Inhibition of Drug Metabolism

Chapter 6_ Drug Interactions Learning Objectives 1. Describe the consequences of drug–drug interactions, the basic mechanisms of drug– drug interactions, and the critical steps in minimizing adverse drug–drug interactions. ● Consequences of drug-drug interactions can include intensifying the effects of one drug, reducing the effects of another, or producing new and unpredictable responses. The basic mechanisms of drug-drug interactions include intensification of effects, reduction of effects, direct chemical or physical interactions, pharmacokinetic interactions (competition for protein binding, altered distribution, altered metabolism), pharmacodynamic interactions (producing new responses), and combined toxicity. To minimize adverse drug-drug interactions, it is important to consider drug-food interactions, the impact of food on drug absorption, metabolism, and toxicity, as well as the timing of drug administration with respect to meals. Drug-supplement interactions should also be taken into account. Additionally, monitoring for inhibitory interactions and taking steps to adjust dosages when necessary can help minimize the risk of adverse drug-drug interactions. 2. Explain the effect of food on drug absorption, on drug metabolism (e.g., grapefruit juice), and on drug toxicity and action, as well as the timing of drug administration with respect to meals. ● Food can have various effects on drug interactions. For drug absorption, some foods can impact the rate and extent of drug absorption, either by enhancing or reducing it. For drug metabolism, grapefruit juice can inhibit enzymes responsible for drug metabolism, leading to increased drug levels and potential toxicity. Food can also affect drug toxicity and action by interacting with drug targets or altering drug effects. Timing of drug administration with meals can be important, as some drugs may need to be taken with food to enhance absorption or reduce gastrointestinal side effects, while others should be taken on an empty stomach to avoid interactions with food components. Chapter 6 Readings Drug-drug interactions can lead to three possible outcomes: intensification of effects, reduction of effects, or the production of a new response. Intensification of effects can be beneficial or detrimental, while reduction of effects can be either beneficial or detrimental as well. It is important to minimize adverse drug-drug interactions to ensure optimal therapeutic outcomes. Bullet points Inhibition of drug metabolism: ● When an inducing agent is taken with another medicine, inhibition of drug metabolism can occur ● ● Inhibition can have undesirable results, such as the need for dosage adjustment of the other medicine Increased levels of another drug due to inhibition can lead to toxicity Altered renal excretion: ● ● Drugs can alter the three phases of renal excretion: filtration, reabsorption, and active secretion One drug can affect the renal excretion of another by reducing glomerular filtration or renal perfusion Specific examples: ● ● ● If drug A inhibits the metabolism of drug B, levels of drug B will rise, which can be beneficial or harmful Some drugs can inhibit specific CYP isoenzymes, affecting the metabolism of other drugs Specific drugs can also induce or inhibit CYP isoenzymes Important Substrates, Inhibitors, or Inducers of Specific CYP Isoenzymes ● ● ● Substrates of CYP3A4: Antibacterials/antifungals, amiodarone, amprenavir, antifungals, anticancer drugs, azole antifungals, calcium channel blockers, chloramphenicol, cimetidine, clarithromycin, cyclosporine, delavirdine, diltiazem, dronedarone, erythromycin, ethosuximide, fluvoxamine, grapefruit juice, HIV drugs, immunosuppressants, macrolides, narcotic analgesics, nevirapine, nifedipine, nitrates, norfloxacin, phenobarbital, phenytoin, prednisone, primidone, protease inhibitors, quinidine, quinine, rifampin, rifapentine, ritonavir, statins, St. John's wort, telithromycin, verapamil, voriconazole, warfarin Inhibitors of CYP3A4: Amiodarone, amiodarone, aprepitant, clarithromycin, cyclosporine, delavirdine, diltiazem, erythromycin, fluvoxamine, grapefruit juice, HIV protease inhibitors, itraconazole, ketoconazole, macrolides, nefazodone, nelfinavir, ritonavir, telithromycin, verapamil, voriconazole Inducers of CYP3A4: Aprepitant, bosentan, carbamazepine, dexamethasone, efavirenz, etravirine, garlic supplements, inducers of CYP3A4, inductors, isoniazid, nevirapine, ● ● oxcarbazepine, phenobarbital, phenytoin, prednisone, primidone, quinupristin, rifabutin, rifampin, rifapentine, ritonavir, St. John's wort, tipranavir Pharmacodynamic Interactions Interactions at the Same Receptor: Usually inhibitory