Mechanism of action
The antianginal effect of nitroglycerin (Nitroglycerinum) is due to a complex of hemodynamic shifts. The drug causes systemic vasodilation, leading to the following changes:
- Reduction of preload: venous dilation decreases venous blood return to the heart.
- Reduction of afterload: arterial dilation leads to a drop in total peripheral vascular resistance.
- Improvement of coronary blood flow: blood is redistributed in favor of ischemic subendocardial layers. In addition, by reducing ventricular wall tension, extravascular compression of subendocardial vessels is decreased.
Important difference: the drug does not slow the pulse (does not cause bradycardia) to reduce oxygen demand, but conversely, can provoke reflex tachycardia.
Pharmacokinetics and routes of administration
According to chemical nomenclature, it is glyceryl trinitrate (nitroglycerol), a colorless oily liquid with high lipophilicity (highly soluble in alcohol, ether, and chloroform). This determines the variety of routes of administration:
- Sublingually: rapidly absorbed through the oral mucosa, bypassing the liver. The latent period is 1–2 minutes, the duration of effect is about 30 minutes, and the half-life ($t_{1/2}$) is very short (1–4 minutes).
- Orally: the first-pass effect is pronounced. After absorption in the intestine, the substance enters the liver via the portal vein, where more than 90% of the drug is eliminated. Therefore, doses for oral intake (per os) must be significantly higher than sublingual ones (e.g., 6.4 mg vs. 0.5 mg).
- Transdermally: ointments and patches (transdermal therapeutic systems) provide resorptive (systemic) action. The lipophilic substance penetrates the skin into the systemic circulation, avoiding presystemic metabolism. The patch maintains a constant concentration and provides an effect for up to 12 hours.
Indications for use
The drug is versatile: it is used for both relief and prevention.
- Angina pectoris (angina pectoris): immediate pain relief (short-acting forms) and prevention of attacks. Interesting fact: taking circadian rhythms into account, attack relief with nitroglycerin is more effective in the morning hours compared to the second half of the day.
- Myocardial infarction: used as a continuous intravenous infusion.
- Acute heart failure: used as a potent vasodilator.
Side effects and tolerance
Adverse reactions are directly related to the main vasodilating effect:
- Central nervous system: severe headache due to dilation of meningeal vessels, dizziness.
- Cardiovascular system: orthostatic collapse (sharp drop in blood pressure upon changing body position) and reflex tachycardia as a baroreceptor response to hypotension.
Phenomenon of tolerance (habituations): the risk of development is low when using short-acting forms, but high when prescribing long-acting forms. To overcome tolerance and restore receptor sensitivity, it is necessary to observe a "nitrate-free interval" (10–12 hours during the day).
Dosage forms and prescription
For immediate relief of attacks, sublingual forms are used: tablets (0.0005 g), capsules with 1% oil solution (0.0005 g and 0.001 g), aerosols/sprays (0.0004 g per dose), or 1% alcohol solution (1–2 drops on a sugar cube). For infusions in expanded indications, a 1% solution in ampoules is used.
Example of a tablet prescription: Rp.: Tab. Nitroglycerini 0.0005 D.t.d. N. 40 S. Take 1-2 tablets sublingually during an anginal attack.
Example of an ampoule prescription (infusion concentrate): Rp.: Sol. Nitroglycerini 1% - 1 ml D.t.d. N. 10 in amp. S. Dilute 5 ml of the drug in 500 ml of 0.9% NaCl solution. Administer intravenously as a drip at a rate of 20 drops/min.
Briefly: answers to topical questions
What is the molecular mechanism of vascular smooth muscle relaxation under the action of nitroglycerin?
The molecular mechanism consists in the release of nitric oxide (NO), which acts as an endothelium-derived relaxing factor.
Cascade of reactions in vascular smooth muscle cells:
- Release of NO and its entry into angiomyocytes.
- Partial conversion to S-nitrosothiols.
- Activation of cytosolic guanylyl cyclase.
- Accumulation of cyclic guanosine monophosphate (cGMP).
- Decrease in cytosolic calcium ion concentration.
- Weakening of the bond between myosin and actin, leading to cell relaxation.
What are the absolute contraindications for prescribing nitroglycerin?
Contraindications to the prescription of nitroglycerin include:
- Arterial hypotension.
- Right ventricular myocardial infarction.
- Hypertrophic obstructive cardiomyopathy (HOCM).
- Severe aortic stenosis.
- Concomitant use of phosphodiesterase type 5 (PDE-5) inhibitors.
Which drug groups must nitroglycerin categorically not be combined with due to the risk of collapse?
Nitroglycerin is contraindicated to combine with phosphodiesterase type 5 inhibitors due to the risk of severe hypotension and fatal complications.
For sildenafil or vardenafil, an interval of 24 hours must be observed; for tadalafil, 48 hours.
Alpha-blockers and calcium channel blockers are listed as groups with which drug interactions are possible.
Preload is VEINS (blood return), afterload is ARTERIES (resistance). Nitroglycerin dilates both, unloading the heart from all sides.
Class and exam questions
Why is nitroglycerin administered sublingually during an anginal attack rather than swallowed?
Upon ingestion, the drug enters the liver via the portal vein, where it undergoes presystemic elimination (more than 90% of the substance is destroyed). Sublingual administration allows the lipophilic drug to be absorbed through the oral mucosa directly into the systemic circulation and take effect within 1–2 minutes.
How to prevent the development of nitrate tolerance?
It is necessary to observe a "nitrate-free interval" lasting 10–12 hours during the day. This time is required to restore receptor sensitivity to the drug.
Why does nitroglycerin cause a headache?
The drug causes systemic vasodilation, including dilation of meningeal vessels. This leads to a throbbing headache, which is the most common side effect.
What else to study on this topic
- Biochemical mechanism of action of nitrates (the role of nitric oxide NO and cGMP accumulation).
- Differences in the pharmacokinetics of isosorbide dinitrate and isosorbide mononitrate from nitroglycerin.
- Danger of co-administering organic nitrates with PDE-5 inhibitors (e.g., sildenafil).
- Withdrawal syndrome upon abrupt discontinuation of long-acting nitrates.
- Hemodynamic features and risks of nitrate use in right ventricular myocardial infarction.
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