Describe the factors which contribute to inter-individual variability in drug response
seen with an induction dose of an intravenous anaesthetic drug.

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College Answer

This question required the candidate to provide some detail why a given dose of intravenous  anaesthetic administered for the purpose of induction may result in a variable response between individuals. A logical division into pharmacokinetic and pharmacodynamic factors pertaining to the drug and how these are impacted by patient physiology, citing appropriate examples, was expected. Extremes of age, pregnancy, low and high cardiac output states, sympathetic tone, body habitus and factors impacting on drug redistribution and elimination should have been addressed. Extra marks were awarded for relevant discussion of pharmacogenetics. Discussion of the “bolus effect” versus slow infusion of an induction drug, relative to these factors should have been included. Mention of drug interactions, idiosyncratic reactions and relevant pathophysiology impairing organ function reserve was appropriate. The consequences of variability in drug response in terms of over- / underdosing, haemodynamic compromise, respiratory depression, delayed recovery and allergic
reactions needed emphasis to demonstrate understanding of the significance of predisposing
factors.

Effective answers to this question utilised either clear headings, or a tabular format, dividing what is a large topic into discrete areas. The lack of a structured approach to this question was invariably unsuccessful.
Syllabus Ref: G2a 2.c,d,e,f,g
Suggested Reading: Pharmacology and Physiology in Anaesthetic Practice / R K Stoelting – 4th ed - 2006. Chapters 4,6.

Discussion

This SAQ, like the near-identical Question 2 from the second paper of 2011, was plagiarised in its entirety from the ANZCA primary (2005 and 2006). The ANZCA examiners comments are actually slightly better, and can be found on Kerry Brandis' website. 

Variability in Drug Response to Anaesthetic Induction Agents
Pharmacokinetic factors
Administration and absorption

Physiological factors

  • Respiratory rate influences the rate of uptake of volatile anaesthetic agents, eg. in the physiologically increased tachypnoea of pregnancy
  • Site of administration (eg. small hand vein vs. central line)
  • Rate of administration ("bolus effect") - rapid administration into the central compartment results in rapid distribution to the CNS target sites; slow infusion allows redistribution to play a significant role, increasing the overall dose requirement

Pathological factors

  • Respiratory failure may impede the rate of uptake of volatile anaesthetic agents
  • Low cardiac output impedes the circulation of IV agents and delays their onset
  • High cardiac output or high proportion of cerebral blood flow (eg. in infancy) increases the delivery of anaesthetic agent to the brain
Distribution

Physiological factors

  • The increased volume of distribution due to increased body water and fat in pregnancy decreases the available agent left in the central compartment
  • Body habitus (which reflects water:fat ratio of total body content) to some extent determines the offset of action (by redistribution into fat stores)

Pathological factors

  • Dehydration or fluid overload change the Vd for water-soluble drugs
  • Serum protein concentration changes with critical illness, changing the available free fraction of the anaesthetic agent
  • Competition with concurrently administered drugs for protein binding sites also increases the available free fraction
  • The rate of distribution between compartments depends on cardiac output and may be slowed in shock states
Metabolism

Physiological factors

  • Age-related changes in metabolism (eg. neonates and the elderly are slower metabolisers)
  • Induction or inhibition of enzymes may occur due to regular medications

Pathological factors

  • Dehydration or fluid overload change the Vd for water-soluble drugs
  • Serum protein concentration changes with critical illness, changing the available free fraction of the anaesthetic agent
  • Competition with concurrently administered drugs for protein binding sites also increases the available free fraction
  • Rate of distribution between compartments depends on cardiac output and may be slowed in shock states
Elimination

Physiological factors

  • Age-related changes in GFR (eg. neonates and the elderly are slower to excrete drugs and their metabolites)
  • Physiological changes of pregnancy increase the clearance of anaesthetic agents (increased cardiac output and respiratory rate)

Pathological factors

  • Renal failure or dialysis dependence decreases the clearance of really eliminated agents and their active metabolites, delaying recovery
  • Respiratory disease can prolong recovery from volatile agents by reducing minute ventilation and therefore their elimination
Pharmacodynamic factors

Physiological factors

  • Pharmacogenetic differences in drug receptors may lead to physiological variability between individuals
  • Age plays a role (decreased requirements in the elderly and in infants)
  • Pregnancy decreases MAC requirements

Pharmacological factors

  • Tolerance to anaesthetic and analgesic agents may exist due to concomitant drug therapy (eg. with opiates)

Pathological factors

  • Pharmacogenetic syndromes change the possible adverse effect profile of anaesthetic agents (eg. malignant hyperthermia and volatile agents)
  • Idiosyncratic reactions could unpredictably take place

References

References

Searle, R., and P. M. Hopkins. "Pharmacogenomic variability and anaesthesia." British journal of anaesthesia 103.1 (2009): 14-25.

Hoffman, WILLIAM D., et al. "Factors that determine the hemodynamic response to inhalation anesthetics." Journal of Applied Physiology 70.5 (1991): 2155-2163.

Smith, Stephen E., and Michael D. Rawlins. Variability in human drug response. Elsevier, 2013.