Adverse Drug Reactions (ADR)

Adverse Drug Reactions (ADR)

·        WHO definition: any response to a drug which is undesirable and unintended, and which occurs at doses used in man, for prophylaxis, diagnosis or therapy, excluding therapeutic failure

·        Responsibility of prescriber is to observe, record and report adverse drug effects and interactions

·        Includes:

o  Side effects

o  Intolerance (side effects occurring at levels normally well tolerated)

o   Anaphylaxis

o   Interactions with other drugs (e.g. pharmacokinetic reaction due to enzyme induction)

·        Classification: includes mistakes (knowledge based errors) and lapses (skill based error)

·        Grading them:

o   Serious: results in death, hospitalisation or persistent disability 

o   Severity: intensity of reaction not seriousness of reaction (ie a severe skin reaction may not be serious)

·        Incidence:

o   True incidence unknown

o   Estimated 3 – 5 % of all hospitalisations due to an ADR

o   Estimated 3 in 1000 hospital deaths due to a drug reaction

o   Common in elderly

·        Monitoring:

o   Medicine Assessment Advisory Committee reviews new drugs prior to licensing 

o   Can be licensed for monitored use through the Intensified Medicines Monitoring Programme (IMMP). Requires reporting of ALL new clinical events in a patient 

o   Voluntary reporting to the Centre for Adverse Reactions Monitoring in Dunedin (reporting rate estimated < 15%) 

o   Danger/Warning Notification System with NHI number. Records potentially life-threatening reactions

·        Difficulties in recognising ADRs:

o   May mimic a common symptom (eg headache)

o   May be so bizarre that a common drug escapes suspicion

o   May be a long delay (eg hepatoxic reactions)

o   The ADR may be confused with the disease (eg antibiotic fever in meningitis)

·        Recognising an ADR: suspicion, how often does this occur without the drug (ie reference rate of the disorder), temporal sequence, what happens when drug is discontinued and/or rechallenged

·        Frequency of effect: 

o   Clinical trials are poor indicators of ADRs. Not sufficient numbers to find rare effects, so post market surveillance important

o   Eg:

·        GI bleed  Agranulocytosis

·        Reference Rate 1:100 1:100,000

·        Rate with NSAID           5:100 5:100,000

·        Rate Ratio           5          5

·        Attributable Fraction  80%    80%

·        Determinants of ADRs:

o   The drug itself: rate, route, formulation, dose

o   The patient: 

§  Age: young (immature conjugating enzymes) and elderly (¯clearance) 

§  Gender: more common in women. ?Effect of sex hormones, ?less gastric acid, compounding effect of ­health seeking behaviour 

§  Disease: diseases of heart, kidneys, liver all affect drug kinetics and dynamics. Eg, AIDs ® ­risk of ADR with co-trimoxazole 

§  Previous history: Previous reaction ®­risk

§  Genetic and ethnic factors, eg altered rates of metabolism

o   Extrinsic factors:

§  Alcohol consumption, tobacco, pollutants 

§  Multiple drug therapy: 1 – 5 drugs ® 3.3% risk, 6+ drugs ® 19.8% risks

·        Mechanisms of ADRs:

o   Type A – predictable. 

§  Exaggerated primary therapeutic effects. Risk is increased with ­dose or ¯ clearance. Rarely serious. Eg anticoagulants ® bleeding, hypotension with antihypertensives 

§  Primary drug effects that are not therapeutic.  Eg b blockers ® bronchospasm 

o   Type B - unpredictable. Dose independent, low incidence, serious. Eg anaphylaxis to penicillins, carcinogenicity, dental discolouration from tetracyclines