Question 16 from the second paper of 2005 asked the candidates to "list potential adverse  drug reactions, and outline  how they may impact on your management of the critically ill patient." Because this is a very broad and generic question, candidates who did not have a structure would have struggled to write anything sensible. Certainly, the model college answer recommends "a structured approach", offering an example of such a structure. They recommended to separate the adverse drug reactions into "expected" and "unexpected". An alternative schema is offered in an excellent article from the Lancet (Edwards et al, 2000). Both are offered in the summary below.

Definition of adverse drug reaction

  • Edwards offers the follwign amendement to the 30-year old WHO definition. An adverse drug reaction is "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.”
  • The old WHO definitiuon was “a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease,  or  for  modification  of  physiological  function”.

CICM model answer classification of drug reactions

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 critical care environment:
    • Clearance by dialysis or plasmapheresis
    • Interaction with devices (eg. adsorption onto ECMO circuit)

Classical pharmacological classification of adverse drug reactions

Dose-related reactions

  • This can include adverse effects at either normal dose or overdose.
  • These may include expected extesions 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 

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

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.

Time related reactions

  • This refers to drug effects which occur due to prolonged use in a drug which doesnt tend to accumulate.
  • An example might be tardive dyskinesia afte decades of using typical antipsychotics

Withdrawal reactions

  • This refers to the undesired effects of ceasing the drug
  • Classical examples might include opiate withdrawal and rebound hypertension after stopping clonidine.

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 alterinc metabolism, and the effects of critical illness on protein bindind and elemination.

Management of adverse drug reactions

Immediate management:

  • ABCs
  • Identification and withdrawal of the offending agent
  • Immediate IM adrenaline (500mcg) for anaphylaxis
  • Hydrocortisone and antihistamines for allergic reactions

Investigation

  • need for thorough drug history
  • search for evidence of previous drug reactions
  • thorough history of allergies
  • search for predisposition to adverse effects
  • Assessment of drug interactions
  • Investigations (such as plasma concentration measurements, biopsies, and allergy tests)
  • Organ system function assessment (EUC, LFTs, TFTs, FBC for neutropenia, etc)
  • Rechallenge with the drug should be considered

Prevention

  • awareness of impaired clearance mechanisms due to organ pathology
  • careful prescribing
  • attention to drug interactions
  • rational management of polypharmacy
  • monitoring of drug levels
  • staff education regarding safe prescribing and administration
  • pharmacist participation in ICU rounds

References

Leape, Lucian L., et al. "Pharmacist participation on physician rounds and adverse drug events in the intensive care unit." Jama 282.3 (1999): 267-270.

Edwards, I. Ralph, and Jeffrey K. Aronson. "Adverse drug reactions: definitions, diagnosis, and management." The Lancet 356.9237 (2000): 1255-1259.

Cullen, David J., et al. "Preventable adverse drug events in hospitalized patients: a comparative study of intensive care and general care units." Critical care medicine25.8 (1997): 1289-1297.

Bates, David W., et al. "Incidence of adverse drug events and potential adverse drug events: implications for prevention." Jama 274.1 (1995): 29-34.