Polypharmacy related symptoms

Polypharmacy related symptoms are symptoms and syndromes caused or worsened by taking several medicines, through adverse effects, drug interactions, drug disease interactions, prescribing cascades, withdrawal, or errors of adherence. Polypharmacy is usually defined as five or more regular medicines and hyperpolypharmacy as ten or more. Some polypharmacy is appropriate, so the issue is whether each drug is still indicated and safe.

Clinical relevance. Adverse drug reactions cause a substantial share of older adult hospital admissions and are usually preventable. Symptoms are often nonspecific (falls, confusion, fatigue, constipation) and are mistaken for ageing.

Pharmacology in older age. Kidney clearance falls, hepatic metabolism of some drugs declines, lipophilic drugs have larger volumes of distribution and longer half lives, albumin falls, and the brain and baroreflexes are more sensitive to sedatives, anticholinergics and vasodilators.

Prescribing cascade. A drug effect is read as a new disease and treated with another drug, for example amlodipine oedema treated with a diuretic, or an antipsychotic causing parkinsonism treated with an anticholinergic.

Classification of presentations.

• Central nervous system: drowsiness, confusion, falls, tremor, extrapyramidal signs.
• Cardiovascular: hypotension, bradycardia, QT prolongation.
• Gastrointestinal: nausea, constipation, bleeding.
• Genitourinary: retention, incontinence.
• Metabolic: hyponatraemia, hyperkalaemia, hypoglycaemia.
• Haematological: bleeding.
• Constitutional: fatigue, weight loss, anorexia.

Key distinctions. Dose related (predictable) reactions are far more common than idiosyncratic ones. Timing matters: symptoms starting days to weeks after a start, dose rise or interacting drug addition suggest causality, while symptoms after stopping a drug suggest withdrawal.

Medication history.

• Collect every medicine from the patient, pharmacy records, carers, and discharge summaries: prescribed, over the counter, herbal (including St John's wort), supplements, eye drops, patches, inhalers, injections.
• Check how each is taken, who administers it, adherence, recent starts, stops and dose changes, and hospital discharges, since errors cluster at transitions.
• Ask about alcohol, tobacco and recreational substances.

Symptom clues.

• Cough: ACE inhibitors.
• Ankle oedema: calcium channel blockers, gabapentinoids, NSAIDs.
• Gynaecomastia: spironolactone.
• Tremor: lithium, valproate, salbutamol, amiodarone.
• Dry mouth, urinary retention, constipation, blurred vision: anticholinergics.
• Myalgia: statins, especially with interacting drugs.
• Dizziness on standing: antihypertensives, nitrates, alpha blockers, tricyclics.
• Bleeding: anticoagulants, antiplatelets, NSAIDs, SSRIs.

Examination. Lying and standing blood pressure, heart rate and rhythm, temperature, hydration, weight, cognition and attention, extrapyramidal signs, tremor, clonus and reflexes, pupil size, bladder scan, rectal loading, skin and bruising.

Red flags.

• Agitation with clonus, hyperreflexia, diaphoresis or temperature over 38 °C (serotonin toxicity).
• Rigidity with hyperthermia and autonomic instability (neuroleptic malignant syndrome).
• Syncope or palpitations with a long QT interval.
• Coarse tremor, ataxia, vomiting or diarrhoea with lithium.
• Nausea, visual disturbance (xanthopsia) or bradycardia with digoxin.
• Drowsiness with slow respiration (opioids, benzodiazepines, gabapentinoids).
• Hot dry skin, dilated pupils, urinary retention with delirium (anticholinergic toxicity).
• Low glucose, melaena or haematemesis, angioedema, severe rash with mucosal involvement, and acute kidney injury.

Special groups. Use Cockcroft-Gault creatinine clearance for drug dosing in frail older adults, since eGFR may overestimate function. Care home residents and people with dementia depend on others to administer medicines, so check for crushed tablets and missed doses.

Drug related causes.

• Anticholinergic burden, sedative hypnotic excess, opioid excess.
• Antihypertensive and diuretic excess, with orthostatic hypotension, hyponatraemia, hypokalaemia and acute kidney injury.
• Hyperkalaemia from ACE inhibitors, angiotensin receptor blockers, spironolactone, trimethoprim and potassium supplements.
• Acute kidney injury from combined NSAID, ACE inhibitor or angiotensin receptor blocker, and diuretic.
• Bleeding from combined anticoagulant, antiplatelet, NSAID or SSRI use.
• Serotonin syndrome, neuroleptic malignant syndrome, torsades de pointes from QT prolonging drugs (macrolides, fluoroquinolones, ondansetron, citalopram, antipsychotics, methadone, amiodarone).
• Digoxin toxicity, lithium toxicity.
• Hypoglycaemia from insulin or sulphonylureas, metformin associated lactic acidosis.
• Statin myopathy and rhabdomyolysis with interacting drugs.
• Drug induced parkinsonism, tardive dyskinesia, steroid induced psychosis, hyperglycaemia and myopathy.
• Withdrawal states: benzodiazepine, alcohol, beta blocker rebound tachycardia, clonidine rebound hypertension, SSRI discontinuation syndrome, opioid withdrawal, corticosteroid withdrawal with adrenal crisis, baclofen withdrawal.
• Angioedema, severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms).

Drug disease interactions. NSAIDs in heart failure or kidney disease, beta blockers in asthma, anticholinergics in dementia or prostatic obstruction, thiazolidinediones in heart failure.

Non-drug mimics. Infection, delirium from other causes, heart failure, anaemia, thyroid disease, electrolyte disorders from disease, malignancy, depression, dementia, diabetes complications, alcohol misuse.

Step 1. Build a timeline of symptoms against each drug start, dose change and addition. A symptom diary helps.

Step 2. Consider each drug for indication, dose for current kidney and liver function, interactions, adverse effect profile, and patient priorities.

Step 3. First line tests:

• ECG: QTc over 500 ms, or a rise of 60 ms or more from baseline, carries high torsades risk. Values over 450 ms in men or over 470 ms in women are borderline.
• Urea and electrolytes, creatinine, glucose, full blood count, liver tests, corrected calcium, TSH, creatine kinase, INR when on warfarin.

Step 4. Drug levels where relevant.

• Digoxin: sample at least 6 hours after the dose. The usual therapeutic range in heart failure is about 0.5 to 0.9 micrograms/L, and toxicity is likely over 2 micrograms/L, but toxicity occurs at lower levels with hypokalaemia, hypomagnesaemia or kidney impairment.
• Lithium: sample 12 hours after the last dose. Usual maintenance range is 0.4 to 0.8 mmol/L, toxicity is likely over 1.5 mmol/L, and over 2.5 mmol/L is severe.

Step 5. Causality assessment (Naranjo scale: 9 or more definite, 5 to 8 probable, 1 to 4 possible) and anticholinergic burden scores (a total of 3 or more is clinically relevant).

Limitations. Drug levels do not always match toxicity, anticholinergic scales differ between versions, and dechallenge (stopping the drug) is the most informative test but can unmask withdrawal effects.

Principles. Stop the offending drug when safe, change one thing at a time, document the plan, and review in 1 to 2 weeks. Avoid abrupt withdrawal of beta blockers, clonidine, benzodiazepines, antiepileptics, SSRIs, opioids, baclofen, and systemic corticosteroids used for over 3 weeks (suppressed adrenal axis).

Benzodiazepine reduction. Convert to an equivalent dose of a long acting agent such as diazepam, then reduce by about 5 to 10% of the dose every 2 to 4 weeks, more slowly near the end.

Emergency management on a monitored bed.

• Opioid respiratory depression: naloxone 0.4 mg IV (opioid naive), repeated every 2 to 3 minutes; in chronic opioid users or frail patients use 0.04 to 0.1 mg increments to avoid withdrawal.
• Titrate naloxone to respiratory rate over 10 breaths/min; maximum about 10 mg before reconsidering diagnosis.
• Naloxone lasts 20 to 90 minutes, shorter than most opioids, so observe and consider an infusion; monitor respiration, saturations and sedation.
• Serotonin syndrome: stop all serotonergic drugs, give oral fluids or IV fluids, control agitation with diazepam 5 to 10 mg IV (repeat as needed, monitor respiration), cool.
• Cyproheptadine 12 mg orally or by nasogastric tube, then 2 mg every 2 hours while symptoms continue, then 8 mg every 6 hours; maximum 32 mg daily.
• Monitor temperature, clonus and sedation; reduce in older adults (sedation, urinary retention, narrow angle glaucoma). Temperature over 41 °C needs paralysis and ventilation.
• Hypoglycaemia: oral glucose 15 to 20 g if able to swallow, repeat after 10 to 15 minutes.
• If not able to swallow, give glucose 10% 150 to 200 mL IV over 15 minutes (or 20% 75 to 100 mL) and glucagon 1 mg IM if no IV access; maximum glucagon 1 mg a dose, may repeat after 10 to 15 minutes.
• Check capillary glucose every 15 minutes initially; glucagon is less effective in starvation, liver disease and alcohol misuse. Sulphonylurea hypoglycaemia recurs, so observe for at least 24 hours.
• Torsades de pointes or long QT with arrhythmia: stop QT prolonging drugs, correct potassium (aim over 4.5 mmol/L) and magnesium, magnesium sulphate 2 g IV over 10 minutes, repeat once if recurrent; continuous ECG; reduce dose in kidney impairment and monitor reflexes and respiration.
• Lithium toxicity: stop lithium and interacting drugs, give isotonic saline to restore euvolaemia and urine output of over 1 mL/kg/hour, repeat levels every 6 hours.
• Haemodialysis for lithium toxicity with neurological impairment, seizures, life threatening arrhythmia, or a level over 4.0 mmol/L with impaired kidney function; consider dialysis for levels over 5.0 mmol/L.
• Digoxin toxicity: stop digoxin, correct potassium and magnesium, treat bradyarrhythmia, and use digoxin specific antibody fragments for life threatening arrhythmia or marked hyperkalaemia, dosed from the product label by amount ingested or serum level (chronic toxicity usually needs 2 to 5 vials). Avoid calcium salts unless immediately life threatening hyperkalaemia.

Hyperkalaemia with ECG changes, serious bleeding, anaphylaxis and angioedema also need emergency management on a monitored bed.

Medication review. Use explicit criteria for potentially inappropriate prescribing and omissions. Stop drugs without a current indication, review long term proton pump inhibitors for step down, and review statins, bisphosphonates and antihypertensives against time to benefit and remaining life expectancy.

Monitoring. Recheck blood pressure, symptoms and relevant bloods 1 to 2 weeks after each change, with a full medicines review every 6 to 12 months.

Referral and escalation. Clinical pharmacist and geriatrician for complex regimens. Poison centre advice for toxicity. Psychiatry for planned withdrawal of antipsychotics or benzodiazepines when severe.

Admission criteria. Serotonin or neuroleptic malignant syndrome, torsades or QT with syncope, severe hypoglycaemia, hyperkalaemia with ECG change, lithium or digoxin toxicity, respiratory depression, acute kidney injury, bleeding, or inability to manage medicines safely at home.

Discharge and safety netting. Give an updated written medicines list, a blister pack or dosette review, and sick day rules. Pause ACE inhibitors, angiotensin receptor blockers, diuretics, metformin, SGLT2 inhibitors and NSAIDs during vomiting, diarrhoea or poor intake, and restart after 24 to 48 hours of normal eating and drinking. Carers are told which symptoms need review.