Mechanism of action at cellular and systemic levels
The action of organic nitrates is extracardiac. They do not directly affect cardiomyocytes, but instead reduce the load on the heart by altering vascular tone. Nitroglycerin acts as a nitric oxide (NO) donor.
The cascade of reactions is as follows: released NO enters vascular smooth muscle cells (angiocytes), where it is partially converted into S-nitrosothiols. This activates the enzyme cytosolic guanylyl cyclase, leading to the accumulation of cyclic guanosine monophosphate (cGMP). As a result, the concentration of calcium ions (Ca2+) in the cytosol decreases, and the vessel relaxes.
Systemic vasodilation produces a dual effect:
- Reduction in oxygen demand: venous tone drops (preload and venous return decrease) and arterial tone drops (afterload and blood pressure decrease). The mechanical work of the heart is reduced.
- Increased oxygen delivery: large coronary arteries and collaterals dilate, blood flow is redistributed in favor of the ischemic zone (the coronary steal phenomenon is eliminated). The decrease in venous return also reduces compression of subendocardial vessels.
Pharmacokinetics and dosage forms
The choice of form depends on whether an attack needs to be relieved right now or prevented in the future. The main problem with nitroglycerin is intensive presystemic metabolism in the liver when swallowed.
- For terminating attacks (short-acting): administered sublingually (under the tongue). These include tablets (0.0005 g), capsules with a 1% oil solution, aerosols, and sprays. The drug immediately enters the systemic circulation. The latent period is only 1–2 minutes, and the effect lasts about 30 minutes.
- For prophylaxis (prolonged-acting): used in the interictal period. These include microencapsulated tablets (Nitrong, Sustac Forte) containing high doses to compensate for hepatic degradation. They act for about 6 hours. Transdermal forms—ointments and patches (Deponit)—are also used, which are applied to the skin and release the substance evenly for up to 10–12 hours.
- Universal (transbuccal): polymer films (Trinitrolong) applied to the gums. They start working in 2 minutes, but the effect lasts up to 4 hours.
Side effects and tolerance development
Adverse reactions are caused by systemic vasodilation. The most frequent symptom is severe headache, resulting from the dilation of meningeal vessels. Dizziness, facial flushing, feeling of warmth, arterial hypotension (up to collapse), and reflex tachycardia are also characteristic. Over time, the intensity of side effects decreases, while the antianginal effect persists.
In addition to blood vessels, nitrates exert a spasmolytic effect on the smooth muscles of internal organs: they reduce the tone of the bronchi, intestines, biliary tract, and ureters. They also possess mild antiplatelet activity.
The problem of tolerance: NO release occurs enzymatically involving tissue sulfhydryl (SH) groups. With frequent use of prolonged forms, SH group stores are depleted, NO production drops, and tolerance develops. To restore receptor sensitivity, a "nitrate-free interval" lasting 10–12 hours per day is required.
To easily remember the hemodynamic effects of nitrates, use the "Two P's" rule: Preload Drops (veins dilate) and Postload Drops (arteries dilate). The heart finds it easier to work.
Class and exam questions
Why is nitroglycerin placed under the tongue during an attack instead of being swallowed?
Upon sublingual administration, the drug is absorbed into the systemic circulation, bypassing the liver. If the tablet is swallowed, about 40% of the substance is inactivated during the "first pass" through the liver, and the effect will occur too late.
What is the coronary steal phenomenon and how do nitrates affect it?
This is a condition where, during the dilation of all vessels, blood rushes to healthy areas, "stealing" from ischemic ones. Nitrates dilate only large arteries and collaterals, redirecting blood flow specifically to the ischemic zone, eliminating this phenomenon.
Why must organic nitrate therapy not be stopped abruptly?
Abrupt withdrawal leads to withdrawal syndrome. Clinically, this manifests as an increase in the frequency and severity of angina attacks due to compensatory reactions of the vascular bed.
What else to study on this topic
- Use of nitroglycerin in myocardial infarction and acute heart failure.
- Comparative characteristics of isosorbide dinitrate and isosorbide mononitrate.
- Mechanism of methemoglobinemia development in organic nitrate overdose.
- Neuroreflex component: how nitrates inhibit the central components of coronary-constricting reflexes.
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