A patient using a transdermal nitroglycerin patch continuously for 24 hours daily notices complete loss of antianginal effect within two weeks. The mechanism underlying this loss of efficacy and its prevention are:

• A Receptor downregulation, prevented by adding an ACE inhibitor
• B Accumulation of cGMP, prevented by adding a PDE5 inhibitor
• C Induction of hepatic first-pass metabolism, prevented by switching to oral isosorbide mononitrate
• D Depletion of reduced sulfhydryl groups, prevented by a 10 to 12 hour nitrate-free interval ✓

Explanation

Continuous nitrate exposure produces tolerance through depletion of reduced sulfhydryl (thiol) groups needed to generate nitric oxide from nitrates. A daily nitrate-free interval of 10 to 12 hours restores responsiveness. Receptor downregulation and enzyme induction are not the accepted mechanisms. Adding a PDE5 inhibitor must be avoided, since combined nitrate and PDE5 inhibition causes catastrophic hypotension.

Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.