Drug Interactions

TL;DR. Most interactions are variations on four mechanisms: something blocks or accelerates the enzymes that clear a drug, something binds it in the gut so it is never absorbed, two drugs push the same physiological lever together, or a food supplies something the drug is fighting. Learn the four and the specific lists stop being arbitrary. The three biggest single offenders in ordinary life are grapefruit, St John's wort, and combining sedatives. And the commonest reason an interaction is missed is that the patient did not think a supplement counted as a medicine.

1. The four mechanisms

Mechanism 1: metabolism (the big one)

Most drugs are cleared by cytochrome P450 enzymes in the liver and gut wall (Chapter 62).

• An inhibitor slows clearance → the drug accumulates → more effect, more toxicity.
• An inducer speeds clearance → the drug is cleared faster → less effect, treatment failure.

Two consequences worth spelling out:

Prodrugs run backwards. Codeine and tramadol need CYP2D6 to become active, and clopidogrel needs CYP2C19. An inhibitor of those enzymes makes the drug not work, rather than accumulate. This is why fluoxetine can render codeine useless, and why omeprazole reduces clopidogrel's antiplatelet effect (pantoprazole is preferred alongside clopidogrel for that reason).

Enzyme induction has a lag. Inducers take days to weeks to take full effect and days to weeks to wear off, so problems appear well after the change and are easy to miss.

Mechanism 2: absorption

Something in the gut physically prevents the drug getting in.

Chelation: polyvalent metal ions bind drugs into insoluble complexes.

Calcium, magnesium, aluminium, iron, and zinc bind tetracyclines, fluoroquinolones, levothyroxine, and bisphosphonates. The sources include supplements, antacids, dairy, and fortified foods. Separate by 2 to 4 hours. This is one of the highest-yield practical rules in the book, and it is routinely ignored.

Binding resins: colestyramine binds many drugs.

pH changes: PPIs and antacids raise stomach pH, reducing absorption of drugs needing acid, including some antifungals (itraconazole, ketoconazole), iron, and B12.

Transporters: fexofenadine absorption is reduced by fruit juice (grapefruit, orange, apple) via OATP transporter inhibition, which is a different mechanism from the CYP3A4 grapefruit story and works in the opposite direction (Chapter 70).

Gut motility: drugs that slow or speed transit change how much of another drug is absorbed.

Mechanism 3: pharmacodynamic (same lever, twice)

No effect on drug levels; the effects simply add.

Anticholinergic burden deserves emphasis because it is cumulative and invisible: several drugs each with mild anticholinergic activity (an antihistamine, a bladder drug, an antidepressant, a nausea tablet) add up to significant confusion and falls risk in an older person.

Mechanism 4: food and drink

Covered per-drug through the book, and gathered in the tables below.

2. The interactions everyone should know

Grapefruit

Furanocoumarins irreversibly inactivate intestinal CYP3A4. Because the inactivation is irreversible, the effect lasts 24 to 72 hours and spacing the fruit and the tablet does not help (Chapter 22).

Affected: simvastatin, atorvastatin, lovastatin (not pravastatin, rosuvastatin, fluvastatin); felodipine, nifedipine, verapamil; ciclosporin, tacrolimus; amiodarone; midazolam, triazolam, buspirone; apixaban, rivaroxaban, ticagrelor; oxycodone, fentanyl, methadone; sildenafil, tadalafil; several antipsychotics and HIV drugs.

Also involved: pomelo, Seville (bitter) oranges and their marmalade, tangelos, and, to a lesser degree, limes. Sweet oranges, mandarins, clementines, and lemons are safe.

St John's wort

A potent CYP3A4 and P-glycoprotein inducer, sold in supermarkets, and the cause of documented contraceptive failures and transplant rejections (Chapter 81).

Reduces: combined oral contraceptives, ciclosporin, tacrolimus, warfarin, DOACs, antiretrovirals, digoxin, statins, anticonvulsants, some chemotherapy.

Adds to: SSRIs, triptans, tramadol → serotonin syndrome.

Sedatives, together

The combination that kills most people: opioid plus benzodiazepine plus alcohol, with gabapentinoids and sedating antihistamines adding to it. Each depresses respiration; together the effect is more than additive (Chapter 68).

Warfarin

The classic narrow-therapeutic-index drug, and almost everything interacts with it.

The dietary rule is consistency, not avoidance (Chapter 38).

Alcohol

3. Food and drink interactions, gathered

Charcoal-grilled food and cruciferous vegetables induce CYP1A2, which is a real but usually minor effect.

Smoking induces CYP1A2 strongly. This matters most for clozapine and theophylline: stopping smoking can raise clozapine levels sharply into the toxic range, and dose adjustment is required. Nicotine replacement does not have this effect, because it is the combustion products, not the nicotine, that induce the enzyme.

4. Serotonin syndrome and QT prolongation

Two pharmacodynamic syndromes worth recognising by name.

Serotonin syndrome develops within hours of adding or increasing a serotonergic drug: agitation, tremor, hyperreflexia and clonus (the most specific signs), sweating, dilated pupils, diarrhoea, fever, and in severe cases rigidity, seizures, and death.

The culprits: SSRIs, SNRIs, tricyclics, MAOIs, tramadol, pethidine, fentanyl, triptans, ondansetron, linezolid, lithium, St John's wort, MDMA, and dextromethorphan.

QT prolongation raises the risk of torsades de pointes, a potentially fatal arrhythmia.

The culprits: amiodarone and other antiarrhythmics, macrolides, fluoroquinolones, several antipsychotics (haloperidol, quetiapine), citalopram and escitalopram at higher doses, ondansetron, methadone, some antifungals, and loperamide in overdose (Chapter 71).

Risk multiplies when combined, and with low potassium and low magnesium, which is why diuretics matter here too.

5. How to protect yourself

1. Keep a complete written list of everything you take: prescriptions, over-the-counter drugs, supplements, herbal products, and recreational substances. Take it to every appointment.
2. Use one pharmacy. Their software checks the whole list; two pharmacies each check half.
3. Say "I take a herbal supplement." Surveys find most people do not mention them, and they are involved in a substantial share of missed interactions.
4. Ask about grapefruit and alcohol whenever you start something new.
5. Ask what to do about a missed dose and what should make you stop and call.
6. Be suspicious of any new symptom after a medication change, including one made weeks earlier, because induction and steady state both take time.
7. Check before adding an over-the-counter medicine to a regular prescription. Ibuprofen is the commonest problem.
8. Tell dentists, surgeons, and anaesthetists everything, including supplements and GLP-1 drugs (Chapter 76).
9. Use an interaction checker as a starting point, and treat a pharmacist as the authority. Free checkers flag enormous numbers of theoretical interactions of no clinical importance, and distinguishing them is exactly what the pharmacist is for.

6. The bottom line

• Four mechanisms cover nearly everything: metabolism (enzyme inhibition or induction), absorption (chelation, pH, transporters), pharmacodynamics (same lever pulled twice), and food.
• Grapefruit inhibits CYP3A4 irreversibly for over a day, so spacing does not help. Sweet oranges, mandarins, and lemons do not.
• St John's wort induces CYP3A4 and causes contraceptive failure and transplant rejection. It is sold in supermarkets and most people do not mention it.
• Combining sedatives is the interaction that kills most people. Opioids, benzodiazepines, alcohol, and gabapentinoids together depress breathing more than any one alone.
• Separate calcium, iron, dairy, and antacids from tetracyclines, quinolones, levothyroxine, and bisphosphonates by 2 to 4 hours.
• Consistency, not avoidance, is the rule for vitamin K on warfarin.
• Stopping smoking raises clozapine levels dangerously. Prodrug interactions run backwards: inhibitors make codeine and clopidogrel stop working.

Sources and notes

Interaction mechanisms follow Rang and Dale and the FDA's drug interaction guidance. CYP substrate, inhibitor, and inducer classifications follow the Indiana University P450 interaction table and the FDA's clinical drug interaction tables. The grapefruit mechanism, its irreversibility, and the affected drug list follow Bailey, Dresser, and Arnold, Canadian Medical Association Journal, 2013. St John's wort induction and its documented consequences follow Izzo and Ernst's reviews and regulatory warnings from the MHRA and FDA. Chelation interactions with tetracyclines, quinolones, levothyroxine, and bisphosphonates follow BNF and product information. Fexofenadine and fruit juice OATP inhibition follows Dresser et al., Clinical Pharmacology and Therapeutics, 2002. The clopidogrel-omeprazole CYP2C19 interaction follows the FDA's 2009 communication and the subsequent COGENT trial. Warfarin interaction lists follow BNF and anticoagulation service guidance. Disulfiram-like reactions with metronidazole follow product information, with the caveat that the strength of that evidence has been questioned. Serotonin syndrome recognition follows the Hunter criteria (Dunkley et al., 2003). QT-prolonging drug lists follow CredibleMeds. Smoking cessation raising clozapine levels follows the CYP1A2 induction literature and psychiatric prescribing guidance. MAOI tyramine restrictions follow standard psychopharmacology references.

Open questions. Interaction checkers flag enormous numbers of theoretical interactions of no clinical importance, and there is no consensus method for ranking clinical significance, which is why pharmacist judgement remains necessary.

👉 Next: side effects: real, imagined, and how to tell.