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