Drug Response Variability: Interactions

Master answer

Pharmaceutical interactions:

• Physicochemical incompatibility b/t drugs
  • causes precipitation of drug (Eg. STP (alkaline) + SCh (acidic))
• Absorption or binding to containers (Eg. GTN + PVC lines)
• Degradation of drug (Eg. insulin denatures in solution of dextrose)

Pharmacodynamic interactions:

• One drug alters the body’s response to another at a given plasma [drug] and can be either
  • antagonistic
    • Direct (morphine and naloxone) or indirect
  • additive
  • synergistic
    • Inhibition of enzymatic inactivation e.g. clavulanic acid and amoxicillin
    • Enhanced agent uptake e.g. gentamicin and penicillin
• Direct interaction
  • Drugs act at same receptor site for effect
    • naloxone + opioids → direct antagonism
    • N2O + volatiles → direct additivity
• Indirect interaction
  • Drugs act at different receptor sites for same effect
    • Opioids + volatiles → indirect synergism
    • atropine + neostigmine → indirect antagonism

Pharmacokinetic interactions:

• Absorption
  • Mainly due to altered oral absorption a/w:
    • Complex formation: tetracycline + Ca in milk/antacids
      • Altered gastric emptying/intestinal motility
      • opiates ↓ intestinal motility → ↓ absorption of drugs absorbed in small intestine (paracetamol)
    • metoclopramide ↑ intestinal motility → ↓ absorption of drugs absorbed in stomach (Eg. cimetidine)
    • Altered gastric and intestinal pH
      • ↑ gastric pH by antacids impairs absorption of weakly acidic drugs
  • Altered parental absorption a/w localised vasoconstriction (Eg. adrenaline + LA)
• Distribution
  • Competition by drugs for plasma protein binding site → affects drugs that:
    • Are highly protein-bound drugs (Eg. warfarin, diazepam, phenytoin)
      • → ↑ unbound % in plasma
    • Have enzyme system close to saturation or zero-order kinetics (Eg. phenytoin)
      • →↑ displacement of drug and ↑ unbound % cannot be cleared effectively
      • → large ↑ unbound % in plasma
  • Drugs that alter C.O. impact on distribution of drugs to target, peripheral tissues
    • β-blockers ↓ C.O. → slow onset/offset times of drugs reliant on distribution
• Metabolism
  • Inhibition/induction of microsomal enzymes (Eg. CYP450)
    • Enzyme induction → resulting in ↓ plasma [drug]
    • Enzyme inhibition → resulting in ↑ plasma [drug]
  • Inhibitors of non-microsomal enzymes (Eg. MAOi, COMTi)
• Elimination
  • ↓ urinary excretion
    • Competition for tubular transport system occurs with weak organic acids (Eg. probenecid + penicillin)
  • Changes in urine pH
    • Alkalinising agents (Eg. NaHCO3/acetazolamide) → ↑ excretion of weak acids
  • Changes in urine volume
  • Changes in biliary excretion
    • Phenobarbital ↑ bile flow and biliary conjugation of drugs

Gladwin 2016

Answer by Gladwin