I. Pharmacological properties of nitrate
1.Mechanism of action
Cellular level
After more than 100 years of clinical application, it was not until the 1980s that people gradually recognized that its mechanism of action was based on the non-endothelium-dependent exogenous nitric oxide (NO) donor, i.e., regardless of the structural and/or functional integrity of the endothelium, it can exert a clear vascular smooth muscle diastolic effect, which is in contrast to the endogenous (endogenous) NO donor. Only when the endothelium is structurally intact and functioning properly can NO and other diastolic substances be synthesized and the balance of diastolic and vasodilatory substances be maintained.
When the endothelium is dysfunctional, the synthesis of NO and other diastolic substances is reduced, while the synthesis of vasoconstrictive substances is increased and their activity is abnormally enhanced, participating in the development of diseases such as atherosclerosis and hypertension, while nitrate can still exert vascular smooth muscle diastolic effects independently in these pathophysiological states.
After entering the body, nitrate completes its biometabolic process in the cell membrane or adjacent sites of static and arterial smooth muscle: it is converted to active NO molecules by specific metabolic enzymes, activates soluble guanylate cyclase (sGC), increases the concentration of cyclic guanosine phosphate (cGMP) in vascular smooth muscle and platelets, and increases the concentration of cGMP-dependent protein kinase C (PKC) by further activating cGMP protein kinase C (PKC), inhibits extracellular Ca2+ inward flow, decreases intracellular Ca2+ release, and increases intracellular Ca2+ efflux, thereby decreasing intracellular Ca2+ levels and causing vascular smooth muscle diastole. The increase in intraplatelet cGMP concentration and the decrease in Ca2+ level inhibit the aggregation reaction of platelets and have antithrombotic effects.
The effect of nitrate on systemic and local circulation
The diastolic effect of nitrate shows a dose-related vascular-specific selectivity. At low doses, the large volume vessels are diastolic, resulting in a decrease in return blood volume, a decrease in left and right ventricular perfusion pressure, a decrease in volume, a consequent decrease in end-diastolic pressure as well as ventricular wall tension, a decrease in cardiac preload, a decrease in cardiac stroke volume, and a decrease in myocardial oxygen demand (MVO2); at moderate doses, the large and medium transmission arteries of the coronary arteries are mainly diastolic, resulting in a decrease in their resistance; at high doses, the small peripheral resistance arteries are diastolic, and blood pressure decreases and cardiac afterload decreases, further reducing MVO2, but this effect is partially counteracted by reflex tachycardia and increased contractility.
Conventional wisdom suggests that the main mechanism of nitrate control and prevention of myocardial ischemic attacks is due to the aforementioned decrease in myocardial oxygen consumption by reducing myocardial preload and afterload. In recent years, there is increasing evidence that its local effects on the coronary circulation play an equally important role in anti-ischemic therapy.
Locally in the coronary circulation, nitrate may prevent or reverse constriction or spasm of coronary arteries, diastole collateral circulation arteries, increase collateral circulation blood flow, improve blood supply to ischemic areas, and dilate coronary arteries narrowed by atherosclerosis, in addition to diastole large epicardial transmitting arteries (5). In myocardial ischemia, distal and collateral arteries are in a state of tense constriction due to the effect of constricting substances, further worsening coronary perfusion, for which nitrate exerts a definite diastolic effect and improves endothelial function of the coronary arteries.
Nitrate selectively dilates the large epicardial transmitter arteries and collateral arteries, but not the micro-arteries, within the dose range of clinical practice, effectively avoiding the phenomenon of “coronary steal” in the treatment of coronary artery disease, in contrast to other vasodilators such as sodium nitroprusside, adenosine and pansentin.
The latter, due to the selective and significant dilatation of micro-arteries and the weak or absent effect on large and medium-sized arteries, causes the flow of blood from the ischemic area to the non-ischemic area, which can easily lead to coronary artery theft. It has been suggested that the cause of the above phenomenon may be related to the lack of specific metabolic enzymes required to convert nitrate to NO in the coronary microcirculation, whereas sodium nitroprusside, for example, produces NO directly in the coronary circulation via a non-enzymatic metabolic pathway, causing microarterial dilation.
The pulmonary circulatory effects of nitrate also play an important clinical role. It reduces perfusion pressure in the left and right ventricles, as well as pulmonary venous pressure and pulmonary capillary wedge pressure, while dilating small resistance arteries, reducing cardiac afterload, decreasing ventricular ejection resistance, and moderately increasing per-pulse output and cardiac output in patients with left heart failure. However, the hemodynamic effect of nitrate on a functioning heart is significantly different, with a decrease rather than an increase in cardiac output. Nitrate dilates the vascular bed of the small pulmonary arteries and provides some clinical relief in secondary pulmonary hypertension, but has no clear beneficial effect in the treatment of primary pulmonary hypertension.
Because nitrate also dilates the cerebral vascular bed and increases blood volume in the brain, it is prohibited to use these drugs when intracranial pressure is elevated.
The antiplatelet aggregation, antithrombotic and antiproliferative effects of nitrate, as well as the improvement of aortic compliance and reduction of aortic systolic pressure, may play a synergistic role in the therapeutic effect.
2, the pharmacokinetic characteristics of nitrate
Nitrate includes: nitroglycerin (NTG), isosorbide dinitrate (ISDN), isosorbide 5-mononitrate (ISMN) and pentaerythritol tetranitrate (PT), and erythritol tetranitrate (ET), the first three of which are widely used in clinical practice. The pharmacokinetic characteristics of the different nitrates are significantly different (10).
NTG is the representative drug of nitrates. It is characterized by its unstable nature, volatile, flammable and explosive, strong hepatic first pass clearance effect and oral bioavailability less than 10%, therefore, it is not suitable for oral administration. NTG has a very short half-life of only a few minutes, and the blood concentration decreases rapidly within 20-40 minutes after stopping intravenous infusion or removing transdermal patches.
NTG is metabolized in the vascular wall, and the uptake of NTG by the venous vasculature is significantly stronger than that of the arteries. Early studies have shown a minimum effective blood concentration of 1 ng/mL after sublingual NTG administration, but it should be emphasized that monitoring plasma concentrations of NTG in the clinic is not practically meaningful because resistance will develop with continued NTG application and there is a lack of correlation between blood concentrations and clinical efficacy.
The nature of NTG sublingual tablets is unstable and the expiration date is only about 3 months. Therefore, in order to ensure its timely therapeutic effect during acute ischemic attacks, patients should be instructed to keep the tablets in the original sealed brown glass vials provided at the factory and store them away from light, with a new bottle every three months. For intravenous infusion of NTG, a special non-adsorbent infusion set should be used for intravenous infusion of NTG because the common PVC plastic infusion set can adsorb a large amount of NTG solution, resulting in 40-50% loss of drug concentration.
Since its introduction in 1947, ISDN has become the most widely used long-acting nitrate, with a significantly lower first pass clearance effect in the liver than NTG. -The latter has a half-life of 4-6 hours and exerts a major subsequent prolonged pharmacological effect (50-60%), while the former is less active and has little practical clinical significance.
ISMN is a new generation of long-acting nitrate developed late and used clinically since 1978, with no first pass clearance effect from the liver after oral administration and nearly 100% bioavailability. The parent drug exerts its pharmacological properties directly without hepatic metabolism and has a half-life of up to 4-5 hours.