Key Facts

Drug interactions are a leading cause of preventable adverse drug events. With increasing polypharmacy, the risk of interactions rises exponentially. Awareness of the most clinically important interactions is essential for safe prescribing.

Epidemiology

• Drug interactions account for ~1% of hospital admissions and ~3–5% of in-hospital adverse drug events
• Risk increases exponentially with number of drugs: 2 drugs = 6% risk; 5 drugs = 50% risk; 8+ drugs = nearly 100%
• Elderly most affected: polypharmacy + altered PK/PD

Classification

Pharmacokinetic Interactions:

• Absorption: chelation (tetracyclines + calcium/iron), altered gastric pH (PPIs reduce ketoconazole absorption)
• Distribution: protein binding displacement (rarely clinically significant)
• Metabolism: CYP450 induction/inhibition (most important mechanism)
• Excretion: competition for renal tubular secretion, altered urinary pH

Pharmacodynamic Interactions:

• Additive: two drugs with same effect (e.g. two sedating drugs → excessive sedation)
• Synergistic: combined effect greater than sum (e.g. trimethoprim + sulfamethoxazole on folate pathway)
• Antagonistic: one drug reduces effect of another (e.g. NSAID antagonises antihypertensive effect)

Pathophysiology

• CYP450 interactions: most clinically significant — see Drug Metabolism topic
• Renal interactions: altered GFR, tubular secretion, reabsorption
• Receptor interactions: additive or competitive effects at shared receptor targets
• Electrolyte effects: hypokalaemia (diuretics) increases digoxin and arrhythmia risk

High-Risk Interaction Scenarios

Serotonin syndrome:

• SSRIs/SNRIs + MAOIs, tramadol, triptans, linezolid, methylene blue
• Features: agitation, clonus, hyperreflexia, hyperthermia, sweating, tachycardia, diarrhoea
• Management: stop serotonergic drugs, supportive; cyproheptadine 4–8 mg (5-HT2A antagonist)

QT prolongation and torsades de pointes:

• Multiple QT-prolonging drugs: amiodarone, sotalol, macrolides, quinolones, ondansetron, antipsychotics, methadone, domperidone
• Plus electrolyte abnormalities (hypokalaemia, hypomagnesaemia) → increased risk
• Management: correct electrolytes, stop offending drugs, IV magnesium

Hyperkalaemia:

• ACE inhibitor/ARB + potassium-sparing diuretic + potassium supplements
• Adding co-trimoxazole to RAAS inhibitor
• Management: stop potassium-elevating drugs, calcium gluconate, insulin/dextrose

Bleeding (warfarin interactions):

• Increased INR: CYP inhibitors (clarithromycin, fluconazole, amiodarone), displaced protein binding, reduced vitamin K (antibiotics altering gut flora)
• Decreased INR: CYP inducers (rifampicin, carbamazepine, St John's wort)

Red Flags

• Any new drug in a patient on warfarin, lithium, digoxin, or immunosuppressants
• Serotonergic drug combinations
• Multiple QT-prolonging drugs
• NSAIDs in patients on anticoagulants or with renal impairment
• Potassium-elevating drug combinations

Before Prescribing

• BNF interactions checker: check ALL current medications
• Electronic prescribing alerts: use and respond to interaction warnings
• Medication review: comprehensive list including OTC, herbal, supplements

Monitoring

• INR: when starting/stopping any drug in warfarin patients
• Renal function (U&Es): when combining nephrotoxic drugs or RAAS inhibitors
• Electrolytes (K+, Mg2+): when using diuretics, digoxin, QT-prolonging drugs
• Lithium levels: when changing co-prescribed drugs (NSAIDs, diuretics, ACE inhibitors)
• ECG: QTc monitoring when combining QT-prolonging drugs
• TDM: for narrow TI drugs when interacting drug started/stopped

Special Tests

• Pharmacogenomic testing: CYP2D6, CYP2C19 — if unexpected drug responses suggest interaction or genetic variant
• Drug level assays: specific assays for digoxin, phenytoin, ciclosporin, etc.

Prevention

• Medication reconciliation: at every care transition (admission, discharge, clinic)
• Structured medication review: at least annually; more frequently in complex patients
• Prescribing guidance: follow BNF interaction guidance, local formulary recommendations
• Avoid unnecessary polypharmacy: deprescribe where possible
• Choose non-interacting alternatives: e.g. use pravastatin instead of simvastatin if on CYP3A4 inhibitor

Management of Interactions

• Dose adjustment: adjust dose of affected drug and monitor
• Change drug: switch to non-interacting alternative
• Monitor closely: TDM, clinical assessment, bloods
• Timing separation: for absorption interactions (separate calcium/iron from levothyroxine by 4 hours)

Emergency Management

• Serotonin syndrome: stop all serotonergic drugs, supportive care, cyproheptadine 4–8 mg PO, benzodiazepines for agitation
• QT prolongation/torsades: stop QT drugs, IV magnesium 2 g, correct K+ to 4.5–5.0 mmol/L, overdrive pacing if refractory
• Bleeding (warfarin): stop warfarin, vitamin K (phytomenadione 5 mg IV), prothrombin complex concentrate if life-threatening
• Lithium toxicity: stop lithium, IV fluids, monitor levels; haemodialysis if severe (>3.5 mmol/L or symptomatic >2.5)

Referral Criteria

• Clinical pharmacology: complex polypharmacy, multiple interactions
• Medicines management team: medication review, deprescribing
• Toxicology: acute poisoning involving drug interactions

• Most drug interactions are preventable with careful prescribing and monitoring
• Serious outcomes (death, hospitalisation) occur with high-risk combinations
• Electronic prescribing reduces interaction-related harm
• Pharmacist involvement in medication review significantly reduces adverse events
• Patient education about interactions (including OTC and herbal products) is essential

Top 10 Drug Interactions for UK Exams

BNF Interaction Severity