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Drug Interactions Not Mediated by Changes in Drug Disposition Drugs may act on separate components of a common process to generate effects greater than either has alone. Antithrombotic therapy with combinations of antiplatelet agents (glycoprotein IIb/IIIa inhibitors, aspirin, clopidogrel) and anticoagulants (warfarin, heparins) are often used in the treatment of vascular disease, although such combinations carry an increased risk of bleeding. Nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastric ulcers, and in patients treated with warfarin, the risk of bleeding from a peptic ulcer is increased almost threefold by concomitant use of an NSAID. . | Chapter 005. Principles of Clinical Pharmacology Part 12 Drug Interactions Not Mediated by Changes in Drug Disposition Drugs may act on separate components of a common process to generate effects greater than either has alone. Antithrombotic therapy with combinations of antiplatelet agents glycoprotein IIb IIIa inhibitors aspirin clopidogrel and anticoagulants warfarin heparins are often used in the treatment of vascular disease although such combinations carry an increased risk of bleeding. Nonsteroidal anti-inflammatory drugs NSAIDs cause gastric ulcers and in patients treated with warfarin the risk of bleeding from a peptic ulcer is increased almost threefold by concomitant use of an NSAID. Indomethacin piroxicam and probably other NSAIDs antagonize the antihypertensive effects of -adrenergic receptor blockers diuretics ACE inhibitors and other drugs. The resulting elevation in blood pressure ranges from trivial to severe. This effect is not seen with aspirin and sulindac but has been found with the cyclooxygenase 2 COX-2 inhibitor celecoxib. Torsades des pointes during administration of QT-prolonging antiarrhythmics quinidine sotalol dofetilide occur much more frequently in patients receiving diuretics probably reflecting hypokalemia. In vitro hypokalemia not only prolongs the QT interval in the absence of drug but also potentiates drug block of ion channels that results in QT prolongation. Also some diuretics have direct electrophysiologic actions that prolong QT. The administration of supplemental potassium leads to more frequent and more severe hyperkalemia when potassium elimination is reduced by concurrent treatment with ACE inhibitors spironolactone amiloride or triamterene. The pharmacologic effects of sildenafil result from inhibition of the phosphodiesterase type 5 isoform that inactivates cyclic GMP in the vasculature. Nitroglycerin and related nitrates used to treat angina produce vasodilation by elevating cyclic GMP. Thus coadministration of these .
