Download PHARMACOKINETICS: What the body does to a drug

PHARMACOKINETICS: What the body does to a drug
PHARMACODYNAMICS: What the drug does to the body
KNOW YOUR TERMINOLOGY
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Bioavailability-extent to which a drug reaches systemic circulation when
administered orally or parenterally versus intravenously
Volume of distribution-The volume of distribution (VD), also known as apparent
volume of distribution, is a term used to quantify the distribution of drug between
plasma and the rest of the body after oral or parenteral dosing. It is the volume in
which the amount of drug would need to be uniformly distributed to produce the
observed blood concentration. It may be increased in renal failure due to fluid
retention and in hepatic dysfunction due to altered body fluid and plasma protein
binding. It may be decreased in dehydration. It can be calculated by dividing the total
amount of drug in the body by the drug concentration in the blood.
First order kinetics-the pattern for most drugs, exponential decline since constant
fraction eliminated per unit of time. Note problems arising from zero order kinetics
e.g. alcohol
Plasma half-life-time taken to decline to half of a drug’s previous level. Only useful
when first order kinetics apply
Steady state-usually reached in dosing after 5 half-lives of the drug have elapsed
(note with depots steady state depends on drug release not removal)
Tolerance-this occurs when dose needs to be increased to obtain same effect; can
be due to either pharmacokinetic (drug more rapidly eliminated when body exposed
to it for longer) or pharmacodynamic reasons (receptor up or down regulation with
antagonists and agonists respectively)
Tachyphylaxis-the very rapid development of tolerance
ABSORPTION
 What factors affect it?
 First pass metabolism
DRUG METABOLISM
 Mainly in liver-phase I involves enzymatic reduction, hydroxylation, demethylation,
hydrolysis or oxidation all increase water solubility and hence renal excretion. Phase
II, conjugation of phase I metabolites by acetylation, sulphation or glucuronic acid
renders drugs very water soluble, but rarely produces active metabolites
 Phase I declines with age, but phase II does not
CYTOCHROME P450 SYSTEM
 Liver microsomal enzyme system
 CYP IID6, important in tricyclic and antipsychotic metabolism
 There are ultra extensive, extensive, intermediate and poor metabolisers
(UEM, EM, IM, and PM respectively in the population, genetically determinedthe science of pharmacogenetics
 See Wijnen PAH et al, 2007. Review article: the prevalence and clinical
relevance of cytochrome P450 polymorphisms. Alimentary Pharmacology and
Therapeutics 26 (suppl 2); 211-219-describes the system and nomenclature,
phase I and II metabolism, useful websites.
Lipid soluble drugs
↓phase I, CYP450
oxidation, reduction, or hydrolysis
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phase II,
conjugation by glucuronyl or sulfonyltransferase
Water soluble drug which can be eliminated in urine and bile