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
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
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?
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?
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?
