Drug safety and drug side-effects

An undesirable effect of drug beyond its anticipated therepeautic effects. WHO: noxious + unintentional drug effect. Account for 6.5% of hosp admissions, 2.3% of these patients die.

Anti-platelet, diuretics, anti-coagulants, NSAIDs account for 50% of cases.

• Pharmacological • Most common type of ADR • Consequence of drug action - predictable • Dose-dependent • Not usually life-threatening • Resolved by lowering dose / withdrawing treatment • Generally picked up + understood during drug testing

• Idiosyncratic or bizarre • Unrealted to pharmaoclogy of drug - unpredictable • Not dose related • Often immune or genetic problem • Can be fatal • Need to withdraw drug - not use again • Need longer term + widespread use in population to identify (pharmacovigilance)

• NSAIDs -> GI bleeds, peptic ulcer, renal impairment, bronchospasm • Diuretics -> hypotension, dehydration, electrolyte changes • Opioids -> vomiting, confusion, constipation, resp depression • Insulin/oral hypoglycaemic drugs -> hypoglycaemia These are all predictable, consequence of drug action

• Hypersensitivity reactions • Anaphylaxis shock -> life-threatening • Amoxicillin (broad-spectrum penicillin), anti-convulsants • Steven Johnson syndrome

• Very severe, very rare, very difficult to predict • Linked to genetics, infections, poor liver metabolism of drug metabolites • Flu like symptoms/high fever • Blistering of skin, mucuous membranes • Skin falls off • < 10% body affected - mortality of 5% • Organ damage, blindness

• Penicillin itself is non-immunogenic with a small mol weight • Penicillin undergoes a chemical rxn w/ plasma protein • The penicillin-plasma protein complex is an immunogenic peniccloyl hapten • This triggers immune response, mast cells -> histamine • Anaphylaxis

• Minor type A reactions may be tolerable • Continue to treat + then treat the ADR w/ another drug • Accept more severe ADRs - risk + reward balance • Be aware of vulnerable groups + drugs - know your pharma • Good drug history essential eg. prev drug rxns • Keep up to date with drug info • Patients/HCPs should report problems ASAP

Enable clinician/patient to balance risk and reward -> benefit should always exceed risk. Can lead to: drug withdrawal, contraindication, warnings given, dose changs.

Thalidomide was not initially tested on pregnant animals - missed teratogenic effects -> polydactyl, syndadctyl, phocomelia. 10,000 - 20,000 people affected. Lead to new safety procedures to prove efficency and reveal all side-effects in testing.

• Yellow card • Black triangle • Green form

Good: • Yellow cards main method of post-marketing surveillance • Now anyone can make a report • Black triangle highlights possible adverse rxns to new meds Bad: • (Originally relied on reporting by doctors) • Gross under-reporting suspected • Numerator data only - nothing to compare to

• Reporting limited to a small number of (usually new) drugs • Recording any significant medical event that occurs whilst patient taking drug • Potential to find rare + unusual side effects that may be ignored by individual doctors • Numerator + denominator data are available - all patients monitored • Return of forms can be poor

• Grapefruit juice inhibits cytochrome P450 enzymes in liver • Prevents metabolism of drugs • Inhibits P-glycoprotein transporters in intestine • Prevent excretion of drugs into intestine • Increased bioavailability (undesirable) • More ADRs