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Drug interactions

Prescribing > Adverse drug reactions

Mechanisms of drug interactions

Cytochrome P450 system interactions 

The cytochrome P450 system is a collection of liver enzymes that make up a key pathway for drug metabolism. The system is a major source of important drug interactions.

Cytochrome P450 inducers

  • Reduce the concentration of drugs metabolised by the cytochrome P450 system
  • CRAPS out drugs: Carbamazepine, Rifampicin, bArbituates, Phenytoin, St Johns wart

Cytochrome P450 inhibitors

  • Increase the concentration of drugs metabolised by the cytochrome P450 system
  • Some Certain Silly Compounds Annoyingly Inhibit Enzymes, Grrrrrrr: Sodium valproate, Ciprofloxacin, Sulphonamides, Cimetidine, Antifungals, Amiodarone, Isoniazid, Erythromycin/clarithromycin/azithromycin, Grapefruit juice

Cytochrome P450 substrates

  • Drugs metabolised by the P450 system that are affected by cytochrome P450 inducers/inhibitors
  • COWPATS: Ciclosporin, Carbamazepine, Citalopram, Oral contraceptive pill, Warfarin, Phenytoin, Protease inhibitors, Acetylcholinesterase inhibitors (e.g. donepezil), Theophylline, Statins, Steroids

High risk drugs

Always look for interactions in the BNF:

  • Narrow therapeutic range drugs
    • Examples (Guys With Large Dongles Totally Make Perfect Internet Connections): Gentamicin, Warfarin, Lithium, Digoxin, Theophylline, Methotrexate, Phenytoin, Insulin, Ciclosporin
    • Interactions are particularly important for narrow therapeutic range drugs because small changes in their concentrations can cause severe toxicity
  • Cytochrome P450 inducers/inhibitors
    • Examples: see above
    • Many interactions!
  • Highly protein-bound drugs
    • Examples (Protein Bound Drugs Normally Fight When Available Space is Sparse): Phenytoin, Benzodiazepines, Digoxin, NSAIDs, Furosemide, Warfarin, Amiodarone, Sulfonylureas/sulfonamides, Statins
    • Often displace each other from protein binding sites, which increases the proportion of the displaced drug in its unbound (active) form
  • Drugs affecting physiology
    • Examples: antihypertensives, hypoglycaemics, anticoagulants
    • Affect the physiological environment and are more likely to have interactions

Test yourself!

A 45 year old who takes warfarin for a mechanical heart valve is admitted with a severe community acquired pneumonia. Although his INR was in range (3-4) on admission, after three days, his INR is checked and is 6.2. Which drug is likely to be responsible? What is the mechanism?

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A 24 year old female patient who is on the combined oral contraceptive pill is seen in TB clinic for latent TB. The options for chemoprophylaxis in latent TB are rifampicin and isoniazid for 3 months (usually preferred for younger patients), or isoniazid for 6 months. What are you concerned about and what would be the best option for chemoprophylaxis?

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A patient takes doxycycline for malaria prophylaxis whilst travelling in Kenya. Despite this, he develops malaria. He says he did not receive any dietary advice when he was prescribed the doxycycline. Which interactions with food/drink/over-the-counter medicines may be responsible for reduced serum doxycycline levels? What is the mechanism?

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Adverse drug reactions