A 71-year-old man with chronic stable angina comes to the office for routine follow-up. He has occasional episodes of chest pain that improve after taking sublingual nitroglycerin. The patient also has a history of hypertension and hypercholesterolemia and takes multiple medications for his conditions. Blood pressure is 140/80 mm Hg and pulse is 68/min and regular. Examination reveals normal heart sounds. While discussing a plan to start isosorbide dinitrate therapy, the patient becomes concerned about the high dose of oral isosorbide dinitrate compared to sublingual nitroglycerin. Which of the following is the most likely reason for using a high dose of oral nitrate?
Nitrates, beta blockers, and calcium channel blockers are the mainstay of therapy for patients with chronic stable angina. Sublingual nitroglycerin is the therapy of choice in acute episodes for immediate relief of angina and for prevention of angina prior to engaging in strenuous physical activity. Chronic nitrate therapy with long-acting oral formulations (isosorbide dinitrate or mononitrate) is used to prevent recurrent anginal episodes in patients with chronic stable angina.
Sublingual nitroglycerin is absorbed rapidly from oral mucosa directly into the venous circulation and has a rapid onset of action within 2-5 minutes. Long-acting isosorbide dinitrate is absorbed via the gastrointestinal tract and undergoes extensive first-pass metabolism in the liver prior to release in the systemic circulation. This leads to low bioavailability and the need for much higher doses of oral formulations as compared to sublingual nitroglycerin.
(Choice A) Chronic nitrate therapy on a regular basis leads to nitrate tolerance, with attenuation of blood pressure response and anti-anginal effects. Higher doses do not prevent nitrate tolerance. On the contrary, use of sublingual nitroglycerin on an intermittent, as-needed basis (nitrate-free intervals) prevents the development of nitrate tolerance.
(Choices C and D) The oral nitrate preparations do not have high serum protein binding or volume of distribution.
(Choice E) Isosorbide dinitrate has rapid and nearly complete intestinal absorption. Its low bioavailability is due to considerable first-pass hepatic metabolism.
Educational objective:
Isosorbide dinitrate has a low bioavailability due to extensive first-pass hepatic metabolism prior to release in systemic circulation. Sublingual nitroglycerin is absorbed directly from oral mucosa into the venous circulation and has a higher bioavailability.