilirubinemia and jaundice.
Triggers: Triggers include moth balls (naphthalene, camphor), stress from a bacterial or viral
infection; foods such as fava beans; certain drugs including aspirin, dapsone, quinine and other
antimalarials derived from quinine (e.g. primaquine, pamaquine, and chloroquine.),
sulfonamides (such as sulfanilamide, sulfamethoxazole, and mafenide). Thiazolesulfone,
methylene blue, certain analgesics (such as phenazopyridine and acetanilide), and some non-
sulfa antibiotics (e.g.nalidixic acid, nitrofurantoin, isoniazid, and furazolidone) should also be
avoided by people with G6PD deficiency as they antagonize folate synthesis. There is evidence
that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses.
Clinical Manifestations
The public health burden of G6PDD is significant. G6PD deficiency causes a clinical spectrum of
illness which includes a purely asymptomatic state, acute hemolytic episodes (elicited by drugs,
infections, ingestion of fava beans, etc.), chronic hemolysis (hereditary non-spherocytic
hemolytic anaemia), and neonatal jaundice. However, many individuals with this disorder
remain asymptomatic throughout their lives and may not be aware of it.
Hemolysis: In G6PD deficient children, exposure to triggers and pro-oxidants could lead to a
rapid imbalance in the redox status in RBCs leading to hemolysis and resultant severe anemia,
heart failure, and death if not recognized early. One of the most curious features of the acute
hemolytic reaction is that it is erratic; the same agent may cause hemolysis in one G6PD
deficient person but not in another, and in the same person at one time but not another.
Neonatal hyperbilirubinemia: G6PD deficiency causes neonatal jaundice which is
accompanied by hyperbilirubinemia and puts infants at risk for kernicterus within the first few
days of life. Kernicterus can lead to hearing deficits, behavior problems, permanent neurologic
damage, spastic cerebral palsy or death.
(d). Glucose-6-phosphate dehydrogenase deficiency and malaria
Pharmacists Council of Nigeria
26 FPGOP Lecture Note on Applied Pharmacology and Toxicology
There is a close association between malaria and G6PD deficiency. Several epidemiological
studies have shown the high frequency of G6PD deficiency in nearly all parts of the world where
malaria is or has been endemic, and that distribution of malaria was nearly the same with
distribution of G6PD deficiency. These infer that (i) G6PD deficiency confers protection against
malaria, particularly Plasmodium falciparum malaria (a similar relationship exists between
malaria and sickle-cell disease); (ii) use of some antimalarial drugs can cause life threatening
hemolytic anaemia in patients with G6PD deficiency; hence, screening for G6PD status is
recommended before treatment with antimalarial drugs.
The protection offered by G6PD deficiency against malaria could be explained by
(i). Cells infected with the Plasmodium parasite are cleared more rapidly by the spleen. This
phenomenon might give G6PD deficiency carriers an evolutionary advantage by increasing their
fitness in malaria endemic environments. In P. falciparum infection, it has been demonstrated
that shorter half-life and rapid clearance of RBCs of G6PD deficient individuals make them less
susceptible to attacks from malaria parasites.
(ii).The G6PD-deficient host has a higher level of oxidative agents, which though generally
tolerated by the host are deadly to the parasite. In vitro studies have demonstrated that P.
falciparum is very sensitive to oxidative damage; hence, there may be impaired growth and
reduced rates of replication of P. falciparum parasites in G6PD deficient RBCs.
(iii). Red cells that are G6PD deficient are resistant to P. falciparum invasion since the parasite
require the enzyme for its normal survival in the host cell.
(e). Management of G6PD deficiency
The main mode of management of G6PD deficiency is avoidance of oxidative stressors. Rarely,
anemia may be severe enough to warrant a blood transfusion, though exchange blood
transfusion may be necessary in some neonates. Phototherapy with bili lights in neonates is
beneficial.
The WHO recommends G6PD status screening in regions where prevalence of G6PD deficiency
is 3–5% or more, but this has yet to become routine practice in Nigeria. Barriers to screening
include cost, underestimation of the public health impact of G6PD deficiency by the medical
community, lack of awareness of G6PD deficiency among lay people, and a paucity of guidelines
Pharmacists Council of Nigeria
27 FPGOP Lecture Note on Applied Pharmacology and Toxicology
regarding which high risk groups should be preferentially screened when general population
screening is not possible.
Bibliography and Further Reading
Ademowo OG, Falushi AG (2002). Molecular epidemiology and activity of erythrocyte G6PD variants in a homogenous Nigerian population. East African Medical Journal, 79(1): 42-44. Bailey DG (2013). Grapefruit-medication interactions: Forbidden fruit or avoidable consequences? Canadian Medical Association Journal, 185(4): 309-316. Buchanan N (1984). Effect of protein-energy malnutrition on drug metabolism in man. World Review of Nutrition and Dietetics, 43: 129-139. Dolan LC, Matulka RA, Burdock GA (2010). Naturally occurring food toxins. Toxins (Basel), 2(9):2289-2332. Egesie OJ, Joseph DE, Isiguzoro I, Egesie UG (2008). Glucose-6-phosphate dehydrogenase (G6PD) activity and deficiency in a population of Nigerian males resident in Jos. Nigerian Journal of Physiological Sciences, 23(1-2): 9-11. Frank JE, Maj MC (2005). Diagnosis and management of G6PD deficiency. American Family Physician, 72: 1277-1282. Howes RE, Dewi M, Piel FB, Monteiro WM, Battle KE, Messina JP, Sakuntabhai A, Satyagraha AW, Williams TN, Baird JK, Hay SI (2013). Spatial distribution of G6PD deficiency variants across malaria-endemic regions. Malaria Journal 12:418. Ibrahim B, Sani AM, Timothy B (2016). Prevalence of glucose-6-phosphate dehydrogenase deficiency among children aged 0-5 years infected with Plasmodium falciparum in Katsina State, Nigeria. Advances in Biochemistry, 4(6): 66-73. Johnson JA, Lima JJ (2003). Drug receptor/effector polymorphisms and pharmacogenetics: Current status and challenges. Pharmacogenetics, 13: 525–534. Luzzatto L, Gordon-Smith EC (2001). Inherited haemolytic anaemia. In: Postgraduate Haemaology. Hoffbrand AV, Lewis SM, Tuddenham EGD (eds.) 4th edition, Arnold, London, pp 120 – 143. Meyer UA, Zanger UM (1997). Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol, 37:269–296. Meyer UA (2000). Pharmacogenetics and adverse drug reactions. Lancet, 356:1667–1671.
Pharmacists Council of Nigeria
28 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Muller O, Krawinkel M (2005). Malnutrition and health in developing countries. Canadian Medical Association Journal, 173: 279-286. Nnakwe N (1995). The effect and causes of protein-energy malnutrition in Nigerian children. Nutrition Research 15: 785-794. Obasa TO, Mokuolu OA, Ojuawo A (2011). Glucose-6-phosphate dehydrogenase levels in babies delivered at the University of Ilorin Teaching Hospital. Nigerian Journal of Paediatrics, 38(4):165-169. Oshikoya KA, Senbanjo IO (2009). Pathophysiological changes that affect drug disposition in protein-energy malnourished children. Nutrition & Metabolism, 6: 50. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001). Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. Journal of American Medical Association, 286:2270–2279. Turkay S, Kus S, Gokalp A, Baskin E, Onal A (1995). Effects of protein energy malnutrition on circulating thyroid hormones. Indian Pediatrics, 32: 193-197. Vesell ES (1991). Genetic and environmental factors causing variation in drug response. Mutation Research, 247:241–257. Weinshilboum R (2003). Inheritance and drug response. New England Journal of Medicine, 348:529–537. Williams O, Gbadero D, Edowhorhu G, Brearley A, Slusher T (2013). Glucose-6-phosphate dehydrogenase deficiency in Nigerian children. PLOS ONE 8(7): 1-8, e68800. World Health Organization Working Group (1989). Glucose-6-phosphate dehydrogenase deficiency. Bull World Health Organ. 67: 601-611. World Health Organization (2000). Management of the child with serious infection or severe malnutrition: Guidelines for care at the first-referral level in developing countries. Yoshida A, Beutler E, Motulsky AG (1971). Human glucose-6-phosphate dehydrogenase variants. Bulletin of the World Health Organization, 45: 243-253.
Pharmacists Council of Nigeria
29 FPGOP Lecture Note on Applied Pharmacology and Toxicology
B. CHEMOTHERAPY
Course Outline
(1). Antimicrobial drugs: Drugs used in tuberculosis and leprosy
(2). Antiprotozoal Drugs: Drugs used in the treatment of malaria, amebiasis,
trypanosomiasis, leishmaniasis
(3). Anthelmintics: Drugs used in ascariasis ancylostomiasis, onchocerciasis,
dracunculiasis, schistosomiasis and tapeworms infestations
Learning Objectives
At the end of the course participants should
(a). State the drugs used in the treatment of tuberculosis, their mechanism of action and
adverse effects, including how some of the adverse effects could be ameliorated.
(b). Mention the drugs used in the treatment of leprosy.
(c). State the drugs used to treat malaria, amebiasis, trypanosomiasis and leishmaniasis.
(d). Mention anthelmintics in clinical use. Delineate drugs for infestations by nematodes, filarial
worms, cestodes and trematodes.
(e). For each infection/infestation, particular attention should be paid to first-line and alternative
drugs.
B1. ANTIMICROBIAL DRUGS: DRUGS USED IN TUBERCULOSIS AND LEPROSY
(i). Drugs used in Tuberculosis
Drugs used in the treatment of tuberculosis are grouped into first-line and second-line agents.
First-line drugs combine the greatest efficacy with an acceptable degree of toxicity, and are the
preferred agents. Second-line drugs are usually considered in case of (1) resistance to first-line
agents; (2) failure of clinical response to conventional therapy; and (3) serious treatment-
limiting adverse drug reactions. Majority of patients with tuberculosis are treated successfully
with first-line drugs; however, occasionally it may be necessary to resort to second-line drugs.
Table 1: Antimicrobial drugs used in the treatment of tuberculosis
First-line Agents Second-line Agents
Pharmacists Council of Nigeria
30 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(in approximate order of preference)
Isoniazid Ethionamide
Rifampicin* Aminosalicylic acid
Pyrazinamide Cycloserine
Ethambutol Capreomycin
Streptomycin Amikacin
*Rifabutin is indicated in place of rifampin for treatment of tuberculosis in HIV-infected
individuals receiving antiretroviral protease or non-nucleoside reverse transcriptase
inhibitors.
(a). First-line Drugs
Isoniazid
Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.
Isoniazid penetrates into macrophages and is active against both extracellular and intracellular
organisms.
Mechanism of Action
Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial
cell wall. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase.
The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM)
and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and
kills the cell.
Pharmacokinetics
Isoniazid is readily absorbed from the gastrointestinal tract. A 300 mg oral dose (5 mg/kg in
children) achieves peak plasma concentrations of 3–5 µg/ml within 1–2 hours. Isoniazid diffuses
readily into all body fluids and tissues, it penetrates well into caseous material. The
concentration in the central nervous system and cerebrospinal fluid is about 20 - 100% of
serum concentration. Isoniazid is metabolized by mainly acetylation by liver N-
acetyltransferase to acetylisoniazid, and enzymatic hydrolysis to isonicotinic acid. Acetylation by
liver N- acetyltransferase, is genetically determined. Human populations show genetic
heterogeneity in the rate of acetylation of isoniazid; there is a bimodal distribution of slow and
fast acetylators. Isoniazid metabolites and a small amount of unchanged drug are excreted,
mainly in the urine. The dose need not be adjusted in renal failure.
Pharmacists Council of Nigeria
31 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Clinical Uses
For the treatment of all types of tuberculosis.
Pyridoxine should be administered with isoniazid to minimize adverse reactions in malnourished
patients and those predisposed to neuropathy (e.g. the elderly, pregnant women, HIV-infected
individuals, diabetics, alcoholics, etc.)
Adverse Effects
Adverse effects include:
(i). Immunologic reactions with fever and skin rashes.
(ii). Hepatotoxicity - Elevated serum aspartate and alanine transaminases are encountered
commonly; however enzyme levels often normalize even with continued therapy. Hepatitis with
loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in about 1%
of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly.
Development of isoniazid hepatitis contraindicates further use of the drug.
(iii). Peripheral neuropathy - Most commonly paraesthesia of feet and hands. Peripheral
neuropathy is more likely to occur in slow acetylators and patients with predisposing conditions
such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative
pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily
reversed by administration of pyridoxine (15 – 50 mg/day).
(iv). Central nervous system toxicity is less common, and includes memory loss, psychosis, and
seizures. These effects may also respond to pyridoxine.
(v). Other adverse effects include hematologic abnormalities, provocation of pyridoxine
deficiency anemia, tinnitus and gastrointestinal discomfort.
Drug Interactions
Isoniazid is a potent inhibitor of CYP2C19, CYP3A, and a weak inhibitor of CYP2D6. However,
isoniazid induces CYP2E1. Drugs that are metabolized by these enzymes will potentially be
affected; for example, isoniazid can reduce the metabolism of phenytoin, diazepam,
carbamazepine, increasing their blood level and toxicity. It can induce the metabolism of
acetaminophen, and potentially increase the level of its toxic metabolites.
Rifampicin (Rifampin)
Pharmacists Council of Nigeria
32 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Rifampicin, also known as rifampin, is a semisynthetic derivative of rifamycin, an antibiotic
produced by Streptomyces mediterranei
Rifampicin is bactericidal for mycobacteria. It readily penetrates most tissues, and also
phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as
intracellular organisms and those sequestered in abscesses and lung cavities.
Mechanism of Action
Rifampin binds to the β subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting
RNA synthesis. Human RNA polymerase does not bind rifampicin and is not inhibited by it.
Pharmacokinetics
Rifampin is well absorbed after oral administration, relatively highly protein bound, and excreted
mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk
excreted as a deacylated metabolite in feces and a small amount excreted in the urine. Dosage
adjustment for renal or hepatic insufficiency is not necessary. It is distributed widely in body
fluids and tissues; however adequate cerebrospinal fluid concentrations are achieved only in the
presence of meningeal inflammation.
Clinical Uses
In combination with other mycobacterial agents to treat tuberculosis and leprosy.
In bacterial infections such as meningococcal disease, staphylococcal infection, and as
prophylaxis in H. influenza type b.
Adverse Effects
Rifampicin imparts an orange-red colour to urine, feces, saliva, sputum, sweat and tears. Other
adverse effects include rashes, nausea, vomiting, thrombocytopenia, nephritis, cholestatic
jaundice, flu-like syndrome (characterized by fever, chills, myalgias and anemia), and rarely
hepatitis.
Drug Interactions
Rifampin strongly induces most cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, and 3A4),
thereby increasing the elimination of many drugs including HIV protease and non-nucleoside
reverse transcriptase inhibitors, coumarin anticoagulants e.g. warfarin, digoxin, ketoconazole,
propranolol, quinidine, methadone, cyclosporine, some anticonvulsants, oral contraceptives, and
others. Co-administration of rifampin results in significantly lower serum levels of these drugs.
Pharmacists Council of Nigeria
33 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Ethambutol
Mechanism of Action
Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB
operon, thereby disrupting arabinogalactan synthesis. Arabinosyl transferases are involved in
the polymerization of arabinogalactan, an essential component of the mycobacterial cell wall.
Disruption of arabinogalactan synthesis results in increased permeability of the mycobacterial
cell wall.
Pharmacokinetics
Ethambutol is well absorbed from the gastrointestinal tract, and well distributed in body tissues
and fluids. After ingestion of 25 mg/kg, a peak blood level of 2–5 µ/ml is reached in 2–4 hours.
About 20% of the unchanged drug is excreted in feces and 50% in urine. Ethambutol
accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is
less than 10 ml/min. Ethambutol crosses the blood-brain barrier only when the meninges are
inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4 - 64% of
serum levels in meningeal inflammation.
Clinical Uses
In the treatment of tuberculosis. As with all antituberculosis drugs, resistance to ethambutol
emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in
combination with other antituberculosis drugs.
Adverse Effects
The most common serious adverse reaction is retrobulbar (optic) neuritis, resulting in loss of
visual acuity and red-green color blindness (i.e. loss of ability to differentiate red from green).
This dose-related adverse effect is more likely to occur at 25 mg/kg/day continued for several
months. At 15 mg/kg/day or less, visual disturbances are rare. Periodic visual acuity testing is
desirable if the 25 mg/kg/day is used. Ethambutol is relatively contraindicated in children too
young to assess visual acuity and red-green color discrimination. Another common adverse
effect is increased concentration of urate in the blood (due to decreased renal excretion of uric
acid). Other adverse effects include rash, fever, pruritus, joint pain, gastrointestinal upset,
mental confusion, disorientation, hallucination, and rarely hypersensitivity reactions.
Pyrazinamide
Pharmacists Council of Nigeria
34 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Pyrazinamide is the synthetic pyrazine analog of nicotinamide. It is stable and slightly soluble in
water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli at concentrations of
approximately 20 µg/ml. Pyrazinamide is taken up by macrophages and exerts its activity
against mycobacteria residing within the acidic environment of lysosomes.
Mechanism of Action
Pyrazinamide is converted to its active metabolite, pyrazinoic acid, by mycobacterial
pyrazinamidase. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport
functions.
Pharmacokinetics
Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body
tissues, including inflamed meninges. On oral administration of 25 mg/kg/day, serum
concentrations of 30–50 µg/ml are achieved after 1–2 hours. The plasma t1/2 is 8–11 hours. The
parent compound is metabolized by the liver, but metabolites are renally cleared; therefore,
pyrazinamide should be administered at 25–35 mg/kg three times weekly (not daily) in
hemodialysis patients and those in whom the creatinine clearance is less than 30 ml/min. In
patients with normal renal function, a dose of 40–50 mg/kg is administered two to three times
weekly.
Clinical Uses
In tuberculosis, in combination with isoniazid and rifampin.
Adverse Effects
Adverse effects include hepatotoxicity, and hyperuricemia due to inhibition of urate excretion
(may provoke acute gouty arthritis). Other untoward effects include arthralgias, anorexia,
nausea and vomiting, dysuria, malaise, and fever.
Streptomycin
Streptomycin, an aminoglycoside, penetrates into cells poorly and is active mainly against
extracellular tubercle bacilli. Streptomycin crosses the blood-brain barrier and achieves
therapeutic concentrations with inflamed meninges.
Clinical Uses
In tuberculosis, especially when parenteral administration is desirable and in cases resistant to
other antituberculosis drugs.
Pharmacists Council of Nigeria
35 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Adverse Reactions
Adverse effects include ototoxicity and nephrotoxicity. Vertigo and hearing loss are the most
common adverse effects and may be permanent. Toxicity is dose-related, and the risk is
increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to
renal function. Toxicity can be reduced by limiting therapy to no more than 6 months when
possible.
(b). Second-line Drugs
Ethionamide
It is poorly water soluble and available only in oral form.
Mechanism of Action
Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids,
with consequent impairment of mycobacterial cell wall synthesis.
Pharmacokinetics
The oral bioavailability of ethionamide approaches 100%, with peak concentrations achieved
about 3 hours after oral administration. It is rapidly and widely distributed in the body, the
concentrations in the blood and various organs including the cerebrospinal fluid are
approximately equal. The t1/2 is about 2 hours. It is metabolized in the liver. Metabolites are
eliminated in the urine, with <1% of ethionamide excreted in an active form.
Clinical Uses
Ethionamide is administered only orally, as a second-line antituberculosis drug.
Adverse Effects
Gastrointestinal distress manifesting as anorexia, nausea, vomiting may occur; this may reduce
compliance and could be ameliorated by taking the drug with food. Other adverse effects
include hepatotoxicity (regular monitoring of liver function is required), metallic taste, central
effects (mental depression, drowsiness, asthenia, psychiatric disturbances, and encephalopathy)
and peripheral neuropathy. The concomitant use of pyridoxine is recommended in patients on
ethionamide, as it may reduce these effects.
Drug Interactions
Pharmacists Council of Nigeria
36 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Ethionamide may worsen the adverse effects of other antituberculosis drugs administered
concurrently, e.g. it increases levels of isoniazid when taken together and can lead to increased
peripheral neuropathy and hepatotoxicity.
Aminosalicylic Acid (para-Aminosalicylic acid; PAS)
Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M.
tuberculosis. It is structurally similar to p- aminobenzoic acid (PABA) and sulphonamides.
Mechanism of Action
Aminosalicylic acid is a structural analog of PABA, the substrate of dihydropteroate synthase
(DHPS; folP1/P2). PAS is recognised by DHPS as efficiently as its natural substrate PABA. PAS is
a pro-drug that is incorporated into the folate pathway by DHPS and dihydrofolate synthase
(DHFS) to generate a hydroxyl dihydrofolate antimetabolite, which in turn inhibits dihydrofolate
reductase (DHFR) enzymatic activity.
Pharmacokinetics
Aminosalicylic acid is readily absorbed from the gastrointestinal tract, with oral bioavailability
>90%. It is widely distributed in tissues and body fluids except the cerebrospinal fluid. It
reaches high concentrations in pleural and caseous fluids. More than 80% is excreted in the
urine, partly as active aminosalicylic acid, and also as the acetylated compound (>50%) and
other metabolic products. Very high concentrations of aminosalicylic acid are reached in the
urine, which can result in crystalluria. Excretion of PAS acid is reduced by renal dysfunction;
thus the dose must be reduced in renal dysfunction.
Clinical Uses
In the treatment of tuberculosis, however, its use has decreased markedly due to availability of
more active and better tolerated drugs.
Adverse Effects
Gastrointestinal symptoms (anorexia, nausea, epigastric pain, abdominal distress, and diarrhea)
are predominant and may be diminished by giving the drug with meals and with antacids.
Gastrointestinal distress often leads to poor compliance. Other adverse effects include, peptic
ulceration and hemorrhage, hematological abnormalities, generalized malaise, joint pains and
sore throat. Hypersensitivity reactions manifested by fever, joint pains, skin rashes,
hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3–8 weeks
Pharmacists Council of Nigeria
37 FPGOP Lecture Note on Applied Pharmacology and Toxicology
of aminosalicylic acid therapy, making it necessary to stop drug administration temporarily or
permanently.
Cycloserine
Mechanism of Action
Cycloserine is an inhibitor of cell wall synthesis.
Pharmacokinetics
Peak concentrations of cycloserine are reached 3 - 4 hours after a single oral dose. It is
distributed throughout body fluids and tissues, and crosses the blood-brain barrier.
Concentrations in cerebrospinal fluid are same as those in plasma. Cycloserine is cleared
renally, mainly as the unchanged drug; the dose should be reduced by half if creatinine
clearance is less than 50 ml/min.
Clinical Uses
It is used along with other antituberculosis drugs when re-treatment is necessary, if one or
more first-line drugs cannot be used, or for active drug resistant tuberculosis especially multiple
drug-resistant and extensively drug-resistant strains of M. tuberculosis.
Adverse Effects
The most serious adverse effects are peripheral neuropathy and central nervous system
dysfunction. Central manifestations include depression, psychotic reactions with suicidal
tendencies, paranoid reactions, headaches, visual disturbance, drowsiness, dizziness, vertigo,
confusion, paresthesia, dysarthria, paresis, hyperirritability, tonic-clonic or absence seizures,
and tremors. Alcohol consumption may increase the risk of seizures.
Pyridoxine (150 mg/day), should be given with cycloserine to ameliorate neurologic toxicity.
Capreomycin
Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces
capreolus.
Clinical Uses
Capreomycin, a second-line antituberculosis drug, is an important injectable agent for treatment
of drug-resistant tuberculosis. Strains of M. tuberculosis that are resistant to streptomycin or
amikacin usually are susceptible to capreomycin.
Pharmacists Council of Nigeria
38 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Adverse Effects
Capreomycin is nephrotoxic and ototoxic; tinnitus, deafness, and vestibular disturbances may
occur. The injection causes significant local pain, and sterile abscesses may occur.
Kanamycin & Amikacin
Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant
strains, but the availability of less toxic alternatives (e.g. capreomycin and amikacin) has
rendered it obsolete.
Amikacin is an aminoglycoside that interferes with the function of the 30S subunit of the
bacterial ribosome, thereby inhibiting protein synthesis. Amikacin is also active against atypical
mycobacteria. Its role in the treatment of tuberculosis has increased with increasing incidence
and prevalence of multidrug-resistant tuberculosis. Prevalence of amikacin-resistant strains is
low, and most multidrug-resistant strains remain amikacin-susceptible. There is no cross-
resistance between streptomycin and amikacin, but kanamycin resistance often indicates
resistance to amikacin as well.
Clinical Uses
Amikacin is indicated for treatment of streptomycin-resistant or multidrug-resistant strains of M.
tuberculosis. It is used in combination with at least one, and preferably two or three other
drugs to which the isolate is susceptible for treatment of drug-resistant cases.
Adverse effects include ototoxicity, nephrotoxicity, and paralysis which may result in inability
to breathe. Its use in pregnancy may cause permanent deafness in the baby.
Fluoroquinolones
In addition to their activity against many gram-positive and gram-negative bacteria,
ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M. tuberculosis at
concentrations less than 2 µg/ml. They are also active against atypical mycobacteria.
Ofloxacin and ciprofloxacin have been second-line antituberculosis drugs for many years, but
their use is limited by the rapid development of resistance. Moxifloxacin is the most active
against M. tuberculosis by weight in vitro. Levofloxacin tends to be slightly more active than
ciprofloxacin against M. tuberculosis, whereas ciprofloxacin is slightly more active against
Pharmacists Council of Nigeria
39 FPGOP Lecture Note on Applied Pharmacology and Toxicology
atypical mycobacteria. Fluoroquinolones are used in combination with two or more active
antituberculosis agents in disease resistant to first-line agents.
Rifabutin
Rifabutin is derived from rifamycin and is related to rifampicin. It has significant activity against
M. tuberculosis, Mycobacterium avium complex (MAC), and M. fortuitum. Its activity is similar to
that of rifampicin, and cross-resistance with rifampin is virtually complete.
Rifabutin is both substrate and inducer of cytochrome P450 enzymes; however, it is a less
potent inducer, and also affects fewer types of CYP enzymes compared to rifampicin. Therefore
it is used in place of rifampicin for treatment of tuberculosis in patients with HIV infection who
are receiving antiretroviral therapy with a protease inhibitor or with a non-nucleoside reverse
transcriptase inhibitor (e.g., efavirenz), drugs that also are cytochrome P450 substrates. The
typical dosage of rifabutin is 300 mg/day, however in patients receiving a protease inhibitor the
dosage should be reduced to 150 mg/day. If efavirenz (also a cytochrome P450 inducer) is
used, the recommended dosage of rifabutin is 450 mg/day. Rifabutin is effective in prevention
and treatment of disseminated atypical mycobacterial infection in AIDS patients with CD4
counts below 50/μL. It is also effective for preventive therapy of tuberculosis, either alone in a
3–4 month regimen or with pyrazinamide in a 2 month regimen.
Rifapentine
Rifapentine, an analog of rifampicin, is active against both M. tuberculosis and MAC. As with all
rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampicin
and rifapentine is complete. Like rifampicin, rifapentine is a potent inducer of cytochrome P450
enzymes, and it has the same drug interaction profile. Compared to rifabutin and rifampin, the
CYP-inducing effects of rifapentine are intermediate. Toxicity is similar to that of rifampicin.
Clinical Uses
Rifapentine is indicated for treatment of tuberculosis caused by rifampicin-susceptible strains
during the continuation phase only (i.e. after the first 2 months of therapy and ideally after
conversion of sputum cultures to negative). Rifapentine should not be used to treat patients
with HIV infection because of high relapse rate with rifampicin resistant organisms.
Pharmacists Council of Nigeria
40 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(ii). Drugs used in Leprosy
Four major clinical types of leprosy are:
(a). Tuberculoid leprosy, also termed paucibacillary leprosy because the bacterial burden is low
and M. leprae is rarely found in smears.
(b). Lepromatous leprosy, characterized by a disseminated infection and high bacillary burden.
(c). Borderline (dimorphous) tuberculoid disease, which has features of both tuberculoid and
lepromatous leprosy.
(d). Indeterminate disease, which has early hypopigmented lesions without features of the
lepromatous and tuberculoid leprosy.
The last two are the major intermediate forms of leprosy.
Multi-drug regimens consisting of rifampicin, clofazimine, and dapsone are used in the
treatment of leprosy. Multidrug therapy is used in leprosy to (i) reduce the development of
resistance, (ii) provide adequate therapy when primary resistance already exists, and (iii)
reduce the duration of therapy.
Dapsone
Mechanism of Action
Dapsone (diaminodiphenylsulfone) is a structural analog of para aminobenzoic acid (PABA) and
a competitive inhibitor of dihydropteroate synthase (folP1/P2) in the folate pathway, ultimately
inhibiting folate synthesis.
Pharmacokinetics
After oral administration, the absorption of dapsone is complete, with elimination half-life of 20-
30 hours. Dapsone is retained in the skin, muscle, liver and kidney. Skin heavily infected with
M. leprae may contain several times more drug than normal skin. Dapsone undergoes N-
acetylation by NAT2, and N-oxidation to dapsone hydroxylamine via CYP2E1 and to a lesser
extent by CYP2C. Dapsone hydroxylamine enters red blood cells, leading to methemoglobin
formation. Intestinal reabsorption of dapsone excreted in the bile contributes to long-term
retention in the bloodstream; consequently, periodic interruption of treatment is recommended.
Approximately 70-80% of a dose of dapsone is excreted in the urine as an acid-labile mono-N-
glucuronide and mono-N-sulphamate.
Pharmacists Council of Nigeria
41 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Clinical Uses
Dapsone is used in combination with rifampin and clofazimine for initial therapy of leprosy as
resistance can emerge, e.g. in lepromatous leprosy, if very low doses are given. Dapsone is
used to prevent and treat Pneumocystis jiroveci pneumonia. It is combined with chlorproguanil
for the treatment of malaria.
Adverse Effects
Dapsone is usually well tolerated. Many patients develop hemolysis, particularly if they have
G6PD deficiency. It is recommended that G6PD deficiency testing should be performed prior to
use of dapsone if possible. Other adverse effects are methemoglobinemia, gastrointestinal
intolerance, fever, pruritus, and rashes. During dapsone therapy of lepromatous leprosy,
erythema nodosum leprosum often develops. It is sometimes difficult to distinguish reactions to
dapsone from manifestations of the underlying illness. Erythema nodosum leprosum may be
suppressed by corticosteroids or by thalidomide.
Rifampicin/Rifampin
Rifampicin is highly effective in lepromatous leprosy. It is given in combination with dapsone or
clofazimine because of the probable risk of emergence of rifampicin-resistant M. leprae.
Clofazimine
The mechanism of action of clofazimine has not been clearly elucidated. Absorption of
clofazimine from the gut is variable, and a major portion of the drug is excreted in feces.
Clofazimine is stored widely in reticuloendothelial tissues and skin, and its crystals can be seen
inside phagocytic reticuloendothelial cells. It is slowly released from these deposits, therefore
the serum t1/2 may be 2 months. Clofazimine is used in dapsone-resistant leprosy or in patients
intolerant to dapsone.
Discoloration of body secretions, eye and skin occur in most patients and can lead to depression
in some patients. Gastrointestinal problems are encountered in 40-50% of patients and include
abdominal pain, diarrhea, nausea, and vomiting.
Treatment of Reactions in Leprosy
Pharmacists Council of Nigeria
42 FPGOP Lecture Note on Applied Pharmacology and Toxicology
During the course of leprosy, immunologically mediated episodes of acute or subacute
inflammation known as reactions may occur in patients. Leprosy reactions include reversal
reaction and erythema nodosum leprosum.
Patients with tuberculoid leprosy may develop reversal reactions, which are manifestations of
delayed hypersensitivity to antigens of M. leprae. Cutaneous ulcerations and deficits of
peripheral nerve function may occur. Early therapy with corticosteroids or clofazimine is
effective.
Erythema nodosum leprosum is an immune-mediated complication of leprosy, characterized by
the presence of multiple, tender inflammatory cutaneous nodules; and systemic symptoms such
as fever, malaise, arthritis, iritis, neuritis and lymphadenitis. It is thought to be initiated by the
release of mycobacterial antigens, which trigger the formation of immune complexes. Antigen-
antibody complexes deposited in the circulation and tissues, activate the complement.
Treatment with clofazimine or thalidomide is effective.
Rifampin is a highly effective anti-leprosy drug, however, due to high kill rates and massive
release of bacterial antigens, it is not often given during a reversal reaction or in patients with
erythema nodosum leprosum. Clofazimine is only bacteriostatic against M. leprae; however, it
also has anti-inflammatory effects and is used to treat reversal reactions and erythema
nodosum leprosum.
B2. ANTIPROTOZOAL DRUGS: DRUGS USED IN THE TREATMENT OF MALARIA, AMOEBIASIS, TRYPANOSOMIASIS, LEISHMANIASIS (i). Drugs Used in the Treatment of Malaria Classification of anitmalarial drugs
Antimalarials can be classified by the stage of parasite that they affect and their clinical uses.
Some drugs have more than one type of antimalarial activity.
(1). Drugs used for casual prophylaxis
These act on primary tissue forms of Plasmodia, which will, in less than one month initiate the
erythrocytic stage of infection. Invasion of erythrocytes and further transmission of infection are
thereby prevented e.g. proguanil (the prototype). Primaquine also has such activity against P.
falciparum, but it is reserved for other clinical applications because of its toxicity.
Pharmacists Council of Nigeria
43 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(2). Drugs used to prevent relapse
These drugs act on latent tissue forms of P. vivax and P. ovale remaining after the primary
hepatic forms have been released into the circulation. Such latent tissue forms eventually
mature, invade the circulation and produce malarial attacks i.e. relapse, months or years after
the initial infection.
Drugs active against latent tissue forms are used for terminal prophylaxis and for radical cure of
relapsing malarial infections. Primaquine is the prototype drug used to prevent relapse. For
terminal prophylaxis, regimens with such a drug are initiated shortly before or after a person
leaves an endemic area. To achieve radical cure, this type of drug is taken either during the
long-term latent period of infection or during an acute attack. In the latter case, the agent is
given together with an appropriate drug, e.g. artemisinins, quinine, chloroquine, etc. to
eradicate erythrocytic stages of P. vivax and P. ovale.
(3). Drugs (blood schizontocides) used for clinical and suppressive cure
These agents act on asexual erythrocytic stages of malarial parasites to interrupt erythrocytic
schizogony and thereby terminate clinical disease i.e. effect clinical cure.
Such drugs also may produce suppressive cure, which refers to complete elimination of
parasites from the body by continued therapy. Inadequate therapy with blood schizontocides
may result in recrudescence of infection due to erythrocytic schizogony.
These agents can be divided into 2 groups:
(a). Rapidly acting blood schizontocides e.g. artemisinins; classical antimalarial alkaloids e.g.
chloroquine, quinine and the related derivatives quinidine and mefloquine; atovaquone and
others.
(b). Slower-acting blood schizontocides e.g. antifolate (e.g. pyrimethamine), and antibacterial
antimalarials (e.g. sulfadoxine, sulfadiazine). These drugs are mostly used in conjunction with
the rapidly acting ones.
(4). Gametocytocides
These agents act against sexual erythrocytic forms of plasmodia, thereby preventing
transmission of malaria to mosquitoes. Chloroquine and quinine have gametocytocidal activity
against P. vivax, P. ovale and P. malariae, whereas primaquine displays especially potent
activity against gametocytes of P. falciparum. However, antimalarials are not used clinically just
for gamecytocidal action.
Pharmacists Council of Nigeria
44 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(5). Sporontocides
They ablate transmission of malaria by preventing or inhibiting formation of malarial oocysts
and sporozoites in infected mosquitoes. They render gametocytes non-infective in the mosquito
e.g. pyrimethamine, proguanil. Although chloroquine prevents normal plasmodia development
within the mosquito, neither it nor other antimalarial agents are used clinically for this purpose.
Antimalarial agents are also classified into:
1. Class I: Are effective against the asexual erythrocytic forms of Plasmodium. They may be
used to prevent or treat clinically symptomatic malaria. They include artemisinins, chloroquine,
mefloquine, quinine, quinidine, pyrimethamine, sulfadoxine, tetracyclines.
2. Class II: Are effective against the asexual erythrocytic forms and the primary liver stages of
P. falciparum. This additional activity shortens to several days the required period for post-
exposure prophylaxis. They include atovaquone and proguanil.
3. Class III: Effective against primary and latent liver stages, as well as gametocytes.
Primaquine is used to eradicate the hypnozoites of P. vivax and P. ovale, which are responsible
for relape.
Antimalarial drugs include: Artemisinin derivatives (artesunate, arthemeter, -dihydroartemisinin,
etc); 4-aminoquinolines (chloroquine, amodiaquine, etc.); 8-aminoquinolines (primaquine);
quinoline-methanols (quinine, mefloquine, etc); drugs affecting the synthesis or utilization of
folate (pyrimethamine, proguanil, some sulfonamides, dapsone, etc); and antibacterial
antimalarials (some sulfonamides, tetracyclines, etc.).
Artemisinins
Chinese scientists isolated qinghaosu (artemisinin), the major antimalarial ingredient from the
weed, Artemisia annua (Qing hao; sweet wormwood; annual wormwood). The Chinese have
been using this plant to cure fevers, and relieve symptoms of malaria for more than 2,000
years. The more potent semi-synthetic derivatives of artemisinin; dihydroartemisinin,
artesunate, artemether, arteether (α/β-arteether) or artemotil (β-arteether) are now in clinical
use.
Mechanism of Action
Pharmacists Council of Nigeria
45 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Artemisinin is a sesquiterpene lactone endoperoxide; the endoperoxide moiety is essential for
antimalarial activity. Artemisinin action involves 2 steps:
(1) Intraparasitic heme iron of infected erythrocytes catalyzes cleavage of the endoperoxide
bridge.
(2) Then intramolecular rearrangement to produce carbon- centered radicals that covalently
modify and damage specific macromolecules in the parasite.
Artemisinin and its derivatives also inhibit an essential calcium adenosine triphosphatase,
PfATPase.
Pharmacokinetics
The semisynthetic artemisinins have been formulated for administration through oral
(dihydroartemisinin, artesunate and artemether), intramuscular (artesunate and artemether),
intravenous (artesunate), and rectal (artesunate) routes. Artemether and artesunate are both
converted extensively to dihydroartemisinin, which elicits their antimalarial activity.
Bioavailability after oral administration is about 30%. Although artemisinins rapidly achieve peak
serum levels; intramuscular administration of the lipid-soluble artemether peaks in 2-6 hours,
due to a depot effect at the injection site. Both artesunate and artemether have modest levels
of plasma protein binding, ranging from 43-82%. These derivatives are extensively metabolized
and converted to dihydroartemisinin, which has a plasma t1/2 of 1-2 hours. Rectal administration
of artesunate is an important administration route, especially in tropical countries including
Nigeria where it can be lifesaving. However, bioavailability via rectal administration is highly
variable among patients. With repeated dosing, artemisinin and artesunate induce their own
CYP-mediated metabolism, primarily via CYPs 2B6 and 3A4. This may enhance clearance by up
to 5-fold.
Clinical Uses
The artemisinins are used to treat malaria, including infections due to chloroquine and
multidrug resistant strains of P. falciparum. They are not recommended for prophylactic use.
Artemisinins act more rapidly and produce less toxicity than the antimalarial alkaloids and they
are just as effective against cerebral malaria. Although artemisinins can be used as single
agents, infections often relapse unless therapy is continued for 5 - 7 days. When given with a
longer acting antimalarial, (e.g a quinoline such as mefloquine; Artequin®) for a shorter course,
relapse and development of drug resistance are usually prevented or delayed. Hence,
Pharmacists Council of Nigeria
46 FPGOP Lecture Note on Applied Pharmacology and Toxicology
artemisinins are currently used as constituents of combination therapy called artemisinin-based
combination therapy or artemisinin combination therapy (ACT).
Adverse Effects
They are relatively safe in humans at therapeutic doses, side effects include those similar to
symptoms of malaria: nausea, vomiting, anorexia and dizziness. Also transient first degree
block, dose-related reversible decreases in reticulocyte and neutrophil counts, and temporary
elevation of serum aspartate aminotransferase activity have been reported. A rare but serious
adverse effect is allergic reaction.
Artemisinin Combination Therapy (ACT)
Artemisinin combination therapy (ACT) is a drug regimen/formulation containing an artemisinin
derivative and other antimalarial drug(s).
Artemisinins are used for the treatment of P. falciparum infections, but low bioavailability, poor
pharmacokinetic properties, high rate of recrudescence, and high cost are a major limitation;
consequently, other drugs are required to clear the body of all parasites and prevent
recurrence. Use of an artemisinins as monotherapy is explicitly discouraged by the WHO, as
there have been signs of development of resistance to the drugs. Due to the limitations of
artemisinins as monotherapy, and to prevent development of resistance, the WHO has
recommended ACT as the first-line therapy for P. falciparum malaria worldwide. Combinations
are effective because the artemisinin component kills the majority of parasites at the start of
the treatment, while the other drug clears the remaining parasites. ACT is well tolerated in
patients, and is now standard treatment worldwide for P. falciparum malaria.
Several fixed-dose ACTs are now available containing an artemisinin component and another
drug which has a long half-life, such as mefloquine (e.g. Artequin®), lumefantrine (e.g
Coartem®, Lokmal®, Lonart®), amodiaquine (e.g. Camosunate®), piperaquine (e.g. Waipa®),
and pyronaridine.
Chloroquine
Chloroquine is a 4 – aminoquinoline that is particularly effective against intra-erythrocytic forms
because it is concentrated within the parasitized erythrocyte, probably due to a preferential
Pharmacists Council of Nigeria
47 FPGOP Lecture Note on Applied Pharmacology and Toxicology
specific uptake mechanism present in the parasite. As with other 4 – aminoquinolines, it does
not produce radical cure.
Mechanism of Action
It acts by inhibition of heme polymerization. Asexual malaria parasites flourish in host
erythrocytes by digesting hemoglobin in their acidic food vacuoles, a process that generate free
radicals and heme (ferriprotoporphyrin IX) as highly reactive by-products. After nucleation aided
by histidine rich proteins and possibly lipids, heme polymerizes into an insoluble, unreactive
non-toxic, malaria pigment termed hemozoin.
Quinoline blood schizontocides that behave as weak bases concentrate in food vacuoles of
susceptible plasmodia, where they increase pH, inhibit the peroxidative activity of heme, and
disrupt its non-enzymatic polymerization to hemozoin. Failure to inactivate heme then kills the
parasites via oxidative damage to membranes, digestive proteases and possibly other critical
biomolecules.
Antimalarial Spectrum
It is effective against all four malaria parasites with the exception of chloroquine – resistant P.
falciparum.The disease will probably relapse in P. vivax and P. ovale malaria, unless the liver
stages are sequentially treated, first with chloroquine and then with primaquine. Chloroquine
also can be used for prophylaxis.
Pharmacokinetics
Chloroquine is rapidly and completely absorbed from the gastrointestinal tract. It is distributed
widely and is extensively bound to body tissues, with the liver containing 500 times the blood
concentration. Due to extensive tissue binding, a loading dose is required to produce effective
concentrations in plasma. Desethylchloroquine (has similar activity against P. falciparum) is the
major metabolite formed by hepatic metabolism. Both the parent compound and its metabolites
are slowly eliminated renally. The t1/2 is 6 - 7 days, with terminal elimination t1/2 of 1 – 2
months.
After parental administration, rapid entry together with a slow exit of chloroquine from a small
compartment can result in transiently high and potentially lethal concentrations of the drug in
plasma. Hence, chloroquine is given either slowly by continuous I.V. infusion or in small divided
doses by S.C or I.M. Absorption is also rapid following I.M and S.C administration.
Pharmacists Council of Nigeria
48 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Resistance is related to genetic changes in transporters (PfCRT, PfMDR), which reduce the
concentration of chloroquine at its site of action, the parasite’s food vacuole.
Clinical Uses
1. As an antimalarial, though its used is limited and has diminished due to resistance.
2. In extraintestinal amoebiasis
3. Chloroquine is used in the treatment of rheumatoid arthritis and lupus erythematosus,
because it concentrates in lysosomes and has anti-inflammatory properties.
4. In photoallergic reactions.
Adverse Effects
Dizziness, headache, itching, skin rash, vomiting, blurred vision may occur at low doses. In
higher doses, these symptoms are more common and exacerbation or unmasking of lupus
erythematosus or discoid lupus as well as toxic effects in skin, blood and eyes can occur. Since
the drug concentrates in melanin containing structures, prolonged administration of high doses
can result in corneal deposits and lead to retinopathy and blindness. Prolonged medication with
suppressive doses may result in headache, blurred vision, diplopia, confusion, convulsions,
bleaching of hair, widening of QRS interval, and T- wave abnormalities.
Chloroquine is contraindicated in the presence of retinal or visual field changes, epilepsy and
myaesthenia gravis.
Chloroquine has a low safety margin, and is very dangerous in overdose.
Amodiaquine
Amodiaquine is also a 4 – aminoquinoline derivative. Its antimalarial spectrum and adverse
reactions are similar to those of chloroquine, although chloroquine resistant parasites may not
be amodiaquine resistant to the same degree. Prolonged treatment may result in pigmentation
of the palate, nail beds and skin.
Primaquine
Primaquine is a very important antimalarial because it is the only drug effective against the liver
(exoerythrocytic) forms of the malarial parasite. It also kills the gametocytes; patients
recovering from P. falciparum malaria can be given primaquine for its gametocytocidal
Pharmacists Council of Nigeria
49 FPGOP Lecture Note on Applied Pharmacology and Toxicology
properties. Primaquine is relatively ineffective against the asexual erythrocyte forms. Its
greatest use is in the radical cure of P. vivax and P. ovale malaria.
Pharmacokinetics
It causes significant hypotension after parenteral administration. And therefore, it is given only
orally. It is readily absorbed from the gastrointestinal tract and unlike chloroquine, it is not
bound extensively to tissues. It is rapidly metabolized to active compounds.
Clinical Uses
Primaquine is primarily used to prevent relapse of malaria due to P. vivax and P. ovale. It is
recommended to be used for primary prophylaxis prior to travel to areas with a high incidence
of P. vivax and P. ovale, and for terminal prophylaxis after travel.
Adverse Effects
Adverse effects of primaquine include gastrointestinal distress, nausea, headache, pruritus,
leucopenia and agranulocytosis especially with higher doses or prolonged use. It is
contraindicated in G6PD deficient individuals as it can cause a lethal hemolysis.
Quinine
Quinine is one of the several alkaloids derived from the bark of the cinchona tree. It also
concentrates in the Plasmodium acidic food vacuoles to inhibit the non-enzymatic
polymerization of the highly reactive toxic heme molecule into the non-toxic polymer pigment,
hemozoin.
Antimalarial Spectrum: It is effective against chloroquine resistant P. falciparum malaria. It
is a blood schizontocide; it has little effect on sporozoites or pre-erythrocytic forms of
plasmodia, therefore it is not used for prophylaxis.
Clinical Uses
(1) Despite its toxicity, it is still an important blood schizontocide for the suppressive treatment
and cure of chloroquine resistant and multi- drug resistant P. falciparum malaria.
(2) Prevention and treatment of nocturnal leg muscle cramps (especially those due to arthritis,
diabetes, thrombophlebitis, arteriosclerosis and varicose veins.
Pharmacokinetics: Quinine is well absorbed on oral or I.M. administration.
Adverse Effects
Pharmacists Council of Nigeria
50 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Adverse effects of quinine include cinchonism, hypoglycemia, and hypotension. Cinchonism is
the toxic state induced by excessive plasma levels of free quinine. Symptoms of cinchonism
include; sweating, ringing in the ears, impaired hearing, blurred vision, nausea, vomiting and
diarrhea. Quinine is a potent stimulus to insulin secretion, and also a gastrointestinal mucosa
irritant. It may produce a variety of relatively rare hematological changes e.g. leucopenia, and
agranulocytosis.
Mefloquine
Mefloquine is a 4–quinoline methanol derivative. It is a more effective and less toxic antimalarial
than cinchona alkaloids. It is a highly effective blood schizontocide especially against mature
trophozoites and schizont forms of malaria parasites. The exact mechanism of action has not
been clearly elucidated.
Pharmacokinetics
It is well absorbed on oral administration, absorption is increased by the presence of food. It is
taken orally because parenteral administration causes severe local reactions. It undergoes
enterohepatic recycling.
Clinical Uses
Prevention and treatment of malaria especially those caused by chloroquine resistant and
multidrug resistant P. falciparum.
Adverse Effects
Adverse effects of mefloquine include nausea, vomiting, abdominal pain, diarrhea, dizziness,
headache, disorientation, seizures and encephalopathy.
Contraindications: In patients with history of seizures, use of quinoline antimalarials (quinine,
chloroquine and quinidine) should be avoided because of increased risk of convulsions and
cardiotoxicity. Although mefloquine can be taken safely 12 hours after a last dose of quinine,
taking quinine shortly after mefloquine can be very hazardous because the latter is eliminated
slowly.
Pyrimethamine
It is a 2, 4 – diaminopyrimidine like trimethoprim (antibacterial agent).
Mechanism of Action
Pharmacists Council of Nigeria
51 FPGOP Lecture Note on Applied Pharmacology and Toxicology
It inhibits DHFR of plasmodia at concentrations far lower than those required to produce
comparable inhibition of the mammalian enzyme, ultimately inhibiting synthesis of folic acid in
the parasite. Parasites cannot use preformed folic acid and therefore must synthesize this
compound from the following precursors obtained from their host; p–amino benzoic acid
(PABA), pteridine and glutamic acid. The dihydrofolic acid formed from these precursors is then
hydrogenated to form tetrahydrofolic acid. Tetrahydrofolic acid is the co-enzyme that acts as an
acceptor of a variety of one–carbon units. The transfer of one carbon units is important in the
synthesis of the pyrimidines and purines which are essential in nucleic acid synthesis.
Note: Inhibition by antifolate is manifested late in the life cycle of malarial parasites by failure
of nuclear division at the time of schizont formation in erythrocytes and the liver. This
mechanism is consistent with the slow onset of action of the antifolates, compared with the
quinoline antimalarials.
Whereas the sulfonamides and sulfones compete with PABA for dihydropteroate synthetase and
inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic
acid, pyimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to
tetrahydrofolic acid, a reaction catalyzed by dihydrofolate reductase.
The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors such as
trimethoprim (Co-trimoxazole, Septrin®) or pyrimethamine (Fansidar®) is a good example of
the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of
the parasite’s metabolism is called sequential blockade. Using drugs that inhibit at two
different points in the same biochemical pathway produces parasite lethality at low drug
concentrations than is possible when either drug is used alone.
Clinical Uses
(1). Prophylaxis of malaria
(2). Treatment of toxoplasmosis at 10-20 times higher doses.
Pyrimethamine is recommended for prophylactic use against all susceptible strains of Plasmodia.
It should not be used as the sole therapeutic agent for treating acute malarial attack.
Sulfonamides should always be co-administered with pyrimethamine since the combined
antimalarial activity of the two drugs is significantly greater than when either drug is used
alone. Resistance also develops more slowly to the combination.
Pharmacists Council of Nigeria
52 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Pharmacokinetics
After oral administration, pyrimethamine is slowly but completely absorbed, reaching peak
plasma levels in 2-6 hours. It is significantly distributed in the tissues and is approximately 90%
bound to plasma proteins. Pyrimethamine is slowly eliminated from plasma with a t1/2 of about
3-4 days. Several metabolites of pyrimethamine appear in the urine; however, they have not
been fully characterized. Pyrimethamine also enters the milk of nursing mothers.
Adverse effects include rashes, insomnia, and depression of hematopoiesis with high doses.
Proguanil /chloroguanide/chlorguanide
Mechanism of Action: The active triazine metabolite of proguanil i.e. cycloguanil selectively
inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase of sensitive plasmodia,
resulting in inhibition of DNA synthesis and depletion of folate cofactors.
This explains the slow antimalarial action of the antifolate biguanides compared to the quinoline
antimalarials. It is slowly but adequately absorbed from the gastrointestinal tract.
Adverse effects include abdominal pain, nausea, diarrhea, headache and fever.
Halofantrine
Halofantrine is a phenanthrene methanol derivative. It is a blood schizontocide, highly effective
against the asexual erythrocytic stage of plasmodia. It has no activity against exoerythrocytic or
gametocytes stages of malaria parasite.
Pharmacokinetics
It is given orally with slow and erratic absorption and bioavailability. The absorption is increased
approximately six–fold when taken with a fatty meal. Therefore, halofantrine should be given
on an empty stomach, and fatty foods avoided 24 hours thereafter.
Adverse effects include nausea, abdominal pain, diarrhea, pruritus, skin rash, serious but rare
fatal ventricular dysrhythmias, and prolongation of the QTc interval.
Clinical Uses: Halofantrine is used in the treatment of acute malaria caused by single or mixed
infections of P. falciparum or P. vivax.
Drug Interactions: There is a further prolongation of the QT interval when halofanrine is
administered with mefloquine, therefore both should not be used concomitantly. It has been
shown to exhibit extensive cross- resistance with mefloquine.
Pharmacists Council of Nigeria
53 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Atovaquone
Atovaquone, a hydroxynaphthoquinone, selectively interferes with mitochondrial electron
transport and related processes such as ATP and pyrimidine biosynthesis. It acts selectively at
the cytochrome bc1 complex of malaria parasite mitochondria to inhibit electron transport and
collapse the mitochondrial membrane potential.
When used alone, there are high rates of relapse especially in patients with uncomplicated P.
falciparum malaria. But when used as a fixed combination of atovaquone with proguanil (e.g.
Malarone®), high cure rates, few relapses and minimal toxicity are achieved.
Synergism between the two is possibly due to the ability of proguanil to enhance the membrane
collapsing activity of atovaquone.
Pharmacokinetics
Its bioavailability depends on the formulation as it has a low water solubility. A microfine
suspension has a two times greater oral bioavailability than tablets. Absorption on a single oral
dose is slow, erratic and variable, it is increased two to three fold by fatty food.
Clinical Uses
Atovaquone is used in combination with a biguanide to treat malaria; e.g. 250 mg of
atovaquone +100mg of proguanil HCl.
Adverse effects are rash, fever, vomiting, diarrhea and headache.
Antibacterial Antimalarials
(1). Sulfonamides and sulfones
They include sulfonamides e.g. sulfadoxine (a long acting sulfonamide) + pyrimethamine
(Fansidar®, Amalar®, etc.); the sulfone, Dapsone + chlorproguanil (Lapdap®) for therapy of
chloroquine resistant falciparum malaria; and pyrimethamine + dapsone (Maloprim®).
The sulfonamides and sulfones are slow-acting blood schizontocides that are more active
against P. falciparum than P. vivax. As p-aminobenzoic acid analogs that competitively inhibit
dihydropteroate synthase of P. falciparum, the sulphonamides are used together with an
inhibitor of parasite dihydrofolate reductase (e.g. pyrimethamine) to enhance their
antiplasmodial action.
Pharmacists Council of Nigeria
54 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(2). Tetracyclines: The tetracyclines, usually tetracycline or doxycycline, are slow-acting blood
schizontocides that are used alone for short-term prophylaxis and combined with quinine for the
treatment of malaria due to multidrug-resistant strains of P. falciparum. They are particularly
useful for the treatment of malaria due to multidrug resistant strains of P. falciparum that show
partial resistance to quinine. Their relatively slow action makes concurrent treatment with
quinine mandatory for rapid control of parasitemia.
NOTE: Tetracyclines are not administered to pregnant women or children less than 8 years,
due to their adverse effects on bones and teeth.
Other antimalarial drugs include:
Lumefantrine (benflumetol): It belongs to the aryl aminoalcohol group of antimalarials,
which include quinine, mefloquine, halofantrine, and it has similar mechanism of action. It is
available as an oral preparation co-formulated with artemether.
- Piperaquine
-Pyronaridine
(ii). Drugs used in the treatment of Amoebiasis
Drugs used to treat amoebiasis are classified into luminal, systemic and mixed amoebicides.
Luminal amoebicides are only active against intestinal forms of amoeba, e.g. diloxanide
furoate, iodoquinol, paromomycin. They can be used alone to treat asymptomatic or mild
intestinal forms of amoebiasis or after a systemic or mixed amoebicide to eradicate the
infection.
Systemic amoebicides are effective only against invasive forms of amoebiasis. They are used
primarily to treat severe amoebic dysentery e.g. dehydroemetine, or hepatic abscesses e.g.
dehydroemetine, chloroquine. However, they are not usually recommended unless other drugs
fail or cause unacceptable side effects.
Mixed amoebicides are active against both intestinal and systemic forms of amoebiasis e.g.
metronidazole (prototype), tinidazole, ornidazole, secnidazole.
Diloxanide furoate
Pharmacists Council of Nigeria
55 FPGOP Lecture Note on Applied Pharmacology and Toxicology
It is a dichloroacetamide derivative; other dichloroacetamides include clefamide, teclozan, and
etofamide.
It is effective in cases of acute intestinal amoebiasis. It is effective against trophozoites in the
intestinal tract. It is only administered orally and is rapidly absorbed from the gastrointestinal
tract following hydrolysis of the ester group (in the intestinal lumen or mucosa). It is hydrolyzed
to diloxanide and furoic acid; only diloxanide appears in the systemic circulation.
Adverse effects are uncommon, but occasionally, flatulence, abdominal distension, anorexia,
nausea, vomiting, diarrhea, pruritus and urticaria occur. Diloxanide is excreted in the urine, and
4 - 9% in the faeces largely as the glucuronide.
Clinical Uses
Used alone, diloxanide furoate is effective for treatment of asymptomatic passers of amoebic
cysts. It is ineffective when administered alone in the treatment of extraintestinal amoebiasis. It
is used with or after an appropriate systemic amoebicide to effect a cure of invasive and
extraintestinal amoebiasis.
Emetine and Dehydroemetine
Emetine an alkaloid from Ipecacuanha (Brazil root), was used years back as a direct-acting
systemic amoebicide. Dehydroemetine has similar pharmacological properties but is less toxic.
Although both drugs have been widely used to treat severe invasive intestinal amoebiasis, they
have been largely replaced by the mixed amoebicide metronidazole, which is as effective and
much safer. Thus emetine and dehydroemetine should not be used unless metronidazole is
ineffective or contraindicated.
Mechanism of Action
They inhibit protein synthesis in eukaryotic cells by preventing translocation of peptidyl- transfer
RNA, from the acceptor site to the donor site on the ribosome. They do not inhibit protein
synthesis in mammalian cells.
Antimicrobial spectrum
They kill the trophozoite stage of E. histolytica, but only when it is in tissues. They have no
effect on either the cyst or trophozoite forms present in the intestinal lumen.
They are rapidly absorbed from the injection site and are concentrated and stored in several
tissues, including the liver, lungs, spleen and kidney. Renal excretion of emetine is slow and the
Pharmacists Council of Nigeria
56 FPGOP Lecture Note on Applied Pharmacology and Toxicology
drug can readily accumulate. Dehydroemetine is excreted more rapidly than emetine, which
probably accounts for its lower toxicity.
Clinical Uses
They are not widely used. They are given in combination with other drugs in alternative
regimens for the treatment of severe intestinal amoebiasis and hepatic abscess caused by
metronidazole resistant E. histolytica.
Adverse Effects
They are irritants and they produce pain, tenderness and muscular weakness at the site of
injection. Other adverse effects are diarrhea, cramps, vomiting, hypotension, tachycardia and
shortness of breath.
Iodoquinol
Iodoquinol (diiodohydroxyquin) is a halogenated 8-hydroxyquinoline derivative, whose precise
mechanism of action is unknown. It kills the trophozoite form of E. histolytica. It is absorbed
from the gastrointestinal tract, and excreted in the urine and feces.
Clinical Uses: In amoebiasis.
Adverse effects are related to the iodine content of the drug; skin reactions, thyroid
enlargement, interference with thyroid function studies, headache, and diarrhea.
Since diloxanide furoate is also available as a luminal amoebicide and is safer, routine use of
iodoquinol is not strongly recommended.
Chronic use of clioquinol (iodochlorhydroxyquin), a closely related agent has been linked to a
myelitis-like illness as well as optic atrophy with permanent loss of vision.
Antibacterial agents
(1). Erythromycin and tetracycline do not have a direct effect on protozoa, but act by altering
intestinal bacterial flora and preventing secondary infection. Tetracycline also reduces the
normal gastrointestinal bacterial flora on which the amoeba depend for growth.
(2). Paromomycin is directly amoebicidal. It is not absorbed from the gastrointestinal tract, and
thus has its primary effect on bacteria, some amebas (e.g. E. histolytica), T. vaginalis, and
some helminths found in the gastrointestinal tract lumen. Adverse effects include diarrhea and
gastrointestinal upset.
Pharmacists Council of Nigeria
57 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Metronidazole
It is a nitroimidazole which exerts activity against most anaerobic bacteria and several protozoa.
Metronidazole freely penetrates protozoal and bacterial cells but not mammalian cells.
Mechanism of Action
Metronidazole is a prodrug. Metronidazole can function as an election sink and because it does
so, its 5-nitro group is reduced. Nitroreductase present in anaerobic organisms, reduces
metronidazole and thereby activates the drug. Reduced metronidazole disrupts replication and
transcription and inhibits DNA repair.
Antibacterial Spectrum
It inhibits E. histolytica, Giardia lamblia, T. vaginalis, Blastocystis hominis, Balantidium coli, and
the helminth Dracunculus medinensis. It is also bactericidal for obligate anaerobic gram-positive
and gram-negative bacteria, with the exception of Actinomyces species. It is not active against
aerobes or facultative anaerobes. Metronidazole resistance is rare.
Pharmacokinetics
Metronidazole is well absorbed from the gastrointestinal tract. Food delays but does not reduce
absorption. It is well distributed in body fluids, vaginal secretions, and seminal fluid. High levels
are found in plasma and cerebrospinal fluid. It is metabolised in the liver and mainly excreted
by the kidney, although small amounts can be found in saliva and breast milk.
Clinical Uses
(1). Metronidazole is the most effective agent available for the treatment of all forms of
amoebiasis with, perhaps, the exception of the person who is asymptomatic but continues to
excrete cysts. In that case, an effective intraluminal amoebicide, such as diloxanide furoate,
paromomycin sulphate or diiodohydroxyquin is indicated. Metronidazole is active against
intestinal and extraintestinal cysts and trophozoites.
Since metronidazole is well absorbed and therefore may not reach the large intestine in
therapeutic concentrations; it is likely to be more effective against systemic amoebiasis than
intestinal amoebiasis. Antibiotics such as paromomycin or a tetracycline can be used in
conjunction with metronidazole to treat severe forms of intestinal amoebiasis. Treatment with
metronidazole is generally followed by a luminal amoebicide e.g. diloxanide to effect a cure.
(2). Treatment of giardiasis.
Pharmacists Council of Nigeria
58 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(3). Treatment of Trichomonas vaginalis infection in males and females.
(4). Treatment of susceptible bacterial infection due to the following anaerobic bacteria;
Bacteroides, Clostridium, Helicobacter, etc.
(5). Prophylaxis of postsurgical mixed bacterial infections.
(6). Gastric infections with H. pylori when taken in various regimens that include proton pump
inhibitors.
Adverse Effects
Most frequent adverse effects of metronidazole are nausea, vomiting, cramps, diarrhea, metallic
taste, urine is often dark or reddish brown. Unsteadiness, vertigo, ataxia, peripheral
neuropathy, encephalopathy and neutropenia may also occur.
Alcohol must be avoided during treatment with metronidazole, which is a weak inhibitor of
alcohol dehydrogenase, since disulfiram- like and psychotic reactions may occur.
Drug Interactions
Metronidazole interferes with the metabolism of warfarin and may potentiate its anticoagulant
activity. Phenobarbital, rifampicin and corticosteroids (e.g. prednisone) lower metronidazole
plasma levels by increasing its metabolism. Cimetidine raises metronidazole levels by reducing
its metabolism.
Metronidazole is not recommended for use during pregnancy.
Others are tinidazole, ornidazole, secnidazole.
Chloroquine
The therapeutic value of chloroquine for extraintestinal amoebiasis in human relates to its direct
toxic action against trophozoites of E. histolytica together with the fact that it is highly
concentrated in the liver.
Chloroquine is used as a systemic amoebicide to treat hepatic amoebiasis only when treatment
with metronidazole is unsuccessful or contraindicated. The clinical response to chloroquine in
patients with hepatic amoebiasis is usually prompt, and there is no evidence of resistance to
chloroquine.
Chloroquine is far less effective in intestinal amoebiasis because it is almost completely
absorbed from the small intestine and attains only low concentrations in the intestinal wall.
Colonic infection with E. histolytica is always the source of extraintestinal amoebiasis, so a drug
Pharmacists Council of Nigeria
59 FPGOP Lecture Note on Applied Pharmacology and Toxicology
effective in intestinal amoebiasis is given routinely to all patients receiving chloroquine for
hepatic amoebiasis; such therapy reduces the relapse rate.
(iii). Drugs used in the Treatment of Trypanosomiasis Trypanosomiasis refers to several diseases in vertebrates caused by parasitic protozoan
trypanosomes of the genus Trypanosoma. In humans this includes African trypanosomiasis and
Chagas disease (American trypanosomiasis). The tsetse fly serves as both a host and vector for
the trypanosome parasites.
There are two types of African trypanosomiasis (sleeping sickness), the East African
(Rhodesian) and West African (Gambian), caused by T. brucei rhodesiense and T. brucei
gambiense, respectively. T. brucei rhodesiense produces a progressive and rapidly fatal disease
marked by early involvement of the central nervous system (CNS) and frequent terminal cardiac
failure; whereas T. brucei gambiense causes illness that is characterized by later involvement of
the CNS and a longer disease course that progresses to the classical symptoms of sleeping
sickness over months to years. Neurological symptoms include confusion, poor coordination,
sensory deficits, an array of psychiatric signs, disruption of the sleep cycle, and eventual
progression into coma and death.
The parasite is entirely extracellular, and early human infection is characterized by the presence
of replicating parasites in the bloodstream or lymph without CNS involvement (stage 1); in
stage 2 disease, the parasite has crossed the blood-brain barrier and infected the CNS.
Symptoms of early-stage disease include fever, lymphadenopathy, splenomegaly, muscle and
joint pains, headache and malaise. In the later stage there is evidence of CNS involvement with
personality changes, daytime sleepiness with night-time sleep disturbance, progressive
confusion, mental deterioration, and other neurologic symptoms.
Stage I of human African trypanosomiasis is usually treated with intramuscular injection or
intravenous infusion (with adequate monitoring) of pentamidine for T. brucei gambiense or
suramin for T. brucei rhodesiense. Stage II of the disease is typically treated with melarsoprol
or eflornithine preferably administered intravenously. Melarsoprol is very effective but has many
serious side effects, including neurological damage, however, the drug is the last hope in many
late stage cases. Eflornithine is expensive and less toxic than melarsoprol. In regions where the
disease is common, eflornithine is provided for free by WHO.
Pharmacists Council of Nigeria
60 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Pentamidine
Pentamidine has activity against trypanosomatid protozoans and against Pneumocystis jirovecii,
but toxicity is significant. Pentamidine is used for the treatment of early-stage T. brucei
gambiense infection, but is ineffective in the treatment of late-stage disease and has reduced
efficacy against T. brucei rhodesiense. The mechanism of action of pentamidine is unknown.
Pharmacokinetics
Pentamidine is administered parenterally or by inhalation. After parenteral administration, it
leaves the circulation rapidly with an initial t1/2 of about 6 hours. It is bound avidly to tissues,
and thus accumulates and is eliminated very slowly with a terminal elimination half-life of about
12 days. The drug can be detected in urine 6 or more weeks after treatment. Only trace
amounts of pentamidine appear in the central nervous system, so it is not effective against
central nervous system African trypanosomiasis. Pentamidine can also be inhaled as a nebulized
powder for the prevention of pneumocystosis. Absorption into the systemic circulation after
inhalation appears to be minimal. Pentamidine is primarily metabolized by hepatic CYP450
enzymes, about 12% is eliminated unchanged in the urine.
Clinical Uses
1. It is the drug of choice to treat the early hemolymphatic stage (first stage) of disease caused
by Trypanosoma brucei gambiense (West African sleeping sickness), before central nervous
system involvement. Pentamidine should not be used to treat late trypanosomiasis with central
nervous system involvement. Pentamidine has also been used for chemoprophylaxis against
African trypanosomiasis.
2. As an alternative to sodium stibogluconate in the treatment of visceral leishmaniasis; it has
similar efficacy, although resistance has been reported.
3. In the treatment and prevention of pneumocystis pneumonia, including in
immunocompromised persons.
Adverse Effects
Pentamidine is a highly toxic drug, with adverse effects noted in about 50% of patients
receiving 4 mg/kg/day. Rapid intravenous administration can lead to severe hypotension,
tachycardia, dizziness, and dyspnea, so the drug should be administered slowly (over 2 hours),
and patients should be recumbent and monitored closely during treatment. With intramuscular
administration, pain at the injection site is common, and sterile abscesses may develop. Other
Pharmacists Council of Nigeria
61 FPGOP Lecture Note on Applied Pharmacology and Toxicology
adverse effects include pancreatic toxicity (hypoglycemia may be followed by hyperglycemia),
reversible renal dysfunction including nephrotoxicity, rash, metallic taste, fever, gastrointestinal
symptoms, abnormal liver function tests, acute pancreatitis, thrombocytopenia, hallucinations,
and cardiac arrhythmias. Inhaled pentamidine is generally well tolerated but may cause cough,
dyspnea, and bronchospasm.
Suramin Suramin’s mechanism of action is unknown. It is administered intravenously and displays
complex pharmacokinetics with very tight protein binding. Suramin has a short initial half-life
but a terminal elimination half-life of about 50 days. It is slowly cleared by renal excretion.
Suramin is administered after a 200-mg intravenous test dose. Regimens that have been used
include 1 g on days 1, 3, 7, 14, and 21 or 1 g each week for 5 weeks. Combination therapy with
pentamidine may improve efficacy.
Clinical Uses
It is the first-line therapy for early hemolymphatic East African trypanosomiasis, but because it
does not enter the central nervous system it is not effective against advanced disease.
Although it shows activity against T. brucei gambiense, suramin is not used in West African
trypanosomiasis because of the availability of other effective drugs that lack the high activity of
suramin against Onchocerca and Brugia, and possible immunological reactions resulting from
killing of these parasites. Since only small amounts of suramin enter the brain, it is used only
for the treatment of early-stage African trypanosomiasis (before CNS involvement). Suramin will
clear the hemolymphatic system of trypanosomes even in late-stage disease, so it is often
administered before initiating melarsoprol to reduce the risk of reactive encephalopathy
associated with the administration of melarsoprol.
Adverse Effects
Adverse reactions are common, and immediate effects include fatigue, nausea and vomiting.
Later reactions include fever, rash, headache, paresthesias, neuropathy, renal abnormalities
including proteinuria, chronic diarrhea, hemolytic anemia and agranulocytosis. Rarely, seizures,
shock, loss of consciousness and death may occur.
Melarsoprol
Pharmacists Council of Nigeria
62 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Melarsoprol is a trivalent arsenical that has been available for the treatment of late-stage
trypanosomiasis since 1949. Despite the fact that it causes an often fatal encephalopathy in 2-
10% of the patients, melarsoprol has remained the only drug for the treatment of late (CNS)
stages of East African trypanosomiasis caused by T. brucei rhodesiense. Although melarsoprol is
also effective against late-stage West African trypanosomiasis caused by T. brucei gambiense,
eflornithine is the first-line treatment for this disease.
Pharmacokinetics
Melarsoprol is always administered intravenously. A small but therapeutically significant amount
of the drug enters the cerebrospinal fluid and has a lethal effect on trypanosomes infecting the
CNS. The compound is excreted rapidly, with 70-80% of the arsenic appearing in the feces.
Clinical Uses
Melarsoprol is used as first-line therapy for advanced central nervous system East African
trypanosomiasis, and second-line therapy (after eflornithine) for advanced West African
trypanosomiasis.
Adverse Effects
Treatment with melarsoprol is associated with significant toxicity and morbidity. The use of such
a toxic drug is justified only by the severity of advanced trypanosomiasis and the lack of
available alternatives. Immediate adverse effects include fever, vomiting, abdominal pain, and
arthralgias. The most important toxicity is a reactive encephalopathy that generally appears
within the first week of therapy, and is probably due to disruption of trypanosomes in the
central nervous system. Common consequences of the encephalopathy include cerebral edema,
seizures, coma, and death. Other serious toxicities include peripheral neuropathy, albuminuria,
hepatic dysfunction, hypertension, myocardial damage, and hypersensitivity reactions.
Failure rates with melarsoprol appear to have increased recently in parts of Africa, suggesting
the possibility of drug resistance.
Eflornithine
Eflornithine (α-D, L difluoromethylornithine; DFMO) is superior to melarsoprol with respect to
both safety and efficacy; the case fatality rate for eflornithine is significantly lower than for
melarsoprol.
Mechanism of Action
Pharmacists Council of Nigeria
63 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Eflornithine is an irreversible catalytic (suicide) inhibitor of ornithine decarboxylase, the enzyme
that catalyzes the first and rate-limiting step in the biosynthesis of polyamines. The
polyamines—putrescine, spermidine, and in mammals, spermine—are required for cell division
and for normal cell differentiation. In trypanosomes, spermidine additionally is required for the
synthesis of trypanothione, which is a conjugate of spermidine and glutathione that replaces
many of the functions of glutathione in the parasite cell.
Pharmacokinetics
Eflornithine is administered intravenously, and adequate levels are achieved in the central
nervous system. The elimination half-life is about 3 hours. There is rapid renal clearance after
intravenous administration with >80% of the drug cleared by the kidney largely in unchanged
form.
Clinical Uses
Eflornithine is the first-line drug for advanced West African trypanosomiasis (adequate care
should be provided for its administration), but is not effective for East African disease.
Eflornithine is safer and has greater efficacy than melarsoprol for late-stage Gambiense sleeping
sickness.
Adverse Effects
Toxicity from eflornithine is significant, but are generally reversible on drug withdrawal. Adverse
effects include reactions at the injection site, abdominal pain, diarrhea, vomiting, headache,
anemia, thrombocytopenia, leukopenia, and seizures.
Nifurtimox
Nifurtimox, a nitrofuran, is the most commonly used drug for American trypanosomiasis
(Chagas’ disease). Nifurtimox is used in combination with eflornithine (nifurtimox-eflornithine
combination treatment; NECT) to treat late stage T. brucei gambiense sleeping sickness.
Adverse effects are common and include nausea, vomiting, abdominal pain, fever, rash,
restlessness, insomnia, neuropathy and seizures. These effects are generally reversible but
often lead to cessation of therapy before completion of a standard course.
Table 2: Drugs used for the treatment of African trypanosomiasis
Disease Stage First-line Alternative drugs
Pharmacists Council of Nigeria
64 FPGOP Lecture Note on Applied Pharmacology and Toxicology
drugs
West African Early Pentamidine Suramin, eflornithine
CNS involvement Eflornithine Melarsoprol, nifurtimox-eflornithine (NECT)
East African Early Suramin Pentamidine
CNS involvement Melarsoprol -
(iv). Drugs used in the treatment of Leishmaniasis
Various forms of leishmaniasis affect people in tropical and subtropical regions of the world, and
southern Europe.
Leishmaniasis is a complex vector-borne zoonosis caused by about 20 different species of
obligate intramacrophage protozoa of the genus Leishmania. Small mammals and canines
generally serve as reservoirs for these pathogens, which can be transmitted to humans by the
bite of about 30 different species of female Phlebotomine sand fly (disease vector).
Flagellated extracellular free promastigotes, regurgitated by feeding flies, enter the host, where
they attach to and become phagocytized by tissue macrophages. These transform into
amastigotes, which reside and multiply within phagolysosomes until the cell bursts. Released
amastigotes then propagate the infection by invading more macrophages. Amastigotes taken up
by feeding sandflies transform back into promastigotes, thereby completing the transformation
cycle.
The particular localized or systemic disease syndrome caused by Leishmania depends on the
species or subspecies of infecting parasite, the distribution of infected macrophages, and
particularly the host’s immune response. In increasing order of systemic involvement and
potential clinical severity, major syndromes of human leishmaniasis is classified into cutaneous,
mucocutaneous, diffuse cutaneous, and visceral (kala azar) forms. Cutaneous forms of
leishmaniasis generally are self-limiting, with cures occurring in 3-18 months after infection.
However, this form of the disease can leave disfiguring scars. The mucocutaneous, diffuse
cutaneous, and visceral forms of the disease do not resolve without therapy. Visceral
leishmaniasis caused by L. donovani is fatal unless treated.
Leishmaniasis is increasingly becoming recognized as an AIDS-associated opportunistic
infection.
Pharmacists Council of Nigeria
65 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Pharmacotherapy of leishmaniasis
Pentavalent antimonials: Sodium stibogluconate and meglumine antimoniate
The mechanism of action of the antimonials is unknown.
Pharmacokinetics
They are rapidly absorbed and distributed after intravenous (preferred) or intramuscular
administration and eliminated in two phases, with short initial half-life (about 2 hours) and
much longer terminal half-life (33 - 76 hours).
Clinical Uses
Sodium stibogluconate (sodium antimony gluconate) and meglumine antimoniate, are generally
considered first-line agents for cutaneous, mucocutaneous and visceral leishmaniasis.
Their efficacy against different species may vary, possibly based on local drug resistance
patterns (e.g. their efficacy has diminished in parts of India).
Adverse Effects
Few adverse effects occur initially, but toxicity of stibogluconate increases over the course of
therapy. Most common are gastrointestinal symptoms, fever, headache, myalgias, arthralgias,
and rash. Intramuscular injections can be very painful and lead to sterile abscesses.
Electrocardiographic changes may occur, most commonly T-wave changes and QT prolongation.
These changes are generally reversible, but continued therapy may lead to dangerous
arrhythmias. Thus, the electrocardiogram should be monitored during therapy. Hemolytic
anemia and serious liver, renal, and cardiac effects are rare.
Miltefosine
Miltefosine is an alkylphosphocholine analog that is the first effective oral drug for visceral
leishmaniasis. Miltefosine is used for the treatment of visceral leishmaniasis.
Adverse effects include vomiting, diarrhea transient elevations in liver enzymes and
nephrotoxicity. Miltefosine is contraindicated in pregnancy or in women who may become
pregnant within 2 months of treatment, because of its teratogenic effects.
Liposomal amphotericin B and Paromomycin are also used to treat leishmaniasis in some
countries.
Pharmacists Council of Nigeria
66 FPGOP Lecture Note on Applied Pharmacology and Toxicology
B3. ANTHELMINTICS: DRUGS USED IN ASCARIASIS, ANCYLOSTOMIASIS, ONCHOCERCIASIS, DRACUNCULIASIS, SCHISTOSOMIASIS AND TAPEWORMS INFESTATIONS Helminths (parasitic worms) pathogenic in humans are nematodes (roundworms), cestodes
(tapeworms), and trematodes (flukes). Cestodes and trematodes are flatworms
(platyhelminthes). In regions of rural poverty in the tropics including Nigeria, with high
prevalence of helminthiasis, simultaneous infection with more than one type of helminth is
common. Soil-transmited helminth (STH) infections such as ascariasis, trichuriasis and
hookworm infestation are among the most prevalent in developing countries.
Anthelmintics are drugs that act either locally within the gut lumen to cause expulsion of worms
from the gastrointestinal tract, or systemically against helminths residing outside the
gastrointestinal tract.
Nematodes (Roundworms)
The major nematode parasites of humans include the soil-transmitted helminths (STHs;
sometimes referred to as geohelminths) and the filarial nematodes.
Soil-transmited helminths include Ascaris lumbricoides (roundworm), Trichuris trichuira
(whipworm), and hookworm (Necator americanus and Ancylostoma duodenale). Other
nematodes are Strongyloides stercoralis (threadworm), Enterobius vermicularis (pinworm),
Trichinella spiralis, etc.
Filarial nematodes include lymphatic filarial and tissue-migrating filarial parasites. Lymphatic
filarial worms are Wuchereria bancrofti, Brugia malayi, Brugia timori. Tissue-migrating filarial
worms are Loa loa, Onchocerca volvulus, Dracunculus medinensis (guinea worm).
Cestodes
Cestodes include Taenia saginata (beef tapeworm), T. solium (pork tapeworm),
Diphyllobothrium latum (fish tapeworm), Hymenolepis nana (dwarf tapeworm), and
Echinococcus species. Humans serve as one of several intermediate hosts for larval forms of
Echinococcus species that cause cystic (E. granulosus) and alveolar (E. multilocularis and E.
vogeli) echinococcosis. Cystic echinococcosis is also known as hydatid disease.
Trematodes (Flukes)
Pharmacists Council of Nigeria
67 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Blood flukes that cause human schistosomiasis include Schistosoma haematobium, S. mansoni
and S. japonicum. Other flukes include Paragonimus westermani and other Paragonimus
species (lung flukes), Clonorchis sinensis, Opisthorchis viverrini, Opisthorchis felineus, Fasciola
hepatica, Fasciolopsis buski (liver flukes), Heterophyes heterophyes, Metagonimus yokogawai,
Nanophyetus salmincola, etc.
Ascariasis is a disease due to infestation by the parasitic Ascaris lumbricoides.
Trichuriasis is an infection by Trichuris trichiura (whipworm).
Ancylostomiasis (anchylostomiasis, ankylostomiasis) is a hookworm disease caused by infection
with Ancylostoma hookworms (N. americanus and A. duodenale). Certain species of hookworms
also cause cutaneous larva migrans (CLM). Cutaneous larva migrans is a zoonotic skin disease
in humans, caused by the larvae of various species of hookworms, most commonly Ancylostoma
braziliense. These parasites live in the intestines of dogs, cats, and wild animals and are
different from Ancylostoma duodenale and Necator americanus, for which humans are definitive
hosts. Enterobiasis is caused by pinworm infection; the most common symptom is itching in the
anal area.
Strongyloidiasis is caused by the nematode, Strongyloides stercoralis, or sometimes S.
fülleborni. Schistosomiasis (snail fever, bilharzia; bilharziasis) is a disease caused by parasitic
flatworms, schistosomes. The urinary tract or the intestines may be infected. The disease is
spread by contact with fresh water contaminated with the parasites; freshwater snails are the
disease vector. Schistosomiasis is especially common among children in developing countries as
they are more likely to play in contaminated water. Other high risk groups include farmers,
fishermen, and people using unclean water.
Onchocerciasis (river blindness), is a disease caused by infection with the parasitic worm
Onchocerca volvulus. Symptoms include severe itching, bumps under the skin, and blindness.
The parasite worm is spread by the bites of Simulium black fly, which live near rivers, hence
river blindess.
Dracunculiasis is an infection by Dracunculus medinensis (guinea worm).
Diseases caused by tapeworm infestations are taeniasis, cysticercosis, neurocysticercosis, and
hydatid disease. Taeniasis is a parasitic disease due to infection with tapeworms belonging to
the genus Taenia; two most important human pathogens in the genus are Taenia solium (pork
Pharmacists Council of Nigeria
68 FPGOP Lecture Note on Applied Pharmacology and Toxicology
tapeworm) and Taenia saginata (beef tapeworm). Cysticercosis is a parasitic tissue infection
caused by larval cysts of the tapeworm Taenia solium. These larval cysts infect the central
nervous system (neurocysticercosis), muscle, or other tissues, and are a major cause of adult
onset seizures in most low-income countries. Hydatid disease in humans is caused mainly by
infection by the larval stage of the dog tapeworm Echinococcus granulosus.
(i). Anthelmintics used to treat infections by nematodes
Benzimidazoles
Anthelmintic benzimidazoles are albendazole, mebendazole and thiabendazole. The primary
mechanism of action of benzimidazoles is inhibition of microtubule polymerization by binding to
β –tubulin.
Albendazole
Mechanism of Action
Albendazole, a benzimidazole, inhibits microtubule synthesis in nematodes. It also has larvicidal
effects in hydatid disease, cysticercosis, ascariasis, and hookworm infection; and ovicidal effects
in ascariasis, ancylostomiasis, and trichuriasis.
Pharmacokinetics
After oral administration, albendazole is erratically absorbed (absorption is increased with a
fatty meal) and then rapidly undergoes first-pass metabolism in the liver to the active
metabolite albendazole sulfoxide. It reaches variable maximum plasma concentrations about 3
hours after a 400 mg oral dose, and its plasma half-life is 8–12 hours. The sulfoxide is mostly
protein-bound, distributes well to tissues, and enters bile, cerebrospinal fluid, and hydatid cysts.
Albendazole metabolites are excreted in the urine.
Clinical Uses
1. It is effective in Ascaris, Trichuris, Hookworm and Pinworm infestations.
2. In hydatid disease, neurocysticercosis, and other infections such as cutaneous larva migrans,
visceral larva migrans, intestinal capillariasis, amongst others.
Albendazole should be administered on an empty stomach when used against intraluminal
parasites, but with a fatty meal when used against tissue parasites.
Adverse Effects
Pharmacists Council of Nigeria
69 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Albendazole is nearly free of significant adverse effects, when used for 1–3 days. However,
adverse effects include mild and transient epigastric distress, diarrhea, headache, nausea,
dizziness, lassitude and insomnia.
Mebendazole
Mechanism of Action
Mebendazole, a benzimidazole, acts by inhibiting microtubule synthesis. It kills hookworm,
Ascaris and Trichuris eggs.
Pharmacokinetics
Less than 10% of orally administered mebendazole is absorbed; absorption is increased if the
drug is ingested with a fatty meal. The absorbed drug is about 95% protein-bound, rapidly
converted to inactive metabolites (primarily during its first pass in the liver) and has a half-life
of 2–6 hours. The low systemic bioavailability of mebendazole results from a combination of
poor absorption and rapid first-pass hepatic metabolism. It is excreted mostly in the urine,
principally as decarboxylated derivatives. Also, a portion of absorbed drug and its derivatives
are excreted in the bile.
Clinical Uses
Mebendazole is used in ascariasis, trichuriasis, hookworm and pinworm infections, and certain
other helminthic infections like intestinal capilliarisis.
Adverse Effects
Short-term mebendazole therapy for intestinal nematodes is nearly free of adverse effects,
however, nausea, vomiting, diarrhea, and abdominal pain may occur. Rare adverse effects,
usually with high-dose therapy, include hypersensitivity reactions (rash, urticaria),
agranulocytosis, alopecia, and elevation of liver enzymes.
Drug Interactions: Concomitant use of carbamazepine or phenytoin may decrease, while
cimetidine may increase the plasma levels of mebendazole.
Thiabendazole
Thiabendazole is active against a wide range of nematodes, but its clinical use has declined
markedly because of its toxicity relative to other equally effective drugs.
Mechanism of Action
Pharmacists Council of Nigeria
70 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Thiabendazole is a benzimidazole compound, its mechanism of action is the same as that of
other benzimidazoles.
Pharmacokinetics
Thiabendazole is rapidly absorbed after ingestion. Peak plasma levels are achieved within 1–2
hours after a standard dose; the half-life is 1.2 hours. The drug is almost completely
metabolized in the liver to the 5-hydroxy form; 90% is excreted in the urine in 48 hours, largely
as the glucuronide or sulfonate conjugate. Thiabendazole can also be absorbed from the skin.
Clinical Uses
Thiabendazole is an alternative to ivermectin or albendazole for the treatment of
strongyloidiasis and cutaneous larva migrans. Thiabendazole is much more toxic than other
benzimidazoles and more toxic than ivermectin, so other agents are now preferred for most
indications.
Adverse Effects
Adverse effects of thiabendazole include dizziness, anorexia, nausea, vomiting, epigastric pain,
abdominal cramps, diarrhea, pruritus, headache, drowsiness, and neuropsychiatric symptoms.
Irreversible liver failure and fatal Stevens-Johnson syndrome may occur.
Cautions and Contraindications
Thiabendazole should not be used in pregnancy or in the presence of hepatic or renal disease.
Pyrantel Pamoate
Pyrantel pamoate, a tetrahydropyrimidine derivative, is a broad-spectrum anthelmintic highly
effective for the treatment of pinworm, Ascaris, and Trichostrongylus orientalis infections. It is
moderately effective against both species of hookworm (N. americanus and A. duodenale). It is
not effective in trichuriasis or strongyloidiasis.
Mechanism of Action
Pyrantel is a depolarizing neuromuscular blocker that causes persistent activation of nicotinic
acetylcholine receptors, resulting in spastic paralysis of the worm. Pyrantel also inhibits
cholinesterases, resulting in paralysis of worms. Consequently, the worm will be expelled from
the body.
Pharmacists Council of Nigeria
71 FPGOP Lecture Note on Applied Pharmacology and Toxicology
It is effective against mature and immature forms of susceptible helminths within the intestinal
tract, but not against migratory stages in the tissues or against ova. It is poorly absorbed from
the gastrointestinal tract and active mainly against luminal organisms.
Pharmacokinetics
Pyrantel pamoate is poorly absorbed from the gastrointestinal tract, peak plasma levels are
reached in 1–3 hours. Less than 15% is excreted in the urine as parent drug and metabolites.
Over 50% of the administered dose is recovered unchanged in the feces.
Clinical Uses
In the treatment of ascariasis, pinworm (enterobiasis) and hookworm infestations.
Adverse Effects
Adverse effects are infrequent, mild, and transient. They include nausea, vomiting, diarrhea,
abdominal cramps, dizziness, drowsiness, headache, insomnia, rash, fever and weakness.
Caution
Pyrantel should be used with caution in patients with liver dysfunction, because low, transient
elevation of aminotransferases may occur.
Piperazine
Piperazine is highly effective against A. lumbricoides and E. vermicularis.
Mechanism of Action
Piperazine acts as a GABA-receptor agonist, thereby increasing chloride ion conductance of the
parasite’s muscle membrane, producing hyperpolarization and reduced excitability that leads to
muscle relaxation and flaccid paralysis. The worm is subsequently expelled by normal
peristalsis.
Pharmacokinetics
Piperazine is available as the hexahydrate, citrate and a variety of salts. It is readily absorbed,
and maximum plasma levels are reached in 2–4 hours. Most of the drug is excreted unchanged
in the urine in 2–6 hours, and excretion is complete within 24 hours.
Clinical Uses
Piperazine has been superseded as a first-line anthelmintic by the better tolerated and more
easily administered benzimidazole anthelmintics. Piperazine is an alternative for the treatment
of ascariasis.
Pharmacists Council of Nigeria
72 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Adverse Effects
Occasional mild adverse effects include nausea, vomiting, diarrhea, abdominal pain, dizziness,
and headache. Neurotoxicity and allergic reactions are rare.
Contraindications
Piperazine compounds are contraindicated in pregnant women, in patients with impaired renal
or hepatic function, or those with a history of epilepsy or chronic neurologic disease.
(ii). Anthelmintics used to treat infections by cestodes and trematodes
Praziquantel
Praziquantel is active against most cestodes and trematodes that infect humans, whereas
nematodes generally are unaffected. The drug is best studied and most commonly used for
treatment of schistosomiasis caused by S. mansoni, S. haematobium, and S. japonicum.
Mechanism of Action
The exact mechanism of action of praziquantel is unclear, but it seems to increase the
permeability of trematode and cestode cell membranes to calcium, resulting in paralysis,
dislodgement and death of the parasites.
Pharmacokinetics
It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum
concentration is reached 1–3 hours after a therapeutic dose. Plasma concentrations of
praziquantel increase when it is taken with a high-carbohydrate meal. Cerebrospinal fluid
concentration is about 14–20% of the drug’s plasma concentration. About 80% of the drug is
bound to plasma proteins. Most of the drug rapidly undergoes hepatic first-pass metabolism to
inactive mono- and polyhydroxylated products, hence only a relatively small amount enters the
systemic circulation. The half-life is 0.8–3 hours, depending on the dose. Praziquantel is
metabolized by CYP3A4. Praziquantel and its metabolites are mainly excreted via the kidneys
(60–80%) and bile (15–35%).
Clinical Uses
Praziquantel is effective in the treatment of schistosome infections of all species
(schistosomiasis) and most other trematode and cestode infections, including taeniasis,
cysticercosis, neurocysticercosis, hydatid disease, clonorchiasis, opisthorchiasis and other
tapeworm and fluke (e.g. Fasciolopsis buski, Heterophyes heterophyes, etc) infections.
Pharmacists Council of Nigeria
73 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Praziquantel is useful in mass treatment of infections by several helminths because of its safety
and effectiveness as a single oral dose.
Praziquantel tablets are taken with liquid after a meal; they should be swallowed without
chewing because their bitter taste can induce retching and vomiting.
Praziquantel should not be used for worm infections of the eye.
Adverse Effects
Mild and transient adverse effects are common, and include headache, dizziness, drowsiness,
and lassitude. Others include mild and transient elevations of liver enzymes, nausea, vomiting,
abdominal pain, loose stools, pruritus, urticaria, arthralgia, myalgia and low-grade fever.
Several days after starting praziquantel, low-grade fever, pruritus, and skin rashes (macular and
urticarial), sometimes associated with worsened eosinophilia, may occur, probably due to the
release of proteins from dying worms and the consequent host immune reaction, rather than
direct drug toxicity.The heavier the parasite burden, the heavier and more frequent the side
effects. The intensity and frequency of adverse effects increase with dosage such that they
occur in up to 50% of patients who receive 25 mg/kg three times in one day.These side effects
may be life-threatening and can be reduced by co-administration of corticosteroids.
In neurocysticercosis, neurologic abnormalities may be exacerbated by inflammatory reactions
around dying parasites. Also, corticosteroids are commonly used with praziquantel in the
treatment of neurocysticercosis to decrease the inflammatory reaction.
The use of corticosteroids to ameliorate the adverse reactions to praziquantel is controversial
and complicated by the observation that corticosteroids decrease the plasma level of
praziquantel up to 50%.
Cautions and Contraindications
Tasks requiring mental alertness (e.g., driving, operating machinery) should be avoided shortly
after taking Praziquantel.
Praziquantel is contraindicated in ocular cysticercosis, because parasite destruction in the eye
may cause irreparable damage. Caution is also advised in the use of the drug in spinal
neurocysticercosis.
Drug Interactions
Inducers of CYP3A4 such as rifampicin, carbamazepine and phenytoin decreases plasma
concentrations of praziquantel. Cimetidine increases its bioavailabilty.
Pharmacists Council of Nigeria
74 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Oxamniquine
Oxamniquine is an alternative to praziquantel for the treatment of Schistosoma mansoni
infections. It has also been used extensively for mass treatment. It is not effective against other
Schistosoma spp -S. haematobium or S. japonicum.
Mechanism of Action
The mechanism of action is unknown. Contraction and paralysis of the worms results in
detachment from terminal venules in the mesentery and transit to the liver, where many die;
surviving females return to the mesenteric vessels but cease to lay eggs.
Oxamniquine is active against both mature and immature stages of S. mansoni but does not
appear to be cercaricidal.
Pharmacokinetics
Oxamniquine is readily absorbed on oral administration; it should be taken with food. Its plasma
t1/2 is about 2.5 hours. The drug is extensively metabolized to inactive metabolites and excreted
in the urine; up to 75% in the first 24 hours.
Clinical Uses
Oxamniquine is safe and effective in all stages of S. mansoni disease, including advanced
hepatosplenomegaly. It is generally less effective in children, who require higher doses than
adults. It is better tolerated with food.
Oxamniquine is effective in praziquantel resistance.
Oxamniquine is used in combination with metrifonate, in the treatment of mixed schistosome
infections.
Optimal dosage schedules for therapy with oxamniquine vary for different regions of the world.
In the western hemisphere and western Africa, the adult oxamniquine dosage is 12–15 mg/kg
given once. In northern and southern Africa, standard schedules are 15 mg/kg twice daily for 2
days. In eastern Africa and the Arabian Peninsula, standard dosage is 15–20 mg/kg twice in 1
day.
Adverse Effects
Adverse effects are generally mild, and include central nervous system symptoms (dizziness,
headache and drowsiness), nausea, vomiting, diarrhea, colic, pruritus, urticaria, low-grade
Pharmacists Council of Nigeria
75 FPGOP Lecture Note on Applied Pharmacology and Toxicology
fever, an orange to red discoloration of the urine, proteinuria, microscopic hematuria, and a
transient decrease in leukocytes.
Cautions and Contraindications
Oxamniquine should be used with caution in patients whose work or activity requires mental
alertness, as it causes dizziness and drowsiness. It should be used with caution in those with a
history of epilepsy. Oxamniquine is contraindicated in pregnancy.
Metrifonate (Trichlorfon)
Metrifonate is a safe, low-cost alternative drug for the treatment of S. haematobium infections.
It is not effective against S. haematobium eggs; live eggs continue to pass in the urine for
several months after all adult worms have been killed. Metrifonate is not active against
S.mansoni or S. japonicum.
Mechanism of Action
Metrifonate is an irreversible organophosphate acetylcholinesterase inhibitor. It is a prodrug
which is activated non-enzymatically into 2,2-dichlorovinyl dimethyl phosphate (DDVP;
dichlorvos). The inhibition of acetylcholinesterase paralyzes the adult worms, resulting in their
shift from the bladder venous plexus to small arterioles of the lungs, where they are trapped,
encased by the immune system, and die.
Pharmacokinetics
Metrifonate is rapidly absorbed after oral administration. After the standard oral dose, peak
blood levels are reached in 1–2 hours; the half-life is about 1.5 hours. Clearance appears to be
through non-enzymatic transformation to dichlorvos, its active metabolite. Metrifonate and
dichlorvos are well distributed to the tissues and are completely eliminated in 24–48 hours.
Clinical Uses
In the treatment of S. haematobium infection.
In prophylaxis of S. haematobium infections, especially in mass treatment programs in highly
endemic areas.
Metrifonate is used in combination with oxamniquine, in the treatment of mixed infections with
S. haematobium and S. mansoni.
Niclosamide
Pharmacists Council of Nigeria
76 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Niclosamide is a second-line drug for the treatment of most tapeworm infestations.
Mechanism of Action
Niclosamide inhibits glucose uptake, oxidative phosphorylation, and anaerobic metabolism in
the tapeworm.
Pharmacokinetics
It appears to be minimally absorbed from the gastrointestinal tract; neither the drug nor its
metabolites have been recovered from the blood or urine.
Clinical Uses
1. In the treatment of Taenia saginata (Beef Tapeworm), T. solium (Pork Tapeworm),
Diphyllobothrium latum (Fish Tapeworm), and some other tapeworm infestations.
Adverse Effects
Infrequent, mild, and transitory adverse effects include nausea, vomiting, diarrhea, and
abdominal discomfort.
Cautions and Contraindications
The consumption of alcohol should be avoided on the day of treatment and for one day
afterward. The safety of the drug has not been established in pregnancy or for children younger
than 2 years of age.
Therapy with niclosamide poses a risk to people infected with T. solium because ova released
from drug-damaged gravid worms develop into larvae that can cause cysticercosis, a dangerous
infection that responds poorly to chemotherapy.
(iii). Anthelmintics used to treat infections by filarial nematodes Ivermectin Ivermectin, a semisynthetic macrocyclic lactone, is a mixture of avermectin B 1a and B 1b. It is
derived from the soil actinomycete, Streptomyces avermitilis. Ivermectin is the drug of choice in
strongyloidiasis and onchocerciasis. It is also an alternative drug for a number of other
helminthic infections.
In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfilarial
counts in the skin and ocular tissues that lasts for 6-12 months. It has little discernible effect on
adult parasites, even at doses as high as 800 μg/kg, but affects developing larvae and blocks
egress of microfilariae from the uterus of adult female worms. By reducing microfilariae in the
Pharmacists Council of Nigeria
77 FPGOP Lecture Note on Applied Pharmacology and Toxicology
skin, ivermectin decreases transmission to the Simulium black fly vector. Regular treatment with
ivermectin is believed to act prophylactically against the development of Onchocerca infection.
Ivermectin also is effective against microfilaria but not against adult worms of W. bancrofti, B.
malayi, L. loa, and M. ozzardi. It is also effective in human against Ascaris lumbricoides,
Strongyloides stercoralis, and cutaneous larva migrans.
Mechanism of Action
Ivermection enhances inhibitory neurotransmission. It binds to glutamate-gated chloride
channels (GluCls) in the membranes of invertebrate nerve and muscle cells, causing increased
permeability to chloride ions, resulting in cellular hyperpolarization, followed by paralysis and
death. GluCls are invertebrate-specific members of the Cys-loop family of ligand-gated ion
channels present in neurons and myocytes. Ivermectin is also known to bind with high affinity
to GABA-gated chloride channels.
In onchocerciasis, ivermectin is microfilaricidal. It does not effectively kill adult worms but
blocks the release of microfilariae for some months after therapy. After a single standard dose,
microfilariae in the skin diminish rapidly within 2–3 days, remain low for months, and then
gradually increase; microfilariae in the anterior chamber of the eye decrease slowly over
months, eventually clear, and then gradually return. Repeated doses of ivermectin, appears to
have a low level macrofilaricidal action and permanently reduce microfilarial production.
Pharmacokinetics
Ivermectin is used only orally in humans. It is rapidly absorbed, reaching peak plasma
concentrations 4-5 hours after oral administration. It has a wide tissue distribution and a
volume of distribution of about 50 L; it is about 93% bound to plasma proteins. Its terminal
half-life is about 57 hours. The drug is extensively converted by hepatic CYP3A4 to at least ten
metabolites, mostly hydroxylated and demethylated derivatives. Ivermectin and its metabolites
are excreted almost exclusively in the feces.
Clinical Uses
1. In the treatment of onchocerciasis. With the first treatment only, patients with microfilariae
in the cornea or anterior chamber may be treated with corticosteroids to avoid inflammatory
eye reactions.
Pharmacists Council of Nigeria
78 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Ivermectin is beneficial in onchocerciasis control in Nigeria and other countries; annual mass
treatments have reduced the transmission of the disease.
2. In the treatment of lymphatic filariasis.
Single annual doses of ivermectin (400 μg/kg) is both effective and safe for mass chemotherapy
of infections with W. bancrofti and B. malayi. Ivermectin is as effective as diethylcarbamazine
(DEC) for controlling lymphatic filariasis, but unlike DEC, it can be used in regions where
onchocerciasis, loiasis, or both are endemic.
Although ivermectin as a single agent can reduce W. bancrofti microfilaremia, a single annual
dose of ivermectin (200 μg/kg) and albendazole (400 mg) is more effective in controlling
lymphatic filariasis than either drug used alone. The duration of treatment is at least 5 years,
based on the estimated fecundity of the adult worms. This dual-drug regimen also reduces
infections with intestinal nematodes. Facilitated by corporate donation of ivermectin and
albendazole, the drug combination now serves as the treatment standard for mass
chemotherapy and control of lymphatic filariasis.
3. In the treatment of strongyloidiasis. Ivermectin administered as a single dose of 150 to 200
μg/kg is the drug of choice for treatment of human strongyloidiasis. It is at least as active as
the older drug of choice, thiabendazole, and significantly better tolerated. It is generally
recommended that a second dose be administered a week following the first dose. It is more
efficacious than a 3-day course of albendazole.
4. Ivermectin is also effective in controlling scabies, lice and cutaneous larva migrans, and in
eliminating a large proportion of ascarid worms.
Adverse Effects
In onchocerciasis treatment, adverse effects are principally due to killing of microfilariae and
may include fever, headache, dizziness, somnolence, weakness, rash, increased pruritus,
diarrhea, joint and muscle pains, hypotension, tachycardia, lymphadenitis, lymphangitis, and
peripheral edema. This reaction starts on the first day and peaks on the second day after
treatment. This reaction occurs in 5–30% of persons and is generally mild, but it may be more
frequent and more severe in individuals who are not long term residents of onchocerciasis-
endemic areas. A more intense reaction occurs in 1–3% of persons and a severe reaction in
0.1%, including high fever, hypotension, and bronchospasm. Corticosteroids are indicated in
these cases, at times for several days. Toxicity diminishes with repeated dosing. Swellings and
Pharmacists Council of Nigeria
79 FPGOP Lecture Note on Applied Pharmacology and Toxicology
abscesses occasionally occur at 1–3 weeks, presumably at sites of adult worms. Some patients
develop corneal opacities and other eye lesions several days after treatment. These are rarely
severe and generally resolve without corticosteroid treatment.
In strongyloidiasis treatment, infrequent adverse effects include fatigue, dizziness, nausea,
vomiting, abdominal pain, and rashes.
Cautions and Contraindications
It is best to avoid concomitant use of ivermectin with other drugs that enhance GABA activity,
eg, barbiturates, benzodiazepines, and valproic acid. Ivermectin should not be used during
pregnancy. Safety in children younger than 5 years has not been established.
Diethylcarbamazine citrate
Diethylcarbamazine (DEC) is a drug of choice in the treatment of filariasis, loiasis, and tropical
eosinophilia. It has been replaced by ivermectin for the treatment of onchocerciasis.
Diethylcarbamazine is active against microfilariae of W. bancrofti, B. malayi, L. loa and O.
volvulus. It has some activity against the adult forms of W. bancrofti, B. malayi, and L. loa but
negligible activity against adult O. volvulus. It is not used for the treatment of onchocerciasis
because it causes severe reactions related to microfilarial destruction, including worsening
ocular lesions. However, diethylcarbamazine remains the best drug available to treat loiasis.
Mechanism of Action
Diethylcarbamazine inhibits arachidonic acid metabolism in microfilaria, thereby immobilising
the microfilariae, altering their surface structure and displacing them from tissues. Ultimately,
the micorfilariae are more susceptible to destruction by host defense mechanisms. The mode of
action against adult worms is unknown.
Pharmacokinetics
Diethylcarbamazine is rapidly absorbed from the gastrointestinal tract; peak plasma levels are
reached within 1–2 hours after a 0.5 mg/kg dose. The plasma half-life is 2–3 hours in the
presence of acidic urine, but about 10 hours if the urine is alkaline. The drug rapidly equilibrates
with all tissues except fat. Diethylcarbamazine is excreted by both urinary and extra-urinary
routes; greater than 50% of an oral dose appears in acidic urine as the unchanged drug, but
this value is decreased when the urine is alkaline. Alkalinizing the urine can elevate plasma
levels, prolong the plasma t1/2, and increase both the therapeutic effect and toxicity of
Pharmacists Council of Nigeria
80 FPGOP Lecture Note on Applied Pharmacology and Toxicology
diethylcarbamazine. Therefore, dosage reduction may be required for people with renal
dysfunction or persistent urinary alkalosis. Metabolism is rapid and extensive; a major
metabolite, diethylcarbamazine-N-oxide, is active.
Clinical Uses
1. Diethylcarbamazine is the drug of choice for treatment of W.bancrofti, B. malayi, B. timori,
and L. loa infections because of its efficacy and lack of serious toxicity. Microfilariae of all the
species are rapidly killed; adult parasites are killed more slowly, often requiring several courses
of treatment. The drug is highly effective against adult L. loa.
These infections are treated for 2 or (for L. loa) 3 weeks, with initial low doses to reduce the
incidence of allergic reactions to dying microfilariae. Antihistamines may be given for the first
few days of therapy to limit allergic reactions, and corticosteroids should be started and doses
of diethylcarbamazine lowered or interrupted if severe reactions occur.
2. An important application of diethylcarbamazine is in mass treatment to reduce the prevalence
of W.bancrofti infection, generally in combination with ivermectin or albendazole.
This strategy has led to excellent progress in disease control in Nigeria and other countries.
3. For tropical eosinophilia in Mansonella streptocerca infections since it kills both adult worms
and microfilariae.
Diethylcarbamazine should be taken after meals.
Adverse Effects
Generally mild and transient adverse reactions to DEC include headache, malaise, anorexia,
weakness, nausea, vomiting, and dizziness.
Adverse effects also occur as a result of the release of proteins from dying microfilariae or adult
worms. Reactions are particularly severe with onchocerciasis (Mazzotti reaction), but
diethylcarbamazine is no longer used for this infection, because ivermectin is equally efficacious
and less toxic. Reactions to dying microfilariae are usually mild in W.bancrofti, more intense in
B. malayi, and occasionally severe in L. loa infections. Reactions include fever, malaise, papular
rash, headache, gastrointestinal symptoms, cough, chest pain, and muscle or joint pain.
Symptoms are most likely to occur in patients with heavy loads of microfilariae.
Other adverse effects include leukocytosis, eosinophilia, proteinuria, retinal hemorrhages and,
rarely, encephalopathy. Between the third and twelfth days of treatment, local reactions may
occur in the vicinity of dying adult or immature worms. These include lymphangitis with
Pharmacists Council of Nigeria
81 FPGOP Lecture Note on Applied Pharmacology and Toxicology
localized swellings in W. bancrofti and B. malayi, small wheals in the skin in L. loa, and flat
papules in M. streptocerca infections. Patients with attacks of lymphangitis due to W. bancrofti
or B. malayi should be treated during a quiescent period between attacks.
Cautions and Contraindications
Population-based therapy with DEC should be avoided where onchocerciasis or loiasis is
endemic.
Note: Annual single dose co-administration of DEC with either albendazole or ivermectin is
effective in reducing microfilaremia, for the control of lymphatic filariasis in regions where
onchocerciasis, loiasis, or both are not endemic.
Dracunculiasis
Dracunculiasis (guinea worm disease) is caused by the parasitic nematode Dracunculus
medinensis (guinea, dragon, or Medina worm). Infection is by drinking water containing
copepods that carry infective larvae. After about 1 year, the adult female worms migrate and
emerge through the skin, usually of the lower legs or feet. Through the advocacy and work of
the Carter Center in partnership with WHO, strategies such as filtering drinking water and
reducing contact of infected individuals with water have markedly reduced the transmission and
prevalence of dracunculiasis in most endemic regions, including Nigeria.
There is no effective drug for treatment or prevention of D. medinensis infection. Traditional
treatment for this disabling condition is to draw the live adult female worm out day by day by
applying gentle traction, and rolling it onto a small piece of wood or matchstick. This procedure
risks significant secondary bacterial infection.
Optimal management of guinea worm disease involves the following steps:
1. First, each day the affected body part is immersed in a container of water to encourage
more of the worm to come out. To prevent contamination, the infected person is not allowed to
enter drinking water sources.
2. Next, the wound is cleaned.
3. Then, gentle traction is applied to the worm to slowly pull it out. Pulling stops when
resistance is met to avoid breaking the worm. Because the worm can be as long as one meter
in length, full extraction can take several days to weeks.
Pharmacists Council of Nigeria
82 FPGOP Lecture Note on Applied Pharmacology and Toxicology
4. The worm is then wrapped around a rolled piece of gauze or a stick to maintain some
tension on the worm and encourage more of the worm to emerge. This also prevents the worm
from slipping back inside.
5. Afterwards, topical antibiotics are applied to the wound to prevent secondary bacterial
infections.
6. The affected body part is then bandaged with fresh gauze to protect the site. Medicines,
such as aspirin or ibuprofen, are given to help ease the pain of this process and reduce
inflammation.
7. These steps are repeated every day until the whole worm is successfully pulled out.
Table 3: Drugs used to treat helminthic infections
Infecting helminth Drug(s) of Choice Alternative Drug(s)
Roundworms (Nematodes)
Ascaris lumbricoides (roundworm) Albendazole, mebendazole, pyrantel pamoate
Piperazine, ivermectin
Trichuris trichiura (whipworm) Mebendazole, albendazole Ivermectin
Necator americanus, Ancylostoma duodunale (hookworms)
Albendazole, mebendazole, pyrantel pamoate
-
Enterobius vermicularis (pinworm) Mebendazole, pyrantel pamoate
Albendazole
Strongyloides stercoralis (threadworm) Ivermectin Albendazole, thiabendazole
Ancylostoma braziliense (Cutaneous larva migrans)
Albendazole, ivermectin Thiabendazole (topical)
Baylisascaris procyonis, Toxocara canis, Toxocara cati, Ascaris suum (Visceral larva migrans)
Albendazole Mebendazole
Wuchereria bancrofti (filariasis); Brugia malayi (filariasis); Loa loa (loiasis); Wuchereria bancrofti (tropical eosinophilia)
Diethylcarbamzine Ivermectin
Onchocerca volvulus (onchocerciasis) Ivermectin -
Capillaria phillippinensis (intestinal capillariasis)
Albendazole Mebendazole
Dracunculus medinensis (guinea worm) - -
Tapeworms (Cestodes)
Taenia saginata (beef tapeworm) Praziquantel Niclosamide
Taenia solium (pork tapeworm) Praziquantel -*
Diphyllobothrium latum (fish tapeworm) Praziquantel Niclosamide
Hymenolepis nana (dwarf tapeworm) Praziquantel Niclosamide
Pharmacists Council of Nigeria
83 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Echinococcus granulosus ; hydatid disease
Albendazole -
Echinococcus multilocularis Albendazole -
Pork tapeworm larva; cysticercosis Albendazole Praziquantel
Flukes (Trematodes)
Schistosoma haematobium Praziquantel Metrifonate
Schistosoma mansoni Praziquantel Oxamniquine
Schistosoma japonicum Praziquantel -
*Niclosamide is effective in T. solium infections, however its use may cause cysticercosis in people infected with T. solium. It is not used in some countries.
Bibliography and Further Reading
Alvar J, Croft S, Olliaro P (2006). Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol, 61:223–274. Balasegaram M, Harris S, Checchi F, Ghorashian S, Hamel C, Karunakara U (2006). Melarsoprol versus eflornithine for treating late-stage Gambian trypanosomiasis in the Republic of the Congo. Bull World Health Organ, 84:783–791. Balasegaram M, Young H, Chappuis F, Priotto G, Raguenaud M, Checchi F (2009). Effectiveness of melarsoprol and eflornithine as first-line regimens for gambiense sleeping sickness in nine Médecins Sans Frontières programmes. Trans R Soc Trop Med Hyg, 103:280–290. Bethony J, Brooker S, Albonico M, Geiger SM, Loukas A, Diement D, Hotez PJ (2006). Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm. Lancet, 367:1521–1532. Blumberg HM, Burman WJ, Chaisson RE, et al (2003). American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America. Treatment of tuberculosis. Am J Respir Crit Care Med, 167:603–662. Brun R, Blum J, Chappuis F, Burri C (2010). Human African trypanosomiasis. Lancet, 375:148 - 159. Chappuis F, Udayraj N, Stietenroth K, Meussen A, Bovier PA (2005). Eflornithine is safer than melarsoprol for the treatment of second-stage Trypanosoma brucei gambiense human African trypanosomiasis. Clinical Infectious Diseases, 41:748–751. Croft SL, Barrett MP, Urbina JA (2005). Chemotherapy of trypanosomiases and leishmaniasis. Trends in Parasitology, 21:508 - 512. Cupp EW, Ochoa AO, Collins RC, Ramberg FR, Zea G (1989). The effect of multiple ivermectin treatments on infection of Simulium ochraceum with Onchocerca volvulus. American Journal of Tropical Medicine and Hygiene, 40: 501–506.
Pharmacists Council of Nigeria
84 FPGOP Lecture Note on Applied Pharmacology and Toxicology
AIDS Info (2018). Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/guidelines Drugs for parasitic infections (2007). Med Lett Drugs Ther, Suppl 1. Drugs for parasitic infections. (2010). Med Lett Drugs Ther, Supplement. Efferth T, Kaina B (2010). Toxicity of the antimalarial artemisinin and its derivatives. Critical Reviews in Toxicology, 40:405 - 421. Fox LM (2006). Ivermectin: Uses and impact 20 years on. Current Opinion in Infectious Diseases, 19:588 - 593. Greenwood BM, Bojang K, Whitty CJM, Targett GAT (2005). Malaria. Lancet, 365:1487 – 1498. Haque R, Huston CD, Hughes M, Houpt E, Petri WA (2003). Amebiasis. New England Journal of Medicine, 348:1565 - 1573. Horton J (2002). Albendazole: A broad spectrum anthelminthic for treatment of individuals and populations. Current Opinion in Infectious Diseases, 15:599 - 608. Keiser J, Utzinger J (2008). Efficacy of current drugs against soil-transmitted helminth infections: Systematic review and meta-analysis. Journal of American Medical Association, 299:1937 - 1948. Levis WR, Ernst JD (2005). Mycobacterium leprae (Leprosy, Hansen’s disease). In: Mandell, Douglas, and Bennett’s Principles and Practices of Infectious Diseases (Mandell GL, Bennett JE, Dolin R, eds.), Elsevier Churchill Livingstone, Philadelphia, pp. 2886–2896. Molyneux DH, Bradley M, Hoerauf A, Kyelem D, Taylor MJ (2003). Mass drug treatment for lymphatic filariasis and onchocerciasis. Trends in Parasitology, 19:516–522. Murray HW, Berman J, Davies CR, Saravia NG (2005). Advances in leishmaniasis. Lancet, 366:1561 - 1577. Nosten F, White NJ (2007). Artemisinin-based combination treatment of falciparum malaria. American Journal of Tropical Mediicne and Hygeine, 77(Suppl 6):181 -192. Petri WA (2003). Therapy of intestinal protozoa. Trends in Parasitology, 19:523 - 526. Pierce KK, Kirkpatrick BD (2009). Update on human infections caused by intestinal protozoa. Current Opinion in Gastroenterology, 25:12 - 17. Priotto G, Kasparian S, Mutombo W, Ngouama D et al (2009). Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: A multicentre, randomised, phase III, non-inferiority trial. Lancet, 374:56 - 64.
Pharmacists Council of Nigeria
85 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Pritt BS, Clark CG (2008). Amebiasis. Mayo Clinic Proceedings, 83:1154 - 1160. Rassi A, Rassi A, Marin-Neto JA (2010). Chagas disease. Lancet, 375:1388 - 1402. Reithinger R, Dujardin J, Louzir H, Primez C, Alexander B, Brooker S (2007). Cutaneous leishmaniasis. Lancet Infectious Diseases, 7:581 - 596. Tisch DJ, Michael E, Kazura JW (2005). Mass chemotherapy options to control lymphatic filariasis: A systematic review. Lancet Infectious Diseases, 5:514 - 523. Udall DN (2007). Recent updates on onchocerciasis: Diagnosis and treatment. Clinical Infectious Diseases, 44:53 - 60. World Health Organization (1998). WHO Model Prescribing Information: Drugs used in leprosy. World Health Organization, Geneva. World Health Organization (2010). Guidelines for the treatment of malaria. Geneva. http://www.who.int/malaria/publications/atoz/9789241547925/en/ index.html
Pharmacists Council of Nigeria
86 FPGOP Lecture Note on Applied Pharmacology and Toxicology
C. TOXICOLOGY
Course Outline
1. Management of poisoning
2. Drug toxicity: Definition and mechanisms
3. Animal poisons: snakebite, scorpion stings, bee stings and their management
4. Local food poisoning
5. Pesticides
6. Solvents, vapours and gases
7. Heavy metals and their antagonists
Learning Objectives
At the end of the course participants should
(a). Outline measures for emergency management of poisoning due to drugs and other
substances.
(b). Mention known specific antidotes for poisons.
(c). Mention the chelators used in the treatment of poisoning by specific heavy metals.
(d). State sources of poisons in the home, workplace and environment.
(e). State the measures and steps involved in the management of snakebite, scorpion and bee
stings.
(f). Outline the dos and don’ts in the management of snake bite.
(g). Name some pesticides that have been banned globally.
(h). Outline the steps involved in the management of poisoning due to commonly used
insecticides (pyrethrins, etc.) and solvents.
(i). State the steps involved in the treatment of carbon monoxide poisoning
(j). Outline the steps involved in the management of cyanide, kerosene and petrol poisoning.
(k). Identify the classes of insecticides commonly used in Nigeria; and management of poisoning due to same. Definition of Toxicology
Pharmacists Council of Nigeria
87 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Toxicology is a discipline concerned with the study of the harmful effects of chemical, biological
and physical agents on biological systems. Toxicology comprises the detection of the toxic
agent, mechanism by which the harmful effect is induced, the condition(s) under which it
occurs, and the treatment of the toxicity.
Divisions of toxicology include environmental toxicology, occupational toxicology, forensic
toxicology, food toxicology, and clinical toxicology.
C1. Management of Poisoning
It is pertinent to discuss the management of poisoning in general, before discussing the
poisons. Management of specific poisons shall be discussed, as appropriate under the individual
poisons.
(i). Poisoning
Poisoning is a condition or process in which an organism, e.g. humans, becomes harmed
(poisoned) by a toxic substance (poison). Poisoning could be acute or chronic.
Poisons are substances which on entering the body by whatever route (ingestion, inhalation,
absorption through the skin, etc) produce harmful effects. The effects may be damage to the
tissues or a disruption of body function. Poisonous substances may be drugs, air pollutants,
water contaminants, food residues or contaminants, soil contaminants, animal venoms, plant
toxins, etc.
Poisoning could be from drugs; industrial exposure of workers and others to toxic substances
(e.g. workers exposed to mercury, arsenic, paraquat, dibromochloropropane, etc); ingestion of
contaminated foo;, snake bites, bee sting and other animal venom or plant toxins; accidental
eating of poisonous food, like poisonous mushrooms or improperly processed food (like
cassava, with cases of cyanide poisoning); and ingestion, inhalation or contact with chemicals
and other poisonous substances.
Some of these potential toxic substances or poisons are normally found in the home as drugs;
household materials for cooking and other purposes like kerosene, fuel, diesel, detergents, etc.;
cosmetics like shampoo, hair dyes; and pesticides. These cause accidental poisoning,
particularly among children. Poisoning in adults may be accidental or suicidal.
Pharmacists Council of Nigeria
88 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Generally, substances involved mostly in acute poisoning include drugs, cleaning substances,
cosmetics and personal care products, animal bites and envenomations, fumes/vapors,
pesticides, plants, food products, food poisoning, alcohols, hydrocarbons, chemical and
solvents.
(ii). Management of acute poisoning
Some general principles are applicable in the management of poisoning, whether due to drugs,
chemicals, gases, pesticides, bacteria, plant and animal toxins etc. These general principles
would be disccussed here, specific and other measures shall be discussed under the individual
poison, as appropriate.
(a). Preventive measures at home and work place
Most of the acute poisoning in the home can be prevented by:
(a). Keeping drugs in tamper-proof containers, out of the reach of children.
(b). Keeping household chemicals, e.g. detergents, bleaches, cosmetics, polish, pesticides
(insecticides, rodenticides, and others), petroleum products, etc. away from foodstuffs, under
lock and key, and out of easy reach. They should also be kept in properly labelled containers.
(c). Ensuring that all medicines are taken as directed; unused medicines should be properly
disposed.
At the workplace, there should be necessary and adequate precautions to avoid exposure to
hazardous substances including:
(a). Provision of personal protective equipment (PPE) such as coveralls, nose masks, etc.
(b). Provision of SoPs for handling and disposal of hazardous substances.
(c). Routine drills and training of staff on health and safety measures, and potential challenges
in the workplace.
(b). Treatment of acute poisoning
Emergency measures at home and work place
The essence of these measures is to remove the poison from the point of contact with the body
and prevent further damage.
Pharmacists Council of Nigeria
89 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(1). If the poison was ingested, vomiting may be induced if the poison is not a corrosive
material (e.g. acid, alkali, etc), a petroleum product (e.g. kerosene, petrol, paint thinner, etc) or
a central nervous system stimulant. Vomiting can also be induced mechanically by stroking the
posterior pharynx.
NOTE: Don’t induce vomiting if the patient is drowsy or if the poison is a central nervous
system stimulant (vomiting may induce convulsion), corrosive material or a petroleum product.
(2). If the poison was inhaled, move the person immediately to area of fresh air, and give
artificial respiration if necessary.
(3). In cases of contamination of the skin, drench the skin with copious amount of water, after
removal of clothing. Then clean the skin with soap and water, if applicable.
(4). In cases of contamination of the eye, wash the affected eye with running water for about
15 minutes.
After the emergency intervention at home or in the work place, the patient should be taken to
the hospital for treatment. The poison in its container should be taken along for identification
and better treatment.
Emergency treatment of acute poisoning
Treatment of acute poisoning must be prompt, and is carried out in the hospital by well trained
personnel. The treatment goals are (i) supportive care and symptomatic treatment to maintain
vital functions; (ii) to keep the concentration of poison in the vital tissues as low as possible by
preventing absorption, and enhancing removal and elimination of the poison; (iii) to combat the
pharmacological and toxicological effects at the effector sites by neutralising the effect of the
poisons by administration of an antidote where available.
It is important to note that specific antidotes are available for only a few toxic agents. Even
these are not always effective, particularly if the poisoning is severe. The best treatment begins
with supportive care and maintenance of vital functions; this includes resuscitation (if
necessary), maintenance of respiratory and cardiovascular functions, correction of fluid and
electrolytes imbalance, etc.
I. General Supportive care and symptomatic treatment of poisoned patients in the
hospital
Pharmacists Council of Nigeria
90 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Supportive care and symptomatic treatment is the mainstay of management of the poisoned
patient. The adage, ‘treat the patient, not the poison,’ remains the most basic and important
principle of management of poisoning. Maintenance of respiration, blood pressure and other
vital functions are crucial. Serial measurement and charting of vital signs and important reflexes
help to judge the progress of intoxication, response to therapy, and need for additional
treatment. This monitoring usually requires hospitalization. Supportive measures and
symptomatic treatment include:
(1). Improvement of respiration: Assisted ventilation and oxygen should be provided if
necessary.
Note: Respiratory stimulants are not beneficial, and are potentially dangerous.
(2). Normalisation of blood pressure: For example hypotension is common in severe poisoning
with central nervous system depressants (barbiturates, benzodiazepine, etc), β-blockers, etc,
and may lead to irreversible brain damage or renal tubular damage, among others. Therefore,
timely normalisation of the blood pressure is important.
(3). Cardiac arrhythmias, and other conduction defects are corrected. Arrhythmias often
respond to corrections of underlying hypoxia or acidosis.
(4). Normalisation of body temperature as there may be hypo- or hyperthermia.
(5). Treatment of convulsions with e.g. diazepam.
(6). Correction of fluid and electrolyte imbalance.
II. Removal and elimination of poisons
(a). Removal of the poison from the skin, eye and gastrointestinal tract
The poison should be removed from the skin, eyes and the gastrointestinal tract (GIT), as
applicable.
(i). Initial treatment of all types of chemical injuries to the eye must be rapid. Thorough
irrigation of the contaminated eye with water for 15 minutes should be performed immediately.
(ii). The contaminated skin should be washed thoroughly with water. Contaminated clothing
should be removed.
(iii). If the poison was inhaled, the patient should be removed immediately from the source of
exposure to area of fresh, uncontaminated air, and artificial respiration administered if
necessary.
Pharmacists Council of Nigeria
91 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(iv). Gastrointestinal tract - Ingestion is the most common route of poisoning. Poison can be
removed from the GIT by the following means:
Emesis
The routine induction of emesis in emergency rooms is declining. Although emesis still may be
indicated for immediate intervention after poisoning by oral ingestion of chemicals, it is
contraindicated if the patient (i) has ingested a corrosive poison, such as a strong acid or alkali
(e.g., drain cleaners) - emesis increases the likelihood of gastric perforation and further necrosis
of the esophagus; (ii) is comatose or in a state of stupor or delirium - emesis may cause
aspiration of the gastric contents; (iii) has ingested a central nervous system stimulant - further
stimulation associated with vomiting may precipitate convulsions; and (iv) has ingested a
petroleum product (e.g., kerosene, petrol, petroleum-based liquid furniture polish, etc) -
regurgitated hydrocarbons can be aspirated readily and cause chemical pneumonitis. The ability
of various hydrocarbons to produce pneumonitis is generally inversely proportional to their
viscosity. If the viscosity is high, as with oils and greases, the risk is limited; if the viscosity is
low, as with mineral seal oil found in liquid furniture polishes, the risk of aspiration is high.
Emesis should be considered if the ingested solution contains potentially dangerous compounds,
such as pesticides.
Vomiting can also be induced mechanically by stroking the posterior pharynx.
Gastric lavage
Gastric lavage is done by inserting a tube into the stomach and washing the stomach with
water, normal saline, or one-half normal saline to remove the unabsorbed poison. The
procedure should be performed as soon as possible, but only if vital functions are adequate or
supportive procedures have been implemented.
The contraindications to this procedure generally are the same as for emesis, and there is the
additional potential complication of mechanical injury to the throat, esophagus, and stomach. It
is recommended that gastric lavage should not be used routinely in the management of the
poisoned patient but should be reserved for patients who have ingested a potentially life-
threatening amount of poison and when the procedure can be undertaken within 60 minutes of
ingestion.
Purgation/Catharsis
Pharmacists Council of Nigeria
92 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Purgation (catharsis) is used to induce the removal of unabsorbed poisons from the
gastrointestinal tract by enhancing their passage through the GIT. The rationale for using an
osmotic cathartic is to minimize absorption by hastening the passage of the toxicant through
the GIT. Cathartics are indicated after the ingestion of enteric coated tablets, when the time
after ingestion is >1 hour, and for poisoning by volatile hydrocarbons. Cathartics generally are
considered harmless unless the poison has injured the GIT.
Osmotic cathartics include sorbitol, sodium sulphate and magnesium sulphate. Sorbitol is the
most effective, but sodium sulfate and magnesium sulfate also are used; all act promptly and
usually have minimal toxicity. However, MgSO4 should be used cautiously in patients with renal
failure or in those likely to develop renal dysfunction, and Na+-containing cathartics should be
avoided in patients with congestive heart failure.
Whole-bowel irrigation
Whole-bowel irrigation (WBI) is a process that involves the rapid administration of large
volumes of an osmotically balanced macrogol solution, either orally or via a nasogatric tube, to
flush out the entire GIT. Whole-bowel irrigation promotes defecation and eliminates the entire
contents of the intestines; usually, a high-molecular-weight polyethylene glycol and isomolar
electrolyte solution (PEG-ES) that does not alter serum electrolytes is used. It is recommended
that WBI should not be used routinely in the management of the poisoned patient, however, it
may be considered in cases of acute poisoning by sustained-release or enteric-coated drugs and
possibly toxic ingestions of iron, lead, zinc, or packets of illicit drugs.
(b). Prevention of absorption of ingested poisons from the gastrointestinal tract
Activated charcoal may be used to prevent absorption of ingested poisons from the GIT.
Activated charcoal avidly adsorbs many drugs and chemicals on the surfaces of the charcoal
particles, thereby preventing absorption and toxicity. Charcoal is ineffective for some poisons,
such as strong acids or alkali, cyanide, iron, arsenic, methanol, ethanol, ethylene glycol and
lithium. The effectiveness of charcoal depends on the time since the ingestion and on the dose
of charcoal; a charcoal–drug ratio of at least 10:1 is optimal. Activated charcoal also can
interrupt the enterohepatic circulation of drugs and enhance the net rate of diffusion of the
chemical from the body into the GIT, e.g. serial doses of activated charcoal have been shown to
enhance the elimination of theophylline and phenobarbital.
Pharmacists Council of Nigeria
93 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Activated charcoal usually is prepared as a mixture of at least 50 g (about 10 heaped
tablespoons) in a glass of water. The mixture is then administered either orally or via a gastric
tube. Because most poisons do not appear to desorb from the charcoal if charcoal is present in
excess, the adsorbed poison need not be removed from the GIT.
Generally, it is recommended that the use of activated charcoal should be considered only if a
patient has ingested a life-threatening amount of some substances such as carbamazepine,
dapsone, phenobarbital, quinine, or theophylline.
Note: Charcoal also may adsorb and decrease the effectiveness of specific antidotes.
(c). Active elimination of drugs and poisons
Drugs and poisons could be actively eliminated from the body by:
(1). Oral administration of repeated doses of activated charcoal
Oral administration of repeated doses (50 g initially, then repeated every 4 hours) of activated
charcoal enhances the elimination of some drugs (after they have been absorbed) e.g.
carbamazepine, phenobarbital, phenytoin, dapsone, theophylline and quinine.
(2). Dialysis
Haemodialysis, peritoneal dialysis and hemoperfusion could be carried out.
(3). Forced diuresis or changes in pH of urine
Renal excretion of poisons is enhanced through forced diuresis or changes in urinary pH.
Forced diuresis is indicated for a poison that is passively reabsorbed after filtration into the
glomeruli. Osmotic diuretics, like mannitol or intrvenous infusion of furosemide are used. They
inhibit sodium and water reabsorption and cause enhanced excretion of the poison.
Changes in urinary pH could also enhance renal excretion of poison. Alkalinization of the urine
using e.g an infusion of sodium bicarbonate will increase the ionization of phenobarbitone,
salicylates, arsine, lithium and isoniazid thereby increasing their excretion in urine. Acidification
of the urine will enhance the excretion of bases like amphetamine, quinine, quinidine and
strychnine. Oral or intravenous infusion of ascorbic acid or ammonium chloride is used to acidify
the urine.
Combination of osmotic diuresis and changes in urinary pH is effective for elimination of poison.
The procedure is normally carried out in the intensive care unit. Blood and urine electrolytes,
Pharmacists Council of Nigeria
94 FPGOP Lecture Note on Applied Pharmacology and Toxicology
pH, fluid intake and urine ouput should be monitored to avoid electrolyte imbalance, acid-base
imbalance, water intoxication, pulmonary and cerebral edema.
III. Neutralisation of the poison
(a). Administration of antidote
Antidotes are substances that neutralise poisons, thereby counteracting the effects of the
poison. There are two types, local and systemic antidotes. Most drugs and poisons do not have
specific antidote, ane there is no universal antidote.
Table 1: Some specific antidotes for drugs, chemicals and other substances
Substance Antidote
Drugs
Paracetamol N-acetylcysteine
Iron salts (e.g. ferrous tablets) Deferoxamine
Narcotics, opioids, diphenoxylate, propoxyphene, other opioid derivatives
Naloxone
Atropine, anticholinergics Physostigmine
Anticholinesterase intoxication: Physostigmine, neostigmine, carbamates
Atropine
Organophosphates Atropine and pralidoxime
Heparin Protamine
Warfarin Vitamin K1
Benzodiazepines Flumazenil
Digoxin and related cardiac glycosides Digoxin antibodies
Benzodiazepines Flumazenil
Calcium channel blockers Calcium
Chemicals and other substances
Methanol Ethanol, Fomepizole
Ethylene glycol Ethanol, Fomepizole
Cyanide Hydroxocobalamin, Sodium nitrate, Sodium thiosulphate, Dicobalt edetate
Fluoride Calcium, e.g. calcium gluconate
C2. Definition and mechanisms of drug toxicity
On the administration of therapeutic doses of a drug, adverse drug reactions (undesirable drug
effects, side effects, adverse effects) could occur. Adverse effects of a drug is a noxious and
Pharmacists Council of Nigeria
95 FPGOP Lecture Note on Applied Pharmacology and Toxicology
unintended response to a drug that occurs at doses normally used in man for the modification
of physiological function , prophylaxis, diagnosis or therapy of disease.
As exposure to the drug increases beyond the therapeutic dose, toxicity occurs. For example
paracetamol (acetaminophen) is an over the counter analgesic and antipyretic that elicits dose-
dependent toxicity; it is safe at therapeutic concentrations but causes severe hepatotoxicity
above therapeutic doses.
(i). Definition: Drug toxicity occurs as a result of accumulation of excess drug in the system,
leading to damage. The accumulation could be incidental and intentional, or accidental and
unintentional.
However, with certain medications, drug toxicity can also occur as an adverse drug reaction
(ADR). In this case, the normally given therapeutic dose of the drug can cause unintentional,
harmful and unwanted side effects. According to Paracelsus, ‘the dose makes the poison.’
The focus of this discourse is on drug toxicity due to incidental or accidental drug overdosage.
Drug overdose/overdose is the ingestion or application of a drug or other substances in
quantities greater than are recommended or used in routinely in clinical practice. An overdose
may result in toxicity or death.
(ii). Mechanisms of drug toxicity
Toxicity produced by a drug may be due to the following general mechanisms:
(a). On-target adverse effects/toxicity: This is as a result of the drug binding to its
intended receptor, but at an inappropriate concentration, with suboptimal kinetics, or in the
incorrect tissue, e.g atropine, barbiturates. The toxic effects of such drugs derive from, and are
extensions of their pharmacological actions.
(b). Off-target adverse effects/toxicity: Due to the drug binding to a target or receptor for
which it was not intended, e.g. anticholinergic toxic effects produced by overdose of
promethazine (H1 receptor antagonist).
(c). Production of toxic metabolites: A typical example of toxicity by this mechanism is that
of acetaminophen (paracetamol). Paracetamol is normally metabolised by conjugation to
sulphate and glucuronide, and these as well as the unchanged paracetamol are not toxic. They
are excreted in the urine. However, a small fraction of paracetamol is converted by CYP450
enzyme to a reactive metabolite, N-acetyl-p-benzoquinoneimine which is hepatotoxic. This toxic
metabolite is normally detoxified by conjugation to glutathione and excreted in the urine.
Pharmacists Council of Nigeria
96 FPGOP Lecture Note on Applied Pharmacology and Toxicology
However, in overdose, the glutathione is readily depleted and the reactive metabolite then
binds to cellular constituents of the liver leading to hepatooxicity.
(d). Production of harmful immune responses: The use of some drugs e.g penicillin,
abacavir, result in serious hypersensitivity reactions.
(e). Genotoxic effects: Many environmental chemicals, including drugs are known to injure DNA
and other genetic materials, and may lead to mutagenic or carcinogenic toxicities. For example,
many cancer chemotherapeutic agents may be genotoxic.
(e). Idiosyncratic reactions: Idiosyncratic reactions are abnormal responses to a drug that is
peculiar to a given individual. The idiosyncratic response may take the form of extreme
sensitivity to low doses or extreme insensitivity to high doses of drugs. Idiosyncratic reactions
can result from genetic polymorphisms that cause individual differences in drug
pharmacokinetics, pharmacodynamic factors such as drug-receptor interactions, or from
variability in expression of enzyme activity, etc.
(iii). Management of acute drug poisoning
Most of the principles, measures and procedures discussed under management of poisoning,
also apply in the management of acute drug poisoning. In addition, when necessary a specific
antidote if available is used.
Pharmacists Council of Nigeria
97 FPGOP Lecture Note on Applied Pharmacology and Toxicology
C3. Animal Poisons: Snakebite, Scorpion stings, Bee stings and Their Management
(i). Snake bite and management
Poisonous snakes include
(1). Pit vipers/Crotalin snakes (Crotalinae)
(2). Sea snakes/Hydrophis (Hydrophiinae; Elapidae)
(3). Elapid snakes/Cobras (Elapidae), e.g Naja melanoleuca (black cobra), Naja nigricollis
(black-necked spitting cobra)
(4). Viperid snakes (Viperidae), e.g. Echis ocellatus, Echis carinatus, Bitis arietans (puff adder,
African puff adder)
(5). Some Colubrids, e.g genus Boiga, Rhabdophis
Some important poisonous species are Echis ocellatus, Naja naja (Indian Cobra), Naja
nigricollis, Naja melanoleuca, Echis carinatus, Bitis arietans, B. gabonica, Dendroaspis viridis, D.
jamesoni, D. angusticeps, Causus maculatus, etc.
Common venomous snakes found in Nigeria include Elapid snakes such as Naja melanoleuca
and Naja nigricollis; and Viperid snakes such as Echis ocellatus and Bitis arietans. Echis
ocellatus (West African carpet viper, ocellated viper) is responsible for more human fatalities
due to snake bite than all other African species combined.
Snake venom is highly modified saliva containing zootoxins which facilitate the immobilization
and digestion of prey, and defense against threats. The glands that store and secrete the
venom are a modification of the parotid salivary gland found in other vertebrates, and are
usually situated on each side of the head, below and behind the eye, and encapsulated in a
muscular sheath. The synthesized vemon is stored in large alveoli of the glands, before being
conveyed by a duct to the base of channeled or tubular fangs through which it is ejected. The
snake venom is injected by unique fangs after a bite, and some species are also able to spit.
About 0.1 – 1.5 ml (5 ml for some large vipers) may be injected. The lethality of the venom
depends on the potency of the venom, quantity injected and size of the victim.
Snake venoms contain more than 20 different compounds, mostly proteins and polypeptides.
Snake venom contains neurotoxins, cytotoxins (some venoms have cytotoxic activity on
erythrocytes, blood vessels, kidney, heart muscles, etc), cardiotoxins, enzymes (e.g.
acetylcholinesterase, phospholipae A2, phosphodiesterase, phosphomonoesterase,
hyaluronidase, etc.), various other peptides, polypeptides and proteins. Some of the proteins
Pharmacists Council of Nigeria
98 FPGOP Lecture Note on Applied Pharmacology and Toxicology
have very specific effects on various biological functions including blood coagulation, blood
pressure regulation, and transmission of impulses, and have been developed for use as
pharmacological or diagnostic tools, and useful drugs.
Snake toxins vary greatly in their functions. Two broad classes of toxins found in snake venoms
are neurotoxins (mostly found in elapids) and hemotoxins (mostly found in viperids). However,
there are exceptions — the venom of Naja nigricollis, an elapid, consists mainly of cytotoxins,
while that of the Mojave rattlesnake (Crotalus scutulatus), a viperid, is primarily neurotoxic.
There are numerous other types of toxins which may be present in the venoms of both elapids
and viperids.
Effects and symptoms of snakebite
Elapid venom contain mainly neurotoxins, although many of them also possess several other
types of toxins, including cardiotoxins and cytotoxins. Elapids bites may produce pain and
slowly developing swelling. There may be drowsiness; weakness; salivation; headache;
hypotension; paralysis (due to the neurotoxin) of facial muscles, tongue, lips, larynx and eyes;
ptosis, blurred vision and respiratory difficulty. Venoms from Elapid snakes may produce death
due to respiratoty paralysis, but do not produce severe local reaction.
Viperid venoms typically contain an abundance of proteases which produce severe local
reactions with pain, swelling, necrosis, bleeding from the wound (due to haemotoxins),
ecchymosis, tissue damage. There may be internal haemorrhage from cardiovascular damage
complicated by disruption of the blood-clotting system and coagulopathy. Death is usually
caused by collapse in blood pressure and shock.
Management of snakebite
The followings steps or stages are often involved in the management of snake bite:
(1). First aid treatment
First aid treatment is carried out immediately or very soon after the bite, before the patient
reaches a dispensary or hospital. It can be performed by the snake-bite victim or anyone else
who is present and able.
Unfortunately, most of the traditional, popular, available and affordable first-aid methods have
proved to be useless or dangerous. These methods include: making local incisions or
Pharmacists Council of Nigeria
99 FPGOP Lecture Note on Applied Pharmacology and Toxicology
pricks/punctures at the site of the bite or in the bitten limb, attempts to suck the venom out of
the wound, use of (black) snake stones, tying tight bands (tourniquets) around the limb,
electric shock, topical instillation or application of chemicals, or ice packs.
It is dangerous to delay medical treatment
The goals of first aid is to (i) attempt to retard systemic absorption of venom; (ii) preserve life
and prevent complications before the victim can receive medical care; (iii) control distressing or
dangerous early symptoms of envenomation; (iv) arrange transport of the victim to a place
where they can receive medical care; (v) do no harm!
Do not attempt to kill the snake as this may be dangerous. However, if the snake has already
been killed, it should be taken to the dispensary or hospital with the victim in case it can be
identified. However, the snake should not be handled with bare hands as even a severed head
can bite (envenomate).
Snakebite first aid recommendations vary, partly because different snakes have different types
of venom. Some have little local effect, but life-threatening systemic effects (e.g Elapids), in
which case containing the venom in the region of the bite by pressure immobilization is
desirable. Other venoms elicit localized tissue damage around the bitten area, and
immobilization may increase the severity of the damage in this area, but also reduce the total
area affected (the benefit of this measure in this case is equivocal).
Recommended first aid measures include:
(i). Reassure the victim who may be very anxious
(ii). Immobilize the whole of the patient’s body by laying him/her down in a comfortable and
safe position and, especially, immobilize the bitten limb with a splint or sling. The patient must
not be allowed to walk, run, and take alcohol or stimulants. Any movement or muscular
contraction increases absorption of venom into the bloodstream and lymphatics.
If the necessary equipment and skills are available, pressure-immobilization or pressure pad (to
contain the venom in the region of the bite) are recommended for bites by neurotoxic elapid
snakes.
Pressure Immobilization: Pressure immobilization serves to contain venom within a bitten
limb and prevent it from moving through the lymphatic system to the vital organs. This therapy
has two components: pressure to prevent lymphatic drainage, and immobilization of the bitten
Pharmacists Council of Nigeria
100 FPGOP Lecture Note on Applied Pharmacology and Toxicology
limb. It is recommended for snakebites due to elapids which are neurotoxic. Generally, it is not
recommended for bites from non-neurotoxic snakes; however, in some regions, pressure
immobilization is recommended in all cases where the type of snake is unknown.
(iii). Avoid any interference with the bite wound (e.g. incisions, rubbing, vigorous cleaning,
massage, application of herbs or chemicals) as this may introduce infection, increase absorption
of the venom and increase local bleeding.
(iv). Tight bands, bandages and ligatures used, should not be released until the patient is under
medical care in hospital, resuscitation facilities are available and antivenom treatment has been
started.
Traditional first aid methods should be discouraged, as they do more harm than good.
List of DO NOTs in management of snake bite
Do not pick up the snake or try to wrap it up or kill it, as this will increase the chance of getting another bite. Even a dead snake is able to bite (envenomate).
Do not apply a tourniquet. Do not cut across the site of the bite marks. Do not try to suck out the venom. Do not apply ice, electric shock, etc. Do not immerse the wounded area in water. Do not take alcohol, beverages with caffeine, other stimulants
(2). Transport to hospital - The greatest fear is that a snakebite victim might develop fatal
respiratory paralysis or shock before reaching a place where they may be resuscitated. This risk
may be reduced by speeding up transport to hospital. The patient must be transported to a
place where he can receive adequate medical care as quickly, but as safely and comfortably, as
possible. Any movement especially movement of the bitten limb, must be reduced to an
absolute minimum to avoid increasing the systemic absorption of venom. Any muscular
contraction will increase the spread of venom from the site of the bite. A stretcher, bicycle,
motorbike, cart, horse, motor vehicle, train or boat, etc. may be used, or the patient can be
carried (e.g. using the Fireman’s Lift technique). If possible, patients should be placed in the
recovery position, in case they vomit.
(3). Rapid clinical assessment and resuscitation - Airway patency, respiratory function, arterial
pulse and level of consciousness must be checked immediately. The patient should also be
protected from cold if necessary.
Pharmacists Council of Nigeria
101 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(4). Detailed clinical assessment and species diagnosis – Detailed clinical assessment include
precise history of the circumstances of the bite and the progression of local and systemic
symptoms and signs, physical and general examination, etc., by the physician.
If the dead snake has been brought, it may be possible to identify it but this requires skill and
even experienced medical personnel may mistake harmless snakes for venomous ones or
confuse different venomous species. Also, the species responsible may be inferred indirectly
from the patient’s description of the snake, circumstances of the bite (e.g. nocturnal bites of
people sleeping on the ground, by kraits) and the clinical syndrome of symptoms and signs. A
wrong species diagnosis may result in futile administration of antivenom.
(5). Investigations/laboratory tests such as 20-minute whole blood clotting test (20WBCT) to
test for coagulopathy, hemoglobin concentration/hematocrit, platelet count, white blood cell
count, liver enzymes, urine examination, etc. may be carried out.
(6). Antivenom treatment - If possible, it should be confirmed if the patient was actually bitten
by a poisonous snake, before treatment with antivenom. If possible, a sensitivity test should be
done before the antivenom is administered.
Monovalent antivenoms treat the bite of a specific type of snake, while polyvalent antivenoms
can treat bites from a number of snakes found in a particular geographic region.
The antisnake venom serum available in any country is determined by the types of poisonous
snakes in that country. In Nigeria, one of the available antisnake venom serums is effective
against Echis, Bitis and Naja.
(7). Observing the response to antivenom - Reactions to antivenom could be treated with
adrenaline, H1- antagonists or corticosteroids.
(8). Deciding whether further dose(s) of antivenom are needed - There is need for close
monitoring of the patient to determine whether the initial dose of the antivenom would be
repeated.
(9). Supportive/ancillary treatment such as treatment of the bitten part and general wound
care; artificial respiration with oxygen if there is respiratory paralysis; administration of tetanus
antitoxin, antibiotics, analgesics, etc. as necessary; treatment of hypovolemic shock, renal
dialysis, etc.
(11). Rehabilitation
(12). Treatment of chronic complications
Pharmacists Council of Nigeria
102 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(ii). Scorpion stings
Some scorpions are poisonous and the stings can cause pain and discomfort. One of the most
poisonous ones is Androctonus australis. Scorpion venom contain neurotoxins and enzymes.
Signs and symptoms of scorpion sting
The sting produces a burning sensation at the site of the sting, and this spreads to extremities.
Spasm in the throat, restlessness, abdominal cramps, muscular fibrillation, convulsion, cardiac
arrhythmia, pulmonary edema and respiratory edema may develop. The smaller the patient, the
greater the effect of the sting.
Treatment of scorpion sting
1. The patient and the bitten part are immobilized and a constriction band applied as in a snake
bite.
2. A cold pack (10-15°C) should be applied on the affected part for a few hours to reduce the
rate of absorption of the venom.
3. Artificial respiration with oxygen should be given if necessary.
4. Calcium gluconate (10 ml of a 10% solution) administered by slow intravenous infusion will
help relieve muscle spasm.
5. A local anaesthetic may be injected into the area of sting, or an analgesic administered to
reduce pain.
6. Convulsion should be treated with diazepam.
7. A specific antiserum should be given as an antidote, after a sensitivity test.
(iii). Bee stings
The venom of a bee sting contains histamine, peptides (apamin and melittin), hyaluronidase,
phospholipase and proteins.
Symptoms of bee sting
Multiple stings induce a fall in blood pressure, peripheral neuritis and difficulty in breathing.
Hypesensivity reactions may lead to bronchial constriction, edema of face and lips, itching,
collapse and death.
Treatment of bee sting
Pharmacists Council of Nigeria
103 FPGOP Lecture Note on Applied Pharmacology and Toxicology
For minor cases, topical antihistamine should be applied, and the sting if present should be
removed.
For severe cases, adrenaline (0.2 – 0.5 ml in 1:1000) should be given by subcutaneous or
intravenous route, followed by an antihistamine.
In severe collapse, hydrocortisone should be administered.
C4. Local food poisoning
Sources of food poisoning include:
(i). Food Additives - Thousands of substances are added to foods to enhance appearance, taste,
texture, storage properties, or nutritive value, any of which may cause toxicity in susceptible
individuals.
(ii). Toxins produced by microorganisms that infest foodstuffs including produce, such as
protozoa, fungi, bacteria, etc.
(iii). Also, microbial contamination (by e.g. fungi, bacteria, etc.) of food in the farm, during
processing or storage can introduce potent toxins into food.
(iv). Chemicals from pesticides, preservatives or containers used to store food.
(v). Poisoning may also result from consumption of poisonous food, e.g. mushrooms, or
improperly processed food (e.g. improperly processed cassava, consumption of which has led to
some deaths in Nigeria).
Food toxins/poisons include:
(a). Mycotoxins
Mycotoxins are toxic substances produced by microscopic fungi which infest food substances.
Ingestion of food containing the toxins causes adverse health effects in human. Four classes of
mycotoxins identified as health hazard to humans and animals are aflatoxins, ochratoxins,
zearalenones and trichothecenes.
Aflatoxins
Aflatoxins are mycotoxins produced by Aspergillus species of fungi, such as A. flavus and A.
parasiticus which contaminate and grow on certain foodstuffs and animal feeds. The fungi may
infect growing crops and the toxin may be produced before harvest, during harvest or storage.
Aflatoxins have been detected on many seeds grown in Nigeria like groundnuts, maize and
beans; and feeds made from them. The fungi could be identified as small discoloured or
Pharmacists Council of Nigeria
104 FPGOP Lecture Note on Applied Pharmacology and Toxicology
differently coloured spots on the seeds which are where the toxin is concentrated; therefore,
visual inspection is important. Furthermore, animals fed contaminated food can pass aflatoxin
transformation products into eggs, milk products and meat. Aflatoxins include aflatoxin B1 and
B2, aflatoxin G1 and G2, aflatoxin M1 and M2, and aflatoxicol.
Toxicokinetics: Aflatoxin is metabolized in the body; aflatoxin B1 is metabolized to aflatoxin
M1, which is further detoxified by conjugation with taurocholic and glucuronic acids and is
excreted in the bile or urine.
Effects: Aflatoxins are hepatotoxic, and may lead to development of liver and gall bladder
cancer.
Ochratoxins
Ochratoxins are mainly found in Aspergillus ochraceus, A. niger and some Penicillium species,
especially P. verrucosum and P. carbonarius. There are three ochratoxins; ochratoxin A, B and
C. Ochratoxin A is the most prevalent, while ochratoxins B and C are of lesser importance.
Ochratoxin A is found in many foodstuffs like dried fruit, maize, wheat, oats, other cereals, and
feeds made from maize.
Toxicokinetics: Ochratoxin A is absorbed from the gastrointestinal tract and distributed in
many tissues, particularly the kidney (highest level), liver and muscles.
Effects: Ochratoxin A is nephrotoxic, and a possible human carcinogen.
C5. Pesticides
Pesticides are agents that kill pests; they are used to control pests. Generally, a pesticide is a
chemical or biological agent (plant, virus, bacterium, fungus, etc.) that deters, incapacitates,
kills, or otherwise discourages pests. Target pests include insects, plant pathogens, weeds,
molluscs, birds, mammals, fish, nematodes, and microbes that destroy property, cause
nuisance, spread disease, or are disease vectors.
Pesticides decrease or prevent the occurrence of diseases such as malaria, yellow fever,
bubonic plague, amongst others. They increase crop and food production, and decrease the
work force needed to produce food. Most pesticides serve as plant protection products (crop
protection products), which in general, protect plants from weeds, fungi, or insects. However,
the use of pesticides in agriculture is declining with use of genetically engineered plants.
Pharmacists Council of Nigeria
105 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Although pesticides have benefits, some also have drawbacks, such as potential toxicity to
humans and other species. Though all produce some degree of toxicity in humans, selective
toxicity of pesticides is extremely desirable and important.
Pesticides include herbicides, insecticides (which may include insect growth regulators,
termiticides, etc.) nematicides, molluscicides, piscicides, avicides, rodenticides, bactericides,
insect repellents, animal repellents, antimicrobials, and fungicides. Our focus here shall be on
insecticides, rodenticides, fungicides, herbicides and fumigants.
I. INSECTICIDES
Incidents of acute poisoning from insecticides have resulted from accidental poisoning,
including in children; eating food that was grossly contaminated in the farm, during storage or
transportation; or exposure to low levels of chemicals retained on produce.
(a). Organophosphorous insecticides
Some commonly used organophosphorous insecticides are parathion, malathion, parathion-
methyl, dichlorvos, fenitrothion, azinphos-methyl, chlorfenvinphos, diazinon, diamethoate,
fenitrothion and trichlorfon.
They have largely replaced the chlorinated hydrocarbons. Organophosphorus pesticides are not
considered to be persistent pesticides, i.e. they do not persist in the environment. They are
relatively unstable and break down in the environment due to hydrolysis and photolysis. They
are considered to have a small impact on the environment despite their acute effects on
organisms. They have an extremely low carcinogenic potential, but they have a much higher
acute toxicity in humans. Parathion is the pesticide most frequently involved in fatal poisoning.
Toxicodynamics
Mechanism of insecticidal action and toxicity
In mammals as well as insects, the main mechanism of action is inhibition of
acetylcholinesterase through phosphorylation of the esteratic site. The signs and symptoms that
characterize acute intoxication are due to inhibition of this enzyme and accumulation of
acetylcholine. Some of the agents also possess direct cholinergic activity.
Also, some of these agents phosphorylate another enzyme present in neural tissue, neuropathy
target esterase. This results in progressive demyelination of the longest nerves; associated with
Pharmacists Council of Nigeria
106 FPGOP Lecture Note on Applied Pharmacology and Toxicology
paralysis and axonal degeneration, this lesion is sometimes called organophosphorus ester-
induced delayed polyneuropathy (OPIDP). Delayed central and autonomic neuropathy may
occur in some patients poisoned with e.g. dichlorvos and trichlorfon.
Toxicokinetics
The organophosphates are absorbed through all routes, including by inhalation, ingestion and
through the skin. All organophosphates except echothiophate are distributed to all parts of the
body, including the central nervous system. Therefore, central nervous system toxicity is an
important component of poisoning with these agents.
Malathion and a few other organophosphate insecticides are also rapidly metabolized by other
pathways to inactive products in birds and mammals but not in insects; therefore they are
considered safe for use by the general public. Fish cannot detoxify malathion, and significant
numbers of fish have died from the heavy use of this agent on and near waterways. Parathion
is not detoxified effectively in vertebrates; thus, it is considerably more dangerous than
malathion to humans and livestock and its use has been banned or restricted in most countries.
Organ system effects
Their primary action is to amplify the actions of endogenous acetylcholine, so they produce the
same pharmacological effects as excess acetylcholoine.
Signs and symptoms of organophosphorous poisoning
The dominant initial signs are those of excessive stimulation of muscarinic receptors; miosis,
salivation, sweating, bronchial constriction, vomiting, and diarrhea. Central nervous system
involvement (manifesting as cognitive disturbances, convulsions, and coma) usually follows
rapidly, accompanied by peripheral nicotinic effects, especially depolarizing neuromuscular
blockade.
Treatment of poisoning by organophosphorus insecticides
Acute intoxication must be recognized and treated promptly.
1. Decontamination to prevent further absorption—this may require removal of all clothing
and washing of the skin in cases of exposure to dusts and sprays.
2. If the poison was ingested, gastric lavage or emesis may be beneficial if applied before
the symptoms appear.
3. Maintenance of vital signs—e.g. respiration may be impaired.
Pharmacists Council of Nigeria
107 FPGOP Lecture Note on Applied Pharmacology and Toxicology
4. Atropine sulphate is administered, 1 - 2 mg IM, every 5 – 15 minutes until the person is
fully atropinized (indicated by the appearance of dry mouth, dilated pupils and fast
pulse). This is maintained with 2 mg atropine.
5. A cholinesterase reactivator like pralidoxime administered by IV infusion (1 -2 g, given
over 15 – 30 minutes), only when the patient is fully atropinized, and if aging has not
occurred. However, pralidoxime is ineffective in reversing the central effects of
organophosphate poisoning because it has positively charged quaternary ammonium
groups that prevent entry into the central nervous system.
6. Administration of benzodiazepines for seizures.
(b). Carbamate insecticides
The carbamates are considered to be non-persistent pesticides, and exert only a small impact
on the environment. Carbamate insecticides include carbaryl, aldicarb, aminocarb, propoxur,
bendiocarb, carbofuran, fenobucarb, oxamyl and methomyl.
The clinical effects due to carbamates are of shorter duration than those observed with
organophosphorus compounds. The range between the doses that cause minor intoxication and
those that result in lethality is larger with carbamates than with the organophosphorus agents.
Spontaneous reactivation of cholinesterase is more rapid after inhibition by the carbamates.
Toxicodynamics
Mechanism of insecticide action and toxicity
Carbamate pesticides inhibit acetylcholinesterase by carbamoylation of the esteratic site.
Treatment of poisoning by carbamate insecticides
Treatment of poisoning by carbamate insecticides is similar to that of organophosphorus
compounds, but pralidoxime is contraindicated.
(c). Organochlorine insecticides
Organochlorine insecticides were used widely in agriculture and malaria control programmes,
from 1940 to 1970. However, they have largely been abandoned because they cause severe
environmental damage. Organochlorine insecticides include
(i). Chlorinated ethane derivatives e.g. dichlorodiphenyltrichloroethane (DDT), methoxychlor,
(ii). Chlorinated cyclodienes e.g. chlordane, aldrin, dieldrin, heptachlor, endrin
Pharmacists Council of Nigeria
108 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(iii). Hexachlorocyclohexanes e.g. lindane, toxaphene, mirex, chlordecone
(i). Chlorinated ethane derivatives
Chlorinated ethane derivatives include dichlorodiphenyltrichloroethane and methoxychlor
Dichlorodiphenyltrichloroethane
Dichlorodiphenyltrichloroethane (chlorophenothane; DDT) is the most common of the
chlorinated ethane derivatives. The use of DDT has been banned in many countries, however, it
is still used in some tropical countries to control malaria. Prior to placement of major restrictions
on its use in many countries, DDT was a widely used synthetic insecticide. DDT is a prime
candidate for biomagnification, as it is degraded very slowly in the environment and is stored in
the fat of animals.
Toxicodynamics
Mechanism of insecticide action and toxicity
In insects, DDT opens Na+ channels across neuronal membranes, resulting in prolonged action
potentials, repetitive firing after a single stimulus and spontaneous trains of action potentials.
Spontaneous firing of neuronal Na+ channels prevents normal repolarization, leading to spasms
and death of the insect.
In humans, DDT disrupts the transfer of nerve impulse by inhibiting K+ and Ca2+ ATPase which
control the active transfer of ions across membranes. It inhibits Na+ influx and K+ efflux in
neurons in the brain and periphery. The resultant excess intracellular K+ in the neuron partially
depolarizes the cell; the threshold for another action potential is decreased leading to
premature depolarization of the neuron.
DDT is also an endocrine disruptor in humans.
Toxicokinetics
DDT is highly soluble in fat but has a very low solubility in water. It is readily absorbed when
dissolved in oils, fats or lipid solvents (e.g. kerosene), but poorly absorbed as an aqueous
suspension or a dry powder. Once absorbed, DDT concentrates in adipose tissues; this is
protective, as it decreases the amount of DDT at its site of toxic action - the brain. At a
constant rate of intake, the concentration of DDT in adipose tissue reaches steady state and
remains relatively constant. DDT crosses the placenta, and its concentration in the umbilical
cord blood is in the same range as that in the blood of the exposed mother. The first step in the
Pharmacists Council of Nigeria
109 FPGOP Lecture Note on Applied Pharmacology and Toxicology
metabolism of DDT is the formation of dichlorodiphenyldichloroethane (DDD) and
dichlorodiphenyldichloroethylene (DDE). These metabolites are usually converted to several
hydroxylated compounds, and eliminated in a conjugated form in bile and urine. DDT, DDE and
to a lesser extend DDD are lipophilic compounds which accumulate in adipose tissue. On
cessation of exposure, DDT is eliminated from the body slowly; about 1% of stored DDT is
excreted daily. The DDD and DDE are the major metabolites and environmental breakdown
products of DDT.
Signs and Symptoms of DDT poisoning
The major effect is central nervous system stimulation, manifesting initially as tremor with
possible progression to convulsions. Other signs and symptoms include paresthesia of the
tongue, lips and face; apprehension; hypersusceptibility to stimuli; irritability; dizziness; tremor;
tonic and clonic convulsions. DDT may cause leukemia, brain and lung cancer (it is classified as
probably carcinogenic in humans). Death probably results from the kerosene solvent.
Treatment of poisoning by DDT and organochlorines
Supportive care and observation for signs of end-organ damage (e.g., central nervous system,
heart, lung and liver) are the mainstays of therapy. No specific antidotes are available for
organochlorine poisoning.
The following measures may be undertaken:
1. Use of activated charcoal followed by gastric lavage or emesis.
2. Catharsis with sodium sulphate helps to remove the organochlorine compound.
3. Artificial respiration with oxygen may be applied if necessary.
4. An anticonvulsant e.g. phenobarbital, diazepam, is useful in severe convulsion.
This treatment serves for all organochlorine derivatives
Note: Adrenaline is contraindicated as it can induce ventricular fibrillation.
Drug interactions
Relatively low doses of DDT induce CYP450 enzymes leading to altered metabolism of drugs,
xenobiotics, steroid hormones, etc.
Methoxychlor
Pharmacists Council of Nigeria
110 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Methoxychlor is a chlorinated ethane derivative. It was intended as an alternative to DDT, but
has been banned due to its acute toxicity, bioaccumulation and endocrine disruption activity. It
is stored in adipose tissues to about 0.2% of the extent of DDT. It has estrogenic activity and
reduces biosynthesis of testosterone.
(ii). Chlorinated cyclodienes
Chlorinated cyclodienes (pesticides derived from hexachlorocyclopentadiene) include aldrin,
dieldrin, endrin, heptachlor, chlordane and endosulfan. They also have carcinogenic potential.
Aldrin and related cyclodiene pesticides are classified as persistent organic pollutants, as they
do not easily break down. Furthermore, they biomagnify as they pass along the food chain.
Long-term exposure has proven toxic to a very wide range of animals including humans, far
greater than to the original insect targets. Consequently, some of them have been banned in
some countries.
Aldrin is not toxic to insects, but it is oxidized in the insect to form dieldrin which is the active
compound. Endrin is a stereoisomer of dieldrin.
Toxicodynamics
Mechanism of Toxicity
The cyclodienes are antagonists at GABAA ionotropic receptors, thereby decreasing the uptake
of Cl-, resulting in partial repolarization of the neurons and a state of uncontrolled excitation.
They produce convulsions before other less serious signs of illness appear.
Toxicokinetics
Like DDT, they are highly lipid soluble and are stored in adipose tissue. They induce CYP450
enzymes, are degraded slowly, persist in the environment and undergo biomagnification
through the food chain of animals.
Signs and symptoms of poisoning
They cause stimulation of the CNS. Symptoms include headache, nausea, vomiting, dizziness,
mild clonic jerking, hyperactivity, lack of coordination, staggering, tremors and convulsions.
(iv). Other chlorinated hydrocarbons; hexachlorobenzene, hexachlorocyclohexanes,
and others
These include hexachlorobenzene, lindane, toxaphene, mirex and chlordecone.
Pharmacists Council of Nigeria
111 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Hexachlorobenzene
Hexachlorobenzene (perchlorobenzene), an organochloride, is a fungicide formerly used to treat
seeds e.g. to control the fungal disease bunt in wheat. It is an animal carcinogen and a
probable human carcinogen. It has been banned globally under the Stockholm Convention on
Persistent Organic Pollutants.
Lindane
Lindane (γ-hexachlorocyclohexane; γ-HCCH; gammallin; gammaxene) is the γ isomer of
hexachlorocyclohexane.
The WHO classifies lindane as ‘moderately hazardous’, and its international trade is restricted
and regulated under the Rotterdam Convention on Prior Informed Consent. In 2009, the
production and agricultural use of lindane was banned under the Stockholm Convention on
persistent organic pollutants. A specific exemption to that ban allows it to be used as a second-
line drug for treatment of lice and scabies.
Lindane is a neurotoxin that binds at the picrotoxin binding site on the GABAA receptor, thereby
blocking the effects of GABA. Signs and symptoms of poisoning resemble those of DDT, and
include tremors, ataxia, convulsions, etc. It persists less in the environment. Lindane induces
cytochrome P450 enzymes. It is used clinically as an ectoparasite for lice and scabies.
Toxaphene
Toxaphene is a synthetic organic mixture composed of over 670 chemicals (mostly
chlorobornanes, chlorocamphenes, and other bicyclic chloroorganic compounds), formed by the
chlorination of camphene to an overall chlorine content of 67–69% by weight. Toxaphene was
banned in some countries in 1990s, and was banned globally by the 2001 Stockholm
Convention on Persistent Organic Pollutants. It is a very persistent chemical that can remain in
the environment for 1–14 years without degrading, particularly in the soil.
Mirex and Chlordecone
Mirex is an organochloride that was used as an insecticide and later banned because of its
impact on the environment. Its used has been banned in several countries, it is prohibited by
the Stockholm Convention on Persistent Organic Pollutants.
Pharmacists Council of Nigeria
112 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Chlordecone (Kepone), a colourless solid, is an organochlorine compound and. It is an obsolete
insecticide related to Mirex and DDT. Its use was so disastrous that it is now prohibited in the
western world, though after many millions of kilograms had been produced. Kepone is a known
persistent organic pollutant (POP), classified among the ‘dirty dozen’ and banned globally by the
Stockholm Convention on Persistent Organic Pollutants as of 2011.
Mirex and Chlordecone are extremely persistent hydrocarbon insecticides, and they are
concentrated several thousand-fold in the food chain. Mirex and chlordecone are classified as
POP, and are among the ‘dirty dozen’ that are banned globally by the Stockholm Convention on
Persistent Organic Pollutants (a United Nations Treaty) as of 2011, because of their impact on
the environment.
Toxicodynamics
Mirex is oxidized to chlordecone. Mirex and chlordecone cause central nervous system
stimulation and hepatic injury. Chlordecone has a direct estrogenic activity resulting in testicular
atrophy, reduced sperm production and motility.
Toxicokinetics
Mirex is oxidized to chlordecone. They induce cytochrome P450 enzymes. Chlordecone is mainly
excreted via the feces.
Chlordecone has been detected in the milk of women, cows and rats; milk from contaminated
cows could be a source of human exposure.
Signs and Symptoms of Toxicity
Signs and symptoms of toxicity include neurological effects (tremors, ocular flutter i.e.
opsoclonus), hepatomegaly, splenomegaly, rashes, mental changes, widened gait, decreased
sperm count and motility.
Treatment of Poisoning
Supportive care and symptomatic therapy is employed. Cholestyramine is administered to
patients poisoned with chlordecone. Cholestyramine increases the faecal excretion of
chlordecone 3 – 18 fold, decreases its plasma t1/2 from 140 – 80 days, and enhances the rate of
recovery from toxic manifestations.
(d). Botanical Insecticides
Pesticides derived from plants include nicotine, rotenone, and pyrethrum.
Pharmacists Council of Nigeria
113 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(i). Pyrethrum and structurally related agents
Pyrethrum is an allergenic insecticide obtained from flowers of Chrysanthemum cinerariifolium
and C. coccineum. Pyrethrins are organic compounds with potent insecticidal activity, derived
from Chrysanthemum cinerariifolium flowers. Naturally occurring pyrethrins are Pyrethrin I,
Cinerin I, Jasmolin I, Pyrethrin II, Cinerin II and Jasmolin II. Pyrethrin I has the greatest
insecticidal activity.
Pyrethroids are synthetic pyrethrin derivatives. Pyrethroids include allethrin (first synthesized
pyrethroid), permethrin (dichlorovinyl derivative of pyrethrin, and the most widely used
pyrethroid), bifenthrin, cyfluthrin, cypermethrin, cyphenothrin, deltamethrin, imiprothrin,
phenothrin, prallethrin, resmethrin, sumithrin, tetramethrin, transfluthrin, amongst others.
Cyfluthrin, prallethrin and transfluthrin are active ingredients in Baygon®.
Preparations containing pyrethrins or synthetic pyrethroids are far less likely to cause allergic
reactions than are preparations made from pyrethrum. Pyrethrins and pyrethroids are widely
used in many household insecticides because of their rapid action and safety profile. Pyrethrum
and analogs are generally rated as the safest insecticides because the primary toxicity is low.
The low toxicity in mammals is largely due to their rapid transformation by ester hydrolysis and
/or hydroxylation. The slow biotransformation of pyrethrum in insects is further decreased by its
formulation with piperonyl butoxide (inhibits cytochrome P450), which increases insecticidal
efficacy.
Aquatic organisms are extremely sensitive to pyrethroids.
Mechanism of insecticide action and toxicity
They cause a remarkable increase in the duration of opening of the neuronal membrane Na+
channel, leading to a prolonged flow of Na+. Consequently, there is elevation and prolongation
of depolarization after potential which on reaching the threshold membrane potential initiates
repetitive after discharges. When the toxin keeps the channels in their open state, the nerves
cannot repolarize, leaving the membrane depolarized for unusually long period, thereby
paralyzing the organism. Pyrethroids are much more toxic to insects than to mammals, due to
species differences in the sodium channels.
Toxicokinetics
Pyrethrum may be absorbed after inhalation or ingestion; absorption from the skin is not
significant. The esters are extensively biotransformed.
Pharmacists Council of Nigeria
114 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(ii). Rotenone
Rotenone the first rotenoid to be described; is an odorless, colorless, crystalline isoflavone used
as a broad-spectrum insecticide, piscicide, and pesticide. It occurs naturally in the roots, stems
and seeds of several tropical and subtropical plants, such as Pachyrhizus erosus (jicama vine
plant), some species of Derris (e.g D. elliptica, D. involuta), Lonchocarpus (e.g. L. nicou, L.
urucu), Millettia and Tephrosia.
Rotenone is classified by WHO as moderately hazardous. It is mildly toxic to humans and other
mammals, but extremely toxic to insects and aquatic life, including fish. This higher toxicity in
fish and insects is because the lipophilic rotenone is easily taken up through the gills or trachea,
but not as easily through the skin or the gastrointestinal tract.
Rotenone rapidly biodegrades under warm conditions, so harmful residues are minimal.
Toxicodynamics
Mechanism of insecticide action and toxicity
Rotenone interferes with the electron transport chain in mitochondria. It inhibits the transfer of
electrons from iron-sulfur centers in NADH ubiquinone oxidoreductase (NADH dehydrogenase;
complex I) to ubiquinone (CoQ). This interferes with NADH during the generation of ATP. It
inhibits the oxidation of NADH to NAD, thereby blocking the oxidation of e.g. glutamate, α-
ketoglutarate and pyruvate by NAD. Complex I is unable to pass off its electron to CoQ,
therefore electrons accumulate within the mitochondrial matrix. Cellular oxygen is reduced to
the radical, creating reactive oxygen species, which can damage DNA and other components of
the mitochondria. Rotenone also inhibits microtubule assembly.
Signs and symptoms of Poisoning
Oral ingestion causes gastrointestinal irritation, nausea and vomiting. Inhalation of the dust is
more hazardous, causing respiratory stimulation followed by depression, and convulsion.
Treatment of rotenone poisoning is symptomatic.
Uses
Rotenone is used as a pesticide, insecticide, and as a non-selective piscicide. Rotenone has
been used as an organic pesticide dust for gardens. Non-selective in action, it kills for example
potato beetles, cucumber beetles, flea beetles, cabbage worms, and most other arthropods. A
Pharmacists Council of Nigeria
115 FPGOP Lecture Note on Applied Pharmacology and Toxicology
light dusting on the leaves of plants will control insects for several days. It is commercially
available alone, or in synergistic combination with other insecticides.
Rotenone is also used in powdered form to treat scabies and head lice on humans, and parasitic
mites on chickens, livestock, and pet animals.
(iii). Nicotine and neonicotinoids
Nicotine is present in the leaves of Nicotiana rustica and in the tobacco plant Nicotiana
tabacum.
Nicotine functions as an antiherbivore compound (secondary metabolite involved in plant
defense); consequently, nicotine was widely used as an insecticide in the past.
Toxicodynamics
Mechanism of insecticide action and toxicity
Nicotine stimulates the nicotinic acetylcholine receptor resulting in depolarization of the
membrane. Nicotine is a depolarizing blocker; i.e. toxic doses cause stimulation rapidly followed
by blockade of transmission.
Toxicokinetics
Nicotine is rapidly absorbed from mucosal surfaces; the free alkaloid, but not the salt, is readily
absorbed from the skin.
Nicotine one of the most toxic insecticides, is regarded as a potentially lethal poison. However,
due to its toxicity profile, nicotine was replaced by neonicotinoids. Today nicotine is less
commonly used in agricultural insecticides, which was a main source of poisoning.
Signs and symptoms of nicotine poisoning
The toxic effects of a large dose of nicotine are extensions of its pharmacological actions. The
most dangerous are (1) central stimulant actions, which cause convulsions and may progress to
coma and respiratory arrest; (2) skeletal muscle end plate depolarization, which may lead to
depolarization blockade and respiratory paralysis; and (3) hypertension and cardiac
arrhythmias.
Treatment of nicotine poisoning
Treatment of nicotine poisoning involves maintenance of vital signs and symptomatic therapy.
Muscarinic excess resulting from parasympathetic ganglion stimulation can be controlled with
atropine. Central stimulation is usually treated with parenteral anticonvulsants such as
Pharmacists Council of Nigeria
116 FPGOP Lecture Note on Applied Pharmacology and Toxicology
diazepam. Neuromuscular blockade is not responsive to pharmacologic treatment and may
require mechanical ventilation. Nicotine is metabolized and excreted relatively rapidly; patients
who survive the first 4 hours usually recover completely if hypoxia and brain damage have not
occurred.
Neonicotinoids
Neonicotinoids (neonics) are a class of neuroactive insecticides chemically similar to nicotine.
Neonicotinoids include acetamiprid, clothianidin, imidacloprid, nitenpyram, nithiazine, thiacloprid
and thiamethoxam. Compared to organophosphate and carbamate insecticides, neonicotinoids
cause less toxicity in birds and mammals than insects. Some metabolic products are also toxic
to insects.
Neonicotinoid use has been linked in a range of studies to adverse ecological effects, including
honey-bee colony collapse disorder and loss of birds due to a reduction in insect populations;
however, the findings have been conflicting, and thus controversial. Their use has been
restricted or banned by several countries and International Treaties, out of concern for
pollinators and bees.
Mechanism of insecticide action and toxicity
Neonicotinoids, like nicotine, bind to and stimulate nicotinic acetylcholine receptors (nAChRs).
In mammals, nicotinic acetylcholine receptors are located in cells of both the central nervous
system and peripheral nervous systems. In insects these receptors are limited to the central
nervous system. Excessive stimulation of nAchRs by neonicotinoids block the receptors, causing
paralysis and death. Acetylcholinesterase cannot deactivate neonicotinoids, thus their binding is
irreversible.
(e). Avermectins
The avermectins were originally isolated from a culture of the soil actinomycete, Streptomyces
avermitilis.The avermectins are a group of drugs and pesticides with potent anthelmintic and
insecticidal properties. They include ivermectin, selamectin, doramectin, and abamectin.
Ivermectin is also used for pediculosis.
(f). Insecticides used as ectoparasiticides
Pharmacists Council of Nigeria
117 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Some insecticides are also ectoparasiticides used as pediculocides and miticides (especially
scabicides). They include:
(i). Lindane is a miticide, used for the treatment of scabies. It is also a very active pediculocide
effective in the treatment of pediculosis pubis (Phthirus pubis), pediculosis capitis, pediculosis
corporis.
(ii). Malathion, an organophosphorous insecticide, is rapidly pediculocidal and niticidal; lice and
their eggs (nits) are killed within 3 seconds by 0.003% and 0.06% malathion in acetone
respectively.
(iii). Permethrin is an insecticide used to treat scabies and pediculosis
(iii). Benzylbenzoate is an insect repellent also used to treat scabies and pediculosis.
Table 2: Active constituents of some brands of insecticides commonly used in Nigeria
Brand of insecticide
Active constituents
Baygon® Imiprothrin 0.05%, prallethrin 0.05%, cyfluthrin 0.015%,
Raid® D-allethrin 0.25%, tetramethrin 0.015%, deltamethrin 0.015%
Mortein® Imiprothrin 0.02%, d-phenothrin 0.03%, D-trans allethrin 0.10%
Mobil® insecticide Neo-pynamin (tetramethrin) 0.25%, prallethrin 0.04%, cyphenothrin 0.05%
II. HERBICIDES
Herbicides are chemicals used for destruction of noxious weeds. Herbicides include:
(a). Chlorophenoxy compounds – 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-
trichlorophenoxyacetic acid (2,4,5-T). They do not accumulate in animals.
(b). Dinitrophenols e.g. dinitroorthocresol (DNOC)
(c). Bipyridyl compounds – e.g. Paraquat
(d). Phosphonomethyl amino acids
(e). Others such as carbamates (e.g. asulam, propham, barban); substituted ureas (e.g.
monuron, diuron); triazines (e.g. atrazine); aniline derivatives (e.g. alachlor, propachlor,
propanil); dinitroaniline derivatives (e.g. triflualin); and benzoic acid derivatives (e.g. amiben).
III. FUNGICIDES
Fungicides are agents used to kill fungi or their spores, and include:
(1). Dithiocarbamates – Dimethyldithiocarbamates and the ethylenebisdithiocarbamates
Pharmacists Council of Nigeria
118 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Dithiocarbamate fungicides are analogs of disulfiram, and they can produce a disulfiram-like
response on concomitant intake with alcohol.
(2). Hexachlorobenzene
(3). Pentachlorophenol – It is used as an insecticide, herbicide, fungicide, with major application
as a wood preservative.
IV. RODENTICIDES
Rodenticides are pesticides used to kill rodents. Rodenticides include:
(1). Warfarin
(2). Bulbs of red squill containing cardiotonic scillaren glycosides
(3). Sodium fluoroacetate (sodium monofluoroacetate; Compound 1080). This is among the
most potent rodenticides. Sodium fluoroacetate produces its toxic action by inhibiting the citric
acid cycle. Fluoroacetate occurs in all parts of Dichapetalum cymosum, a plant which grows in
Nigeria, and is used as rat poison.
(4). Strychnine, an alkaloid present in Strychnous nux vomica - is a highly toxic, colorless,
bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as
birds and rodents. Strychnine, when inhaled, ingested, or absorbed through the eyes or mouth,
causes poisoning which results in muscular convulsions, including opisthotonus and eventually
death through asphyxia.
(5). White or yellow elemental phosphorous has poisoned human beings on ingestion of bread
on which it was spread to bait rodents. Shortly after ingestion, phosphorus produces severe
gastrointestinal irritation, and with sufficient doses haemorrhage and cardiovascular failure may
result in death within 24 hours.
(6). Zinc phosphide - Zinc phosphide reacts with water and hydrochloric acid in the
gastrointestinal tract to produce phosphine gas, which causes severe gastrointestinal tract
irritation.
(7). α-naphthylthiourea
(8). Thallium salts – They lack selective toxicity; therefore, their use has been restricted or
banned in many countries.
V. FUMIGANTS
Pharmacists Council of Nigeria
119 FPGOP Lecture Note on Applied Pharmacology and Toxicology
A fumigant is a gaseous pesticide used to control insects, rodents, soil nematodes, and other
animals or plants that damage stored foods or seeds, human dwellings, clothing, nursery stock,
etc. It is used to control pests in buildings, soil, grain, and produce, and also during processing
of goods to be imported or exported to prevent transfer of certain organisms. Fumigants exert
pesticidal action in gaseous form and are used because they can penetrate otherwise
inaccessible areas. Fumigation is a method of pest control that completely fills an area with
gaseous pesticides (fumigants), to poison the pests therein.
Fumigants used to protect stored food stuffs include hydrogen cyanide, carbon tetrachloride,
acrylonitrile, carbon disulphide, dibromochloropropane, ethylene dibromide, chloropicrin,
ethylene oxide, methyl bromide, phosphine, amongst others.
Hydrogen cyanide
Cyanide (hydrocyanic acid; prussic acid; HCN) is one of the most rapidly acting poisons; victims
may die within minutes of exposure. Cyanide is used:
(i).To fumigate ships and buildings
(ii). To sterilize soil
(iii). In metallurgy, electroplating and metal cleaning, because of its ability to form
complexes with metals.
(iv). As a constituent of silver polish, insecticides, rodenticides
(v). Cyanide is found in some plants e.g. cassava, and fruit seeds e.g. apple, apricot,
almond, etc.
(vi). It is a metabolite of organic nitriles, organic thiocyanates, nitroprusside, and nitrogen
containing plastics
(vii). It is used for executions in gas chambers.
Toxicodynamics
Mechanism of Toxicity
Cyanide has a very high affinity for ferric iron (Fe3+). On absorption, HCN reacts readily with
Fe3+ of cytochrome oxidase in mitochondria. Consequently, cellular respiration is inhibited,
resulting in lactic acidosis and cytotoxic hypoxia.
Since cellular respiration is inhibited, and utilization of oxygen is blocked, venous blood is
oxygenated and is almost as bright red as arterial blood. Respiration is stimulated because
Pharmacists Council of Nigeria
120 FPGOP Lecture Note on Applied Pharmacology and Toxicology
chemoreceptors respond as they do in hypoxia. A transient stage of central nervous system
stimulation with hyperpnea and headache occurs; finally hypoxic convulsions occur, and death
is due to respiratory arrest.
Treatment of cyanide poisoning
Treatment must be rapid to be effective. Diagnosis may be aided by the characteristic odour of
cyanide (oil of bitter almonds).
1. Cyanide is removed from the body through its enzymatic conversion by the
mitochondrial enzyme rhodanese (transsulfurase), to thiocyanate, which is relatively
non-toxic.
To accelerate detoxification sodium thiosulphate (50 ml of a 25% aqueous solution) is
administered IV, and the thiocyanate formed is readily excreted in the urine.
Sodium thiosulphate accelerates the conversion of cyanide to thiocyanide, therefore
facilitating detoxification.
2. Hydroxocobalamin is also used to treat cyanide poisoning as it combines with cyanide to
form cyanocobalamin (vitamin B12).
3. Administration of substances that oxidize hemoglobin to methemoglobin (MetHb). Such
substances are:
(a). Nitrite e.g. amyl nitrite administered by inhalation and sodium nitrite for intravenous
administration.
MetHb competes with cytochrome oxidase for the cyanide ion; MetHb is favoured in the
reaction because of mass action. CyanmetHb is formed, and cytochrome oxidase is
restored (spared). The cyanmetHb slowly releases the cyanide, which is converted to
thiocyanate. Thiocyanate is relatively non-toxic and is excreted in urine.
(b). 4-dimethylaminophenol (3 mg/kg IV) also oxidizes hemoglobin to MetHb.
4. Oxygen alone, even at hyperbaric pressure has only a slight protective effect in cyanide
poisoning. However, oxygen markedly potentiates the protective effects of thiosulphate,
or nitrite and thiosulphate.
5. Cobalt compounds have a high affinity for cyanide; e.g. Dicobalt edetate (dicobalt
ethylenediaminetetraacetate; Co2EDTA).
6. If HCN has been ingested, gastric lavage should follow, and not precede initiation of
more specific treatment.
Pharmacists Council of Nigeria
121 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(ii). Methyl bromide
Methyl bromide (bromomethane) is used as an insecticidal fumigant for soil, stored dried
foodstuffs, and disinfection of fresh fruits and vegetables. It is used as a refrigerant, and is also
a constituent of some fire extinguishers. Since it is very toxic, chloropicrin (2%w/w) a powerful
stimulator of lacrimation is added as a warning of methyl bromide exposure.
(iii). Dibromochloropropane and ethylene dibromide (dibromoethane) are soil
fumigants used to control nematodes. Dibromochloropropane was observed to cause sterility
and/or abnormally low sperm counts in workmen engaged in its manufacture, while ethylene
dibromide is a known carcinogen. Their use has decreased due to carcinogenic and adverse
effects on reproductive function.
(iv). Phosphine
Phosphine (PH3) is a fumigant for grain. Following the ban of the use of methyl bromide in most
countries under the Montreal Protocol, phosphine is a widely used, cost-effective, rapidly acting
fumigant that does not leave residues on the stored product.
Phosphine is more toxic than methyl bromide; however, as less phosphine is needed to
fumigate a given volume of grain, phosphine has been proven to be safer. Deaths have resulted
from accidental exposure to fumigation materials containing aluminum phosphide or phosphine.
Phosphine gas is heavier than air so stays nearer the floor where children are likely to play.
Nevertheless, the use of phosphine gas is strictly regulated in most countries, and permitted to
be used only as an agricultural pesticide; and not to be used in spaces like homes or hotels.
Fumigators are required to acquire six months of training before they are able and authorized
to handle the toxin.
Phosphine is released gradually from pellets/tablets of aluminum phosphide, calcium
phosphide, or zinc phosphide upon contact with atmospheric water or rodents' stomach acid.
These pellets also contain agents to reduce the potential for ignition or explosion of the
released phosphine. An alternative is the use of phosphine gas itself which requires dilution with
either CO2, N2 or air to bring it below the flammability point. Use of the gas avoids issues
related with solid residues left by metal phosphide and results in faster, more efficient control of
target pests.
Pharmacists Council of Nigeria
122 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Phosphine gas can be absorbed either by inhalation or transdermally. It acts on the central
nervous system, respiratory and other body systems. It affects the transport of oxygen and
interferes with the utilization of oxygen by various cells in the body.
Signs and symptoms of poisoning include a fall in blood pressure, pulmonary edema, convulsion
and coma. The first sign of chronic poisoning is toothache followed by swelling of the jaw and
necrosis of the mandible (phossy jaw). There may be anaemia and spontaneous fractures.
Treatment of phosphine poisoning is mainly symptomatic. Calcium gluconate (10 ml of 10%
solution) may be given intravenously to maintain serum calcium.
C6. SOLVENTS, VAPOURS, GASES
(i). Halogenated aliphatic hydrocarbons
The halogenated hydrocarbons are among the most widely used industrial solvents, due to their
excellent solvent properties and low flammability.
Halogenated aliphatic hydrocarbons include carbon tetrachloride, chloroform, trichloroethylene,
tetrachloroethylene (perchloroethylene), dichloromethane (used as paint stripper), 1,1,1-
trichloroethane (methyl chloroform), bromodichloromethane. Chloroform is produced from
naturally occurring precursors during chlorination of water. Halogenated hydrocarbons were
formerly widely use as industrial solvents, degreasing and cleaning agents. Due to their
carcinogenic potential, carbon tetrachloride and trichloroethylene have largely been removed
from the workplace. Perchloroethylene and trichloroethane are still in use for dry cleaning and
degreasing, but it is likely that their use will be very limited in the future. Dry cleaning as an
occupation is classified as a carcinogenic activity.
The common halogenated aliphatic solvents are persistent water pollutants. They are widely
found in both groundwater and drinking water as a result of poor disposal practices. The
halogenated hydrocarbons are also common at toxic waste sites, and thus have the potential to
contaminate drinking water supply. Several are also carcinogenic in animals and are considered
probable carcinogens in humans. This has raised concern about the exposure of a large
percentage of the population to these chemicals in drinking water.
Chlorinated HCs e.g. chlorofluorocarbons (CFCs) have a detrimental effect on the ozone layer.
Filtration or treatment of water with chemicals prior to chlorination effectively reduces formation
of chlorinated hydrocarbons.
Pharmacists Council of Nigeria
123 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Toxicokinetics
They are readily absorbed after ingestion or inhalation, as they are extremely lipid soluble.
Effects on body organs/systems
They depress the central nervous system in humans; chloroform is the most potent. Chronic
exposure to tetrachloroethylene and possibly 1,1,1-trichloroethane can cause impaired memory
and peripheral neuropathy. Hepatotoxicity is also a common toxic effect that can occur in
humans after acute or chronic exposures; carbon tetrachloride is the most potent.
Nephrotoxicity can occur in humans exposed to carbon tetrachloride, chloroform, and
trichloroethylene. With chloroform, carbon tetrachloride, trichloroethylene, and
tetrachloroethylene, carcinogenicity has been observed in lifetime exposure studies performed
in rats and mice and in some human epidemiologic studies. Several studies have shown
statistically significant associations between exposure to various halogenated aliphatic
hydrocarbon solvents including trichloroethylene and tetrachloroethylene and renal, prostate,
and testicular cancer.
Carbon tetrachloride
Carbon tetrachloride (CCl4) was once commonly used as spot remover and carpet cleaner, but
safer alternatives are now available. It is still used in the fumigation of grain and as an
insecticide.
Transient exposure to toxic concentrations of CCl4 vapour result in the following symptoms,
which disappear on termination of exposure: irritation of the eyes, nose, throat, nausea and
vomiting, a sense of fullness of the head, dizziness and headache. Continued exposure or
absorption of larger quantities, may cause stupor, convulsions, coma or death from CNS
depression. Sudden death may result from ventricular fibrillation or depression of vital
medullary centers. Delayed toxic effects include nausea, vomiting, abdominal pain, diarrhea and
hematemesis. The most serious delayed toxic effects result from its hepatotoxic and
nephrotoxic actions.
Carbon tetrachloride is one of the most potent hepatotoxins; it is widely used in scientific
research to induce hepatotoxicity.
Other halogenated aliphatic hydrocarbons
Chloroform, trichloroethylene and tetrachloroethylene produce majorly similar toxic effects as
carbon tetrachloride. They are hepatotoxic and also have the potential to sensitize the heart to
Pharmacists Council of Nigeria
124 FPGOP Lecture Note on Applied Pharmacology and Toxicology
arrhythmias produced by catecholamines. Chloroform and tetrachloroethylene are nephrotoxic.
Trichloroethylene and tetrachloroethylene are widely used as dry cleaning agents and industrial
solvents, because they produce less organ damage than carbon tetrachloride and chloroform.
Treatment of acute poisoning by halogenated aliphatic hydrocarbons
There is no specific treatment for acute intoxication resulting from exposure to halogenated
aliphatic hydrocarbons. Supportive and symptomatic management is given, depending on the
organ system involved.
1. Move patient to area with fresh, uncontaminated air.
2. Gastrointestinal decontamination with activated charcoal
3. Prevent hypoxia, if patient is first seen in the stage of advanced CNS depression.
4. Treat acute hepatic and renal insufficiency.
Note: Do not use sympathomimetic drugs because of the risk of producing serious arrhythmias
in the sensitized myocardium.
(ii). Aliphatic alcohols
Ethanol
Ethanol (alcohol, ethyl alcohol, grain alcohol, drinking alcohol) is a volatile, flammable, colorless
liquid with a slight characteristic odor. It is a psychoactive substance and is the main type of
alcohol found in alcoholic drinks.
Ethanol is naturally produced by the fermentation of sugars by yeasts or via petrochemical
processes, and is most commonly consumed as a popular recreational substance. Ethanol is a
versatile solvent, miscible with water and many organic solvents. Ethanol is widely used as a
solvent in various laboratory procedures, including synthesis of other organic compounds; as a
vital substance in different manufacturing industries; as an engine fuel and fuel additive,
amongst other uses. It also has medical applications as an antiseptic and disinfectant; and as
an antidote in methanol and ethylene glycol poisoning.
Due to its wide availability and versatility, ethanol could be a potential source of poisoning.
Toxicokinetics
After oral administration, ethanol is absorbed rapidly into the bloodstream from the stomach
and small intestine and distributes into total-body water (0.5-0.7 L/kg). Peak blood levels occur
about 30 minutes after ingestion of ethanol when the stomach is empty. Because absorption
Pharmacists Council of Nigeria
125 FPGOP Lecture Note on Applied Pharmacology and Toxicology
occurs more rapidly from the small intestine than from the stomach, delay in gastric emptying
(e.g. due to the presence of food) slows ethanol absorption.
Gastric metabolism of ethanol is lower in women than in men, which may contribute to the
greater susceptibility of women to ethanol. Ethanol undergoes first-pass metabolism by gastric
and liver alcohol dehydrogenase (ADH); this leads to lower blood alcohol level (BAL) after oral
ingestion, than would be obtained if the same quantity were administered intravenously.
Ethanol is metabolized largely by sequential hepatic oxidation, first to acetaldehyde by ADH and
then to acetic acid by aldehyde dehydrogenase (ALDH).
Although, 90-98% of ingested ethanol is metabolized to acetate, mostly by hepatic ADH and
ADLH, small amounts are excreted in urine, sweat, and breath.
Signs and symptoms of ethanol poisoning
Ingestion of lower doses of ethanol could produce symptoms such as mild sedation and poor
coordination. At higher doses, there may be slurred speech, difficulty walking, and vomiting.
Toxic doses may result in respiratory depression, coma, or death. Complications may include
seizures, aspiration pneumonia, injuries including suicide, and hypoglycemia.
Alcohol intoxication, also known as drunkenness or alcohol poisoning, is negative behavior and
physical effects due to the recent consumption / drinking of large amounts of ethanol (alcohol).
Legally, alcohol intoxication is often defined as a blood alcohol level (BAL) of greater than 25–
80 mg/dL or 0.025-0.080%. This can be measured using the blood or breath.
Management of Ethanol poisoning
Management of ethanol intoxication involves supportive care and symptomatic treatment, based
on the severity of respiratory and CNS depression. Measures include:
(1). Keep the patient warm, and in the recovery position.
(2). Ensure adequate breathing, maintain patent airways, provide artificial oxygen if needed.
Patients who are comatose and who exhibit evidence of respiratory depression should be
intubated to protect the airway and to provide ventilatory assistance.
(3). Since ethanol is freely miscible with water, ethanol can be removed from blood by
hemodialysis.
(4). Acute alcohol intoxication is not always associated with coma, and careful observation is
fundamental. Repeated assessments may be required to rule out other potential causes of a
person’s symptoms.
Pharmacists Council of Nigeria
126 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Usual care involves observing the patient in the emergency room for 4-6 hours while the patient
metabolizes the ingested ethanol. Blood alcohol levels will be reduced by approximately 15
mg/dl per hour.
Methanol
Methanol (methyl alcohol, wood alcohol) is a common industrial solvent. It is used as an
antifreeze fluid, a solvent for shellac and some paints and varnishes, and a component of paint
removers.
Methanol poisoning majorly results from ingestion, though there are rare cases of poisoning by
inhalation and dermal absorption.
Mechanism of Toxicity
Methanol has relatively low toxicity, but it is transformed to toxic metabolites. Methanol is
oxidized by alcohol dehydrogenase (ADH) to formaldehyde. Formaldehyde is oxidized to formic
acid in a reaction catalyzed by formaldehyde dehydrogenase. Formic acid is converted to
carbon dioxide and water by 10-formyl tetrahydrofolate synthetase.
In methanol poisoning, there is accumulation of formic acid leading to acidosis, ocular toxicity,
and some other toxic effects of methanol poisoning
Toxicokinetics
Methanol is rapidly absorbed via the oral route, inhalation, and through the skin; the latter two
routes are most pertinent to industrial settings.Peak methanol concentrations occur within 30 –
60 minutes following oral absorption. It is metabolized in humans by the same enzymes that
metabolize ethanol, i.e. alcohol dehydrogenase and aldehyde dehydrogenase, to toxic
intermediates formaldehyde and formic acid.
Signs and symptoms of methanol poisoning
Signs and symptoms of methanol poisoning include headache, difficulty in breathing, dilation of
pupils, blurred vision, blindness (complete or partial), hypotension, difficulty walking, confusion,
dizziness, seizures, bluish-coloured lips and fingernails, abdominal pain, nausea, vomiting,
diarrhea, pancreatitis, hepatotoxicity (including jaundice), weakness and fatigue. The most
pronounced laboratory finding is severe anion-gap metabolic acidosis - the result of oxidation of
methanol to formic acid, which accumulates. The elevated concentration of formic acid also
causes ocular toxicity, which results in bilateral blindness. Death is usually due to respiratory
Pharmacists Council of Nigeria
127 FPGOP Lecture Note on Applied Pharmacology and Toxicology
failure. Death from methanol is nearly always preceded by blindness. As little as 15 ml of
methanol can cause blindness; ingestion of 70-100 ml is usually fatal unless the patient is
treated.
Management of methanol poisoning
(i). Standard supportive care.
(ii). The correction of metabolic acidosis, by administration of sodium bicarbonate IV.
(iii). Administration of antidotes - fomepizole, ethanol. This will stop further generation of the
toxic metabolite (formic acid).
For example, 10% ethanol solution administered IV. Ethanol is recommended when plasma
methanol concentrations are >20 mg/dl, when ingested doses are> 30 ml and there is evidence
of acidosis or visual abnormalities.
(iv). Administration of intravenous folinic acid to enhanve metabolism of formic acid.
(v). Hemolysis may be necessary to correct severe metabolic abnormalities, and to enhance
elimination of methanol and formate.
Competition between methanol and ethanol for alcohol dehydrogenase (ADH) forms the basis
of the use of ethanol in methanol poisoning. Ethanol is a competitive substrate for ADH as it
has about 100x greater affinity for ADH than methanol. Inhibition of methanol metabolism
decreases the concentration of formaldehyde and formic acid in the blood, and thereby
decreases the toxicity.
Fomepizole (4-methylpyrazole) is a competitive inhibitor of ADH that inhibits the metabolism of
methanol to its toxic metabolite, formic acid. It is used in methanol and ethylene glycol
poisoning. By competitively inhibiting the first enzyme in the metabolism of methanol and
ethylene glycol, fomepizole slows the production of formic acid. The slower rate of metabolite
production allows the liver to process and excrete the metabolites as they are produced, limiting
the accumulation in tissues such as the kidney and eye. As a result, much of the organ damage
is avoided. Fomepizole is most effective when given soon after ingestion of ethylene glycol or
methanol. Delaying its administration allows for the generation of harmful metabolites.
Fomepizole reduced the rate of elimination of ethanol in healthy volunteers.
(iii). Aromatic hydrocarbon solvents
Pharmacists Council of Nigeria
128 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Benzene
Benzene is a versatile solvent, classified as a known human carcinogen. It is widely used as an
intermediate in the synthesis of other chemicals; and it is a natural and important constituent of
automobile fuels.
The acute toxic effect of benzene is depression of the central nervous system. Exposure to
concentrations ranging from 250 to 500 ppm may result in vertigo, drowsiness, headache, and
nausea. Exposure to concentrations larger than 3000 ppm may cause euphoria, nausea,
locomotor problems, and coma. Exposure to 7500 ppm for 30 minutes can be fatal.
Chronic exposure to benzene can result in very serious toxic effects, the most significant of
which is bone marrow injury leading to aplastic anemia with associated pancytopenia, leukemia,
lymphomas, myeloma, and myelodysplastic syndrome.
Treatment of poisoning with benzene and other aromatic hydrocarbon solvents
Treatment of benzene poisoning is by providing supportive care and management of symptoms.
Toluene (methylbenzene) does not possess the myelotoxic properties of benzene, nor has it
been associated with leukemia. It is a central nervous system depressant and a skin and eye
irritant. It is also fetotoxic.
Xylenes (dimethylbenzene) has been substituted for benzene in many solvent degreasing
operations. Like toluene, xylenes do not possess the myelotoxic properties of benzene, nor have
they been associated with leukemia. Xylene is a central nervous system depressant and a skin
irritant.
Less refined grades of toluene and xylenes contain benzene.
Kerosene and Petrol
Kerosene and petrol are petroleum distillates gotten from the fractionation of crude petroleum
oil. They contain aliphatic, aromatic and a variety of branched and unsaturated hydrocarbons.
They are used as fuels (motor, illuminating and heating fuels), vehicles for many pesticides,
cleaning agents and paint thinners. Petrol contains benzene (up to 5% v/v), and has the
potential to cause leukemia on chronic exposure.
Workers and other individuals where these solvents are used are exposed to it. In addition,
because they are often stored in containers previously used for bevarages, or similar to, or
Pharmacists Council of Nigeria
129 FPGOP Lecture Note on Applied Pharmacology and Toxicology
same one for other household use, they are a common cause of accidental poisoning in homes,
especially in children.
Routes of exposure
Exposure to kerosene and petrol, and poisoning thereof could be by ingestion, inhalation of the
vapour, skin and eye contact. Ingestion is more hazardous, because the liquids have a low
surface tension and can be easily aspirated into the respiratory tract by vomiting or eructation.
Signs and symptoms of poisoning
Ingestion of kerosene or petrol produces initial cough and maybe vomiting; later persistent
cough; cyanosis; burning in the stomach; aspiration pneumonitis leading to hypoxia and
respiratory distress; lethargy; coma; seizures; and arrhythmias.
Treatment of kerosene or petrol poisoning
Treatment of poisoning due to kerosene or petrol is by symptomatic and supportive care.
(i). Immediately remove the victim from the source of poisoning, and ensure patent airway.
(ii). Remove contaminated clothing and thoroughly wash the skin with soap and water.
(iii). Perform pulse oximetry if possible, and give oxygen if indicated. Intubation and mechanical
ventilation may be required in a patient with severe hupoxia, respiratory distress or decreased
consciousness.
(iv). Catharsis may be induced with Mg or Na sulphate.
(v). Fluid and electrolyte imbalances should be corrected.
(vi). Antibiotics are used if there is a specific indication e.g. bacterial pneumonitis.
(vii). Emesis or gastric lavage should be avoided because of the danger of inhalation/aspiration
and possibly pneumonitis. However, if very large quantities have been ingested less than an
hour earlier or if the risk is justified by the presence of additional toxic substances in the
petroleum product, then gastric lavage may be considered if the airway can be protected by
expert intubation.
Adrenaline and related substances should be avoided as they may induce cardiac arrhythmias.
(iv). Carbon monoxide
Carbon monoxide (CO) is an air pollutant. Five substances account for nearly 98% of air
pollution: CO (52%), sulphur oxides (14%), nitrogen oxides (14%), volatile organic compounds
(14%) and particulate matter (4%). The sources of these pollutants in increasing order of
Pharmacists Council of Nigeria
130 FPGOP Lecture Note on Applied Pharmacology and Toxicology
significance are; transportation, industry, generation of electric power, space heating, and
refuse disposal. The average atmospheric concentration of CO is about 0.1 ppm; in heavy
traffic, the concentration may exceed 100 ppm. About 90% of atmospheric CO is from natural
sources (forest fires, ocean [microorganisms produce CO], atmospheric oxidation of methane,
etc.), 10% is from human activity (cars, inadequate venting of furnaces, smoking). Most victims
of closed-space fire die from acute CO poisoning rather than from burns.
Carbon monoxide (CO), a colorless, tasteless, odorless, and non-irritating gas, is a by-product
of incomplete combustion of organic matter. It is the most abundant pollutant found in lower
atmosphere, and a large number of accidental and suicidal deaths occur yearly from its
inhalation.
Ambient air pollution has been implicated as a contributing factor in various repiratory diseases
such as bronchitis, obstructive pulmonary disease, pulmonary emphysema, bronchial asthma,
lung cancer, amongst others.
Carbon monoxide is synthesized in the body during the degradation of heme, however, its
physiological role is unclear.
Toxicodynamics
Mechanism of Toxicity
The toxicity of CO is due to
(a). Its reaction with hemoglobin (Hb) to form carboxyhemoglobin (CoHb). Carbon monoxide
acts by (i) reducing the oxygen carrying capacity of Hb, (ii) inhibiting the dissociation of oxygen
from oxyhemoglobin (O2Hb), thereby preventing O2 from interacting with body cells.
Carbon monoxide combines reversibly with the oxygen-binding sites of hemoglobin and has an
affinity for hemoglobin that is about 220 times that of oxygen. The product formed—
carboxyhemoglobin— cannot transport oxygen. Furthermore, the presence of
carboxyhemoglobin inhibits the dissociation of oxygen from the remaining oxyhemoglobin, thus
reducing the transfer of oxygen to tissues.
(b). Direct toxic effect by binding to myoglobin and mitochondrial cytochrome oxidase. The
brain and the heart are the organs most affected.
Normal non-smoking adults have carboxyhemoglobin levels of less than 1% saturation (1% of
total hemoglobin is in the form of carboxyhemoglobin); this level has been attributed to the
endogenous formation of CO from heme catabolism. Smokers may exhibit 5–10% saturation,
Pharmacists Council of Nigeria
131 FPGOP Lecture Note on Applied Pharmacology and Toxicology
depending on their smoking habits. A person breathing air containing 0.1% CO (1000 ppm)
would have a carboxyhemoglobin level of about 50%.
Signs and Symptoms of CO intoxication
The principal signs of CO intoxication are those of hypoxia and progress in the following
sequence: (1) psychomotor impairment; (2) headache and tightness in the temporal area; (3)
confusion and loss of visual acuity; (4) tachycardia, tachypnea, syncope, and coma; and (5)
deep coma, convulsions, shock, respiratory failure, irreversible damage to the brain and
myocardium, death. There is great variability in individual responses to a given
carboxyhemoglobin concentration.
Treatment of carbon monoxide poisoning
Treatment is directed toward the relief of tissue hypoxia and the removal of CO from the body.
Carboxyhemoglobin is fully dissociable, and once acute exposure is terminated, the CO is
excreted via the lungs; only small quantity is oxidized to CO2.
In cases of acute intoxication, removal of the individual from the source of exposure and
maintenance of respiration are essential, followed by administration of oxygen—the specific
antagonist to CO—within the limits of oxygen toxicity.
1. The patient is removed from the source of exposure, and transferred to area with fresh,
uncontaminated air.
2. If there is respiratory failure, artificial respiration is instituted immediately.
3. Provision of adequate supply of O2.
4. Rapid elimination of CO, e.g. by rapid administration of 100% O2 (normobaric) or in
severe poisoning, 100% O2 in a hyperbaric chamber (hyperbaric oxygen therapy; air
pressure is about 2-3x higher than normal pressure).
5. Hypotension and acidosis should be treated and corrected.
6. Respiratory and cardiac functions should be monitored, and symptomatic treatment
given if required.
7. Treatment of seizures, hypotension, cardiac abnormalities, pulmonary edema, etc. as
applicable.
8. Close and extensive follow-up in case of delayed neurological or other damage.
Pharmacists Council of Nigeria
132 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Note: With room air at 1 atm, the elimination half-time of CO is about 320 minutes; with 100%
oxygen, the half-time is about 80 minutes; and with hyperbaric oxygen (2–3 atm), the half-time
can be reduced to about 20 minutes. If a hyperbaric oxygen chamber is readily available, it
should be used in the treatment of CO poisoning for severely poisoned patients; however, there
remain questions about its effectiveness.
Progressive recovery from effectively treated CO poisoning, even of a severe degree, is often
complete, although some patients demonstrate persistent impairment for a prolonged period of
time.
Corrosives
Corrosives, as environmental toxic agents, include acids and acid-like substances as well as
bases/ alkalis. They are widely used in industries and many are found in the home.
Acids
Corrosive acids include inorganic acids such as sulfuric, hydrochloric and nitric acids; and
organic acids like acetic, trichloroacetic and formic acids. They are found in the homes as
battery acids (e.g sulphuric acid), drain and toilet bowl cleaners (may contain e.g. sodium
bisulphite which forms sulphuric acid with water) and some dishwasher detergents, which
contain substances such as sodium hydroxide and sulfuric acid. Industrial products are usually
more concentrated than household products and are more damaging.
Alkalis
Alkalis, e.g. sodium hydroxide and potassium hydroxide are used widely in the manufacture of
many chemicals and household products; thus they are possible sources of poisoning, including
in the home.
Signs and symptoms of poisoning by corrosives
When ingested, corrosives burn upper GIT tissues, sometimes resulting in esophageal or gastric
perforation. Symptoms may include drooling, dysphagia, and pain in the mouth, chest, or
stomach; strictures may develop later. Diagnostic endoscopy may be required.
Treatment of poisoning by corrosives
Treatment is supportive and symptomatic. Gastric emptying and activated charcoal are
contraindicated. Gastric emptying by emesis or lavage on ingestion of a corrosive re-exposes
the upper GIT to the corrosive. The caustic should be diluted as soon as possible after ingestion
Pharmacists Council of Nigeria
133 FPGOP Lecture Note on Applied Pharmacology and Toxicology
by administration of water or milk (about 100 times the volume of ingested caustic). Perforation
is treated with antibiotics and surgery. Do not attempt to neutralize an acid with an alkaline
substance, and vice versa, because heat will be produced that may worsen tissue damage.
For eye contact, the eyes should be washed with a lot of water for 15 minutes. An
ophthalmologist should be consulted for eye examination
Bleaching agents, soaps and detergents
Bleaching agents, soaps and detergents are available in the home. In many homes, they are
accessible to children, and constitute environmental hazards. They should be kept out of the
reach of children.
Bleaching agents
Bleach refers to any chemical product used industrially and domestically to disinfect surfaces,
remove stains and whiten clothes. Household bleaching solutions are usually 3-6% solutions of
sodium hypochlorite in water. Products for industrial use contain higher concentrations and are
as corrosive as sodium hydroxide. Some contain sodium peroxide or sodium perborate.
Bleaching agents are mild irritants and can induce skin, eye or gastrointestinal tract irritation.
Ingetion can cause vomiting, oral burns, damage to the esophagus and stomach, possibly
leading to death. Contact with the skin or eyes, may cause irritation, drying and burns.
Inhalation of bleach fumes can damage the lungs.
Treatment of poisoning by bleaching agents
Treatment is supportive and symptomatic. Milk may be administered to dilute the ingested
bleaching agent. Emesis and gastric lavage are contraindicated. Skin or eye contact should be
treated by irrigation with copious amount of water.
Soaps and detergents
Generally, soaps have low toxicity and can produce mild irritation of the eye, skin and
gastrointestinal tract. Ingestion of a large amount may cause emesis or diarrhea.
Non-ionic detergents have low toxicity, and may not produce any serious harm on ingestion.
Anionic detergents are skin irritants, and may cause cracking and blistering of the skin,
particularly in sensitive persons. Ingestion of anionic detergents may cause irritation of the
pharynx and mouth, abdominal discomfort, diarrhea and vomitiong. Cationic detergents are
more toxic than anionic or non-ionic detergents. Ingestion of cationic detergents may lead to
Pharmacists Council of Nigeria
134 FPGOP Lecture Note on Applied Pharmacology and Toxicology
nausea, vomiting, irritation, corrosion of the oesophagus and mucus membranes, hypotension,
convulsion, coma and death.
Treatment of poisoning by soaps and detergents
Milk may be administered to dilute the ingested soap or detergent. Skin or eye contact should
be treated by irrigation with copious amount of water. Supportive care and symptomatic
treatment should be given.
C7. HEAVY METALS AND THEIR ANTAGONISTS
(i). Heavy Metals
(a). Basic mechanism of toxicity
Heavy metals exert their toxic effects by combining with one or more reactive groups (ligands)
essential for normal physiological functions. Heavy metals, particularly those in the transition
series, may react in the body with ligands containing oxygen (=OH, - COOH, -OPO3H-, >C=O),
sulfur (-SH, -S-S-), and nitrogen (-NH2, >NH). The resultant metal-ligand complex (coordination
compound) affect cellular components, thus interfering with cellular metabolism and function.
Heavy metal antagonists are designed specifically to compete with the ligands for the metals;
and thus prevent or reverse the toxic effects, and enhance the excretion of the heavy metals.
(b). Poisoning by some heavy metals
Lead
Lead exists (i) in its metallic form (ii) as divalent or (iii) tetravalent cation. Divalent lead is the
primary environmental form. Inorganic tetravalent lead compounds do not occur naturally;
however, organo-lead complexes primarily occur with tetravalent lead e.g. tetraethyl lead.
Sources of exposure
Notwithstanding the bans and elimination of the use of lead pipes for water, lead carbonate and
lead oxide in paint, and tetraethyl lead in petrol, their erstwhile use remains the primary
sources of lead exposure. Lead is not degradable and remains throughout the environment in
dust, soil, and the paint of older homes. Young children often are exposed to lead by nibbling
sweet-tasting paint chips or eating dust and soil in and around older homes. Renovation or
demolition of older buildings may cause substantial lead exposure. Lead was commonly used in
plumbing and can leach into drinking water. Acidic foods and beverages dissolve lead when
Pharmacists Council of Nigeria
135 FPGOP Lecture Note on Applied Pharmacology and Toxicology
stored in containers with lead in their glaze or lead-soldered cans. Other sources of exposure to
lead include lead toys, calabash chalk (‘nzu’ in Igbo dialect) eaten by Nigerians, cosmetics,
retained bullets, artists’ paint pigments, ashes and fumes from painted wood, jewelers’ wastes,
and home battery manufacture.
Occupational exposure generally is through inhalation of lead containing dust and lead fumes.
Workers in lead smelters and in storage battery factories are at a great risk of exposure to lead
because fumes are generated and dust containing lead oxide is deposited in their environment.
Other workers at risk of exposure to lead are those associated with steel welding or cutting,
construction, rubber and plastic industries, printing, firing ranges, radiator repair shops, and any
industry where lead is flame soldered. Occupational exposure to lead also has decreased
markedly because of protective regulations.
Toxicodynamics
Mechanism of Toxicity
Lead toxicity results from molecular mimicry of other divalent metals. Lead takes the place of
zinc or calcium in some important proteins. Because of its size and electron affinity, lead alters
protein structure and can inappropriately activate or inhibit protein function.
Toxicokinetics
Exposure to lead occurs through ingestion or inhalation. Gastrointestinal absorption of lead
varies considerably with age and diet. Children absorb a much higher percentage of ingested
lead (about 40% on average) than adults (<20%). Absorption of ingested lead is increased by
fasting, dietary calcium or iron deficiencies. The absorption of inhaled lead generally is much
more efficient (about 90%), particularly with smaller particles. Tetraethyl lead is readily
absorbed through the skin, but this is not a route of exposure for inorganic lead.
About 99% of lead in the bloodstream binds to hemoglobin. Lead initially distributes in the soft
tissues, particularly in the tubular epithelium of the kidney and the liver. Over time, lead is
redistributed and deposited in bone, teeth, and hair. About 95% of the adult body burden of
lead is found in bone. Growing bones will accumulate higher levels of lead and can form lead
lines visible by radiography. Bone lead is very slowly reabsorbed into the bloodstream, except
when calcium levels are depleted, such as during pregnancy. Small quantities of lead
accumulate in the brain, mostly in gray matter and the basal ganglia. Lead readily crosses the
placenta.
Pharmacists Council of Nigeria
136 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Lead is excreted primarily in the urine, although there is some biliary excretion. The
concentration of lead in urine is directly proportional to its concentration in plasma, but because
most lead is in erythrocytes, only a small quantity of total lead is removed by glomerular
filtration. Lead is excreted in milk and sweat and deposited in hair and nails. The serum t1/2 of
lead is 1-2 months, with a steady state achieved in about 6 months. Lead accumulates in bone,
where its t1/2 is estimated to be 20-30 years.
Effects on body /biological systems and body functions
Nervous system: Lead is neurotoxic. The developing nervous system is very sensitive to the
toxic effects of lead, leading to cognitive delays and behavior changes in children. Lead
interferes with the pruning of synapses, neuronal migration, and the interactions between
neurons and glial cells. Together, these alterations in brain development result in decreased IQ,
poor performance on examinations, and behavioral problems such as distractibility. Children
with very high lead levels (>70 μg/dL) are at risk for encephalopathy. Symptoms of lead-
induced encephalopathy include lethargy, vomiting, irritability, anorexia, and vertigo, which can
progress to ataxia, delirium, and eventually coma and death. Most survivors of lead-induced
encephalopathy develop long-term sequelae such as seizures and severe cognitive deficits.
Adults also develop lead-induced encephalopathy (at blood lead levels >100 μg/dL), although
they are less sensitive than children. Workers chronically exposed to lead may develop lead
palsy, characterized by neuromuscular deficits with symptoms including wrist drop and foot
drop; these symptoms were commonly associated with painters and other workers exposed to
lead; currently these are very rare. Lead induces degeneration of motor neurons, usually
without affecting sensory neurons. Studies in older adults have shown associations between
lead exposure and decreased performance on cognitive function tests, suggesting that lead
accelerates neurodegeneration due to aging.
Cardiovascular system: Lead exposure causes elevated blood pressure, and an increased risk
of death due to cardiovascular and cerebrovascular disease.
Renal: Lead poisoning results in lead nephropathy. Low level lead exposure (blood levels <10
μg/dL) depresses glomerular filtration. Higher levels (>30 μg/dL) cause proteinuria and
impaired transport, while very high levels (>50 μg/dL) cause permanent morphological damage,
Pharmacists Council of Nigeria
137 FPGOP Lecture Note on Applied Pharmacology and Toxicology
including proximal tubular nephropathy and glomerulosclerosis. Impaired glomerular filtration
and elevated blood pressure are closely interrelated and may likely affect one another.
Hematological effects: Chronic lead intoxication is associated with hypochromic microcytic
anemia, which is observed more frequently in children and is morphologically similar to iron-
deficient anemia.
Gastrointestinal system: Lead affects the gastrointestinal smooth muscles, initially causing a
persistent metallic taste, mild anorexia, muscle discomfort, malaise, headache, and usually
constipation. Occasionally, diarrhea replaces constipation. As intoxication advances, symptoms
worsen and include intestinal spasms that cause severe intestinal pain (lead colic). Intravenous
calcium gluconate can relieve this pain.
Carcinogenesis: Epidemiological studies have shown associations between lead exposure and
cancers of the lung, brain, kidney, and stomach. Lead is classified as probably carcinogenic to
humans.
Treatment of lead poisoning
Management of lead poisoning involves supportive measures and symptomatic treatment.
(1). Prevention of further exposure
(2). Supportive measures and symptomatic treatment. Seizures are treated with diazepam; fluid
and electrolyte balances are maintained; cerebral edema is treated with mannitol and
dexamethasone.
(3). Chelation therapy with CaNa2EDTA, dimercaprol, D-penicillamine or succimer. The blood
lead concentration should be determined, or a blood sample for analysis obtained, prior to
initiation of chelation therapy.
Mercury
There are three forms of mercury of concern to human health:
(i). Metallic, or elemental, mercury (Hg0) is the liquid metal found in thermometers and dental
amalgam; it is volatile, and exposure is often to the vapor form.
(ii). Inorganic mercury can be either monovalent (mercurous, Hg+) or divalent (mercuric, Hg2+)
and forms a variety of salts.
(iii). Organic mercury compounds consist of divalent mercury complexed with one or two alkyl
groups, e.g. methyl mercury, ethyl mercury. Methyl mercury (MeHg+) is of toxicological
Pharmacists Council of Nigeria
138 FPGOP Lecture Note on Applied Pharmacology and Toxicology
importance, and is formed in the environment by interaction between inorganic mercury and
aquatic microorganisms.
Sources of exposure
Inorganic mercury cations and metallic mercury are found in the Earth’s crust, and mercury
vapor is released naturally into the environment through volcanic activity and off-gassing from
soils. Mercury also enters the atmosphere through human activities such as combustion of fossil
fuels. Once in the air, metallic mercury is photooxidized to inorganic mercury, which is
deposited in aquatic environments during rain. Aquatic microorganisms then conjugate
inorganic mercury to form methyl mercury. Methyl mercury concentrates in lipids and
bioaccumulates up the food chain so that concentrations in aquatic organisms at the top of the
food chain, such as swordfish or sharks, are quite high.
The primary source of exposure to metallic mercury in the general population is vaporization of
mercury in dental amalgam, which often contains >50% Hg0 mixed with silver and other
metals; chewing enhances release of mercury. There is also limited exposure through broken
thermometers and other mercury-containing devices. Human exposure to organic mercury
primarily is through the consumption of fish. Other foods contain lower levels of inorganic
mercury.
Workers are exposed to metallic and inorganic mercury, most commonly though exposure to
vapors. The highest risk for exposure is in the chloralkali industry and other chemical processes
in which mercury is used as a catalyst. Mercury is a component of many devices, including
alkaline batteries, fluorescent bulbs, thermometers, and scientific equipment, and exposure
occurs during the production of these devices. Dentists also are exposed to mercury from
amalgam. Mercury can be used to extract gold during mining, which results in substantial
occupational exposure, because the last step involves vaporization of the mercury. This process
is still commonly used in developing countries. Mercuric salts are used as pigments in paints.
Mercury salts were once found in a number of medications, including antiseptics, antidiuretics,
skin-lightening creams, and laxatives; these have been replaced by safer and more effective
agents. Thimerosal is an antimicrobial agent once widely used as a preservative in vaccines.
Toxicodynamics
Mechanism of Toxicity
Pharmacists Council of Nigeria
139 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Both Hg2+ and MeHg+ readily form covalent bonds with sulfur, which causes most of the
biological effects of mercury. At very low concentrations, mercury reacts with sulfhydryl
residues on proteins thereby disrupting their functions.
Toxicokinetics
Shortly after exposure, some Hg0 vapour is eliminated in exhaled air, and some are readily
absorbed through the lungs (70-80%); gastrointestinal absorption of metallic mercury (Hg0) is
negligible. Once absorbed, Hg0 distributes throughout the body and crosses the blood-brain
barrier, placenta and other body membranes via diffusion. Hg0 is oxidized by catalase in the
erythrocytes and other cells to form Hg2+. After a few hours, distribution and elimination of Hg0
resemble that of Hg2+.
Hg2+ is primarily excreted in the urine and feces; a small amount is reduced to Hg0 and exhaled.
With acute exposure, the fecal pathway predominates, but following chronic exposure, urinary
excretion is dominant. All forms of mercury also are excreted in sweat and breast milk, and
deposited in hair and nails. The t1/2 of inorganic mercury is approximately 1-2 months.
Orally ingested MeHg+ is almost completely absorbed from the gastrointestinal tract. MeHg+
readily crosses the blood-brain barrier and the placenta and distributes evenly to the tissues,
with highest concentration in the kidneys. MeHg+ can be demethylated to form inorganic Hg2+.
The liver and kidney exhibit the highest rates of demethylation, but this also occurs in the brain.
MeHg+ is excreted in the urine and feces, with the fecal pathway dominating. The t1/2 of MeHg+
is about 2 months.
Toxic Effects
Effects on body systems and functions
Metallic mercury: Inhalation of high levels of mercury vapor over a short duration is acutely
toxic to the lung, with symptoms such as cough, tightness in the chest, interstitial pneumonitis
and severely compromised respiratory function. Other initial symptoms include weakness, chills,
metallic taste, nausea, vomiting, diarrhea, and dyspnea. Acute exposure to high doses of
mercury is also toxic to the central nervous system, with symptoms similar to those of chronic
exposure. These symptoms include tremors (particularly of the hands), irritability, shyness, loss
of confidence, nervousness, insomnia, memory loss, muscular atrophy, weakness, paresthesia,
and cognitive deficits. These symptoms intensify and become irreversible, as duration and
concentration of exposure increase.
Pharmacists Council of Nigeria
140 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Other common symptoms of chronic mercury exposure include tachycardia, labile pulse, severe
salivation, and gingivitis. Prolonged exposure to mercury also causes kidney damage.
Inorganic salts of mercury: Precipitation of mucous membrane proteins by mercuric salts
results in intense irritation of the GIT mucosa and an ashen-gray appearance of the mucosa of
the mouth, pharynx, and intestine; this also causes intense pain, which may be accompanied by
vomiting and diarrhea. The local corrosive effect of ionic inorganic mercury on the
gastrointestinal mucosa results in severe hematochezia with evidence of mucosal sloughing in
the stool.
Both acute and chronic poisoning with inorganic mercury produces renal toxicity resulting in
tubular necrosis, decreased urine output and often renal failure.
Organic mercury. The CNS is the primary target of methyl mercury toxicity, with symptoms
such as visual disturbances, ataxia, paresthesia, fatigue, hearing loss, dysarthria, cognitive
deficits, muscle tremor, movement disorders; and following severe exposure, paralysis and
death. The developing nervous system exhibits increased sensitivity to methyl mercury. Children
exposed in utero can develop severe symptoms, including mental retardation and
neuromuscular deficits, even in the absence of symptoms in the mother.
Treatment of mercury poisoning
With exposure to metallic mercury, termination of exposure is critical and respiratory support
may be required. Emesis maybe used within 30-60 minutes of exposure to inorganic mercury,
provided the patient is awake and alert and there is no corrosive injury. Maintenance of
electrolyte balance and fluids is important for patients exposed to inorganic mercury. Chelation
therapy is beneficial in patients with acute inorganic or metallic mercury exposure.Chelation
therapy with dimercaprol for high-level exposures or symptomatic patients; penicillamine for
low-level exposures or asymptomatic patients is routinely used to treat poisoning with either
inorganic or elemental mercury. Succimer is also beneficial.
There are limited treatment options for methyl mercury poisoning. Chelation therapy does not
provide clinical benefits, and several chelators potentiate the toxic effects of methyl mercury.
Non-absorbed thiol resins may be beneficial by preventing reabsorption of methyl mercury from
the gastrointestinal tract.
Arsenic
Pharmacists Council of Nigeria
141 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Arsenic is a metalloid that is common in rocks and soil. Arsenic compounds have been used for
over 2400 years as both therapeutic agents and poisons. The organic arsenic compound
arsphenamine was once used for the treatment of syphilis and trypanosomiasis. The use of
arsenic in drugs has been mostly phased out, but arsenic trioxide (ATO) is still used as an
effective chemotherapy agent for acute promyelocytic leukemia.
Arsenic exists in its elemental form, trivalent (arsenites/arsenious acid) and pentavalent
(arsenates/arsenic acid) states. Arsine is a gaseous hydride of trivalent arsenic that exhibits
toxicities that are distinct from other forms. Organic compounds containing either valence state
of arsenic are formed in animals. The toxicity of a given arsenical is related to the rate of its
clearance from the body and its ability to concentrate in tissues. In general, toxicity increases in
the sequence: organic arsenicals < As5+ < As3+ < arsine gas (AsH3).
Sources of exposure
The primary source of exposure to arsenic is through drinking water. Arsenic naturally leaches
out of soil and rocks into well and spring water. Arsenic also can enter the environment through
the use of arsenic-containing pesticides, mining, and burning of coal. Food, particularly seafood,
often is contaminated with arsenic.
The major source of occupational exposure to arsenic is in the production and use of organic
arsenicals as herbicides and insecticides. Exposure to metallic arsenic, arsine, arsenic trioxide,
and gallium arsenide also occurs in high technology industries, such as the manufacture of
computer chips and semiconductors.
Toxicodynamics
Mechanism of Toxicity
Like mercury, trivalent arsenic compounds form covalent bonds with sulfhydryl groups. The
pyruvate dehydrogenase system is particularly sensitive to inhibition by trivalent arsenicals
because the two sulfhydryl groups of lipoic acid react with arsenic to form a six-membered ring.
Inorganic arsenate (pentavalent) inhibits the electron transport chain. Arsenate appears to
competitively substitute for phosphate during the formation of adenosine triphosphate, forming
an unstable arsenate ester that is rapidly hydrolyzed.
Toxicokinetics
The absorption of arsenic compounds is directly related to their solubility. Poorly water-soluble
forms such as arsenic sulfide, lead arsenate, and arsenic trioxide are not well absorbed. Water-
Pharmacists Council of Nigeria
142 FPGOP Lecture Note on Applied Pharmacology and Toxicology
soluble arsenic compounds are readily absorbed afer both inhalation and ingestion.
Gastrointestinal absorption of arsenic dissolved in drinking water is >90%.
At low doses, arsenic is evenly distributed throughout the tissues of the body, with high
concentrations in nails and hair due to their high sulfhydryl content. After an acute high dose of
arsenic (i.e., fatal poisoning), arsenic is preferentially deposited in the liver and, to a lesser
extent, kidney, with elevated levels also observed in the muscle, heart, spleen, pancreas, lungs,
and cerebellum. Arsenic readily crosses the placenta and blood-brain barrier. Arsenic undergoes
biotransformation in humans to monomethylarsenic compounds.
Elimination of arsenicals by humans primarily is in the urine, although some are also excreted in
feces, sweat, hair, nails, skin, and exhaled air.
Effects on body systems and functions
Though humans are the most sensitive species to the toxic effects of inorganic arsenic, they are
exposed to large amounts organic arsenic compounds in fish, which are relatively nontoxic.
Inorganic arsenic exhibits a broad range of toxicities, although some body systems are much
more sensitive than others. With the exception of arsine gas, the various forms of inorganic
arsenic exhibit similar toxic effects.
Acute exposure to large doses of arsenic (>70 - 180 mg) often is fatal. Death immediately
following arsenic poisoning typically is the result of its effects on the heart and GIT. Death
sometimes occurs later as a result of arsenic’s combined effect on multiple organs.
Cardiovascular system: Acute and chronic arsenic exposure cause myocardial depolarization,
cardiac arrhythmias, and ischemic heart disease; these are also known adverse effects of
arsenic trioxide in the treatment of leukemia. Chronic exposure to arsenic causes peripheral
vascular diseases, e.g. ‘blackfoot disease,’ a condition characterized by cyanosis of the
extremities, particularly the feet, progressing to gangrene.
Skin: The skin is very sensitive to chronic arsenic exposure. Dermal symptoms often are
diagnostic of arsenic exposure. Arsenic induces hyperkeratinization of the skin (including
formation of multiple corns or warts), particularly of the palms of the hands and the soles of the
feet. It also causes areas of hyperpigmentation interspersed with spots of hypopigmentation.
Hyperpigmentation can be observed after 6 months of exposure, while hyperkeratinization takes
years. Children are more likely to develop these effects than adults.
Pharmacists Council of Nigeria
143 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Gastrointestinal tract: Acute or subacute exposure to high-dose arsenic by ingestion is
associated with GIT symptoms ranging from mild cramps, diarrhea, and vomiting to
hemorrhage and death; these symptoms are caused by increased capillary permeability, leading
to fluid loss. At higher doses, fluid forms vesicles that can burst, leading to inflammation and
necrosis of the submucosa and then rupture of the intestinal wall.
Nervous System: The most common neurological effect of acute or subacute arsenic
exposure is peripheral neuropathy involving both sensory and motor neuron, characterized by
the loss of sensation in the hands and feet, followed by muscle weakness. Neuropathy occurs
several days after exposure to arsenic and can be reversible following cessation of exposure,
although recovery usually is not complete. Acute high-dose arsenic causes encephalopathy in
rare cases, with symptoms such as headache, lethargy, mental confusion, hallucination,
seizures, and coma.
Other body systems: Acute and chronic arsenic exposures induce anemia and leukopenia.
Arsenic also may inhibit heme synthesis. In the liver, arsenic causes fatty infiltrations, central
necrosis, and cirrhosis of varying severity. The action of arsenic on renal capillaries, tubules,
and glomeruli can cause severe kidney damage. Inhaled arsenic is irritating to the lungs, and
ingested arsenic may induce bronchitis progressing to bronchopneumonia in some individuals.
Chronic exposure to arsenic is associated with an increased risk of diabetes.
Carcinogenesis: Arsenic compounds were among the first recognized human carcinogens,
arsenic is classified as a carcinogenic to humans. Exposure to arsenic has been associated with
cancer of the skin, bladder, lung, liver, kidney, and prostate.
Arsine Gas. Arsine gas, formed by electrolytic or metallic reduction of arsenic, is a rare cause
of industrial poisoning. Arsine induces rapid and often fatal hemolysis, headache, anorexia,
vomiting, paresthesia, abdominal pain, chills, hemoglobinuria, bilirubinemia, anuria, jaundice,
and renal toxicities that can progress to kidney failure and death.
Treatment of arsenic poisoning
Following acute exposure to arsenic,
(1). The patient should be stabilized and further absorption of the poison prevented.
(2). Close monitoring of fluid levels is important because arsenic can cause fatal hypovolemic
shock. Hypotension may necessitate fluid replacement and use of pressor agents (e.g.
dopamine).
Pharmacists Council of Nigeria
144 FPGOP Lecture Note on Applied Pharmacology and Toxicology
(3). Chelation therapy is effective following short-term exposure to arsenic but has very little or
no benefit in chronically exposed individuals. Chelators used in arsenic poisoning include
dimercaprol, penicillamine, and succimer
(4).Exchange transfusion to restore blood cells and remove arsenic often is necessary following
arsine gas exposure.
(ii). Heavy Metal Antagonists
Treatment of acute heavy metal intoxications often involves the use of heavy metal antagonists
or chelators. A chelator is a compound that forms stable complexes with metals, typically as
five- or six-membered rings. Formation of complexes between chelators and metals should
prevent or reverse metal binding to biological ligands.
(a).Properties of an ideal chelating agent
The ideal chelator should have the following properties:
(i). High solubility in water.
(ii). Resistance to biotransformation.
(iii). Ability to reach sites of metal storage.
(iv). Ability to form stable and non-toxic complexes with toxic metals.
(v). Ready excretion of the metal-chelator complex.
(vi). A low affinity for the essential metals – such as calcium and zinc – is also desirable,
because toxic metals often act through competition with these metals for protein binding.
(b). Chelating agents
Dimercaprol
Dimercaprol (British anti-lewisite; BAL) was developed during World War II as a therapeutic
antidote against poisoning by the arsenic-containing warfare agent lewisite.
Dimercaprol is an oily, colourless liquid with pungent, disagreeable odour. Because aqueous
solutions of dimercaprol are unstable and oxidize readily, it is dispensed in 10% solution in
peanut oil and must be administered by intramuscular injection, which is often painful.
Mechanism of Action
Pharmacists Council of Nigeria
145 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Dimercaprol acts through the formation of chelation complexes between its sulfhydryl groups (-
SH) and metals. Dimercaprol is more effective when given soon after exposure to the metal,
because it more effectively prevents inhibition of sulfhydryl enzyme than in reactivating them.
Pharmacokinetics
Dimercaprol cannot be administered orally; it is given by deep intramuscular injection as a 100
mg/ml solution in peanut oil and should not be used in patients who are allergic to peanuts or
peanut products. Peak concentrations in blood are attained in 30-60 minutes. The t1/2 is short,
and metabolic degradation and excretion are complete within 4 hours. Dimercaprol and its
chelates are excreted in both urine and bile.
Adverse Effects
Adverse effects of dimercaprol include hypertension; tachycardia; nausea and vomiting;
headache; a burning sensation in the lips, mouth and throat, and a feeling of constriction,
sometimes pain in the throat, chest or hands; conjunctivitis; lacrimation; salivation; fever
(particularly in children); pain at the injection site; thrombocytopenia and increased
prothrombin time (these may limit intramuscular injection because of the risk of hematoma
formation at the injection site).
Ethylenediaminetetracetic acid (EDTA) and its derivatives
Ethylenediaminetetracetic acid and its various salts are effective chelators of divalent and
trivalent metals. However, not all salts are used therapeutically, for example rapid intravenous
administration of Na2EDTA causes hypocalcemic tetany. In contrast, CaNa2EDTA can be
administered intravenously with negligible change in the concentration of Ca2+ in plasma and
total body. Therefore, to prevent potentially life-threatening depletion of calcium, the calcium
disodium salt is used.
Calcium disodium EDTA (CaNa2EDTA) is the preferred EDTA salt for metal poisoning, provided
that the metal has a higher affinity for EDTA than calcium. CaNa2EDTA is effective for the
treatment of acute lead poisoning, particularly in combination with dimercaprol, but is not an
effective chelator of mercury or arsenic in vivo.
Mechanism of Action
The pharmacological effects of CaNa2EDTA result from chelation of divalent and trivalent metals
in the body. Accessible metal ions (both exogenous and endogenous) with a higher affinity for
Pharmacists Council of Nigeria
146 FPGOP Lecture Note on Applied Pharmacology and Toxicology
CaNa2EDTA than Ca2+ are chelated, mobilized, and usually excreted. CaNa2EDTA mobilizes
several endogenous metallic cations, including those of zinc, manganese, and iron. Additional
supplementation with zinc following chelation therapy may be beneficial. Since it is charged at
physiological pH, EDTA does not significantly penetrate cell membranes and therefore chelates
extracellular metal ions much more effectively than intracellular ions.
Pharmacokinetics
Less than 5% of CaNa2EDTA is absorbed from the GIT, hence it is not used orally. After
intravenous administration, CaNa2EDTA has a t1/2 of 20-60 minutes. In blood, CaNa2EDTA is
found only in the plasma. It is distributed mainly in the extracellular fluids; very little enters the
spinal fluid (5% of the plasma concentration). There is very little metabolic degradation of
EDTA. CaNa2EDTA is excreted in the urine by glomerular filtration, so adequate renal function is
necessary for successful therapy. Altering either the pH or the rate of urine flow has no effect
on the rate of excretion.
Adverse Effects
The principal toxic effect of CaNa2EDTA is renal toxicity. Other adverse effects include malaise,
fatigue and excessive thirst, followed by the sudden appearance of chills and fever and
subsequent myalgia; frontal headache; anorexia; occasional nausea and vomiting; and rarely,
increased urinary frequency and urgency. Sneezing, nasal congestion and lacrimation;
glycosuria; anemia; dermatitis with lesions strikingly similar to those of vitamin B6 deficiency;
transient lowering of systolic and diastolic blood pressures; prolonged prothrombin time; and T-
wave inversion on the electrocardiogram, may also occur.
Penicillamine
Penicillamine is a white crystalline, water-soluble derivative of penicillin. D-Penicillamine is less
toxic than the L-isomer, and consequently is the preferred therapeutic form. Penicillamine is an
effective chelator of copper, mercury, zinc and lead, and promotes the excretion of these
metals in the urine.
Penicillamine is more toxic and is less potent and selective for chelation of heavy metals relative
to other available chelators. It is therefore not a first-line treatment for acute intoxication with
lead, mercury, or arsenic. However, because it is inexpensive and orally bioavailable, it is often
given at fairly low doses following treatment with CaNa2EDTA and/or dimercaprol to ensure that
Pharmacists Council of Nigeria
147 FPGOP Lecture Note on Applied Pharmacology and Toxicology
the concentration of metal in the blood stays low following the patient’s release from the
hospital.
Mechanism of Action
Penicillamine binds to some heavy metals; the penicillamine-metal complex is then eliminated
from the body.
Pharmacokinetics
Penicillamine is available for oral administration. It should be given on an empty stomach to
avoid interference by metals in food. Penicillamine is well absorbed (40-70%) from the GIT.
Food, antacids, and iron reduce its absorption. Peak concentrations in blood are obtained
between 1 and 3 hours after administration. Penicillamine is primarily degraded by hepatic
biotransformation, and very little drug is excreted unchanged. Metabolites are found in both
urine and feces.
Adverse Effects
Most common adverse effect of penicillamine is hypersensitivity reactions including rash,
pruritus, and drug fever. Penicillamine should be used with extreme caution, if at all, in patients
with a history of penicillin allergy. Other adverse effects include renal toxicity with proteinuria
and haematuria; haematological reactions with leukopenia, aplastic anaemia, pancytopenia and
agranulocytosis. Toxicity to the pulmonary system is uncommon, but severe dyspnea has been
reported from penicillamine-induced bronchoalveolitis. Less serious side effects include nausea,
vomiting, diarrhea, dyspepsia, anorexia, and a transient loss of taste for sweet and salt, which
is relieved by supplementation of the diet with copper.
With long-term use, penicillamine induces several cutaneous lesions, including urticaria, macular
or papular reactions, pemphigoid lesions, lupus erythematosus, dermatomyositis, adverse
effects on collagen; and other less serious reactions, such as dryness and scaling. Cross-
reactivity with penicillin may be responsible for some episodes of urticarial or maculopapular
reactions with generalized edema, pruritus, and fever that occur in as many as one-third of
patients taking penicillamine.
Contraindications to penicillamine therapy include pregnancy, renal insufficiency, or a previous
history of penicillamine-induced agranulocytosis or aplastic anemia.
Succimer
Pharmacists Council of Nigeria
148 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Succimer (2,3-dimercaptosuccinic acid; DMSA) is an orally effective chelator that is chemically
similar to dimercaprol but contains two carboxylic acids that modify the spectrum of absorption,
distribution, and chelation of the drug. It has an improved toxicity profile over dimercaprol.
Succimer has several desirable features over other chelators. It is orally bioavailable, and
because of its hydrophilic nature, does not mobilize metals to the brain or enter cells. It also
does not significantly chelate essential metals such as zinc, copper, or iron. As a result of these
properties, succimer exhibits a much better toxicity profile relative to other chelators. Succimer
is a chelator of lead, arsenic, cadmium, mercury, and other toxic metals.
Mechanisms of Action
Succimer binds to some heavy metals, leading to the elimination of the metal from the body.
Adverse Effects
Succimer is much less toxic than dimercaprol. Adverse effects include nausea, vomiting,
diarrhea, loss of appetite, rashes and transient elevations in hepatic transaminases.
Deferoxamine mesylate
Deferoxamine is isolated as the iron chelate from Streptomyces pilosus; and it undergoes
chemical modification to obtain the metal-free ligand.
Deferoxamine has some desirable properties such as, a remarkably high affinity for ferric iron, a
very low affinity for calcium, and it does not remove iron from hemoglobin or cytochromes.
Mechanism of Action
Deferoxamine binds with high affinity to iron, thereby enhancing its elimination from the body.
Pharmacokinetics
Deferoxamine is poorly absorbed after oral administration, and may increase iron absorption
when given by this route. Hence, parenteral administration is preferred. In severe iron toxicity
(serum iron levels >500 μg/dL), the intravenous route is preferred. Deferoxamine is
metabolized, but the pathways are unknown. The iron- chelator complex is excreted in the
urine, often turning the urine an orange-red color.
Adverse Effects
Deferoxamine causes a number of allergic reactions, including pruritus, wheals, rash, and
anaphylaxis. Other adverse effects include dysuria, abdominal discomfort, diarrhea, fever, leg
cramps, tachycardia, and cataract formation. Pulmonary complications (e.g., acute respiratory
Pharmacists Council of Nigeria
149 FPGOP Lecture Note on Applied Pharmacology and Toxicology
distress syndrome; tachypnea, hypoxemia, fever, and eosinophilia are prominent symptoms)
have been reported in some patients undergoing deferoxamine infusions lasting longer than 24
hours; and neurotoxicity and increased susceptibility to certain infections (e.g., with Yersinia
enterocolitica) have been reported after long-term therapy of iron overload conditions (e.g.,
thalassemia major).
Deferoxamine is contraindicated in renal insufficiency and anuria. It should be used during
pregnancy only if clearly indicated.
Deferasirox
Deferasirox is an orally administered chelator of iron, with a high affinity for iron and low
affinity for other metals, e.g., zinc and copper. It is well absorbed on oral administration. It
binds iron in the circulation, and the complex is excreted in bile.
Adverse Effects
Long-term daily use of deferasirox is generally well tolerated, most common adverse effects
include mild to moderate gastrointestinal disturbances and skin rash.
Trientine
Trientine (triethylenetetramine dihydrochloride) is an orally effective acceptable alternative to
penicillamine in Wilson’s disease. Although it may be less potent than penicillamine, it could be
used in patients that may not tolerate the undesirable effects/toxicities of penicillamine.
Trientine may cause iron deficiency; this can be overcome with short courses of iron therapy,
but iron and trientine should not be ingested within 2 hours of each other.
Unithiol
Unithiol (Sodium 2,3-Dimercaptopropane Sulfonate; DMPS), a dimercapto chelating agent, is a
water-soluble analog of dimercaprol. Unithiol is a clinically effective chelator of lead, arsenic,
and especially mercury. It is negatively charged and exhibits distribution properties similar to
those of succimer. It is less toxic than dimercaprol, but mobilizes zinc and copper and thus is
more toxic than succimer.
Unithiol can be administered orally and intravenously. Bioavailability by the oral route is
approximately 50%, with peak blood levels occurring in approximately 3.7 hours. It is rapidly
Pharmacists Council of Nigeria
150 FPGOP Lecture Note on Applied Pharmacology and Toxicology
excreted, primarily through the kidneys. Over 80% of an intravenous dose is excreted in the
urine, mainly as cyclic DMPS sulfides. Unithiol increases the excretion of mercury, arsenic, and
lead in humans.
Bibliography and Further Reading
Agency for Toxic Substances and Disease Registry (ATSDR) (1999). Toxicological Profile for
Mercury. ATSDR, Atlanta.
Agency for Toxic Substances and Disease Registry (ATSDR) (2007a). Toxicological Profile for
Arsenic. ATSDR, Atlanta.
Agency for Toxic Substances and Disease Registry (ATSDR) (2007b). Toxicological Profile for
Lead. ATSDR, Atlanta.
American Academy of Clinical Toxicology, and the European Association of Poisons Centres and
Clinical Toxicologists (1999). Position statement and practice guidelines on the use of multidose
activated charcoal in the treatment of acute poisoning. Clinical Toxicolology, 37:731–751.
American Academy of Clinical Toxicology, and the European Association of Poisons Centres and
Clinical Toxicologists (2004). Position paper: Gastric lavage. Journal of Toxicology CLINICAL
TOXICOLOGY, 42:933–943.
American Academy of Clinical Toxicology, and the European Association of Poisons Centres and
Clinical Toxicologists (2005). Position paper: Single-dose activated charcoal. Clinical Toxicology,
43:61–87.
American Academy of Pediatrics Committee on Injury, Violence, and Poison Prevention (2003). Poison treatment in the home. Pediatrics, 112:1182–1185. Andersen O, Aaseth J (2002). Molecular mechanisms of in vivo metal chelation: Implications for clinical treatment of metal intoxications. Environmental Health Perspectives, 110 (suppl): 887–890. Clarkson TW, Magos L (2006). The toxicology of mercury and its chemical compounds. Critical Reviews in Toxicology, 36:609-662. Kao JW, Nanagas KA (2004). Carbon monoxide poisoning. Emergency Medicine Clinics of North
America, 22:985-1018.
Klaassen CD (2007). Casarett and Doull’s Toxicology, 7th ed. McGraw-Hill.
Kosnett MJ, Wedeen RP, Rothenberg SJ, Hipkins KL, Materna BL, Schwartz BS, Hu H, Woolf A
(2007). Recommendations for medical management of adult lead exposure. Environmental
Health Perspectives, 115:463-471.
Pharmacists Council of Nigeria
151 FPGOP Lecture Note on Applied Pharmacology and Toxicology
Kosnett MJ (2010). Chelation for heavy metals (arsenic, lead, and mercury): Protective or
perilous? Clinical Pharmacology & Therapeutics, 88:412-415.
O’Malley GF and O’Malley R (2018). Caustic ingestion. Merck manual.
O’Malley GF and O’Malley R (2018). Hydrocarbon poisoning. Merck manual.
Stockholm Convention (2011). Listing of POPs in the Stockholm Convention: Annex A
(Elimination.)
Warrell DA (2010). Guidelines for the management of snake bite. A publication of World Health
Organization.
Winchester JF (2002). Dialysis and hemoperfusion in poisoning. Advances in Renal Replacement
Therapy, 9:26–30.
World Health Organization (2005). The WHO recommended classification of pesticides by
hazard.