Potassium channel blocker. Calcium channel blockers, also known as calcium antagonists: classification, mechanism of action and list of drugs for hypertension. Pharmacological list of slow calcium channel blockers by chemical composition of structure

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Calcium channel blockers, widely used in practical medicine, represent a heterogeneous class of drugs. It consists of 4 groups of chemicals, divided into three generations, according to the time of discovery of a particular representative. They have been used for more than 30 years, and the first drug of the group was verapamil, synthesized by A. Fleckenstein. There are also calcium antagonists (CA), the chemical structure of which does not allow them to be classified into specific categories.

The complete list of calcium channel blockers consists of more than 20 medicinal substances (DS), each of which has its own characteristics of influence on human biological tissues. Due to differences in chemical structure, their effect is not the same and is expressed differently in representatives of different generations of drugs of the class. A number of CCBs have found application in the therapeutic industry, while some are used in neurology and gynecology.

Despite the difference in effects, all known calcium channel blockers have a common mechanism of pharmacological action - they prevent the flow of calcium ions into the cell through voltage-gated slow channels. The latter are called L-channels and are embedded in the membranes of vascular smooth muscle cells, contractile cardiomyocytes, and skeletal muscle sarcolemmas. They are also found in the membranes of neurons in the cerebral cortex (in dendrites and dendritic spines of neurons).

In addition to L-channels, there are 4 more types of specific proteins in the body, changes in the structure of which change the intracellular and membrane concentration of calcium. The most important, in addition to the previously mentioned L-type channels, are the T-type voltage-gated channels. They are located in cells with pacemaker activity. They are atypical cardiomyocytes that automatically generate an impulse to contract the myocardium at a given rhythm.

Known calcium channel blockers are characterized by competitive inhibition of L-type receptors, during which the intracellular calcium concentration changes. This disrupts the processes of muscle contraction, makes contraction weak and incomplete due to the impossibility of complete contact between the actin and myosin chains of muscle proteins. In atypical cardiomyocytes, the effects of calcium channel blockers allow inhibition of the automaticity of atypical cardiomyocytes, providing a beneficial antiarrhythmic effect.

Classification by chemical structure

In the chemical classification, calcium channel blockers, the list of drugs of which is slightly expanding with new research, consists of 4 main classes: representatives of the group of diphenylalkylamines, diphenylpiperazines, benzodiazepines and dihydropyridines. All derivatives of these chemicals are (or were) medicinal substances.

Substances of the diphenylalkylamine group are the very first of those compounds of the class that began to be used as new galenic drugs. Benzothiazepines are considered the next branch into which calcium channel blockers branched off. Now the drugs of this group are used widely in therapeutic and obstetric practice.

The most dynamically developing and most promising group is the group of dihydropyridines. It consists of a maximum number of medicinal substances, a number of which are included in standard protocols for the treatment of diseases. Of slightly less importance are diphenylpiperazines, blockers of slow calcium channels, drugs based on which are often used in neurology.

Generations of calcium antagonist drugs

CCBs (or slow calcium channel blockers) are drugs with different types of structures. They were developed based on the 4 classes of substances indicated above. Medicinal substances that had fewer side effects and had important therapeutic significance were isolated in advance and became the progenitors of the group of drugs (first generation). Other drugs that are superior to the first generation CCBs in terms of clinically important effects were classified as II and III generation CCBs in the classification.

Below is a classification of phenylalkylamines, diphenylpiperazines and benzodiazepines by generation, where the original drugs are assigned to a specific class. They are listed as international nonproprietary names.

Diphenylpiperazines and benzodiazepines are different in structure, but these blockers of slow calcium channels have a common disadvantage - they are quickly cleared from the blood and have a small breadth of therapeutic action. In approximately 3 hours, half of the entire dose of the drug is eliminated, therefore, to create a stable therapeutic concentration, it was necessary to prescribe 3- and 4-fold doses during the day.

Due to the small differences between the therapeutic and toxic doses, an increase in the frequency of taking first-generation drugs causes a risk of intoxication of the body. However, first generation dihydropyridine calcium channel blockers are poorly tolerated when prescribed in such doses. For this reason, their use is limited and their therapeutic effects are weakened, making them unsuitable for monotherapy.

To replace them, 3rd generation calcium channel blockers were synthesized and tested, which are presented only in the group of dihydroperidines. These are drugs that can remain in the blood longer and exert their therapeutic effect. They are more effective and safer, and can be used more widely for a number of pathologies. The classification of these drugs is presented below.

Modern dihydropyridine calcium channel blockers are drugs with an extended duration of action. Their pharmacodynamic characteristics make it possible to prescribe them for 2-fold and single doses during the day. Also, drugs of a number of dihydropyridines are characterized by tissue specificity in relation to the heart and peripheral vessels.

Among the representatives of the third generation there are blockers of slow calcium channels, drugs based on which are already widely used in therapy today. Lercanidipine and lacidipine are capable of dilating blood vessels, allowing a significant increase in antihypertensive treatment. More often they are combined with diuretics and traditional ACE inhibitors.

Phenylalkylamine series BKK

This section contains calcium channel blockers, the drugs of which have been used for about 30 years. The first is verapamil, which is presented on the pharmacy market in the form of the following drugs: Isoptin, Finoptin, Verogolide. The drug "Tarka" also contains verapamil in combination with trandolapril.

Substances such as anipamil, falipamil, gallopamil and tiapamil are not listed as available and are not registered in the pharmacopoeia. For some, trials have not yet been completed to allow them for clinical use. Therefore, among the BCP phenylalkylamines, the safest and most accessible is verapamil, which is used as an antiarrhythmic.

Series of dihydropyridines

Among the dihydropyridines there are calcium channel blockers, the list of drugs based on which is the widest. These drugs are used very often due to their antispasmodic activity. The third generation dihydropyridines are now considered the safest. Among them are lercanidipine and lacidipine.

Lercanidipine is produced by only two pharmacological companies and is available in the form of the drug "Lerkamen" and "Zanidip-Recordati". Lacidipine is available in a wider variety: "Latsipin", "Latsipil" and "Sakur". These drug trade names are more common, although as the evidence base expands, lacidipine will become more firmly established in therapeutic practice.

Among the representatives of the second generation of dihydropyridines are calcium channel blockers, the drugs of which have the maximum possible number of generics. For example, only amlodipine is produced by more than 20 pharmacological companies under the following names: "Amlodipine-Pharma", "Tenox", "Norvasc", "Amlocordin", "Asomex", "Vaskopin", "Kalchek", "Cardiolopin", " Stamlo", "Normodipin", "Amlotop".

Isradipine does not have a list of generics, since this drug is represented by only one trade name - “Lomir” and its modification “Lomir SRO”. Also weak distribution is characterized by felodipine, riodipine, nitrendipine and nisoldipine. This trend is mainly due to the presence of Amlodipine, a cheap and effective drug. However, if there are allergic reactions to Amlodipine, patients are forced to look for a replacement among other representatives of the dihydropyridine class.

The medicinal substance riodipine is represented on the market by the drug "Foridon", and nitrendipine - by "Octidipine". There are two generic versions of Felodipine in the pharmacy chain - "Felodip" and "Plendil". Nisoldipine is not yet produced by any pharmacological company, and therefore is not available to patients. Nimodipine is offered in the form of the drug "Nimotop" and "Nitop".

Despite the diminishing importance of the first generations, calcium channel blockers, the drugs for which were previously used, are widely available on the market. Nifedipine is the most widespread of all short-acting CCBs, as it has the maximum number of generics: “Adalat”, “Vero-nifedipine”, “Calcigard”, “Zanifed”, “Kordaflex”, “Corinfar”, “Kordipin”, “Nicardia” , "Nifadil", "Nifedex", "Nifedikor", "Nifekard", "Osmo", "Nifelat", "Phenigidin". These drugs are affordable, but their prevalence is gradually decreasing due to the emergence of more effective drugs.

Classification of nonspecific BCCs

This group of drugs contains calcium channel blockers, the list of drugs of which is limited to 5 substances. These are mibefradil, perhexiline, lidoflazin, caroverine and bepridil. The latter belongs to the class of benzodiazepines, but has a different receptor. It selectively limits the passage of calcium ions through the T-channels of pacemakers and is capable of blocking sodium channels of the cardiac conduction system. Due to this mechanism of action, bepridil is used as an antiarrhythmic.

An even more promising drug is Mebefradil, which is being tested as an antianginal agent. At the moment, there are a number of publications by authors proving its effectiveness in myocardial infarction and angina. Therefore, it will be classified as a substance that contains slow calcium channel blockers that can prolong the life of a patient with acute coronary pathology. There are still very few accessible and highly effective products in this group.

An exception may be the more affordable Lidoflazin. Research suggests that the latter has the ability not only to dilate the arteries of the heart, while simultaneously reducing blood pressure, but also to stimulate the growth of new blood vessels. The development of collateral circulation in the heart is of great importance. Since calcium channel blockers are predominantly heterogeneous drugs, and lidoflazin is structurally similar to phenylalkylamine, it is natural that it has similar side effects and can only be used outside of acute coronary pathology.

Therapeutic use of "Lidoflazin"

"Lidoflazin" is a representative of the category of drugs that have a weak blocking ability against calcium channels. The therapeutic effect of Lidoflazin is similar to that of flunarizine, but differs in the expansion of the coronary arteries of the heart, and therefore is used for ischemic myocardial disease outside of acute manifestations. Preparations in which the active ingredient is lidoflazin have several trade names: “Ordiflazin”, “Clinium”, “Claviden”, “Clintab” and “Corflazin”. They can be used for mild angina, not associated with the presence of extensive stenosis of the coronary arteries of the heart.

The daily dose of Lidoflazin is 240-360 mg. In this mode (2-3 times a day), the substance is used for almost six months. The safety of the drug is proven by a number of studies, while the drugs caroverine and perhexiline do not have them. These substances are being studied for clinical efficacy and toxicity.

Areas of application of BKK

Modern calcium channel blockers, the list of drugs of which is replenished with new substances, are used in therapeutic practice to achieve several types of effects: hypotensive, antianginal, anti-ischemic and antiarrhythmic. For this purpose, BCCs are used in the following cases:

• for angina pectoris to dilate the blood vessels of the heart (dihydroperidines, mainly amlodipine);
• for vasospastic angina (amlodipine);
• for Raynaud's syndrome (dihydropiperidines, mainly amlodipine);
• for arterial hypertension (dihydroperidines, mainly amlodipine, less often lercanidipine and lacidipine);
• for supraventricular tachyarrhythmias (phenylalkylamines, mainly verapamil).

In other cases, it is believed that calcium channel blockers, the classification of which is indicated above, are not indicated. The only exception is the group of diphenylpiperazines, represented by Cinnarizine and Flunarizine. These drugs can be used for arterial hypertension in adolescents and pregnant women, as well as for the prevention of vascular disorders in the brain provoked by hypertensive crises.

Main therapeutic effects of calcium antagonists

Due to the blockade of voltage-gated calcium channels, AK has a number of useful therapeutic effects that are important in the treatment of angina pectoris, arterial hypertension, and arrhythmias. This allows the use of selective calcium channel blockers for their treatment along with a number of auxiliary drugs of other classes.

In angina pectoris, due to calcium antagonists, dilation of the arterial vessels of the myocardium occurs and a beneficial inhibition of the contractility of the heart muscle occurs. This improves the nutrition of myocardial cells while simultaneously reducing their need for oxygen. With therapy, anginal attacks develop less frequently and are shorter lasting. Also, for vasospastic angina, calcium antagonists are considered the most effective drugs for preventing and relieving an attack of anginal pain.

The drugs of this group help to increase endocardial-epicardial blood flow, improving blood supply to the myocardium against the background of its hypertrophy. AKs have the property of reducing preload by significantly reducing the amount of blood flowing to the heart. Medicinal substances from the group of calcium channel blockers also reduce cardiac afterload, helping to stabilize metabolic processes in ischemic myocardial disease.

In arterial hypertension, calcium channel blockers mediate a decrease in total peripheral vascular resistance. The effect is achieved by expanding the muscular walls of the arteries and is accompanied by a decrease in systolic and diastolic pressure in the vessels. Also, calcium blockers weaken the effects of angiotensin on the vascular wall, preventing the increase in blood pressure. They are also second-line drugs necessary for the treatment of hypertension in pregnant women.

Related therapeutic effects

Any calcium channel blockers, the mechanism of action of which has not been sufficiently studied, also have secondary effects. Also, their use is limited by the insufficient information content of available scientific studies designed to prove the appropriateness of the use of this medicinal substance for chronic myocardial ischemia. The following effects of a group of drugs are also useful here:

• blockade of calcium channels in platelets with a decrease in the rate of their aggregation;
• improvement of renal blood flow with weakening of the RAAS activity and a drop in blood pressure.

Nimodipine is selective for cerebral vessels, and therefore reduces the likelihood of developing secondary vasospasm in subarachnoid hemorrhages. But in case of CHF, BCCs are undesirable, as they worsen the prognosis for life. Only taking amlodipine and felodipine is allowed if there is severe arterial hypertension or angina pectoris that is not corrected by beta blockers, ACE inhibitors, or diuretics. Lercanidipine and lacidipine can be used for the same purpose.

Side effects

Regular use of short-acting CCBs (nifedipine) is unacceptable, as it causes reflex activation of the sympathetic nervous system and can develop postural hypotension, increasing the risk of ischemic stroke and myocardial infarction. They can also cause a repeated hypertensive crisis or angina attack due to withdrawal syndrome.

Short-acting CCB drugs are only suitable for relieving crises and angina attacks, but then long-acting ACE inhibitors and beta blockers must be added. The combined use of CCBs with nitrates and ACE inhibitors leads to swelling of the extremities, redness of the skin and face. Without nitrates the side effect is weaker.

Dihydropyridines cause gingival hyperplasia with long-term use. These same drugs are contraindicated for stenosis of the aorta and carotid vessels due to the risk of ischemic stroke. Their use is unacceptable in the acute phase of MI and unstable angina (steal syndrome), and their effectiveness in the secondary prevention of MI has also not been proven.

A detailed description of the most commonly prescribed calcium channel blockers.

Calcium channel blockers (abbreviated CCB), or calcium antagonists (abbreviated AK) are a group of medications whose members prevent the entry of calcium into cells through calcium channels. BKK act on:

1. Cardiomyocytes (heart muscle cells) - reduce the contractility of the heart.
2. Conducting system of the heart - slows down the heart rate (HR).
3. Vascular smooth muscles - dilate coronary and peripheral arteries.
4. Myometrium - reduces the contractile activity of the uterus.

Calcium channels are proteins in the cell membrane that contain pores that allow calcium to pass through. Due to the entry of calcium into the cells, muscle contraction and the release of neurotransmitters and hormones occur. There are many types of calcium channels, but most CCBs (except cilnidipine) act only on their slow L type. It is this type of calcium channel that plays a major role in the entry of calcium ions into smooth muscle cells and cardiomyocytes.

Click on photo to enlarge

There are also other types of calcium channels:

• P-type – located in the cells of the cerebellum.
• N-type – localized in the brain.
• R - located in the cells of the cerebellum and other neurons.
• T – located in neurons, cells with pacemaker activity, osteocytes (bone tissue cells).

CCBs are most often prescribed for the treatment of arterial hypertension (AH) and angina pectoris (CHD), especially when these diseases are combined with diabetes mellitus. ACs are used to treat certain arrhythmias, subarachnoid hemorrhage, Raynaud's phenomenon, prevent cluster headaches, and prevent preterm labor.

Most often, CCBs are prescribed by cardiologists and therapists. Independent use of CCBs is prohibited due to the risk of developing severe complications.

BKK Groups

In clinical practice, the following groups of BCCs are distinguished:

• Dihydropyridines (nifedipine group) act mainly on blood vessels, therefore they are used to treat hypertension.
• Phenylalkylamines (verapamil group) - act on the myocardium and conduction system of the heart, therefore they are prescribed mainly for the treatment of angina pectoris and arrhythmias.
• Benzodiazepines (diltiazem group) are an intermediate group with the properties of dihydropyridines and phenylalkylamines.

There are 4 generations of BCC:

1. 1st generation – nifedipine, verapamil, diltiazem.
2. 2nd generation – felodipine, isradipine, nimodipine.
3. 3rd generation – amlodipine, lercanidipine.
4. 4th generation – cilnidipine.

Mechanism of action

CCBs bind to the receptors of slow calcium channels, through which most calcium ions enter the cell. Calcium is involved in the functioning of the sinus and atrioventricular nodes (regulate heart rate), in the contractions of cardiomyocytes and vascular smooth muscles.

By influencing these channels, BKK:

• They weaken the contractions of the heart, reducing its need for oxygen.
• They reduce vascular tone and eliminate their spasm, reducing blood pressure (BP).
• Reduce spasm of the coronary arteries, thereby increasing blood supply to the myocardium.
• Slow down heart rate.
• Impair platelet aggregation.
• They counteract the formation of new atherosclerotic plaques and suppress the division of smooth muscle cells of the vascular wall.

Each of the individual drugs does not have all these properties at once. Some of them have a greater effect on blood vessels, others on the heart.

Indications for use

Doctors prescribe calcium channel blockers to treat the following diseases:

• AH (high blood pressure). By causing vasodilation, CCBs reduce systemic vascular resistance, which lowers blood pressure levels. These drugs primarily affect the arteries and have minimal effect on the veins. CCBs are included in five main groups of antihypertensive drugs.
• Angina (pain in the heart area). CCBs dilate blood vessels and reduce cardiac contractility. Systemic vasodilation caused by the use of dihydropyridines lowers blood pressure, thereby reducing the load on the heart, which leads to a decrease in its oxygen requirements. CCBs that act primarily on the heart (verapamil, diltiazem) reduce heart rate and weaken heart contractions, which leads to a decrease in its oxygen demand, making them effective against angina. CCBs can also dilate the coronary arteries and prevent their spasm, improving blood supply to the myocardium. Due to these effects, CCBs – together with beta blockers – are the mainstay of pharmacotherapy for stable angina.
• Supraventricular arrhythmias. Some CCBs (verapamil, diltiazem) affect the sinus and atrioventricular nodes, so they can effectively restore normal heart rhythm in patients with atrial fibrillation or flutter.
• Raynaud's disease (spastic vasoconstriction, most often affecting the hands and feet). The use of nifedipine helps eliminate arterial spasm, thereby reducing the frequency and severity of attacks of Raynaud's disease. Sometimes amlodipine or diltiazem are used for this purpose.
• Cluster headache (repeated attacks of very severe pain on one side of the head, usually around the eye). Verapamil helps reduce the severity of attacks.
• Relaxation of the uterine muscles (tocolysis). Doctors sometimes use nifedipine to prevent premature birth.
• Hypertrophic cardiomyopathy (a disease in which severe thickening of the walls of the heart occurs). Calcium channel blockers (verapamil) weaken the contractions of the heart, so they are prescribed to treat hypertrophic cardiomyopathy if patients have contraindications to taking beta blockers.
• Pulmonary hypertension (increased pressure in the pulmonary artery). Pulmonary hypertension is treated with nifedipine, diltiazem, or amlodipine.
• Subarachnoid hemorrhage (bleeding into the space surrounding the brain). To prevent vasospasm, nimodipine is used, which has a selective effect on cerebral arteries.

Contraindications

Calcium channel blocker drugs have their own contraindications, which are clearly stated in the instructions for the drug. For example:

1. Drugs from the verapamil and diltiazem groups are contraindicated in patients with bradycardia, pathology of the cardiac conduction system, or systolic heart failure. They should also not be prescribed to patients already taking beta blockers.
2. All calcium antagonists are contraindicated in patients with low blood pressure, unstable angina, or severe aortic stenosis.
3. CCBs are not used in pregnant or breastfeeding women.

Side effects

Side effects of CCBs depend on the properties of the group of these drugs:

• The effect on the myocardium can cause hypotension and heart failure.
• The effect on the conduction system of the heart can lead to blockades or arrhythmias.
• The effect on blood vessels sometimes causes hot flashes, swelling, headaches, and rashes.
• Other side effects include constipation, gynecomastia, and increased sensitivity to sunlight.

Dihydropyridine BCPs

Dihydropyridines are the most commonly prescribed calcium antagonists. These drugs are used primarily to lower blood pressure. The most famous drugs from this group include:

• Nifedipine is one of the first CCBs that acts primarily on blood vessels. Prescribed to lower blood pressure during hypertensive crises, eliminate symptoms of vasospastic angina, and treat Raynaud's disease. Nifedipine rarely worsens heart failure, since the deterioration of myocardial contractility is compensated by a decrease in the load on the heart. There are long-acting drugs that are used to treat hypertension and angina.
• Nicardipine - this drug, like nifedipine, affects blood vessels. Used to prevent angina attacks and treat hypertension.
• Amlodipine and felodipine are among the most commonly prescribed CCBs. They act on blood vessels and do not impair cardiac contractility. They have a long-lasting effect, making them convenient to use for the treatment of hypertension and angina pectoris. Their use is especially useful in vasospastic angina. Side effects are associated with dilation of the arteries (headache, hot flashes) and may subside within a few days.
• Lercanidipine and isradipine are similar in characteristics to nifedipine and are used only for the treatment of arterial hypertension.
• Nimodipine - this drug has a selective effect on the cerebral artery. Due to this property, nimodipine is used to prevent secondary spasm of the cerebral arteries during subarachnoid hemorrhage. Nimodipine is not used for the treatment of other cerebrovascular diseases, since there is no evidence of the effectiveness of its use for these purposes.

Side effects of all dihydropyridine CCBs are associated with vasodilation (headache, hot flashes), they may disappear within a few days. Swelling in the legs also often develops, which is difficult to eliminate with diuretics.

Phenylalkylamines

Calcium channel blockers from this group primarily affect the myocardium and conduction system of the heart, therefore they are most often prescribed for the treatment of angina pectoris and arrhythmias.

Almost the only CCB from the phenylalkylamine group used in clinical medicine is verapamil. This drug impairs cardiac contractility and also affects conduction in the atrioventricular node. Because of these effects, verapamil is used to treat angina and supraventricular tachycardia. Side effects include increased heart failure, bradycardia, drop in blood pressure, and worsening conduction disturbances in the heart. The use of verapamil is contraindicated in patients already taking beta blockers.

Benzodiazepines

Benzodiazepines occupy an intermediate position between dihydropyridines and phenylalkylamines, so they can both dilate blood vessels and worsen cardiac contractility.

An example of a benzodiazep is diltiazem. This drug is most often used for angina. There is a long-acting release form that is prescribed for the treatment of hypertension. Because diltiazem affects the conduction system of the heart, it should be combined with beta blockers with caution.

Other precautions when using CCBs

Any drug from the CCB group can be used only as prescribed by a doctor. The following points should be taken into account:

1. If you are taking a CCB drug, you should not drink grapefruit juice. This prohibition is due to the fact that it increases the amount of the drug entering the blood. As a result, your blood pressure may suddenly drop, which can sometimes be quite dangerous. Grapefruit juice affects almost all calcium channel blockers except amlodipine and diltiazem. You can drink juice from oranges and other fruits.
2. Consult your doctor before taking any medications, including herbal remedies, in combination with calcium antagonists.
3. Be prepared for long-term use of CCBs in the treatment of hypertension. Some patients stop taking antihypertensive medications on their own once their blood pressure levels are normal, but doing so can put their health at risk.
4. If you have angina and suddenly stop taking these blockers, you may experience pain in the heart area.

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Work pages

Calcium channels: the view of a clinical pharmacologist

Kukes V.G., Sychev D.A., Ramenskaya G.V., Starodubtsev A.K.

MMA im. THEM. Sechenov, IKF NTsEGKLS

Drugs from the group of slow calcium channel blockers have found widespread use in medicine. They are used not only in the treatment of cardiovascular diseases (coronary artery disease, arterial hypertension, rhythm disturbances), but also in neurological, gastroenterological practice and in other areas of medicine. Recently, with the receipt of the results of multicenter controlled studies proving the high effectiveness of this group of drugs, a kind of “renaissance” of slow calcium channel blockers has begun. In this regard, interest has increased in calcium-regulating cell structures as potential pharmacological targets for more effective and safe drugs.

Key words: calcium, slow calcium channels, copper calcium channel blockers.

1.Physiological role of calcium

Calcium ions occupy a special place in maintaining cellular life processes. Due to their unique physicochemical properties (the ability to selectively bind to complex bioorganic molecules and change their conformation), they are the most universal intermediaries connecting processes on the surface of the cell membrane with intracellular mechanisms. Each living cell spends a significant part of its metabolic energy on the excretion of calcium ions through systems of special calcium pumps, maintaining a very low level in the cytoplasm at rest (about 10 -8 M). The resulting huge transmembrane gradient of calcium ions can “inject” these ions into the cell at high speed and create a short-term increase in their concentration (“calcium signal”), which in turn can trigger or modulate almost all cell functions. One of the most important physiological functions of calcium ions is to ensure the coupling of the processes of excitation and contraction in smooth muscle cells and skeletal muscle cells. Calcium ions are also necessary for the processes of platelet aggregation, the release of neurotransmitters, ensure the normal functioning of the endo- and exocrine glands, etc. The main structure that ensures the generation of calcium signals are specialized protein molecules built into cell membranes and capable of opening a path for movement under the influence of external influences ions along an electrochemical gradient – ​​ion channels.

2. Calcium channels and their role in coupling excitation and contraction

2.1 Classification of calcium channels

Based on location, calcium channels can be divided into cytoplasmic or sacrolemmal located on the surface of the cytoplasmic membrane (sarcolemma) and intracellular. The latter are localized mainly in the sarcoplasmic reticulum (SRR).

In turn, among cytoplasmic calcium channels, according to the mechanism of activation, it is customary to distinguish receptor dependent calcium channels and voltage-dependent or voltage dependent calcium channels.

Receptor-gated calcium channels are coupled via a G-protein system to various receptors. After the interaction of a specific agonist with the corresponding receptor, conformational changes occur in the receptor itself, G-proteins and finally the receptor-dependent calcium channel, which leads to its opening, the entry of calcium ions into the cell and the implementation of a biological or pharmacological effect.

Voltage-gated calcium channels open in response to depolarization of the cytoplasmic membrane. The entry of calcium ions through voltage-gated calcium channels after depolarization occurs more slowly than the entry of sodium ions through sodium channels, so voltage-gated calcium channels are still called slow calcium channels. Voltage-dependent calcium channels, which open under the influence of changes in membrane potential and have high selectivity for calcium ions, are of particular importance for providing calcium signals. It is the activation of these channels that underlies the launch of such important vital functions as contraction of myocardial muscle fibers, smooth muscles, striated (skeletal) muscles, pacemaker activity of cells of the cardiac conduction system, release of mediators by nerve cells, secretion of enzymes and hormones by exo- and endocrine cells etc. Therefore, the search for means to control the function of calcium channels reveals the most effective ways to influence the corresponding functions. Voltage-gated calcium channels, according to their structure and electrophysiological properties, are divided into the following types of channels:

L-type calcium channels,

T-type calcium channels,

P-type calcium channels,

N-type calcium channels,

R-type calcium channels.

The most well studied voltage-gated channels are L-type and T-type. P-, N-, R-type channels are neuronal and their physiology and biochemistry have not been sufficiently studied.

Voltage-gated calcium channels L-type localized on the surface of the cytoplasmic membrane of working myocardial cardiomyocytes, cells of the sinus and atrioventricular nodes of the conduction system of the heart, cells of smooth and striated muscles. As already indicated, voltage-gated L-type calcium channels open in response to depolarization of the cytoplasmic membrane. The electrophysiological features of L-type calcium channels are a high threshold (therefore, this type of calcium channels is also called high threshold calcium channels) and slow inactivation. The main function of voltage-dependent L-type calcium channels in the myocardium, smooth and striated muscles is to couple the processes of excitation and contraction, in sinus cells - to ensure pacemaker activity, in the cells of the atrioventricular node - atrioventricular conduction (Table 1). Voltage-gated L-type calcium channels are pharmacological targets for the slow calcium channel blockers phenylalkylamine derivatives, dihydropyridine and benzothiazepane.

• AltGTU 419
• AltSU 113
• AmPGU 296
• ASTU 266
• BITTU 794
• BSTU "Voenmekh" 1191
• BSMU 172
• BSTU 602
• BGU 153
• BSUIR 391
• BelGUT 4908
• BSEU 962
• BNTU 1070
• BTEU PC 689
• BrGU 179
• VNTU 119
• VGUES 426
• VlGU 645
• VmedA 611
• VolgSTU 235
• VNU named after Dalia 166
• VZFEI 245
• VyatGSHA 101
• VyatGSU 139
• VyatGU 559
• GGDSK 171
• GomGMK 501
• GGMU 1967
• GGTU named after. Sukhoi 4467
• GSU named after Skorina 1590
• GMA named after. Makarova 300
• DSPU 159
• DalGAU 279
• DVGGU 134
• DVGMU 409
• DVGTU 936
• DVGUPS 305
• FEFU 949
• DonSTU 497
• DITM MNTU 109
• IvGMA 488
• IGHTU 130
• IzhSTU 143
• KemGPPK 171
• KemSU 507
• KGMTU 269
• KirovAT 147
• KGKSEP 407
• KSTA im. Degtyareva 174
• KnAGTU 2909
• KrasGAU 370
• KrasGMU 630
• KSPU named after. Astafieva 133
• KSTU (SFU) 567
• KGTEI (SFU) 112
• PDA No. 2 177
• KubGTU 139
• KubSU 107
• KuzGPA 182
• KuzGTU 789
• MSTU im. Nosova 367
• MSEU named after. Sakharova 232
• MGEC 249
• MGPU 165
• MAI 144
• MADI 151
• MGIU 1179
• MGOU 121
• MGSU 330
• MSU 273
• MGUKI 101
• MGUPI 225
• MGUPS (MIIT) 636
• MSUTU 122
• MTUSI 179
• KhAI 656
• TPU 454
• NRU MEI 641
• NMSU "Mining" 1701
• KhPI 1534
• NTUU "KPI" 212
• NUK them. Makarova 542
• HB 777
• NGAVT 362
• NSAU 411
• NGASU 817
• NSMU 665
• NGPU 214
• NSTU 4610
• NSU 1992
• NSUEU 499
• Research Institute 201
• OmSTU 301
• OmGUPS 230
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Calcium antagonists: list of drugs, action, indications

A “silent” health problem, as arterial hypertension is called, requires mandatory medical intervention. The best minds in the world are constantly searching for new drugs that regulate blood pressure, improve blood circulation and prevent such dangerous consequences of hypertension as heart attack or stroke. There are many different groups of pharmaceuticals that are assigned this task.

Calcium antagonists (CA) represent one of these groups and, having a number of positive qualities, are considered one of the best options among antihypertensive drugs in general. They act relatively mildly and are not rich in side effects, which, if they occur, are rather weak.

When does calcium become too much?

Experts call drugs in this group (calcium antagonists) as you like: blockers of “slow” calcium channels (SCBs), calcium ion entry blockers, calcium ion antagonists. However, what does calcium have to do with it, why should it not be allowed into the cell if it contracts muscles, including the heart, where these channels are located, for what reason is there so much attention to them, and in general - what is the essence of the mechanism of action of these drugs?

Physiological activity is characteristic exclusively of ionized calcium (Ca ++), that is, not associated with proteins. Ca ions are greatly needed by muscle cells, which use it for their functioning (contraction), therefore, the more of this element is in the cells and tissues, the greater the force of contraction they have. But is this always useful? Excessive accumulation of calcium ions leads to excessive tension in muscle fibers and overload, so it must be present in the cell in a constant amount, otherwise the processes dependent on this element will be disrupted and lose their periodicity and rhythm.

scheme of cardiomyocyte overload with calcium ions

Each cell itself maintains the concentration of calcium (sodium, potassium) at the required level through channels located in the phospholipid membrane that separates the cytoplasm from the intercellular space. The task of each channel is to control the passage in one direction (either into the cell or out) and the distribution of certain ions (in this case, calcium) within the cell itself or outside it. As for calcium, it should be noted that it has a very high desire to get into the cell from the intercellular space by any means. Therefore, some ACs need to be blocked so that they do not allow excess calcium ions trying to enter the cell to pass through and thus protect the muscle fibers from excess tension (the mechanism of action of ACs).

For the normal functioning of calcium channels, in addition to Ca ++, catecholamines (adrenaline and norepinephrine) are necessary, which activate CC; however, in this regard, the combined use of calcium ion antagonists and β-blockers (with the exception of drugs belonging to the nifedipine group) is undesirable , since excessive inhibition of channel function is possible. The blood vessels will not suffer much from this, but the myocardium, having received a double effect, may respond by developing atrioventricular block.

There are several types of calcium channels, but the mechanism of action of calcium ion antagonists is directed only at slow CCs (L-type), which contain various smooth muscle tissues:

• Sinoatrial tract;
• Atrioventricular pathways;
• Purkinje fibers;
• Myofibrils of the heart muscle;
• Smooth muscle of blood vessels;
• Skeletal muscles.

Of course, complex biochemical processes take place there, the description of which is not our task. We just need to note that:

The automaticity of the heart muscle is supported by calcium, which, being in the cells of the muscle fibers of the heart, triggers the mechanism of its contraction, therefore a change in the level of calcium ions will inevitably lead to a disruption in the functioning of the heart.

Calcium antagonist abilities

Calcium channel antagonists are represented by various chemical compounds that, in addition to lowering blood pressure, have a number of other capabilities:

1. They are able to regulate the rhythm of heart contractions, so they are often used as antiarrhythmic drugs.
2. It has been noted that drugs of this pharmaceutical group have a positive effect on cerebral blood flow during the atherosclerotic process in the vessels of the head and for this purpose are used to treat patients after a stroke.
3. By blocking the path of ionized calcium into cells, these drugs reduce mechanical tension in the myocardium and reduce its contractility. Thanks to the antispastic effect on the walls of the coronary arteries, the latter expand, which helps to increase blood circulation in the heart. The effect on peripheral arterial vessels is reduced to a decrease in upper (systolic) blood pressure and, of course, peripheral resistance. Thus, as a result of the influence of these pharmaceuticals, the need of the heart muscle for oxygen decreases, and the supply of nutrients to the myocardium and, first of all, oxygen increases.
4. Calcium antagonists, by inhibiting Ca ++ metabolism in cells, inhibit platelet aggregation, that is, they prevent the formation of blood clots.
5. Drugs in this group have antiatherogenic properties, reduce pressure in the pulmonary artery and cause dilation of the bronchi, which makes it possible to use them not only as antihypertensive drugs.

Scheme: mechanism of action and capabilities of AK 1-2 generations

Forefathers and followers

Medicines used to treat arterial hypertension and heart disease, belonging to the class of selective calcium ion antagonists, are classified into three groups:

• The first group is represented by phenylalkylamine derivatives, the founder of which is verapamil. In addition to verapamil, the list of drugs includes second-generation drugs: anipamil, tiapamil, falipamin, the site of application of which is the heart muscle, conduction tracts and vessel walls. They cannot be combined with β-blockers, since the myocardium will receive a double effect, which is fraught with disruption (slowing) of atrioventricular conduction. Patients who have a large number of antihypertensive drugs of various pharmaceutical classes in their arsenal,

You should know these features of the drugs and keep this in mind when trying to reduce blood pressure in any way.

Table: list of calcium antagonists registered in the Russian Federation

Interestingly, there is another group of calcium ion antagonists, which is not included in the classification and is not included in them. These are non-selective AKs, including piperazine derivatives (cinnarizine, belredil, flunarizine, etc.). Cinnarizine is considered the most popular and well-known in the Russian Federation. It has long been sold in pharmacies and is often used as a vasodilator for headaches, dizziness, tinnitus and impaired coordination of movements caused by spasm of the blood vessels in the head, which impedes cerebral circulation. The drug practically does not change blood pressure, patients love it, often note a noticeable improvement in their general condition, so they take it for a long time for atherosclerosis of the vessels of the brain, upper and lower extremities, as well as after an ischemic stroke.

Phenylalkylamine derivatives

The first group of calcium channel blockers - phenylalkylamine derivatives or the verapamil group makes up a small list of drugs, where the most famous and frequently used is verapamil itself (isoptin, finoptin).

Verapamil

The drug is able to have an effect not only on blood vessels, but also on the heart muscle, while reducing the frequency of myocardial contractions. Verapamil reduces blood pressure in normal doses little, so it is used to suppress conduction along the atrioventricular pathways and depression of automatism in the sinus node, that is, basically, this mechanism of action of the drug is used for heart rhythm disturbances (supraventricular arrhythmia). In injection solutions (intravenous administration), the drug begins to act after 5 minutes, so it is often used by emergency doctors.

The effect of isoptin and finoptin tablets begins within two hours; therefore, they are prescribed to be taken at home by patients with exertional angina, with combined forms of angina and supraventricular arrhythmia, but in the case of Prinzmetal's angina, verapamil is considered the drug of choice. Patients do not prescribe such medications to themselves; this is a matter for the doctor, who knows that for elderly people, the dose of verapamil should be reduced, since their metabolic rate in the liver is reduced. In addition, the drug can be used to correct blood pressure in pregnant women or even as an antiarrhythmic agent for tachycardia in the fetus.

Second generation drugs

Other drugs of the verapamil group belonging to the second generation drugs have also found their use in clinical practice:

1. Anipamil It has a more powerful (compared to verapamil) effect, which lasts about 1.5 days. The drug primarily affects the heart muscle and vascular walls, but does not affect atrioventricular conduction.
2. Falipamil acts selectively against the sinus node, practically does not change blood pressure, therefore, it is mainly used in the treatment of supraventricular tachycardia, resting and exertional angina.
3. Tiapamil it is 10 times inferior in power to verapamil, tissue selectivity is also not typical for it, but it can significantly block sodium ion channels, and therefore has proven itself well for the treatment of ventricular arrhythmias.

Dihydroperidine derivatives

The list of dihydropyridine derivative drugs includes:

Nifedipine (Corinfar, Adalat)

It is an active systemic vasodilator, which has virtually no antiarrhythmic abilities inherent in drugs from the verapamil group.

Nifedipine lowers blood pressure, slightly increases the heart rate (reflexively), and has antiaggregation properties, which prevents unnecessary thrombus formation. Due to its antispastic properties, the drug is often used to eliminate spasms that occur with vasospastic angina at rest, as well as for preventive purposes (to prevent the development of an attack) if the patient has exertional angina.

In clinical practice, rapidly soluble forms of nifedipine are widely used (adalat-retard, procardia XL, nificard), which begin to act in approximately half an hour and retain the effect for up to 6 hours, but if you chew them, the medicine will help within 5-10 minutes, although it is antianginal its effect will still not be as pronounced as that of nitroglycerin. Nifedipine tablets with the so-called two-phase release begin to act in 10-15 minutes, while the duration can be about a day. Nifedipine tablets are sometimes used to quickly lower blood pressure (10 mg sublingually - the effect occurs in 20 minutes to an hour).

Now in European clinics nifedipine prolonged action is becoming increasingly popular, due to the fact that it has fewer side effects and can be taken once a day. However, the unique system of using nifedipine continuous release is recognized as the best, which ensures normal concentrations of the drug in the blood plasma for up to 30 hours and is successfully used not only as an antihypertensive agent for the treatment of high blood pressure, but is also involved in the relief of paroxysms of resting and exertional angina. It should be noted that in such cases the number of adverse events is reduced by half when comparing nifedipine continuous release with other forms of this drug.

Nicardipine (perdipine)

The vasodilating effect is considered to be prevalent; the drug is mainly included in therapeutic measures in the fight against angina pectoris and arterial hypertension. In addition, nicardipine is suitable as a fast-acting remedy for relieving hypertensive crisis.

Nisoldipine (baymicard)

The mechanism of action is similar to nicardipine.

Nitrendipine (bypress)

Structurally, it is very similar to nifedipine, has a vasodilating effect, does not affect the atrioventricular and sinus nodes, and can be combined with beta-blockers. When used simultaneously with digoxin, bypress can double the concentration of the latter, which should not be forgotten if there is a need to combine these two drugs.

Amlodipine (Norvasc)

Some sources classify it as a 3rd generation drug, although others claim that, along with felodipine, isradipine, diltaezem, nimodipine, it belongs to the second generation calcium antagonists. However, this is not so important, since the determining factor is the fact that the listed drugs act gently, selectively and for a long time.

Amlodipine has high tissue selectivity, ignoring the myocardium, atrioventricular conduction and sinus node and is effective for up to one and a half days. Along with amlodipine, you can often find lacidipine and lercanidipine, which are also used for the treatment of arterial hypertension and are classified as 3rd generation calcium ion entry blockers.

Felodipine (Plendil)

It has high selectivity for blood vessels, which is 7 times greater than that of nifedipine. The drug combines well with beta-blockers and is prescribed for the treatment of coronary heart disease, vascular insufficiency, and arterial hypertension at a dose prescribed by a doctor. Felodipine can increase digoxin concentrations by up to 50%.

Isradipin (lomir)

The duration of the antianginal effect is up to 9 hours; when taken orally, side effects may occur in the form of facial flushing and swelling of the feet. In case of circulatory failure caused by stagnation, it is advisable to administer intravenously (very slowly!) in a dose calculated by the doctor (0.1 mg/kg of body weight per 1 minute - 1 administration, then 0.3 mg/kg - 2 administration). Obviously, the patient himself cannot make such calculations or administer the drug, therefore injection solutions of this drug are used only in hospital settings.

Nimodipine (Nimotop)

The drug is rapidly absorbed, the hypotensive effect occurs after about an hour. A good effect was noted from intravenous administration of the drug at the initial stage of acute cerebrovascular accident and in the case of subarachnoid hemorrhage. The use of nimodipine for the treatment of cerebral accidents is due to the drug’s high affinity for cerebral vessels.

New drugs from the class of calcium antagonists

Diltiazem

New types of calcium ion blockers, which can also be called 3rd generation drugs, include diltiazem. It, as stated earlier, occupies the position: “verapamil - diltiazem - nifedipine”. It is similar to verapamil in that it is also “not indifferent” to the sinus node and atrioventricular conduction, suppressing, although to a lesser extent, their function. Like nifedipine, diltiazem lowers blood pressure, but does so more gently.

Diltiazem is prescribed for coronary heart disease, Prinzmetal's angina and various types of hypertension, and only reduces high blood pressure (upper and lower). With normal blood pressure, the drug remains indifferent to the vessels, so there is no fear of an excessive drop in pressure and the development of hypotension. The combination of this drug with thiazide diuretics enhances the antihypertensive properties of diltiazem. However, despite the numerous advantages of the new product, a number of contraindications to its use should be noted:

Bepredil

The drug bepredil has a unique ability to block slow calcium and sodium channels, which due to this can affect both the vascular wall and the conduction system of the heart. Like verapamil and diltiazem, it acts on the AV node, however, in the case of hypokalemia, it can lead to the development of ventricular arrhythmia, so when prescribing bepredil, these qualities are taken into account, and the level of magnesium and potassium ions is constantly monitored. It should be noted that this drug generally requires special caution; it is not compatible with thiazide diuretics, quinidine, sotalol, or some antidepressants, so the patient’s initiative may have various consequences and will be absolutely inappropriate.

Foridon

To the list of drugs I would like to add an original antianginal drug produced in the Russian Federation, called foridon, which in adequate doses can replace nifedipine and diltiazem.

Features to Keep in Mind

Calcium antagonists do not have many contraindications, but they still exist and must be taken into account:

• As a rule, nifedipine is not prescribed if the initial pressure is low, in case of sinus node weakness or pregnancy.
• They try to bypass verapamil if the patient is diagnosed with AV conduction disorders, sick sinus syndrome, severe heart failure and, of course, arterial hypotension.

Although cases of overdose of calcium channel blockers have not been officially recorded, if such a fact is suspected, the patient is administered calcium chloride intravenously. In addition, drugs in this group, like any pharmacological agent, have some side effects:

1. Redness of the skin of the face and décolleté.
2. Reduced blood pressure.
3. “Hot flashes”, as during menopause, heaviness and pain in the head, dizziness.
4. Intestinal disorders (constipation).
5. Increased heart rate, swelling, affecting mainly the ankle and lower leg - a side effect of nifedipine;
6. A decrease in heart rate and atrioventricular block may result from the use of verapamil.

Table: side effects of AK and contraindications

Considering the fact that calcium channel blockers are often prescribed in combination with beta-blockers and diuretics, it is necessary to know the undesirable effects of their interaction: beta blockers potentiate a decrease in heart rate and impaired atrioventricular conduction, and diuretics enhance the hypotensive effect of AK, which should be kept in mind when selection of dosage of these medications.