• Any undesirable reaction, whether expected, predictable or not that results in a detriment to the wellbeing of the patient in any way, whether symptomatic, detectable or not, in the absence of another biologically plausible explanation that can be proven
• Most common in: elderly and frail, multimorbid, polypharmacy, drugs with narrow therapeutic index

Stages of ADR detection

• Drug development phase (pre-clinical)
  • Most efficient with least attrition (financial cost, morbidity/mortality)
• Clinical trials (phases I-III)
  • Limited sample size - low frequency ADRs/ time-lag ADRs
  • Exclusion of frail patients
• Post-marketing surveillance (phase IV and beyond)
  • Less 'efficient', highest attrition (financial cost, morbidity/mortality) BUT most data avaliable

Phases of drug metabolism

• Phase I - usually through oxidation, reduction, and hydrolysis via cyo P450
• Phase II - conjugation (water soluble) which enables excretion in urine/bile
• ADRs almost always due to phase I interactions

Classification of ADRs

Type A

• Augmented pharmacological effects, dose dependent and predictable

Mechanisms and examples

• Pre-renal failure (hypotension, hypovolcaemia)
  • e.g. diuretics (HF), ACEi/ARBs (various)
• Renal (AIN/ATN)
  • e.g. gentamicin (sepsis), sulphonamides (RA), aspirin (CV disease)
• Post-renal (retroperitoneal fibrosis, crystaluria, urinary caliculi)
  • e.g. methysergide (cluster headaches), chemotherapy (acute leukaemias)
• Drug interactions
  • Drug-drug interactions
  • Drug-disease interactions
  • Drug-food interactions

Type B

• Bizarre effects, dose independent and unpredictable