Avoiding drug interactions: Here’s help
You can’t count on an electronic prescribing system to catch all potential drug-drug interactions. These at-a-glance tables will help you minimize risk.
How is the drug metabolized?
DDIs may occur as a result of pharmaco-dynamic interaction (when 2 drugs act on the same receptor, site of action, or physiologic system) or pharmacokinetic changes (interference with absorption, albumin binding, distribution, metabolism, or elimination).23 As already noted, age-related changes in pharmacokinetics and pharmacodynamics contribute to the high prevalence of DDIs in elderly patients.
In the liver, drug metabolism, particularly via the cytochrome P450 (CYP450) system, is the cornerstone of drug transformation.23 Al-though the CYP system consists of “superfami-lies” with more than 100 types of enzymes, only a few are responsible for the majority of biotransformation.23 The CYP system is also subject to genetic polymorphism, making some patients especially prone to DDIs.
P-glycoproteins (PGPs), which regulate drug absorption by transporting the drugs across cell membranes, also play a key role. PGP inhibitors or inducers help determine whether the accumulation of the molecule or the increased delivery of toxic metabolites leads to adverse effects.10
Reviewing the mechanism of action of any drug you prescribe for a patient taking other medications may alert you to a potential DDI—and the need to either switch the newly prescribed agent or alter the individual’s drug regimen in some other way.
CASE When John was readmitted to the hospital, he was taken off both the lovastatin and amiodarone and hydrated with forced alkaline diuresis. After a week, his symptoms resolved, and he was discharged soon after. His blood tests normalized 1 month later. The severe DDI he experienced occurred because lovastatin (which is metabolized primarily by CYP3A4) and amiodarone (a CYP3A4 inhibitor) were taken together. (Statins that are substrates of CYP3A4 have the greatest potential for interacting with drugs known to inhibit the CYP450 system [eg, cyclosporine, morphine derivatives, ketoconazole, and amiodarone].)
This adverse interaction could have been avoided if the physician who started John on amiodarone had been aware of the potential DDI—and switched him to an HMG-CoA inhibitor other than lovastatin. Pravastatin, which is not metabolized via CYP450, would have been an excellent choice.
Warfarin warrants special attention
Medications that have a particularly high potential for adverse interactions require special attention and patient monitoring, warfarin foremost among them. Warfarin metabolism and its anticoagulant effects can be dramatically changed if it is administered with a drug with a higher affinity for PGPs or an agent that competes with it within the CYP450 system.24 Because of warfarin’s narrow therapeutic range, there are many drugs and drug classes that patients on warfarin should avoid (TABLE 3)—a fact that patients as well as their physicians need to be aware of.24 Indeed, warfarin is often involved in drug-related hospital admissions for DDIs, especially in elderly patients and in those who are also taking nonsteroidal anti-inflamma-tory drugs (NSAIDs) or macrolides—2 of the many drug classes that patients taking warfarin should avoid.24
TABLE 3
Patient on warfarin? Steer clear of these drugs10,20,23
| Drug class: agent(s) |
|---|
| Antiarrhythmics: amiodarone, propafenone |
| Antibiotics: ciprofloxacin, metronidazole, rifampin, trimethoprim/sulfamethoxazole |
| Anticonvulsants: carbamazepine, valproate |
| Antidepressants: fluoxetine, fluvoxamine, paroxetine, sertraline, trazodone |
| Antidiabetics: chlorpropamide |
| Antifungals: danazol, fluconazole, itraconazole, miconazole |
| Antimalarial agents: quinidine |
| Antineoplastics: azathioprine, fluorouracil, flutamide, ifosfamide, tamoxifen |
| Antiplatelet agents: ticlopidine |
| Antipsychotics: clozapine |
| Diuretics: spironolactone |
| GI drugs: cimetidine, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, ranitidine |
| Gout treatment: allopurinol |
| Hypolipidemics: atorvastatin, cholestyramine, ezetimibe, fenofibrate, fluvastatin, gemfibrozil, lovastatin, pravastatin, simvastatin |
| NSAIDs: aspirin, celecoxib, diclofenac, ibuprofen, indomethacin, ketoprofen, ketorolac, naproxen, piroxicam, sulindac |
| Thrombolytics: heparin, tissue plasminogen activator |
| Thyroid drugs: methimazole, propylthiouracil |
| Uricosuric agents: sulfinpyrazone |
| GI, gastrointestinal; NSAIDs, nonsteroidal anti-inflammatory drugs. |
Keep an eye on these drug combinations, as well
Among the many combinations likely to result in clinically significant DDIs (TABLE 2), the following are worth mentioning:
Clopidogrel + certain proton pump inhibitors. The addition of a PPI to clopidogrel has been associated with a significant increase of recurrent infarction.25 This may occur because clopidogrel is a prodrug and is converted in the liver to its active form by CYP2C19, an enzyme specifically inhibited by various PPIs—thereby altering the effectiveness of the antiplatelet agent. However, a recent analysis suggests that there is no need to avoid the concomitant use of a PPI and clopidogrel—and that the interference appears to be limited to omeprazole and esomeprazole.26
Oral contraceptives (OCs) + penicillins, phenobarbital, or tetracycline. Each of these drugs reduces the effect of OCs, and women who are taking them concomitantly need to be advised to use another means of contraception.
Phenobarbital + simvastatin. Pheno-barbital (a CYP3A4 inducer) may reduce the efficacy of simvastatin.
Repaglinide + diltiazem. Diltiazem inhibits the metabolism of repaglinide (a CYP3A4 substrate), thus increasing the risk of hypoglycemia.
