Drug interactions

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