Dvii: Discuss factors contributing to the inter-individual variability in response to opioid analgesics

  • Inter-individual variability = variations in a drug’s PK & PD parameters, resulting in different plasma [ ] profiles following admin of the same dose in different patients
  • Opioids = natural/semisynthetic/synthetic compounds which act on opioid receptor with an agonistic effect

PK

A

  • Opioids = weak bases (pKa 6.5 – 8/7)
  • Acidic stomach → highly ionised → poor absorption → ↓OBA
  • Alkaline SI → unionised → good absorption but extensive 1st pass metabolism
  • With pathology (post op ileus, Crohn’s) → further ↓A & OBA
  • Transdermal: variable BF/thickness → unreliable absorption (i.e. obese/cachectic)

D

  • Extensive VD, exceeding TBW
  • ↓VD (hypovolaemia) = ↓dose or ↑VD (pregnancy) = ↑dose
  • PPB = all bind to plasma protein → but UNIONISED unbound opioid is the active drug
    • ↓PPB = ↑free drug → ↑effect + speed of onset
  • Ionisation
    • Weak base → ∴ ↓pH (sepsis) → ↑ionisation → ↓VD = ↑dose required
    • Impaired BBB → ↑onset & ↑sensitivity

M

  • Metabolised by liver into active & inactive compounds
  • Hepatic failure → ↓metabolism → ↑DoA (except Remifentanyl → metabolised by Plasma Esterases)
  • Hypothermia → ↓metabolism
  • Enzyme induction (cimetidine) → ↑M → ↑dose requirement
  • Enzyme inhibitor (phenytoin) → ↓M → ↓dose requirement
  • Genetic variation of P450, CYP2D6
    • ↓conversion of tramadol/codeine to active metabolites
    • ↓efficacy
  • Fast variant → ↑↑conversion → ↑free drug → NARCOSIS

E

  • Rena/Biliary excretion
  • Renal failure → ↓excretion of active metabolites (M6G) = ↑DoA

PD

  • Age: less effective elimination and increased sensitivity in elderly/newborn
  • CBF: increased delivery to effect site (ie newborns have increased % CO to brain cf adults)
  • Genetics: polymorphism of m-opioid gene; require larger dose
  • Tolerance: increased dose required for same therapeutic effect (due to alteration in receptor affinity/up regulator of receptor numbers)
  • Drug Interactions:
    • Synergism (NSAIDs) = ↓dose
    • a2 agonist – ↓cAMP = ↓NT release = ↓dose required
    • Naloxone = competitive antagonist = ↑dose required