Variability of response to anaesthetic agents

This chapter is vaguely relevant to Section D(iii) and D(iv) of the 2017 CICM Primary Syllabus, which expect the exam candidate to "Describe alterations to drug response due to physiological change, [and] pathological disturbance with particular reference to cardiac, respiratory, renal and hepatic disease." It is more directly relevant to Question 2 from the second paper of 2011 and Question 11(p.2) from the second paper of 2008. Both SAQs asked the trainees to "describe the factors contributing to inter-individual variability in drug response seen with an induction dose of an intravenous anaesthetic drug", again with some perplexing and meaningless changes of stem wording ("contributing" in 2011 vs. "which contribute" in 2008). Looking more closely, one discovers that this question was plagiarised in its entirety from the ANZCA primary papers of 2005 and 2006 (see Amanda Diaz' excellent answer to the original question).

Of the college comments, those from 2011 were short and uninformative. In 2008 the examiners put a little bit of thought into their discussion of the answers, and the following summary was to some extent shaped by these. The ANZCA examiners' responses to this stolen question can be found on Kerry Brandis' website, and are also worth reading. The CICM examiners pointed out that a tabular format and a "logical division into pharmacokinetic and pharmacodynamic factors" was the only acceptable structure, or rather that a failure to have clear structure was fatal to the answer. Thus, a table is offered here, which is reproduced in the discussion sections for both SAQs. Both colleges' contributions were considered.

In terms of a good peer-reviewed reference for this specific topic, there is nothing really to find. All the factors assembled here were scraped up from all the other chapters which discuss more theoretical and generalised applications of pharmacology to the variability of drug response. The CICM examiners recommended Stoelting (ch. 4 and 5) of the 5th edition, which were chapters on inhaled and IV anaesthetic agents. These chapters contain some vaguely relevant sections, for instance, the table on "Factors Determining Partial Pressure Gradients Necessary for Establishment of Anesthesia"

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. At the same time, the increased cardiac output of pregnancy slows the rate of inhalational induction (by allowing the molecules of the agent to be more efficiently delivered to their fatty tissue sinks), and the two effects cancel each other out, like two fighting fish in the same bowl. 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. Low cardiac output enhances the rate of inhalational induction, particularly for volatile agents with high solubility. High cardiac output or high proportion of cerebral blood flow (eg. in infancy) increases the delivery of intravenous anaesthetic agent to the brain A high cardiac output decreases the rate of inhalational anaesthetic induction (again, highly fat-soluble agents are more affected)
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 Idiosyncratic differences in metabolism are present in population groups, eg. redheads require about 19% more inhalational anaesthetic agent then the rest of the population (a weirdly suspicious study by Liem et al, 2004, actually tested the hair in a laboratory to make sure their subjects were natural gingers) 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

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.

Liem, Edwin B., et al. "Anesthetic requirement is increased in redheads." The Journal of the American Society of Anesthesiologists 101.2 (2004): 279-283.

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