Paper I
2022 July (Supplementary) (2019 Scheme) · 100 marks · 180 min

Question

Factors modifying drug action.

Q48 marksShort Essays

Answer

Variation in drug response — between different patients, and even in the same patient on different occasions — is the rule, not the exception. Sources of variation fall into two broad effects: quantitative (plasma concentration or magnitude of action changes, correctable by dose adjustment) and qualitative (the type of response itself changes, as in allergy or idiosyncrasy — not correctable by dose adjustment at all).

Body size — dose is calculated on body weight (or, for a handful of drug classes such as anticancer drugs, body surface area), since the same absolute dose reaches a different effective concentration depending on distribution volume.

Age

  • Neonates and infants: immature renal and hepatic elimination prolongs the half-life of many drugs (e.g. chloramphenicol → grey baby syndrome from inadequate glucuronidation); a more permeable blood-brain barrier (unconjugated bilirubin causing kernicterus); differing absorption (slower gastric emptying, but faster transdermal/rectal absorption — the basis for rectal diazepam in febrile seizures).
  • The elderly: declining renal function and hepatic blood flow, reduced gut motility, lower plasma albumin (altering free-drug fraction), and altered adrenergic receptor responsiveness — together producing a much higher incidence of adverse drug reactions, compounded by polypharmacy.

Sex and pregnancy — women generally need doses toward the lower end of the standard range given smaller average body size; pregnancy alters absorption (reduced GI motility), volume of distribution (expanded plasma volume), protein binding, and elimination (increased renal blood flow, hepatic enzyme induction) simultaneously.

Genetics (pharmacogenetics) — dose needed for the same effect can vary several-fold on a purely genetic basis, since every determinant of drug handling (transporters, metabolizing enzymes, receptors) is under genetic control. Examples: slow/fast acetylator status for isoniazid, low-activity CYP2C9 variants metabolizing warfarin slowly, G6PD deficiency precipitating hemolysis with oxidant drugs.

Species and race — real inter-racial differences exist (e.g. beta-blockers being less effective antihypertensives in Afro-Caribbean populations).

Concurrent disease and drug interactions — renal/hepatic impairment alters pharmacokinetics; co-administered drugs can produce pharmacodynamic synergism or antagonism.

Route of administration and cumulation — different routes alter onset and bioavailability; drugs given faster than they are eliminated accumulate with chronic dosing even without a dosing error.

Tolerance and tachyphylaxis — some individuals show natural (inherent) tolerance; others develop acquired tolerance with repeated use, via pharmacokinetic (enhanced own metabolism) or pharmacodynamic (receptor desensitization/downregulation) mechanisms; tachyphylaxis is rapid tolerance developing within a short succession of closely-spaced doses.

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