Describe the factors contributing to inter-individual variability in drug response seen with an induction dose of an intravenous anaesthetic drug
College Answer
This was a broad question that required some structure and organisation to score well. The issues around variability in both pharmacokinetics and pharmacodynamics, of which there are many, needed be covered. For example variability due to differences in organ function, age, metabolism, body composition, were just a few of the factors expected to be mentioned.
Discussion
This SAQ, like the near-identical Question 11(p.2) from the second paper of 2008, was plagiarised in its entirety from the ANZCA primary (2005 and 2006). The ANZCA examiners comments are actually significantly 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
|