Adverse drug reactions

1. Augmented: dose-related and predictable, avoidable (e.g. insulin causing hypos, warfarin causing bleeding)

2. Bizarre: not dose-related and unpredictable (e.g. anaphylaxis from penicillin)

3. Chronic: variable, occur with prolonged duration of treatment (e.g. steroid-induced Cushing's syndrome/osteoporosis)

4. Delayed effects: variable, occur some time after treatment is discontinued (e.g. drug-induced fetal abnormalities, drug-induced cancers)

5. End of treatment: variable, occurs on withdrawal of drug (e.g. Addisonian crisis on steroid withdrawal)

Pharmacogenetics: the study of genetic basis for variability in drug response, deals with genetic influence on drug action and drug handling by the body

Pharmacogenomics: the use of genetic information to guide choice of drug and dose on an individual basis (with a goal of personalised therapy)

• NSAIDs: renal impairment (nephrotoxic), GI ulcers, increased risk of CVS disease
• diuretics: electrolyte disturbances, urinary frequency, headache, dizziness, postural hypotension, thirst, hyperglycaemia, muscle cramps, rash, gout, diarrhoea
• warfarin: bleeding risk, GI bleed, ICH, bleeding into joints
• ACE inhibitors: dry cough, AKI, teratogenic, hyperkalaemia, postural hypotension, headache, drowsiness, metallic taste
• beta blockers: bradycardia, bronchospasm (beware in asthma/COPD), cold fingers/toes, sleep disturbance
• opiates: respiratory depression, tolerance, withdrawal, dependence, constipation, confusion, N+V, urinary retention
• digoxin: dose-related toxicity, dizziness, confusion, depression, anhedonia, anxiety, N/V/D, headache, rash, gynaecomastia, weakness, palpitations, visual problems, thrombocytopenia
• prednisolone/steroids: Cushing's syndrome, adrenal suppression, Addisonian crisis on withdrawal, osteoporosis, diabetes/impaired glucose metabolism, hypertension
• clopidogrel: paresis/paraesthesia, sudden headache, confusion, problems with vision/speech/balance, pallor, fever, jaundice, dyspepsia, bleeding risk

A clinically meaningful alteration in the effect of 1 drug (object) as a result of co-administration of another drug/food/chemical (precipitant)

May cause: no clinically significant effect, clinical harm/effect, increased effect (summative/synergistic), decreased effect (antagonistic)

Consequences: increased hospital admission, increased length of stay, decreased confidence, increased morbidity/mortality

Drugs act on same target site of clinical effect (receptor or body system)

May be:

• Synergistic/summative (additive effects): rifampicin + isoniazid at Mycobacterium tuberculosis (antimicrobial), alcohol + benzodiazepines (sedative)
• Antagonistic (opposing effects): salbutamol + atenolol at beta-adrenoreceptors (bronchodilation vs bronchoconstriction), naloxone + morphine

Altered drug concentration at target site of clinical effect (interaction affects absorption/distribution/ metabolism/excretion):

• Absorption: faster/slower rate, more/less complete e.g. antacids -> less acidic stomach contents -> more drug ionisation (acidic drug) -> slower absorption
• Distribution: displacement from plasma protein binding leads to increased circulating free drug concentration, involves drugs with high plasma protein binding, usually minor and transient due to compensatory increase in metabolism + excretion
• Metabolism: mainly due to shared hepatic metabolism pathway through CYP450 system
• Excretion: inhibtion of active tubular secretion e.g. lithium + thiazide, potassium chloride + spironolactone, theophylline + ciprofloxacin, methotrexate + trimethoprim

Inducers increase P450 in the liver so increases hepatic function, which increases clearance of drugs. Effect takes days-weeks and continues to have an effect for a while after withdrawal. Examples include:

• phenytoin
• carbamazepine
• barbiturates
• rifampicin
• chronic alcohol use
• St John's Wort

Decreased effect of P450 with immediate onset, leading to decreased clearance of drug. Examples include:

• cimetidine
• erythromycin/clarithromycin
• ciprofloxacin
• sulphonamides
• isoniazid
• verapamil
• metronidazole
• omeprazole
• grapefruit juice
• acute alcohol intoxication
• amiodarone
• antifungals