Drug Response Variability: genetic

Master answer

Pharmacokinetic factors

(Amount of drug reaching the receptor)

• Absorption
  • IV dose so should be 100%
  • dose variability between patients
• Distribution
  • Volume of distrib:
    • Body mass and ratio of fat:muscle di­fferences
    • pregnancy, cardiac output states
  • Protein binding:
    • low albumin states, other protein bound drugs
    • propofol has 98% protein binding and will be influenced
  • Blood pH
    • affects degree unionised which can cross lipid membranes
    • eg alkalotic state with thiopentone pKa 7.6
• Metabolism
  • Hepatic factors
    • liver disease may reduce metabolism
    • CYP enzymes (inhibited or upregulated) eg Ketamine
• Excretion
  • Renal impairment: on­set of eff­ect more dependent of redistribution, but can be prolonged if renally excreted

Pharmacodynamic factors

• Presence of endogenous or exogenous ligands
  • Endogenous: increased catecholamines may necessitate a higher induction dose
  • Exogenous:
    • medications which potentiate sedation opioids, benzodiazepines, volatiles
    • medications which reduce sedation – amphetamines
  • Variation in the number of receptors
    • Extremes of age
    • Previous exposure to the drug or similar – tolerance, tachyphylaxis

Variability in the response distal to the receptor

• Pharmocogenetic factors
  • idiosyncrasy
  • anaphylaxis
• Pathological and physiological factors
  • sepsis
  • CNS function

JC 2019

Answer by JC