This chapter answers parts from Section D(viii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "Explain the mechanisms and significance of pharmacogenetic disorders (e.g. malignant hyperthermia, porphyria, atypical cholinesterase and disturbance of cytochrome function)". It could also be said to address Section D(vii), "Outline genetic variability". However, one might argue that even within the constraints of pharmacology, genetic variability is a rather broad topic, and to outline it in satisfactory detail would stretch the patience of any reader who is revising for an exam in a last-minute panic. As such, only brief unsupported motherhood statements will be used to outline genetic variability in the context of pharmacogenetics for this summary. 

In summary:

  • Pharmacogenetics is the study of variability in drug response due to heredity.
  • Variability in drug response is in part due to the genetic polymorphism of the human species
  • Pharmacogenetics exerts its influence on drug response by influencing:
    • Absorption eg. mutations of intestinal trasnport porteins
    • Distribution eg. mutatiosn of carrier proteins such as α1-acid glycoprotei
    • Metabolism eg. mutations of CYP enzymes
    • Elimination eg. mutations of tubular transport proteins
    • Pharmacodynamics eg. polymorphisms in the  drug target or in downstrream regulator mechansisms
  • Specific pharmacogenetic disorders need to be mentioned:
    • Malignant hyperthermia, a mutation of the ryanodine calcium channel receptor which causes a hypermettabolic crisis in response to volatile anaesthetics
    • Porphyria, a mutation of haem synthesis enzymes which causes a build-up of neurotoxic intermediate metabolites in response to various drugs (anticonvulsants, antibiotics, thiopentone)
    • Atypical plasma cholinesterase, which fails to metabolise suxamethonium and causes "sux apnoea"
    • G6PD deficiency, a mutation of glucose 6-phosphate dehydrogenase which produces acute haemolysis in response to oxidative stress due to dapsone, methylene blue, fluoroquinolones, antimalarialas and rasburicase

This fascinating topic has never appeared in any of the written exam paper SAQ, and one might argue that to study it would waste precious bytes of pre-exam short-term memory.  It would therefore be reasonable to limit oneself to brief pithy revision resources such as the Part One pharmacogenetics section which is literally everything you need to know and nothing extra. This chapter can be viewed as the extended long-form footnotes for this section.

In terms of references and peer-reviewed resources, there is a surprising amount of material out there.  UpToDate has a chapter on this for the paying customer. Wang et al (2010) and Evans et al (2009) are free and contain much of the same information. In general, anything by William E. Evans seems to be good (Evans et al, 1999; Evans et al, 2001).

Pharmacogenetics, "pharmacogenomics" and drug response

Pirmohamed (2001) and Nerbert (1999) define pharmacogenetics as 

"the study of variability in drug response due to heredity"

As for "pharmacogenomics", the term is some mutant product of the recent "fashion for adding the suffix ‘… omics’ to areas of research" which seems to be used interchangeably with the other term and which does not appear to have any distinct meaning of its own. For some people, the "pharmacogenomics" version encompasses all genetic influences on drug response, whereas "pharmacogenetics" is more related to genes determining drug metabolism, but these weirdos are in the minority. For the purposes of this summary, the two terms will be used randomly with total disregard for the style rules of written communication.

Genetic variability in drug response

To "outline" this would require the broadest strokes. In case one does require a deeper understanding, the best starting point would probably be Madian et al (2012). In summary:

  • Human populations express significant genetic polymorphism, i.e. there are several distinct alleles possible at each specific locus; hair and skin pigmentation are just one of the examples.
  • This polymorphism extends to drug receptor targets, secondary messenger system and other homeostatic or regulatory pathways.
  • As a result, these polymorphisms produce individual variability in drug response, including the susceptibility to adverse drug reactions.
  • Ergo, knowledge of these polymorphisms can be exploited to personalise drug therapy.
  • Existing examples are almost totally limited to the genetic testing of cancer cells for the purpose of targeted antitumour monoclonal antibodies and enzyme blockers. Familiar examples would include the Philadelphia chromosome and the BRCA genes.

Influence of pharmacogenetics on drug response

Pharmacognetic variations can give rise to altered pharmacokinetics and/or pharmacodynamics. An exam candidate somewhere may one day be called upon to discuss this with examples. 

  • Absorption can be altered: for example, intestinal drug transporter polymorphisms can cause individual variation in oral bioavailability, as with the ABGG2 transport and rosuvastatin (Nakamura et al, 2006)
  • Distribution can be altered: for example, polymorphisms of α1-acid glycoprotein can change the free fraction of amitriptyline and nortryptyline. When albumin molecules are mutated, it is not such a big issue provided one is heterozygous, because available sites on "normal" albumin molecules will make up for the decreased protein binding by the mutants (Hervé et al, 1994)
  • Metabolism is definitely altered: Evans et al (2009) list numerous CYP enzymes which are subject to genetic polymorphisms which affect drug metabolism. Notable examples include warfarin (CYP2C9) and CYP2D6 (codeine and some antipsychotic drugs) 
  • Elimination may be altered: for instance polymorphism of organic anion transport proteins in the proximal tubule may alter the excretion of beta-lactam antibiotics, loop diuretics and methotrexate (Al-Dosari et al, 2016)
  • Pharmacodynamics is certainly affected. Polymorphism of the drug target itself can affect drug response (eg. in the case of vitamin K epoxide reductase complex, where genetic variants account for 25% of the variability in dosing). Alternatively, something completely unrelated to the drug target could be subject to interindividual genetic variation, altering the effect of the drug. Evans et al (2003) gives the example of the oral contraceptive pill and the risk of venous thromboembolism

Pharmacogenetic disorders

The college syllabus clearly names "malignant hyperthermia, porphyria, atypical cholinesterase and disturbance of cytochrome function" and therefore these definitely need to be mentioned. They probably even deserve a <h3> level subheading. In addition to the above, Part One authors also added G6PD which is a perfectly appropriate step. Rather than digress extensively on each disorder, a good reference is offered to those who need to read deeper. For the rest of us, even the point-form summary below will be too much.

Malignant hyperthermia

  • Single best reference: Stratman et al (2009)
  • Genetic mechanism: autosomal-dominant mutations within the ryanodine receptor, a calcium channel receptor within the sarcoplasmic reticulum. Present in some unknown number of people, as well as pigs dogs and horses. Incidence in human anaesthesia varies from 1:10,000 to 1: 250,000 anaesthetic encounters (Rosenberg et al, 2015) through virtually every article or textbook gives a different number.
  • Pathophysiology: The mutant receptor permits an unregulated release of calcium from the sarcoplasmic reticulum leading to a prolonged and sustained muscle contraction. massive amounts of ATP are used, releasing significant amounts of heat and depleting ATP reserves. The consequences of this "hypermetabolic crisis" are hyperthermia, lactic acidosis, electrolyte bewilderment and DIC. These people mainly die from hyperkalemic cardiac arrest.
  • Pharmacological link: this response is triggered by volatile anesthetic gases and suxamethonium. Also, apparently by stressors such as vigorous exercise and heat.
  • Management is basically to withdraw the initiating agent and to give dantrolene in 2.5mg/kg increments.


  • Single best reference: Roveri et al (2015)
  • Genetic mechanism: autosomal-dominant mutations which affect the enzymes of heme synthesis, resulting in the accumulation of neurotoxic heme precursor molecules such as delta-aminolevulinic acid and porphobilinogen. There are multiple possible variants (eg.acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, etc etc).
  • Pathophysiology: The accumulation of toxic metabolites in response to a trigger agent results in photosensitivity, abdominal pain, altered level of consciousness and acute neuropathy. Production of these metabolites is triggered by drugs which induce specific CYP metabolic enzymes, which by association also induce the expression of 5-aminolevulinate synthase, a crucial enzyme in the synthesis of heme.
  • Pharmacological link: Porphyric crisis can be stimulated by numerous drugs (Roveri et al have a whole table). Of these, some in frequent use in Australia include antiepileptic drugs (phenytoin carbamazepine and valproate), sulfadiazine, sulfamethoxazole, erythromycin, rifampicin, ketoconazole, ketamine, clonidine, thiopentone, methyldopa, risperidone and medroxyprogesterone.
  • Management is also to withdraw the initiating agent and to give a preparation of heme, as this has a negative feedback effect on heme synthesis (as one might expect it to). 

Atypical cholinesterase (pseudocholinesterase)

  • Single best reference: Goodall (2004)
  • Genetic mechanism: A mutation of butylcholinesterase, also known as "pseudocholinesterase" or plasma cholinesterase.  Usually, this is a mutation of two autosomal co-dominant alleles, i.e. "i.e. two alleles at the same locus that exert an equal effect such that the presence of both genes together produces an intermediate effect". 
  • Pathophysiology: Failure to metabolise choline esters predictably leads to the accumulation or persistent effect of the aforementioned esters. This may be just fine if the ester is cocaine, but perhaps less fine if the ester is suxamethonium. 
  • Pharmacological link: drugs which are metabolised by butylcholinesterase are affected, which include suxamethonium, mivacurium, cocaine, procaine, and heroin.
  • Management is to wait. Usually, once the patient is intubated, it is quite safe for them to remain so for the several hours it takes for the prolonged suxamethonium effect to wear off. An alternative would be to give exogenous cholinesterase by means of FFP transfusion, which is expensive and associated with a nonzero risk of transfusion reaction. 

Disturbance of cytochrome function

The textbook Anaesthetic toxicity by Susan A. Rice (1994) has dedicated a considerable proportion of its page surface area, probably because there are a massive number of CYP450 gene families, producing at least 20 different isoforms of the enzyme, and polymorphisms in these enzymes can give rise to numerous pharmacogenetic profiles, not all of which produce a loss of function. A more recent piece by Johansson et al (2010)  produces some examples:

  • Polymorphisms of CYP3A4:  cyclosporine, nifedipine, midazolam, and verapamil
  • Polymorphisms of CYP2C9:  phenytoin
  • Polymorphisms of CYP2D6:  codeine, tramadol, 
  • Polymorphisms of CYP2B6:  methadone
  • Polymorphisms of CYP2C9:  warfarin 

And many others. The possible outcomes of such polymorphisms include the following variants:

  • Non-metabolisers who carry two defective alleles and completely lack the enzyme
  • Intermediate metabolisers, heterozygous  (thus, decreased enzyme activity)
  • Extensive metabolisers who get two functional alleles
  • Ultrarapid metabolisers, carrying two or more active gene copies.

Glucose 6-Phosphate dehydrogenase (G6PD) deficiency

  • Single best reference: Luzzatto & Seneca, 2014
  • Genetic mechanism: An x-linked recessive mutation of glucose 6-phosphate dehydrogenase, the main role of which (in erythrocytes) is to provide reductive potential in the form of NADPH. 
  • Pathophysiology: Failure to produce enough NADPH in the context of oxidative stress has the tendency to deplete glutathione through its conversion to glutathione disulfide. With ongoing oxidative stress, the sulfhydryl groups of haemoglobin and various other proteins are oxidized to disulfides or sulfoxides. These denatured products precipitate into Heinz bodies. This sort of molecular garbage damages red cell membranes and marks red cells to be destroyed by the reticuloendothelial system, hence the acute haemolytic reaction and jaundice.
  • Pharmacological link: drugs which cause such oxidative stress include dapsone, methylene blue, cotrimoxazole, sulfamethoxazole, fluoroquinolones and rasburicase (old-school antimalarials like primaquine can probably  be omitted)
  • Management is "supportive", where one transfuses the patient and keeps them hydrated so that they do not go on to develop renal tubular necrosis.


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