Pathophysiology of ischemia and pain syndrome
In stenosing atherosclerosis, the coronary bed undergoes major hemodynamic changes. In the area distal to the occlusion (distal to the atherosclerotic plaque), vessels are constantly in a state of maximum dilation. This compensatory dilation occurs due to tissue hypoxia and the accumulation of local vasodilator metabolites, primarily adenosine.
However, such compensation proves insufficient. Due to the mechanical obstruction in the form of stenosis, oxygen delivery to the heart muscle remains limited. During physical or emotional exertion, a critical imbalance occurs: myocardial oxygen demand increases sharply, while the ability to adequately increase blood flow is absent because the vessels are already maximally dilated.
The molecular mechanism of ischemic pain is directly related to biochemical shifts. Against the background of hypoxia, protons ($H^+$) accumulate in the tissues. They locally stimulate vanilloid receptors, the irritation of which is perceived by the central nervous system as characteristic pain impulses.
Clinical and pathogenetic forms of angina pectoris
Clinically, coronary circulatory insufficiency manifests as angina pectoris (angina pectoris, obsolete term — "angina"). These are episodes of squeezing, pressing pain behind the sternum. Depending on the mechanism of the imbalance between oxygen demand and delivery, three main forms of the disease are distinguished:
- Stable (classic) exertional angina. Develops against the background of stenosing atherosclerosis. The attack is triggered by physical or emotional stress, when the heart's oxygen demand increases and the affected vessels are mechanically incapable of dilating. The main pharmacological goal is to use substances that reduce myocardial oxygen demand.
- Vasospastic (variant, Prinzmetal's) angina. A rare form (occurring in no more than 1% of cases) caused by coronary spasm. Attacks occur spontaneously, often at rest or during sleep, without visible triggering factors. The likely cause is a deficiency of endothelium-derived relaxing factor. The goal of treatment is to eliminate spasm using agents that dilate coronary vessels.
- Unstable angina. Caused by massive thrombus formation in the coronary arteries, leading to severe impairment of trophism. Attacks appear at rest and are poorly relieved by standard antianginal drugs. It is considered a dangerous pre-infarction condition requiring the prescription of agents that prevent thrombus formation.
Classification of antianginal agents
Drugs for the treatment of angina are classified according to how they affect two key factors: the heart muscle's oxygen demand and its actual delivery.
- Group I. Agents that simultaneously lower oxygen demand and increase its delivery. These include organic nitrates, calcium channel blockers, potassium channel activators, and certain other drugs.
- Group II. Agents that lower myocardial oxygen demand. This category includes $\beta$-blockers and bradicardic agents.
- Agents that increase oxygen delivery. These are drugs that increase coronary blood flow. They can act myotropically (directly affecting the smooth muscle of the vascular wall) or reflexively (causing vasodilation via reflex mechanisms).
Principles of combined pharmacotherapy
Pharmacotherapy of angina pursues two global goals: rapid relief of an already developed pain attack and systematic prophylaxis (course treatment in the interictal period to prevent episodes of ischemia).
Therapy is always comprehensive. In addition to specific antianginal drugs, patients are prescribed:
- Antiplatelet agents (to prevent blood clots).
- Lipid-lowering agents (to control lipid levels and inhibit atherosclerosis).
- Angioprotectors (for vascular wall protection).
A special new direction in treatment is cytoprotection. It involves the use of cardioprotectors that provide metabolic protection to cardiomyocytes and increase their resistance to ischemic conditions.
Briefly: answers to topical questions
Which specific drugs are included in the group of organic nitrates?
The group of organic nitrates includes the following main drugs:
- Nitroglycerin — the reference drug of the group, used for the relief and prevention of attacks.
- Isosorbide dinitrate — a long-acting drug providing a prolonged effect.
- Isosorbide mononitrate — an active metabolite of isosorbide dinitrate with higher bioavailability and a longer half-life.
What is the cellular mechanism of action of bradymetic agents in the treatment of angina pectoris?
The cellular mechanism of action of bradycardic agents consists in the selective blockade of $I_f$ channels in sinoatrial node cells. This leads to the prolongation of the spontaneous diastolic depolarization phase. As a result, the frequency of impulse generation decreases and bradycardia develops, while ventricular conduction and contractility are not reduced. An increase in diastole duration helps increase main and collateral blood flow, which ultimately reduces myocardial oxygen demand.
Which drugs belong to myotropic agents that increase oxygen delivery to the myocardium?
Coronary vasodilators of myotropic action that increase oxygen delivery to the myocardium include dipyridamole. These drugs have a direct effect on the smooth muscles of the coronary vessels, causing them to dilate.
- Dipyridamole — a pyrimidine derivative that is a typical representative of this pharmacological group.
The main mechanism of action of such agents is the direct relaxation of the vascular wall, which increases coronary blood flow and improves the oxygen supply to the heart muscle.
Which specific drugs are used as cardioprotectors (cytoprotectors) in coronary artery disease?
Trimetazidine is used as a cardioprotector (cytoprotector) in ischemic heart disease.
- Trimetazidine optimizes the impaired energy metabolism of cardiomyocytes: it suppresses $\beta$-oxidation of fatty acids by inhibiting 3-ketoacyl-CoA thiolase, shifts oxidation reactions towards glucose oxidation, promotes more complete ATP synthesis, and reduces acidosis.
The drug increases the resistance of cardiomyocytes to ischemia through metabolic protection.
Which drugs belong to calcium channel blockers used as antianginal agents?
The following calcium channel blockers are used as antianginal agents:
- Verapamil and diltiazem — nondihydropyridine derivatives. Used to control heart rate and relieve symptoms of vasospastic angina.
- Amlodipine and nifedipine — dihydropyridine derivatives. Long-acting drugs of this group are added when ischemia persists or are used for vasospastic angina.
These drugs block slow calcium channels, preventing the entry of calcium ions into cells, which causes relaxation of vascular smooth muscle.
To memorize the treatment goals for different forms of angina: Stable — decrease Load (demand), Prinzmetal's — eliminate the Problem of spasm (dilate vessels), Unstable — urgently combat blood clots.
Class and exam questions
Why can vessels not provide blood flow during physical exertion in atherosclerosis?
Distal to the atherosclerotic plaque, vessels are already in a state of maximum dilation due to tissue hypoxia and adenosine accumulation. There is simply no reserve for further dilation when oxygen demand increases.
What is the molecular mechanism of pain during an anginal attack?
Due to a lack of oxygen in myocardial tissues, protons ($H^+$) accumulate. They locally irritate vanilloid receptors, which is perceived by the nervous system as characteristic ischemic pain.
What is the main difference between unstable and stable angina?
Stable angina occurs upon exertion due to a mechanical obstruction (atherosclerosis), while unstable angina occurs at rest due to massive thrombus formation. The unstable form is less responsive to conventional drugs and is considered a pre-infarction state.
What else to study on this topic
- Mechanism of action of organic nitrates and calcium channel blockers
- Pharmacodynamics of $\beta$-blockers and bradicardic agents in coronary artery disease
- Agents affecting hemostasis (antiplatelet agents, anticoagulants, fibrinolytics)
- Cardioprotectors and principles of metabolic myocardial protection
- Differences between myotropic and reflex actions of coronary vasodilators
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