Mechanism of Action at Cellular and Systemic Levels
The action of organic nitrates is extracardiac. They do not directly affect cardiomyocytes, but instead reduce cardiac workload by altering vascular tone. Nitroglycerin acts as a nitric oxide (NO) donor.
The reaction cascade proceeds as follows: released NO enters vascular smooth muscle cells (angiocytes), where it is partially converted into S-nitrosothiols. This activates the cytosolic guanylyl cyclase enzyme, leading to the accumulation of cyclic guanosine monophosphate (cGMP). As a result, the cytosolic concentration of calcium ions (Ca2+) decreases, causing vascular smooth muscle relaxation.
Systemic vasodilation produces a dual effect:
- Reduction in oxygen demand: Venous tone decreases (reducing preload and venous return) alongside arterial tone (reducing afterload and blood pressure). The mechanical work of the heart is diminished.
- Increased oxygen delivery: Large coronary arteries and collaterals dilate, redistributing blood flow in favor of the ischemic zone (reversing the coronary steal phenomenon). Decreased venous return also relieves compression on subendocardial vessels.
Pharmacokinetics and Dosage Forms
The choice of formulation depends on whether acute relief or long-term prevention is required. The main challenge with nitroglycerin is its intensive presystemic hepatic metabolism when swallowed.
- For acute relief (short-acting): Administered sublingually (under the tongue). These include tablets (0.0005 g), capsules containing a 1% oil solution, aerosols, and sprays. The drug enters the systemic circulation immediately. The latent period is only 1–2 minutes, and the effect lasts for about 30 minutes.
- For prophylaxis (extended-release): Used in the interictal period. These include microencapsulated tablets (e.g., Nitrong, Sustac Forte) containing high doses to compensate for hepatic degradation. They act for about 6 hours. Transdermal forms—ointments and patches (e.g., Deponit)—are also used, applied to the skin to provide uniform drug release for up to 10–12 hours.
- Universal (transbuccal): Polymer films (Trinitrolong) adhered to the gums. They begin acting within 2 minutes, with effects lasting up to 4 hours.
Side Effects and Development of Tolerance
Adverse reactions stem from systemic vasodilation. The most frequent symptom is severe headache, caused by the dilation of meningeal blood vessels. Dizziness, facial flushing, a sensation of warmth, arterial hypotension (potentially leading to collapse), and reflex tachycardia are also characteristic. Over time, the intensity of side effects diminishes while the antianginal efficacy persists.
Beyond blood vessels, nitrates exert a spasmolytic effect on the smooth muscle of internal organs: they reduce the tone of bronchi, the intestines, biliary tracts, and ureters. They also possess mild antiplatelet activity.
The tolerance issue: NO release occurs enzymatically via tissue sulfhydryl (SH) groups. With frequent use of extended-release formulations, SH group reserves become depleted, NO production drops, and tolerance develops. To restore receptor sensitivity, a "nitrate-free interval" lasting 10–12 hours per day is required.