Classification of adverse drug reactions

This chapter is related to one of the aims of Section D(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "classify and describe adverse drug reactions". This topic has come up in Question 16 from the second paper of 2017, where the college demonstrated a surprising degree of constructive alignment by literally asking the trainees to "classify and describe adverse drug reactions", with examples. Additionally, in Question 14 from the first paper of 2012, the college also wanted a definition of adverse drug rection.  In the pre-Primary era, the topic also appeared in the Fellowship exam as Question 16 from the second paper of 2005, and some minimal attention is dedicated to it in the Required reading section on Pharmacology and Toxicology.

There is actually quite a wide range of possible classification systems for adverse drug reactions, and from the college comments it would appear that any widely accepted system would make a reasonable written response, provided one sticks with the same system for the entire answer. It is unclear whether candidates who couldn't make up their minds and used fragments from different systems were marked down for their promiscuity, but it certainly "led to a less structured answer" and we all know how much the examiners love those.  

In summary:

For peer-reviewed resources, the official college textbook (Katzung, 14th ed) has a section on adverse drug reactions (Ch.2, Drug Receptors & Pharmacodynamics - p.39), but this single page summary is probably not enough to pass Question 16 or any future CICM Part I SAQs which might crop up to explore this subject matter.  A slightly more comprehensive resource is the article from Schatz et al (2015), which gives the impression of being more recent, even though it reproduces the classification system from Edwards et al (2000). 

Definition of an adverse drug reaction

Edwards et al (2000) define an adverse drug reaction as

“an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.”

For the purpose of SAQ answers, the abovestated definition will suffice. In fact even this sentence may be too verbose. One might want to instead quote the abbreviated version from Schatz et al (2015):

"An adverse drug reaction (ADR) is an unwanted, undesirable effect of a medication that occurs during usual clinical use"

Or, one could take a minimalist approach and use Katzung (14th ed):

"An adverse drug event (ADE) or reaction to a drug (ADR) is a harmful or unintended response."

Likely, there is little to be gained by going into greater depth. The exam candidate fatigued by memorising definitions will be consoled by the knowledge that virtually every author who has ever published on this subject seems to have created their own wording for the definition of this term. However, it would be valuable to discuss the difference between an adverse drug reaction and an adverse drug event , as these are distinct:

• An adverse drug event is “any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment” (WHO definition, 2005)
• An adverse drug reaction is “a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.” (WHO definition, 2005)

In other words, the reaction is where the drug does something nasty, and an event is something nasty which potentially happens randomly and might be totally unrelated to the drug. The basic requirements for an ADR are therefore:

• The reaction is directly related to the drug
• The drug was being used correctly and appropriately
• The reaction is harmful

Thus, prescribing errors and intentional overdoses do not fall under the definition of an adverse drug reaction.

A common classification system

This system, in a form originally described by  Edwards et al (2000), has a reasonable level of brevity and memorability which makes it suitable for exam preparation. It originated from a book chapter by Rawlin & Thompson (1977) which is obviously not easily available to the casual Googler. The authors classified ADRs into "dose-related" and "not dose-related",  which were arbitrarily designated "Type A" and "Type B". Four years later (1981) the same authors decided to rename these as “Augmented” and “Bizarre”, for what other authors describe as "mnemonic purposes". The other belowlisted classification categories were added over the subsequent years by other authors.

A: Dose-related reactions	This can include adverse effects at either normal dose or overdose. These may include expected extensions of the therapeutic effect of the drug, eg. bleeding in heparin. Toxic effects eg. serotonin syndrome Side effects are included, eg. anticholinergic effects of tricyclics
B: Non-dose-related reactions	This refers to drug effects which are totally unrelated to the dose (i.e. any exposure is enough to trigger such a reaction). Allergic reactions Anaphylaxis Idiosyncratic reactions, eg. purpura or drug-induced SLE
C: Dose and time-related reactions	This refers to drug effects which occur due to dose accumulation, or with prolonged use Adrenal suppression with corticosteroids is one example.
D: Time related reactions	This refers to drug effects which occur due to prolonged use in a drug which doesn't tend to accumulate. An example might be tardive dyskinesia after decades of using typical antipsychotics
E: Withdrawal reactions	This refers to the undesired effects of ceasing the drug Classical examples might include opiate withdrawal and rebound hypertension after stopping clonidine.
F: Unexpected failure of therapy	This category has been added to describe an undesirable reduction in the drug's efficacy (or, the undesirable increase thereof) Examples may include increased clearance by dialysis and plasmapheresis, drug interactions altering metabolism, and the effects of critical illness on protein binding and elimination.

Other classification systems for adverse drug reactions

Vervloet et al (1998), in their article on adverse drug reactions, suggested we classify them according to whether they could take place in any patient, or in a specific susceptible population. This is not associated with any reference.

• Reactions that may occur in anyone

  • Drug overdose—Toxic reactions linked to excess dose or impaired excretion, or to both

  • Drug side effect—Undesirable pharmacological effect at recommended doses

  • Drug interaction—Action of a drug on the effectiveness or toxicity of another drug

• Reactions that occur only in susceptible subjects

  • Drug intolerance—A low threshold to the normal pharmacological action of a drug

  • Drug idiosyncrasy—A genetically determined, qualitatively abnormal reaction to a drug related to a metabolic or enzyme deficiency

  • Drug allergy—An immunologically mediated reaction, characterised by specificity, transferability by antibodies or lymphocytes, and recurrence on re-exposure

  • Pseudoallergic reaction—A reaction with the same clinical manifestations as an allergic reaction (eg, as a result of histamine release) but lacking immunological specificity

The college answer to Question 16 from the second paper of 2005 has offered another classification system, which is probably no less valid than any of the others. Like Vervloet et al,  it is unclear where it comes from. 

• Expected reactions:
  • Extensions of therapeutic effect
  • Undesirable side-effects
  • Interactions with other drugs
• Unexpected reactions:
  • anaphylaxis
  • allergic reactions
  • prescription error
  • administration errors
  • idiosyncratic metabolism reactions, leading to increased or decreased clearance
  • Interaction with the critical care environment:
    • Clearance by dialysis or plasmapheresis
    • Interaction with devices (eg. adsorption onto ECMO circuit)

WHO classification

This system was described as "comprehensive and logical" in the college answer to Question 16 from the second paper of 2017, which is as good a praise as anything has ever received in that forum. Unfortunately, it is probably undeserved. The WHO Adverse Reaction terminology statement, which was subsequently replaced by the very similar Medical Dictionary for Regulatory Activities, is an insanely complex system designed to classify every possible adverse drug reaction to a truly ridiculous level of granularity. As an example: in 2003 (before an iterative expansion) it had 32 system-organ classes and body organ groups, 180 high level terms for grouping preferred terms, - 2000 preferred principal terms for describing adverse reactions, and 3032 synonyms to preferred terms. There is no merit in exploring this any further for the purposes of the CICM Primary Exam.