Idiosyncratic drug reactions

This chapter is directly related to Section D(v) from the 2023 CICM Primary Syllabus, which expects the exam candidate to "define... idiosyncrasy..." along with several other related terms. Even though this appears in the syllabus, it is extremely unlikely for this specific definition to ever appear in the written exam, considering its relative unimportance. Rather than the definition, the recognition and management of these syndromes is probably the more relevant matter.

In terms of peer-reviewed resources dealing with this topic, Goodman & Gillman (12th ed) probably has the best all-round definition of idiosyncrasy on page 76 of the 12th edition. (around page 1.49). The Textbook of Pharmacology by Seth has a competing definition (around page 1.49). Those definitions are approximately one paragraph, which is probably enough for the pragmatic exam candidate. If for whatever reason a substantial depth of knowledge is called for, the article by Uetrecht & Naisbitt (2013) would be the single best resource.

In summary:

  • Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual. It could be:
    • An abnormally exaggerated response, or an abnormal lack of response
    • A response unusual because it requires an unusually small or unusually large dose
    • An extension of the normal physiological drug effect
    • A reaction which is unrelated to the expected physiological effect
  • Idiosyncrasy is not a drug allergy, but both are forms of adverse drug reaction
  • Idiosyncratic drug reactions are unrelated to the dose of the drug
  • Common lifethreatening idiosyncratic drug reactions include DRESS syndrome, toxic epidermal necrolysis and Stevens-Johnson syndrome

Pharmacological definition of idiosyncrasy 

The definition from Textbook of Pharmacology by Seth is:

"an unusual response or a highly exaggerated usual response to usual doses to some drugs in few individuals"

That's probably as good as it gets. It is impossible to give a clear official definition for exam purposes because the term, as Uetrecht and Nasibitt put it, "has been used in various ways and has no clear definition". These authors decided to describe it as

"an adverse reaction that does not occur in most patients treated with a drug and does not involve the therapeutic effect of the drug".

 That is quite different from Goodman & Gillman:

"Idiosyncrasy is an abnormal reactivity to a chemical that is peculiar to a given individual"

This definition is probably the most suitable because it is short and generic. It also allows for an idiosyncratic lack of a reaction, i.e an individual who is uniquely insensitive to a substance. It opens the possibility that the reaction is an extension of the therapeutic effect of the drug (unlike Uetrecht & Nasibitt) and it does not restrict it to reactions resulting from "usual" doses, allowing for situations where a laughably small or comically large dose of the drug produces the unexpected effect.

The ability to define this term is probably quite irrelevant from the perspective of actually practising intensive care medicine. The more interesting elements would probably be the causes, consequences and management of idiopathic drug reactions.

Pathophysiology of idiosyncratic drug reactions

Idiosyncratic reactions are generally thought to be immune-mediated. There is no agreement on their precise mechanism, and there are many exceptions to contradict every hypothesis. In summary:

  • Either the drug itself, or a reactive metabolite, binds to a protein 
  • That protein undergoes a chemical and morphological change, breaking self-tolerance
  • The immune system reacts to this altered protein in a multitude of ways, which usually resemble an adaptive immune response but can also feature eosinophilia

Virtually every idiosyncratic response has a distinct syndrome of symptoms and organ dysfunction, but some shared characteristics do exist.

  • Multi-organ involvement is very common
  • There is usually a (long) delay between starting the drug and the onset of symptoms
  •  Risk of an idiosyncratic reaction does not seem to increase with dose
  • A skin rash is almost always involved
  • They will frequently resolve in spite of continuing treatment with the offending drug because of the development of tolerance.

Classical examples of drug-induced idiosyncratic reactions

There is the distinct possibility that some cruel viva scenario will call for the sweating exam candidate to produce a list of idiosyncratic drug reactions as examples. A solid offering from the literature is hard to find. Here is a short list which was generated by combing through the article by Knowles et al (2000) and Park et al (1992)

Idiosyncratic Drug Reaction Syndromes
Syndrome Drugs Features
Stevens-Johnson syndrome and toxic epidermal necrolysis
  • Phenytoin
  • Sulfonamides
  • Allopurinol
  • NSAIDs
  • Beta-lactams
  • Epidermal necrosis and detachment
  • Mucous membrane erosions
  • "Target" lesions
Serum sickness-like reaction
  • Cefaclor
  • Cefprozil
  • Fevers
  • Rash
  • Arthralgias
  • Eosinophilia
Drug-induced lupus
  • Procainamide
  • Hydralazine
  • Chlorpromazine
  • Isoniazid
  • Methyldopa
  • Penicillamine
  • Minocycline
  • Pleuritis
  • Musculoskeletal complaints, eg. arthralgias
  • Fever
  • Weight loss
Drug-induced hepatitis
  • Azathioprine
  • Antiretrovirals
  • Statins
  • NSAIDs
  • Phenytoin
  • Imipramine
  • Amiodarone
  • Ranges from asymptomatic LFT derangement to fulminant liver failure
Aplastic anaemia, agranulocytosis
  • Chloramphenicol
  • Dapsone
  • Clozapine
  • Carbimazole
  • Can be selective (eg. neutropenia) or affecting multiple cell lineages


Knowles, Sandra R., Jack Uetrecht, and Neil H. Shear. "Idiosyncratic drug reactions: the reactive metabolite syndromes." The Lancet 356.9241 (2000): 1587-1591.

Uetrecht, Jack. "Idiosyncratic drug reactions: current understanding." Annu. Rev. Pharmacol. Toxicol. 47 (2007): 513-539.

Seth, S. D. "Textbook of pharmacology." 

Uetrecht, Jack, and Dean J. Naisbitt. "Idiosyncratic adverse drug reactions: current concepts." Pharmacological reviews65.2 (2013): 779-808.