Table of Contents Mechanisms of drug interactionsCytochrome P450 system interactions Cytochrome P450 inducersCytochrome P450 inhibitorsCytochrome P450 substratesHigh risk drugs Test yourself! 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? Oops! This section is restricted to members. 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? Oops! This section is restricted to members. 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? Oops! This section is restricted to members.