22.13 — Side Effects, Interactions and the Combinations That Kill

An 82-year-old is brought in confused and unsteady after a fall. She is taking eleven medications.

Two of them cause drowsiness. One lowers her blood pressure when she stands. One has quietly dropped her sodium. One was started three months ago to treat a side effect of another. Nobody has reviewed the list in four years.

There is no single culprit here, and that is exactly the point.

Adverse drug reactions account for around 5 to 10 percent of hospital admissions, and a large share of them are judged preventable.

The rule that catches most of it

Any new symptom in someone taking medication is a drug effect until proven otherwise.

This one habit catches more harm than any interaction checker, because the default assumption is usually the opposite — a new symptom gets a new diagnosis, and the new diagnosis gets a new drug.

Which is the prescribing cascade, and it is worth naming because once you see it you see it everywhere:

A blood pressure drug causes ankle swelling. A diuretic is added. The diuretic causes gout. Colchicine or an NSAID is added. The NSAID damages the kidneys and raises blood pressure. Another blood pressure drug is added.

Four drugs, and the correct answer at step one was to change or reduce the first.

Common cascades worth recognising: amlodipine causing swelling treated with a diuretic; a cholinesterase inhibitor causing urinary urgency treated with an anticholinergic, which then worsens the dementia the first drug was for (Chapter 22.11); and a proton pump inhibitor started for NSAID indigestion when the NSAID could have been stopped.

The interactions that cause the most harm

Not an exhaustive list — the ones with the highest body count.

Opioids plus benzodiazepines plus alcohol

Three central nervous system depressants that each suppress breathing.

Together the effect is more than additive. This combination accounts for a large share of accidental overdose deaths, and it frequently occurs entirely with prescribed medication in people who were not misusing anything.

If someone is on both an opioid and a benzodiazepine, that is a combination to question rather than to accept.

Warfarin plus almost anything

Warfarin has a narrow therapeutic index and is metabolised by enzymes that many drugs affect (Chapter 22.2).

Raising the effect and causing bleeding: antibiotics — particularly macrolides, metronidazole, ciprofloxacin and trimethoprim; antifungals; amiodarone; NSAIDs and aspirin, which add bleeding risk independently; and alcohol binges.

Reducing the effect and risking clots: rifampicin, carbamazepine, St John's wort, and a sudden increase in dietary vitamin K.

Any new drug in someone on warfarin means an INR check within days.

NSAID plus ACE inhibitor plus diuretic

Three drugs that each reduce the kidney's ability to maintain filtration (Chapter 22.5).

Together, in someone dehydrated or unwell, they cause acute kidney injury reliably.

And this combination is extremely common, because each drug arrives for a good reason from a different direction.

Serotonin syndrome

Too much serotonin activity, from combining serotonergic drugs.

The culprits: SSRIs and SNRIs, tramadol, triptans, linezolid, MAO inhibitors, St John's wort, and some illicit drugs.

The picture, which is distinctive once known: agitation and confusion; increased reflexes and clonus, particularly in the ankles; muscle rigidity; tremor; sweating; fever; and dilated pupils.

Onset is usually within hours of a dose change, which distinguishes it from most other causes.

Severe cases are life-threatening. Treatment is stopping the drugs and supportive care.

And the distinction from neuroleptic malignant syndrome (Chapter 22.11): serotonin syndrome comes on fast with overactive reflexes; the neuroleptic syndrome comes on over days with lead-pipe rigidity and reduced reflexes.

Drugs that prolong the QT interval

The QT interval is the time the heart takes to reset electrically (Chapter 7.3). Prolonging it risks a dangerous rhythm called torsades de pointes.

Common offenders: some antibiotics including macrolides and quinolones; antipsychotics including haloperidol; citalopram and escitalopram; ondansetron; amiodarone and sotalol; and some antifungals and antimalarials.

The risk multiplies when two are combined, and when potassium or magnesium is low — which is why a diuretic that drops potassium plus a QT-prolonging antibiotic is a worse combination than either alone.

Potassium

Several common drugs raise it: ACE inhibitors, ARBs, spironolactone, trimethoprim, and potassium supplements.

And high potassium causes cardiac arrest with very little warning (Chapter 7.3).

The combination of an ACE inhibitor, spironolactone and trimethoprim for a urinary infection is a documented and repeated cause of serious harm — three potassium-raising drugs at once in someone whose kidney function is often already reduced.

Statins plus enzyme inhibitors

Clarithromycin, some antifungals, and grapefruit raise statin levels, increasing the risk of muscle damage.

Simvastatin and atorvastatin are affected; pravastatin and rosuvastatin much less (Chapter 22.7).

The usual practical answer is to pause the statin for the week of the antibiotic, which costs nothing.

Anticholinergic burden

And this is the interaction that is least recognised because no single drug seems responsible.

Many drugs block acetylcholine as a side effect (Chapter 11.9): older antihistamines, tricyclics, oxybutynin for bladder, some antipsychotics, hyoscine, and several others.

None of them may be a problem alone. Added together, the total load causes confusion, memory problems, falls, constipation, urinary retention, dry mouth and blurred vision.

High cumulative anticholinergic burden is associated with increased dementia risk, and it is one of the most reversible causes of apparent cognitive decline in older people.

Which makes totalling it up across the whole list a genuinely valuable exercise.

The food and supplement interactions

Grapefruit — inhibits CYP3A4 in the gut wall, raising levels of some statins, calcium channel blockers, and immunosuppressants (Chapter 22.2). One glass can matter for more than a day.

St John's wort — a powerful enzyme inducer. Has caused contraceptive failure, transplant rejection and HIV treatment failure. The clearest demonstration that "herbal" does not mean "inert".

Vitamin K — consistency matters for warfarin, not avoidance.

Calcium, iron, magnesium and antacids — bind several drugs in the gut, including levothyroxine, tetracyclines and quinolones. Separate by a few hours.

Alcohol — with metronidazole; with sedatives; with paracetamol in chronic heavy use; and with anything that lowers blood pressure.

Cranberry — modest effect on warfarin.

Fish oil, ginkgo and garlic supplements — added bleeding risk with anticoagulants.

And the general point: tell the pharmacist about supplements. Most people do not, because they do not think of them as drugs.

Allergy versus side effect

And getting this right matters, because a wrong allergy label narrows the options for life (Chapter 22.6).

A side effect is a predictable pharmacological consequence — nausea from an antibiotic, drowsiness from an antihistamine. Usually manageable by dose or timing.

An intolerance is an unpleasant reaction without an immune mechanism.

A true allergy is an immune reaction: hives, swelling of lips, tongue or face, wheeze, or anaphylaxis, typically within an hour.

Or a severe delayed reaction: widespread rash with fever, blistering, or organ involvement — Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS (Chapter 14.5). These are never re-challenged.

"It made me sick" is not an allergy. Recording it as one removes an entire drug class from someone's future for no reason.

Special populations

Older people — reduced kidney and liver clearance, more fat and less water, and greater sensitivity to sedatives and anticholinergics. Explicit lists of drugs to avoid in older people exist — the Beers criteria and the STOPP/START tool — and using them reduces harm.

Children — dosed by weight, and a decimal error is the classic route to a tenfold overdose. Never assume a smaller adult dose.

Pregnancy — most drugs cross the placenta (Chapter 4.6). Known teratogens include isotretinoin, sodium valproate, warfarin, ACE inhibitors and ARBs, and methotrexate.

And the balance runs both ways: untreated epilepsy, untreated depression and untreated asthma all carry real risks to the pregnancy. Stopping a necessary medicine on discovering pregnancy is frequently the more dangerous decision, and it is one to make with advice rather than alone.

Breastfeeding — most drugs pass in small amounts; many are compatible; specific advice exists per drug.

Kidney and liver disease — dose adjustment for many drugs.

Polypharmacy

Taking five or more medications, which is very common over 65.

And it is not automatically wrong. Someone with heart failure, diabetes and atrial fibrillation may need eight drugs, each of which is genuinely improving their outlook.

The distinction is between appropriate polypharmacy and problematic polypharmacy — where drugs no longer have an indication, where the harm outweighs the benefit, or where the burden of taking them exceeds what they deliver.

Deprescribing — the deliberate, supervised reduction or stopping of medicines that are no longer helping.

Candidates: proton pump inhibitors started years ago; sleeping tablets; long-term antipsychotics in dementia; multiple blood pressure drugs in someone now getting dizzy; preventive drugs whose benefit takes ten years in someone with a shorter horizon.

And that last one deserves saying plainly rather than delicately: a statin taking five years to deliver benefit is not helping someone in the last year of life, and stopping it is good care rather than giving up.

What you can actually do

Keep one accurate list — every prescribed drug, every over-the-counter product, every supplement. Take it to every appointment.

Ask three questions about any new drug: what is it for, how will I know it is working, and when should it be reviewed.

Use one pharmacy where possible, so one system sees the whole list.

Ask for an annual medication review, and specifically ask "is there anything here I could stop".

Report new symptoms as possible drug effects rather than as new problems.

Do not stop things silently. Abrupt stopping is dangerous for steroids, beta blockers, antiepileptics, benzodiazepines, antidepressants and anticoagulants.

And check before adding anything, including herbal products — the pharmacist is free, available without an appointment, and better at this than almost anyone.

What the next page fixes

Chapter 22.14 covers the household medicine box — what to actually keep at home, item by item, and what each one is for.