PHARMACOKINETICS: What the body does to a drug

PHARMACODYNAMICS: What the drug does to the body

KNOW YOUR TERMINOLOGY

  • 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 areultra extensive, extensive, intermediate and poor metabolisers (UEM, EM, IM, and PM respectively in the population, genetically determined-the 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

↓phase II,

conjugation by glucuronyl or sulfonyltransferase

Water soluble drug which can be eliminated in urine and bile