pharmaco kinetics
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PHARMACOKINETICS
INTRODUCTION:
The scope of pharmacy practice includes more traditional roles such as compounding and
dispensing medications, and it also includes more modern services related to health care,
including clinical services, reviewing medications for safety and efficacy, and providing drug
information. Pharmacists, therefore, are the experts on drug therapy and are the primary health
professionals who optimize medication use to provide patients with positive health outcomes.
The word pharmacy is derived from its root word pharma which was a term used since the 15th–
17th centuries. In addition to pharma responsibilities, the pharma offered general medical advice
and a range of services that are now performed solely by other specialist practitioners, such as
surgery and midwifery. The pharma (as it was referred to) often operated through a retail shop
which, in addition to ingredients for medicines, sold tobacco and patient medicines. The pharmas
also used many other herbs.
In its investigation of herbal and chemical ingredients, the work of the pharma may be regarded
as a precursor of the modern sciences of chemistry and pharmacology, prior to the formulation of
the scientific method.
An establishment in which pharmacy (in the first sense) is practiced is called a pharmacy,
chemists or drug store.
The etymological roots are: pharmakon (Greek), “drug;” and vigilare (Latin), “to keep awake or
alert, to keep watch.”
TERMINOLOGY:
Pharmacy is the health profession that links the health sciences with the chemical sciences and it
is charged with ensuring the safe and effective use of pharmaceutical drugs. The word derives
from the Greek word (pharmakon), meaning "drug" or "medicine”
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Pharmacogenomics is the branch of pharmacology which deals with the influence of genetic
variation on drug response in patients by correlating gene expression or single-nucleotide
polymorphisms with a drug's efficacy or toxicity.
Pharmacogenomics is the whole genome application of pharmaco genetics, which examines the
single gene interactions with drugs.
Pharmacogenomics is being used all critical illnesses like cancer, cardio vascular disorders, HIV,
tuberculosis, asthma, and diabetes.
Pharmacodynamics is the study of the physiological effects of drugs on the body or on
microorganisms or parasites within or on the body and the mechanisms of drug action and the
relationship between drug concentration and effect.
Pharmacovigilance (abbreviated PV or PhV) is the pharmacological science relating to the
detection, assessment, understanding and prevention of adverse effects, particularly long term
and short term side effects of medicines with a view to:
identifying new information about hazards associated with medicines
preventing harm to patients.
Pharmacognosy is the study of medicines derived from natural sources.
The American Society of Pharmacognosy defines pharmacognosy as "the study of the physical,
chemical, biochemical and biological properties of drugs, drug substances or potential drugs or
drug substances of natural origin as well as the search for new drugs from natural sources.
The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably.
DEFINITION:
Pharmacokinetics, sometimes abbreviated as PK, (derived from Ancient Greek pharmakon
"drug" and kinetikos "to do with motion";) is a branch of pharmacology dedicated to the
determination of the fate of substances administered externally to a living organism.
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Pharmacokinetics is the study of the fate of a pharmaceutical product (drug) when administered
to a living organism. The word is derived from the term "pharmacon", meaning drug or the
science of preparing and dispensing medicines, and "kinetics", meaning motion.
The study of the action of a drug in living cells or organisms can include the rate of absorption,
which organs it migrates to, whether or not it is metabolized or simply excreted/eliminated. This
is the main focus of Phase I clinical trials, which use healthy volunteer test subjects to study the
pharmacokinetics of a new drug. These studies also evaluate the consequences of ingestion,
injection, absorption or other modes of exposure to the drug, since some pharmaceuticals can
interfere with normal metabolic processes, through various modes of action that include inducing
or inhibiting biochemical reactions, competing with enzymes for active sites, or binding to DNA
to initiate or prevent transcription.
Pharmacokinetics is often studied in conjunction with pharmacodynamics. Pharmacokinetics
includes the study of the mechanisms of absorption and distribution of an administered drug, the
rate at which a drug action begins and the duration of the effect, the chemical changes of the
substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites
of the drug.
Pharmacokinetics is the study of what the body does to a drug.
Pharmacodynamics is the study of what a drug does to the body.
PHARMACOKINETIC PROCESS:
All pharmacokinetic process involves transport of the drug across biological membranes. Drugs
are transported across the membranes by:
Passive diffusion and filtration.
Specialized transport.
PASSIVE DIFFUSION:
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The drug diffuses across the membrane in the direction of its concentration gradient, the
membrane playing no active role in the process. Lipid soluble drugs acts through this process.
FILTRATION:
It is passage of drugs through aqueous pores in the membrane or through paracellar spaces. Lipid
insoluble drugs takes place through this action.
SPECIALISED TRANSPORT:
This can be carrier mediated or by pinocytosis.
Carrier mediated: the drug combines with a carrier present in the membrane and the complex
then translocates from one face of the membrane to another. The carriers for polar molecules
appear to form a hydrophobic coating over the hydrophilic groups and thus facilitate passage
through the membrane. This is of two types:
Active transport
Facilitated diffusion.
Active transport: movement occurs against the concentration gradient, needs energy and is
inhibited by metabolic poisons. It results in selective accumulation of the substance on one side
of the membrane. Eg: levodopa.
Facilitated diffusion: this proceeds more rapidly than simple diffusion and translocates even non
diffusible substrates, but along their concentration gradient, therefore, does not need energy.
Pinocytosis: it is the process of transport across the cell in particulate form by formation of
vesicles.
ABSORPTION:
Absorption is the movement of drug from its site of administration into the circulation. Except
when given through IV the drug has to cross biological membranes. Factors affecting absorption
are:
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Aqueous solubility: drugs given in solid form must dissolve in the aqueous biophase before they
are absorbed. Obviously a drug given as watery solution is absorbed faster than from dilute
solution.
Concentration: passive transport depends on concentration gradient. Drug given a concentrated
solution is absorbed faster than the diluted solution.
Area of absorbing surface: larger it is faster the absorption.
Vascularity of the absorbing surface: blood circulation removes the drug from the site of
absorption and maintains the concentration gradient across the membrane. Increased blood flow
hastens drug absorption.
Route of administration: this affects drug absorption, because each route has its own
peculiarities.
ORAL: the effective barrier to orally administered drugs is the epithelial lining of the
gastrointestinal tract, which is lipoidal. Acidic drugs eg: salicylates are predominantly unionized
in the acid gastric juice and are absorbed from stomach, while basic drugs eg: morphine are
largely ionized and are absorbed only on reaching the duodenum. However even for acidic drugs
absorption from stomach is slower, because the mucosa is thick covered with mucus and the
surface area is small. Thus faster gastric emptying accelerates drug absorption in general.
SUBCUTANEOUS AND INTRAMUSCULAR: By these routes the drug is deposited directly in
the vicinity to the capillaries. Lipid soluble drugs pass readily across the whole surface of the
capillary endothelium. Capillary highly porous do not obstruct absorption of even large lipid
insoluble molecules or ions. Very large molecules are absorbed through lymphatics. Thus many
drugs not absorbed orally are absorbed parenterally.
TOPICAL SITES: (SKIN, CORNEA MUCOUS MEMBRANES):
Systemic absorption after topical application depends primarily on lipid solubility of the drugs.
However only few drugs significantly penetrate intact skin.
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Eg: corticosteroids applied over extensive areas can produce systemic effects and pituitary
adrenal suppression. Cornea is permeable to lipid soluble, unionized but not to highly ionized
drugs.
Mucous membranes of mouth, rectum, and vagina absorb lipophilic drugs.
CLASSIFICATION:
ADME
Pharmacokinetics is divided into several areas including the extent and rate of absorption,
distribution, metabolism and excretion. This is commonly referred to as the ADME scheme.
However recent understanding about the drug-body interactions brought about the inclusion of
new term Liberation. Now Pharmacokinetics can be better described as LADME.
Liberation - the process of release of drug from the formulation.
Absorption - the process of a substance entering the blood circulation.
Distribution - the dispersion or dissemination of substances throughout the fluids and
tissues of the body.
Metabolism - the irreversible transformation of parent compounds into daughter
metabolites.
Excretion - the elimination of the substances from the body. In rare cases, some drugs
irreversibly accumulate in body tissue.
Pharmacokinetics describes how the body affects a specific drug after administration.
Pharmacokinetic properties of drugs may be affected by elements such as the site of
administration and the dose of administered drug. These may affect the absorption rate.
Parameters
The following are the most commonly measured pharmacokinetic parameters:
Variable DescriptionExample
valueAbbreviation(s) Formula
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Dose
loading dose (LD), or steady
state /maintenance dose
(MD)
1000 mg
Volume of
distribution
The apparent volume in
which a drug is distributed
immediately after it has been
injected intravenously and
equilibrated between plasma
and the surrounding tissues.
25 L
Concentration
initial or steady-state
concentration of drug in
plasma
40.0 mg/L
Biological
half-life
The time required for the
concentration of the drug to
reach half of its original
value.
14 hr
Elimination
rate constant
The rate at which drugs are
removed from the body.0.05 /hr
Elimination
rate
rate of infusion required to
balance elimination50 mg/hr
Area under the
curve
The integral of the plasma
drug concentration (Cp) after
it is administered.
0.1
mg/mL×hr
Clearance
The volume of plasma
cleared of the drug per unit
time.
1.25 L/hr
BioavailabilityThe fraction of drug that is
absorbed.1
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Cmax
The peak plasma
concentration of a drug after
oral administration.
40.0 mg/Ldirect
measurement
Cmin
The lowest (trough)
concentration that a drug
reaches before the next dose
is administered.
1.0 mg/Ldirect
measurement
Analysis
Pharmacokinetic analysis is performed by non compartmental (model independent) or
compartmental methods. Noncompartmental methods estimate the exposure to a drug by
estimating the area under the curve of a concentration-time graph. Compartmental methods
estimate the concentration-time graph using kinetic models.
Population pharmacokinetics
Population pharmacokinetics is the study of the sources and correlates of variability in drug
concentrations among individuals who are the target patient population receiving clinically
relevant doses of a drug of interest. Certain patient demographic, pathophysiological, and
therapeutical features, such as body weight, excretory and metabolic functions, and the presence
of other therapies, can regularly alter dose-concentration relationships. For example, steady-state
concentrations of drugs eliminated mostly by the kidney are usually greater in patients suffering
from renal failure than they are in patients with normal renal function receiving the same drug
dosage.
Population pharmacokinetics seeks to identify the measurable pathophysiologic factors that cause
changes in the dose-concentration relationship and the extent of these changes so that, if such
changes are associated with clinically significant shifts in the therapeutic index, dosage can be
appropriately modified.
Software packages used in population pharmacokinetics modeling include NONMEM.
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Routes of Drug Administration:
1. Intravenous
2. Oral
3. Buccal
4. Sublingual
5. Rectal
6. Intramuscular
7. Transdermal
8. Subcutaneous
9. Inhalational
10. Topical
Of all of these routes most likely to be asked about the transdermal, as it is fashionable.
Otherwise, most other basic pharmacology questions tend to concern the pharmacology of
intravenous agents; that is what is discussed below.
First Order Kinetics:
A constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is
proportional to the amount of drug in the body. The majority of drugs are eliminated in this way.
The Volume of Distribution (Vd) is the amount of drug in the body divided by the concentration
in the blood. Drugs that are highly lipid soluble, such as digoxin, have a very high volume of
distribution (500 litres). Drugs which are lipid insoluble, such as neuromuscular blockers, remain
in the blood, and have a low Vd.
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The Clearance (Cl) of a drug is the volume of plasma from which the drug is completely
removed per unit time. The amount eliminated is proportional to the concentration of the drug in
the blood.
The fraction of the drug in the body eliminated per unit time is determined by the elimination
constant (kel).
Rate of elimination = clearance x concentration in the blood.
Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50%. After 4
half lives, elimination is 94% complete.
It can be shown that the kel = the log of 2 divided by the t1/2 = 0.693/t1/2.
Likewise, Cl = kel x Vd, so, Cl = 0.693Vd/t1/2.
And t1/2 = 0.693 x Vd / cl
The rate of elimination is the clearance times and the concentration in the plasma
Roe = Cl x Cp
Fraction of the total drug removed per unit time = Cl/Vd.
If the volume of distribution is increased, then the kel will decrease, the t1/2 will increase, but the
clearance won't change.
Example: You have a 10ml container of orange squash. You put this into a litre (990ml) of water.
The Vd of the orange squash is 1000ml. If, each minute, you empty 10ml of the orange liquid
into the 10ml container, discard this, and replace it with 10ml of water. The clearance is 10 ml
per minute. The elimination half life is: 70 minutes . The kel is Cl/Vd = 10/1000 = 0.01.
If the volume of the container is increased to 2000ml, then the clearance remains the same, but
the Vd, and consequently the t1/2, increases (to 140 minutes).
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What is described above is a single compartment model, what would occur if the bloodstream
was the only compartment in the body (or if the Vd = the blood volume). But the human body is
more complex than this: there are many compartments: muscle, fat, brain tissue etc. In order to
describe this, we use multicompartment models.
Multicompartment Models:
Why does a patient wake up after 5 minutes after an injection of thiopentone when we know that
it takes several hours to eliminate this drug from the body? What happens is that, initially the
drug is all in the blood and this blood goes to "vessel rich" organs; principally the brain. After a
few minutes the drug starts to venture off into other tissues (fat, muscle etc) it redistributes, the
concentration in the brain decreases and the patient wakes up! The drug thus redistributes into
other compartments.
If you were to represent this phenomenon graphically, you would follow a picture of rapid fall in
blood concentration, a plateau, and then a slower gradual fall. The first part is the rapid
redistribution phase, the alpha phase, the plateau is the equilibrium phase (where blood
concentration = tissue concentration), and the slower phase, the beta phase, is the elimination
phase where blood and tissue concentrations fall in tandem. This is a simple two compartment
model.
An couple of interesting pieces of information can be derived from the log concentration versus
time graph. If you extrapolate back the elimination line to the y axis, then you get to a point
called the CP0 - a theoretical point representing the concentration that would have existed at the
start if the dose had been instantly distributed (dose/Vd). From this new straight line you can
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figure out how long it takes for the concentration to drop by 50%: the elimination half life.
Likewise, a similar procedure can be performed on the phase: the redistribution half life.
Bioavailability
This is the fraction of the administered dose that reaches the systemic circulation. Bioavailability
is 100% for intravenous injection. It varies for other routes depending on incomplete absorption,
first pass hepatic metabolism etc. Thus one plots plasma concentration against time, and the
bioavailability is the area under the curve.
Zero Order Elimination
When a patient had ethyl alcohol before midnight he will fail a breath analyzer test at 8 am the
following morning. What happens is that the metabolic pathways responsible for alcohol
metabolism are rapidly saturated and that clearance is determined by how fast these pathways can
work. The metabolic pathways work to their limit. This is known as zero order kinetics: a
constant amount of drug is eliminated per unit time. This form of kinetics occurs with several
important drugs at high dosage concentrations: phenytoin, salicylates, theophylline, and
thiopentone (at very large doses). Because high dose this is very slow to clear, we no longer use it
in infusion for status epileptic us
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Dosage regimens
The strategy for treating patients with drugs is to give sufficient amounts that the required
therapeutic effect arises, but not a toxic dose.
The maintenance dose is equal to the rate of elimination at steady state (i.e.at steady state, rate of
elimination = rate of administration):
Dosing rate = clearance x desired plasma concentration.
Drugs will accumulate within the body if the drug has not been fully eliminated before the next
dose. Steady state concentration is thus arrived at after four half lives.
The loading dose = the volume of distribution x the desired concentration (i.e. the
concentration at steady state).
Hepatic Drug Clearance
Many drugs are extensively metabolized by the liver. The rate of elimination depends on 1) The
liver's inherent ability to metabolize the drug, 2) the amount of drug presented to the liver for
metabolism. This is important because drugs administered orally are delivered from the gut to the
portal vein to the liver: the liver gobbles up a varying chunk of the administered drug (pre-
systemic elimination) and less is available to the body for therapeutic effect. This is why you
have to give a higher dose of morphine, for example, orally, than intravenously.
Hepatic drug clearance (i.e. the amount of each drug gobbled up by the liver) depends on:
1) The Intrinsic clearance (Cl int).
2) Hepatic blood flow.
These two factors are independent of one another, and their combined effect is the proportion of
drug gobbled up: the extraction ratio.
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For drugs that have a low intrinsic clearance, this effect can be increased by giving a second
agent that boosts the effect of the liver's enzyme system; these are enzyme inducers. Examples of
such drugs are antiepileptic (carbamazepine & phenytoin), rifampicin, alcohol and spironolactone
[also barbiturates]. Enzyme inhibitors have the opposite effect: examples are flagyl, allopurinol,
cimetidine, and erythromycin.
Likewise, if the blood flow increases, the liver has less chance to gobble up the drug, and the
extraction ratio falls. This is particularly the case, as you would expect, of the intrinsic clearance
is low.
Drug distribution
Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially
had no drug, concentration gradient being in the direction of plasma to tissues.
Apparent volume of distribution (V);
V= dose administered i.v
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Plasma concentration.
Redistribution: highly lipid soluble drugs given iv or by inhalation initially get distributed to
organs with high blood flow eg. Brain, heart, kidney etc. later, less vascular but more bulky
tissues (muscle, fat) take up the drug- plasma concentration falls and the drug is withdrawn from
these sites.
Penetration into brain and CSF: the capillary endothelial cells in brain have tight junctions and
lack large intercellular pores. Further an investment of neural tissue covers the capillaries.
Together they constitute so called blood brain barrier. A similar blood CSF barrier is located in
the choroid plexus. Both these barriers are lipoidal and limit the entry of entry of non lipid
soluble drugs. Eg: streptomycin, neostigmine. Only lipid soluble drugs are therefore are able to
penetrate and have action on the central nervous system.
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Passage across placenta: placental membranes are lipoidal and allow free passage of lipophilic
drugs, while restricting hydrophilic drugs. The placental efflux P-glycoprotein also serves to limit
fetal exposure to maternally administered drugs.
TISSUE STORAGE:
Drugs may also accumulate in specific organs or get bound to specific tissue constituents.
organ Drug
Skeletal muscle, heart Digoxin,emetine (to muscle proteins)
liver Chloroquine, digoxin.
kidney Chloroquine, digoxin.
thyroid Iodine
brain Isoniazid, chlorpromazine.
retina Chloroquine
iris Atropine, ephedrine.
Bone and teeth Tetracyclines, heavy metals.
Adipose tissue Thiopentone, ether.
When a drug is introduced into the body, where it ends up depends on a number of factors:
1) blood flow, tissues with the highest blood flow receive the drug first,
2) protein binding, drugs stuck to plasma proteins are crippled, they can only go where the
proteins go
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3) lipid solubility and the degree of ionization, this describes the ability of drugs to enter tissues
(highly lipid soluble / unionized drugs can basically go anywhere).
Protein Binding
Most drugs bind to proteins, either albumin or alpha-1 acid glycoprotein (AAG), to a greater or
lesser extent. Drugs prefer to be free, it is in this state that they can travel throughout the body, in
and out of tissues and have their biological effect. The downside of this is that they are easy prey
for metabolizing enzymes.
The amount of albumin does not appear to be hugely relevant. In disease states such as sepsis, the
serum albumin drops drastically, but the free drug concentration does not appear to increase.
Degree of ionization
This is really important with regard to local anesthetics. The essential fact to know is that highly
ionized drugs cannot cross lipid membranes (basically they can't go anywhere) and unionized
drugs can cross freely. Morphine is highly ionized, fentanyl is the opposite. Consequently the
latter has a faster onset of action. The degree of ionization depends on the pKa of the drug and
the pH of the local environment. The pKa is the pH at which the drug is 50% ionized. Most drugs
are either weak acids or weak bases. Acids are most highly ionized at a high pH (i.e. in an
alkaline environment). Bases are most highly ionized in an acidic environment (low pH). For a
weak acid, the more acidic the environment, the less ionized the drug, and the more easily it
crosses lipid membranes. If you take this acid, at pKa it is 50% ionized, if you add 2 pH points to
this (more alkaline), it becomes 90% ionized, if you reduce the pH (more acidic) by two units, it
becomes 10% ionized. Weak bases have the opposite effect.
Local anesthetics are weak bases: the closer the pKa of the local anesthetic to the local tissue pH,
the more unionized the drug is. That is why lignocaine (pKa 7.7) has a faster onset of action than
bupivicaine (pKa 8.3). If the local tissues are alkalinized (e.g. by adding bicarbonate to the local
anesthetic), then the tissue pH is brought closer to the pKa, and the onset of action is hastened.
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BIOTRANSFORMATION:The primary site for drug metabolism is liver; others are kidney, intestine, lungs and plasma. Bio
transformation of drugs may lead to the following:
Inactivation: most drugs and their active metabolites are rendered inactive or less active. Eg:
morphine.
Active metabolite from an active drug: many drugs have been found to be partially converted
to one or more active metabolite. The effects observed are the sum total of that due to the parent
drug and its active metabolites.
Activation of inactive drug: few drugs are inactive as such and need conversion in the body to
one or more active metabolites. Such a drug is called a pro drug.
Bio transformation reactions can be classified into:
Non synthetic /phase I reactions- metabolite may be active or inactive.
Synthetic/conjugation/phaseII reactions-metabolite is mostly inactive.
Non synthetic reactions:
Oxidation: this reaction involves addition of oxygen / negatively charged radical or removal of
hydrogen/positively charged radical. Oxidations are the most important drug metabolizing
reactions.
Ex:paracetamol, phenothiazines.
Reduction: this reaction is the converse of oxidation and involves cytochrome P-450 enzymes
working in the opposite direction. Ex: halothane.
Hydrolysis: this is cleavage of drug molecule by taking up a molecule of water. It occurs in liver,
intestines, plasma and other tissues.
Cyclization: this is formation of ring structure from a straight chain compound. Eg: proguanil.
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Decyclization: this is opening up of ring structure of the cyclic drug molecule ex: barbiturates.
SYNTHETIC REACTIONS:
These involve the conjugation of the drug or its phase I metabolite with an endogenous substrate,
generally derived from carbohydrate or amino acid, to form a polar highly ionized organic acid
which is easily excreted in the urine or bile.
Glucuronide conjugation: compounds with a hydroxyl or carboxylic group are easily
conjugated with a glucuronic acid which is derived from glucose. Ex: Morphine.
Acetylation: compounds having amino or hydrazine residues are conjugated with the help of
acetyl coenzyme. Ex: sulphonamides.
Methylation: the amines and phenols can be methylated Ex: adrenaline
Sulphate conjugation: the phenolic compounds and steroids are suphated by the suphokinases.
Ex: chloramphenicol.
Glycine conjugation: salicylates and other drugs having carboxylic acid group are conjugated
with glycine, but this is not a major pathway of metabolism.
Ribo nucleoside or nucleotide synthesis: it is important for the activation of many purine and
pyrimidine antimetabolites used in cancer chemotherapy.
EXCRETION:
Excretion is the passage out of systematically absorbed drug. Drugs and their metabolites are
excreted in
Urine
Faeces
Exhaled air
Saliva
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Sweat
Milk
Urine: it is the most important channel of excretion of most drugs.
Renal excretion: the kidney is responsible for all water soluble substances. The amount of drug
or its metabolites ultimately present in urine is the sum total of glomerular filtration, tubular re
absorption and tubular secretion.
Glomerular filtration: Glomerular capillaries have pores larger than usual; all protein bound
drug (whether lipid soluble or insoluble) presented to the glomerulus is filtered. Thus it depends
on the plasma protein binding and renal blood flow.
Tubular re absorption: this depends upon the lipid solubility and the ionization of the drug at
the existing urinary PH. Lipid soluble drugs filtered at the glomerulus diffuse back in the tubules
because 99% of glomerular filtrate is re absorbed, but lipid insoluble and highly ionized drugs are
unable to do so. Thus rate of excretion of drug such as amino glycoside antibiotics parallels
GFR.
Tubular secretion: this is the active transfer of organic acids and bases by two separate non
specific mechanisms which operate in the proximal tubules.
Organic acid transport: penicillin, salicylates.
Organic base transport: thiazides, cimetidine.
Both transport process are bi directional i.e they can transport their substrates from blood to
tubular fluid and vice versa.
Faeces: apart from unabsorbed fraction, most of the drug present in faeces is derived from bile.
Liver actively transports into bile organic acids (especially glucoranides), organic bases and
steroids by separate non specific active transport mechanisms. Relatively larger molecules are
eliminated in the bile most of the drug including that released by deconjugation of glucoranides
by bacteria in the intestine is reabsorbed.
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Ex: erythromycin, ampicillin.
Certain drugs excreted directly in the colon. Eg: purgatives.
Exhaled air: gases and volatile liquids are eliminated by lungs, irrespective of their lipid
solubility. Alveolar transfer of the gas/vapour depends on its partial pressure in the blood.
Saliva and sweat: these are of minor importance for drug excretion. Lithium, heavy metals and
rifampicin are excreted through these secretions.
Milk: the excretion of drug is not important for the mother, but the suckling infant inadvertently
receives the drug. Most drugs enter breast milk by passive diffusion. Lipid soluble and less
protein bound drugs cross better.
Ex: morphine, monteleukast, theophylline.
PROLONGATION OF DRUG ACTION:
It is sometimes advantageous to modify a drug in such a way that it acts for a longer period. By
doing so,
Frequency of administration is reduced.
Improved patient compliance.
Large fluctuations in plasma concentration.
Drug effect could be maintained overnight without disturbing sleep.
By prolonging absorption from site of administration:
Oral: by administering sustained release tablets.
Parenteral: subcutaneous and intramuscular injections in insoluble form (ex: lente insulin) or as
oily solution (depot progestin) and inclusion of vasoconstrictor with the drug (adrenaline with
local anesthetics).
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Transdermal: the drugs impregnated in adhesive patches, strips or as ointment applied on the skin
ex: nitroglycerine.
By retarding rate of metabolism: small chemical modification markedly affects the rate of
metabolism without affecting the biological action. Ex : addition of ethinyl group to estradiol
makes it longer acting and suitable for use as oral contraceptive.
By retarding renal excretion: the tubular secretion of drug being an active process can be
suppressed by a competing substance ex: probenecid prolongs the action of penicillin and
ampicillin.
EXAMPLE FOR AMLODIPINE:
Amlodipine is a dihydropyridine calcium antagonist drug with distinctive pharmacokinetic
characteristics which appear to be attributable to a high degree of ionisation. Following oral
administration, bioavailability is 60 to 65% and plasma concentrations rise gradually to peak 6 to
8h after administration. Amlodipine is extensively metabolised in the liver (but there is no
significant presystemic or first-pass metabolism) and is slowly cleared with a terminal
elimination half-life of 40 to 50h. Volume of distribution is large (21 L/kg) and there is a high
degree of protein binding (98%). There is some evidence that age, severe hepatic impairment and
severe renal impairment influence the pharmacokinetic profile leading to higher plasma
concentrations and longer half-lives. There is no evidence of pharmacokinetic drug interactions.
Amlodipine shows linear dose-related pharmacokinetic characteristics and, at steady-state, there
are relatively small fluctuations in plasma concentrations across a dosage interval. Thus, although
structurally related to other dihydropyridine derivatives, amlodipine displays significantly
different pharmacokinetic characteristics and is suitable for administration in a single daily dose.
ROLE OF NURSE:
1.Rightclient
2.right drug
3.right dose
4.right time
5. Right route
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5 Additional Rights
1. right assessment
2. right documentation
3. client’s right to education
4. right evaluation
5. client’s right to refuse
A. Right Client
Nurse must do:
verify client check ID bracelet & room number
have client state his name
distinguish between 2 client’s with same last names
B. Right Drug
Components of a drug order:
1.date & time the order is written
2.drug name (genericpreferred)
3.drug dosage
4.frequency & duration of administration
5.any special instructions for withholding or adjusting dosage.
6.physician or other health care provider’s signature or name.
7.signature of licensed practitioner.
Nurse must do:
• check medication order is complete & legible.
• know general purpose or action, dosage & route of drug
• compare drug card with drug label three times.
1. at time of contact with drug bottle/ container
2. before pouring drug
3. after pouring drug
4 Categories of Drug Orders:
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Standing Order / Routine Order
ongoing order
may have special instructions to base administration
include PRN orders
ex. digoxin 0.2 mg PO q.d., maintain blood level at 0.5 – 2.0 ng/ml
2.One-time (single) order
given only once, at a specific time
ex. Cefixime 2mg IM at 7 AM on 12-1-05
3. PRN order
given at client’s request & nurse’s judgement for need & safety
ex Mefenamic Acid 500mg q 4h PRN for pain
4. STAT order
given once, immediately
ex. Morphine 2mg IV STAT
C. Right Dose
Nurse must do:
Calculate and check drug dose accurately.
Check PDR, drug package insert or drug handbook for recommended range of
specific drugs.
D. Right Time
Nurse must do:
Administer drugs at specified times.
Administer drugs that are affected by foods, before meals.
Administer drugs that can irritate stomach, with food.
Drug administration may be adjusted to fit schedule of client’s lifestyle, &
activities. & diagnostic procedures.
Check expiration date.
Antibiotics should be administered at even intervals. 23
E. Right Route
Nurse must do:
assess ability to swallow before giving oral meds.
Do not crush or mix meds in other substances before consultation with
physician or pharmacist
Use aseptic technique when administering drugs.
Administer drug at appropriate sites.
Stay with client until oral drugs have been swallowed.
F. Right Assessment
Get baseline data before administration.
Assess the colour of the urine, sweat etc.
Check blood urea , creatinine level for nephrotoxic drugs.
Investigate for liver function if the drug is acting through liver.
Check for any adverse reactions.
G. Right Documentation
Immediately record appropriate information
• Name, dose, route,time & date, nurse’s initial or signature
Client’s response:
• narcotics
• analgesics
• antiemetics
• sedatives
unexpected reactions to medications.
Use correct abbreviations & symbols.
H. Right to Education
Client teaching :
• therapeuticpurpose
• side-effects
• diet restrictions or requirements
• skill of administration
• laboratory monitoring
Principle of Informed Consent 24
I. Right Evaluation
client’s response to medications.
effectiveness
extent of side-effects or any adverse reactions.
J. Right to Refuse
Nurse must do:
determine, when possible, reason for refusal.
explain risk for refusing medications & reinforce the reason for medication.
Refusal should be documented immediately.
Head nurse or health care provider should be informed when omission pose
Reference:biotech.about.com/od/.../g/pharmacokin.htm
http://www.4um.com/tutorial/science/pharmak.htm
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