DRUG TOXICITY

• Toxicology is the science that deals with the amount of an agent that causes an adverse action in some living system

•‘All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.’- Paracelus (16th century physician-alchemist)

•‘A poison is any substance or matter which, when applied to the body outwardly, or in any way introduced into it, can destroy life by its own inherent qualities, without acting mechanically, and irrespective of temperature.’

Some definitions

• Another term for poison is toxicant

• Toxin is used to describe ‘biological poisons’

• Toxicosis a disease state that results from exposure to a poison.

What are the sources of toxicants?

Can be defined as, ‘an unwanted or harmful Can be defined as, ‘an unwanted or harmful reaction experienced following administration of a reaction experienced following administration of a drug, or combination of drugs, drug, or combination of drugs, under normal under normal conditions of use conditions of use and is suspected as being related to and is suspected as being related to the drug (or combination)’the drug (or combination)’

Adverse Drug Reactions: ADRsAdverse Drug Reactions: ADRs

Causes considerable morbidity and mortality; treating this is very expensive

Data on incidence is poor considering the scope of the problem

UK Studies suggest:-― 6.5% of Hospital admissions― Associated mortality 0.15%― Cost estimate £466m annually

How much of a problem is poisoning?

• Poisoning accounts for 2-3% of A + E department admissions

• Poisoning 7% of Accidents in Under 5’s

• Severe in children : Iron, Methadone, Tricyclic antidepressants.

• Adults: Paracetamol, Ibuprofen, Aspirin

NPIS annual report 2005/2006

Disposition of Toxic Compounds

Factors influencing toxicity:

1. Absorption• oral• pulmonary • sublingual• injection (I.V., I.P., subcut, I.A.)• topical

3. Metabolism• Mainly liver (some in GI tract, kidneys, lungs)• Phase I – introduce or expose a functional group on the

parent compound – losing pharmacological effect• Phase II – produces polar conjugates – generally

inactive and easily excreted in urine and/or faeces

4. excretion

2. Distribution• binding – plasma proteins, tissue (liver, bone, fat)

All these factors determine the drug/toxin bioavailability

Pharmacokinetics

1. Clearance (Cl)• Ratio relating to the rate of elimination (usually in ml/min)• High values for efficient clearance• Most important index of the capacity of an organ to remove a drug

3. Half life (t1/2)• The time it take for the plasma concentration of drug in

the body to be reduced by 50%• For practical purposes the drug is considered eliminated

after 7 half-lives.

4. Bioavailability (F)• The fraction of the dose that reaches the systemic circulation

2. Volume of Distribution (Vd)• Relates the amount of drug in the body to the

concentration of drug in the plasma• Reflects the extent to which it is present in the extravascular tissue

and not in the plasma

Absorption

rate can be by zero-order kinetics•rate is constant and independent of amount of drug absorbed•e.g continuous intravenous drip

or:

rate can be by first-order kinetics•diminishing and always in proportion to the amount of drug still to be absorbed•most drug absorption follows first-order kinetics

If drug is injected then consider drug is absorbed instantaneously

Clearance:

plasma concentration – time curves

Drug eliminated from a single compartment by a first order processhalf life ~ 4hrs

If sample before 2 hrs, reveals drug elimination is a multiexponential process

The dose-response curve

• Most Basic and fundamental concept• Dose (mg/Kg)• Either Quantal ‘All or None’ or Graded response• Assume

– 1) response proportional to concentration at target site

– 2) concentration at target related to dose – 3) response is causally related to compound

administered.• Shape depends on toxic effect and mechanism

Dosage (mg/kg)

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MEDMTD

ED50- dose which will be therapeutically effective in 50% of animals (median effective dose)LD50- dose which will, on average, kill 50% of animals in a population

MED- minimum effective dose (the least dose that is likely to be effective).Also called toxic dose-low(TDL)

MTD- maximum tolerated dose (or minimum toxic dose) (more than this will produce signs of toxicity).Also called highest nontoxic dose (HNTD)

Other terms:

Therapeutic Index (TI) = LD50

ED50 - indicates relative safety of drug

Therapeutically: MTD MED - For: barbiturate anaesthesia – 3-4

benzodiazepines >20ie: represents a therapeutic window

Standard Safety Margin (SSM) = LD1

ED99 – more conservative estimate than TILD1 – dose required to kill 1%ED99 – dose therapeutically effective in 99%

Principle causes of drug toxicity/side effects

a. the predictable

b. the less predictable

c. the unpredictable

a. the predictable

• excessive action at a primary site (overdosage)e.g. anaesthetics, warfarin

• non-selectivity: acting at unrelated sites (more likely with overdosage)

e.g. chlorpromazine

• incomplete selective toxicity: acts against the host as well as the target organism or cell

e.g. protein synthesis inhibitors, antimicrobials, antifungals

• tolerance (dependence & abuse potential)e.g. benzodiazepines, opioids

• unavoidable side-effectse.g. immunosuppression by corticosteroids – opportunistic infections

a. the predictable

Pharmacokinectic Drug interactions:

•absorptione.g. gastric emptying, gut motility

Atropine and metoclopramide

•distributione.g. displacement from plasma proteins

aspirin and warfarin

•metabolisme.g. increased by enzyme induction

barbiturates and steroids

excretione.g. active transport competition

NSAIDS and methotrexate

a. the predictable

•age- most drugs tested on young to middle-aged volunteers-causing problems such as: -drug clearance mechanisms (renal and hepatic) are limited in newborns-clearance is reduced in elderly (increasing half life)

reduction in lean body mass, serum albumin, total body water. increased body fat

declined renal functionreduced hepatic blood flowreduced activities of cytochrome P450 enzymes

•gender-a relative increase of body fat in females-Pregnancy / Breast feeding

b. the less predictable

Genetic factors

e.g. polymorphism in NAT2 in the liver (N-acetyltransferase2).-metabolises about 16 common drugs (phenytoin, hydralazine)

Plasma esterase – suxamethonium (about 1 in 3,000 individuals)

Malignant Hyperthermia – Halothane (1 in 20,000)

• Non-dose related drug reactions– Commonly called ‘idiosyncratic’– Immunological pathogenesis

• Hypersensitivity syndrome• Drug allergy (e.g. Penicillin 1 in 50, 000

patients exposed)

c. the unpredictable

Chemical forms that produce toxicity

The parent drug is often the cause of toxic effects

However, toxic effects may result from metabolites:

For example: paracetamol

Most common cause of death following self-poisoning in UK

Induction of microsomal enzymes

A number of drugs such as ethanol and carbamazepine, increase the activity of microsomal oxidase and conjugating systems when administered repeatedly.For example: phenobarbitone significantly increases phase I microsomal oxidases

Phase I metabolism causes accumulation of toxic metabolites of paracetamol

Target Organs: adverse effect is dependent upon the concentration

of active compound at the target site for enough time

• Not all organs are affected equally– greater susceptibility of the target organ– higher concentration of active compound

• Liver--high blood flow, oxidative reactions• Kidney--high blood flow, concentrates chemicals• Lung--high blood flow, site of exposure• Neurons--oxygen dependent, irreversible

damage• Myocardium--oxygen dependent• Bone marrow, intestinal mucosa--rapidly divide

Toxic Mechanisms

• 3 Basic Mechanisms– Primary

• Occurs at the molecular level– Secondary

• Events resulting from primary events• Damage to macromolecules changes in

structure/function– Tertiary

• Necrosis, Apoptosis, Steatosis

Examples of Toxicants:

Mineral or Inorganic Poisons: • metals, metalloids and non-metalse.g. lead, mercury, arsenic, phosphorus, sulphur

• salts of metals and non-metalse.g. copper sulphate, arsenious oxide, zinc phosphide

• acids and alkalis

Organic Poisons:• pesticidese.g. fungicides, herbicides and insecticides• plantse.g. ergot– fungus grows on wheat/rye, aflatoxins – ground nut meal

oxalic acid– rhubarb,

• drugse.g. Methadone, TCA’s Aspirin.

Mineral or Inorganic Poisons:

• metals, metalloids and non-metals

metal source symptoms

lead

inorganic oil paint, batteries

organic petrol

ataxia, diarrhoea, convulsions

Hair loss, joint swelling, anaemia

barium Insecticides salivation, sweating, muscular cramps, convulsions

Iron Supplement Vomiting, Shock, Abdominal pain, diarrhoea, rectal bleeding, Coma

ataxia, diarrhoea, convulsions

salivation, sweating, muscular cramps, convulsions

Organic Poisons:

plants

source symptomsactive principles

nutscorn

aflatoxins (B1, B2) anaphylactic shock, ataxia, blindness, jaundice

corn with aflatoxin Ergot on wheat

Organic Poisons:

plants

source symptomsactive principles

nuts aflatoxins (B1, B2) anaphylactic shock, ataxia, blindness, jaundice

rhubarb oxalic acid (in leaf) nausea, vomiting, convulsions

solanum familydeadly nightshade

potato

atropinescopolamine (hyoscine)

glycoalkaloids

anaphylactic shock, ataxia, blindness, jaundice

nausea, vomiting, convulsions

Dry mouth, hyperthermiaTachycardia CNS depression/ stimulant

(AChE inhibitors) Salivation, hypothermia, bradycardia, neuromuscular block

Organic Poisons:

drugs

drug use symptom

Methadone Pain relief, Drug addiction

TCA’s(Tricyclic antidepresants)

Depression Anticholinergic

Aspirin (salicylates) neuroleptic Hyperventilation, tinnitus, deafness, vasodilation, sweating

CV effects, CNS effects

Coma, Respiratory depression, pinpoint pupils