Deadly drug-drug interactions every doctor should know

By Naveed Saleh, MD, MS
Published December 8, 2020

Key Takeaways

Drug-drug interactions come in two forms: pharmacodynamic or pharmacokinetic. Pharmacodynamic interactions involve the concomitant administration of two drugs that have additive or canceling effects, whereas pharmacokinetic interactions involve drug interactions that affect absorption, distribution, metabolism, or excretion.

Authors of a review article published in American Family Physician wrote, “Drug interactions based on altered metabolism are mostly attributable to effects on cytochrome P450 (CYP450) isozymes. Inhibition or induction of CYP450 drug metabolizing isozymes is the most common mechanism by which clinically important drug interactions occur. The most common isozyme is CYP3A4, followed by 2C19, 2C9, 1A2, 2E6, and 2D6. Drugs interacting with CYP450 isozymes can be classified as substrates, inducers, or inhibitors.”

They added, “Several drugs are substrates of transport-protein-complexes, such as P-glycoprotein (P-gp), which are expressed in hepatocytes and enterocytes, as well as in the epithelial cells of the renal tubules, the blood brain barrier, and the placenta. These transporters are subject to inhibition or induction that can elicit drug interactions.”

Here are some common drug-drug interactions worth noting:

Warfarin and antimicrobials

Antimicrobials can interfere with protein-binding and the action of CYP450 isoenzymes, as well as reduce the absorption of vitamin K by changing gut flora. Offending agents most likely to alter International Normalized Ratio (INR) values include trimethoprim/sulfamethoxazole, metronidazole (Flagyl), and fluconazole (Diflucan). Administration of these antimicrobial agents may require warfarin-dosage adjustments. Moreover, all patients co-administered any type of antimicrobial and warfarin, should receive INR checks between 3 and 5 days of administration and discontinuation.

Amiodarone and statins

The antiarrhythmic drug amiodarone inhibits CYP3A4, likely altering the metabolism of some statins including simvastatin and atorvastatin, increasing the risk of statin-related muscle toxicity. This risk is highest in the elderly, as well as those with obesity or renal/hepatic impairment. Of note, fluvastatin and pravastatin metabolism do not interfere with amiodarone metabolism; therefore, these drugs are preferred over simvastatin and atorvastatin in those taking amiodarone. Alternatively, dosages of simvastatin can be limited to 20 mg/day, and dosages of lovastatin can be limited to 40 mg/day in those taking amiodarone.

Warfarin and NSAIDs

NSAIDs result in gastric irritation and erosion of the stomach lining, leading to ulcers and bleeding. Warfarin can exacerbate these bleeds—a risk unrelated to INR. Instead, patients on both NSAIDs and warfarin should be notified of, and asked about, abdominal pain and signs of gastrointestinal bleeds. 

According to the authors of the aforementioned review, “If concomitant therapy with warfarin and aspirin/dipyridamole (Aggrenox) is necessary, the dosage of aspirin/dipyridamole should be limited to 100 mg per day or less to minimize bleeding risk.”

They added, “It is preferable to use alternatives to NSAIDs, such as acetaminophen, topical therapy, or judiciously prescribed opioid analgesics when indicated. Acetaminophen does not alter platelet function, but concomitant use may increase the pharmacodynamic effect of warfarin, increasing the INR. To be cautious, limit the acetaminophen dosage to 2 g per day for no more than 7 days and complete more frequent INR testing.”

PDE-5 inhibitors and nitrates

Because phosphodiesterase-5 (PDE-5) inhibitors potentiate the vasodilatory effects of nitrates, which are mediated by cyclic guanosine monophosphate (cGMP), the combination of nitrates and PDE-5 inhibitors can drop blood pressure dangerously low. 

In joint guidelines for the management of ST-elevation myocardial infarction, the American College of Cardiology Foundation/American Heart Association recommended the following: “Nitrates should not be given to patients with hypotension, marked bradycardia or tachycardia, RV [right ventricular] infarction, or [PDE-5] inhibitor use within the previous 24 to 48 hours.” In other words, when medically necessary, nitrates can be taken 24 hours after sildenafil (Viagra) and 48 hours after tadalafil (Cialis).

Calcium-channel blockers and statins

Although the mechanism remains to be elucidated—with the inhibition of CYP3A4 possibly contributory—statins don’t play well with calcium-channel blockers.

Results of a population-based study out of Taiwan support the role of CYP3A4. The authors concluded that “the associated risks of acute kidney injury, hyperkalemia, acute myocardial infarction, and acute ischemic stroke were higher following the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4. Further, the risks were lower in the coprescription of non-CYP3A4-metabolized statins and CCBs. Therefore, clinicians could take into account the potential adverse events during the coprescription of CYP3A4-metabolized statins and CCBs that inhibit CYP3A4.”

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