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).
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.
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:
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.
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.
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:
And many others. The possible outcomes of such polymorphisms include the following variants:
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Nebert, Daniel W. "Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist?." Clinical genetics 56.4 (1999): 247-258.
Madian, Ashraf G., et al. "Relating human genetic variation to variation in drug responses." Trends in genetics 28.10 (2012): 487-495.
Nakamura, Tsutomu, Motohiro Yamamori, and Toshiyuki Sakaeda. "Pharmacogenetics of intestinal absorption." Current drug delivery 5.3 (2008): 153-169.
Wang, Liewei. "Pharmacogenomics: a systems approach." Wiley Interdisciplinary Reviews: Systems Biology and Medicine 2.1 (2010): 3-22.
Evans, William E., and Howard L. McLeod. "Pharmacogenomics—drug disposition, drug targets, and side effects." New England journal of medicine 348.6 (2003): 538-549.
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Rosenberg, Henry, et al. "Malignant hyperthermia: a review." Orphanet journal of rare diseases 10.1 (2015): 93.
Roveri, Giulia, et al. "Drugs and acute porphyrias: reasons for a hazardous relationship." Postgraduate medicine 126.7 (2014): 108-120.
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