Morphine and Clopidogrel

A mainstay of cardiovascular disease treatment, clopidogrel blocks adenosine-diphosphate (ADP)-induced platelet function and is metabolically activated by CYP3A4 enzymes.8 And morphine is often used for pain relief in myocardial infarction, but is associated with poor clinical outcome.8 Opiates inhibit gastric emptying, delaying absorption, thereby decreasing peak plasma levels of oral drugs; therefore it is possible that morphine lowers plasma levels of clopidogrel.8

To investigate this hypothesis, the researchers compared 24 healthy subjects who received a loading dose of 600mg clopidogrel together with either placebo or 5mg of intravenous morphine intravenously. They found that morphine delayed clopidogrel resorption, compared to placebo (P=0.025) and reduced the area under the curve levels of its active metabolite by 53% (P=0.001). Morphine delayed the maximal inhibition of platelet aggregation on average by two hours (P<0.001). Residual platelet aggregation was higher 1–4 hours after morphine injection (P<0.005). The researchers concluded that morphine “delays clopidogrel resorption, decreases plasma levels of clopidogrel active metabolite, and retards and diminishes its effects, which can lead to treatment failure in susceptible individuals.”

Drug-Drug Interactions with New Oral Anticoagulants in Patients with Atrial Fibrillation

For over 50 years, the oral anticoagulant warfarin was the cornerstone of stroke prophylaxis in patients with atrial fibrillation (AF). However, warfarin is associated with several serious limitations, including potential DDIs and drug-food interactions, necessitating close laboratory monitoring and frequent dose adjustments to prevent fluctuations in anticoagulant levels.9 Newer anticoagulants offer more predictable pharmacokinetic and pharmacodynamic profiles, enabling fixed daily dosing without routine coagulation monitoring.9 The three new agents are dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban, both direct factor Xa inhibitors.

Despite their superior DDI profile, these novel agents also carry risk of DDIs with common drugs prescribed for patients with AF. A recent article by Hellwig and Gulseth9 analyzed published studies, prescribing information, and Food and Drug Administration (FDA) briefing documents to review pharmacokinetic and pharmacodynamic DDIs involving the new oral anticoagulants. The authors focused on drugs affecting the permeability glycoprotein (P-gp) efflux transporter protein and/or CYP3A4 enzymes, and pharmacodynamic DDIs when drugs are administered concomitantly.

The authors found that combining the three novel anticoagulants with other agents of similar mechanism of action (either P-gp inhibitors or CYP3A4 inhibitors) can lead to negative pharmacokinetic effects, either increasing or decreasing one of the agents in question. The authors cautioned against interactions between oral anticoagulants and CYP3A and P-gp inhibitors in other classes, such as amiodarone, clarithromycin, and grapefruit juice; combined CYP4A and P-gp inhibitors, such as verapamil and erythromycin; and combined strong CYP3A and P-gp inducers, such as carbamazepine and phenytoin.

Regarding combining newer anticoagulants with nonsteroidal anti-inflammatory agents (NSAIDS), the authors found that concomitant acetylsalicylic acid (ASA) increased rates of major bleeding, but there was no data to raise concern about interactions with diclofenac or naproxen. Increased rates of bleeding were associated with concomitant administration of clopidogrel with either dabigatran or apixaban. Interactions between dabigatran and warfarin or apixaban and warfarin were not investigated, but there were increased INR measurements associated with the combination of warfarin and rivaroxaban.