Calcium channel blockers prolong life. Calcium antagonists: list of drugs, action, indications. Coronary artery disease
The L-type calcium channels found in the plasma membrane are structurally different from the calcium release channels in the sarcoplasmic reticulum. Both membranes contain ATP-dependent calcium pumps, which, although regulated differently, are members of the ATPase family of ion pumps, which also includes a sodium pump. The main transport system from the cytosol to the extracellular space is the Na+-Ca2+ exchanger, which has no equivalent in the sarcoplasmic reticulum. Unlike the plasma membrane, where the flow of calcium generates electrical current, the sarcoplasmic reticulum membrane contains non-selective anion channels that neutralize the charge transfer associated with the transmembrane movement of calcium.
The ion channels of the plasma membrane, which are commonly named after the transported ions, are oligomers containing up to 5 subunits. Ions pass through the hydrophobic core of the bilayer membrane through ion-selective pores contained within large proteins.
The alpha and c subunits of sodium and calcium channels, as well as the delayed rectification potassium channel, consist of four domains, each of which contains six a-helical transmembrane segments. The "pores" of the channels consist of a-helical transmembrane segments S5 and S6 and an intermediate sequence of amino acids. S4 transmembrane segments, rich in positively charged amino acids, are “voltage sensors” that open the channel in response to membrane depolarization. Several classes of ion channels are inactivated by the intracellular peptide chain linking domains III and IV, which, in a depolarized cell, undergo a conformational change to create an "inactivation particle" that blocks the internal opening of the pore. The four domains of most of the sodium and calcium channels of the plasma membrane are covalently linked into one large protein, while the domains of the delayed rectification potassium channels, which also function as tetramers, are not covalently linked.
There are several classes of calcium channels in the plasma membrane. In the heart, the most important are the L-type calcium channels, so named because of their relatively long-lasting opening. These channels bind known classes of calcium channel blockers and are sometimes referred to as dihydropyridine receptors due to their high binding affinity for this class of calcium channel blockers. The second class of calcium channels, which are called T-type channels, open only transiently; these channels play an important role in the sinoatrial nodal pacemaker, but they are practically absent in working ventricular myocytes. The content of T-type channels is increased in the hypertrophied heart, where they are thought to be involved in proliferative signaling.
The heart contains an even greater variety of potassium channels. They include potassium channels of delayed rectification, which show rectification outward. The latter term refers to the ability of these channels to open in response to membrane depolarization, which generates an electrical current that restores the resting potential. Another class of potassium channels, referred to as inward rectifying channels, is open when the cell is at rest but closes in response to depolarization; closure of these channels lengthens the action potential of the heart and contributes to the characteristic plateau phase. The main subunits of inwardly rectifying potassium channels are smaller than those of delayed rectifying potassium channels and consist of regions homologous to the a-helical transmembrane segments S5 and S6 and an intermediate sequence of amino acids that correspond to the pore region of the larger channel domains.
This information is intended for healthcare and pharmaceutical professionals. Patients should not use this information as medical advice or recommendations.
Calcium channel blockers
Most of the Russian market for calcium channel blockers is formed by imports. The demand for cinnarizine and nifedipine is almost completely met by imports.
Mechanism of action of calcium channel blockers
Calcium ions are essential for maintaining the work of the heart. Entering the cell, calcium ions activate metabolic processes, increase oxygen consumption, cause muscle contraction, increase excitability and conductivity. Ca 2+ ions enter the cell through ion-selective calcium channels, which are located in the phospholipid membrane of heart cells. The membrane separates the cytoplasm from the intercellular environment. All Ca 2+ channels are divided into two large groups: voltage-gated and receptor-gated. In turn, depending on the conductivity, lifetime in the open state, the rate of activation or inactivation, voltage-dependent Ca 2+ channels are divided into four types: dihydropyridine-sensitive Ca 2+ channels of the L-type, Ca 2+ - and R-type. In the cardiovascular system, there are L-type calcium channels that regulate the entry of calcium into smooth muscle fibers and directly affect the contraction process. When activated, the channels form instantaneous ion-selective pores through which Ca 2+ ions penetrate into the cell in the direction of the concentration gradient. This results in a potential difference, which is measured as a membrane potential between the cytoplasm and the extracellular fluid. The movement of ions into and out of the cell returns the membrane potential to its original level.
With an increased load on the heart, compensatory mechanisms cannot cope with the overload and acute heart failure develops. At the same time, in the heart muscle there is an excessive accumulation of sodium and calcium ions inside the cells, a violation of the synthesis of high-energy compounds, acidification of the intracellular environment, followed by a violation of the processes of contraction and relaxation of the cardiac muscle fiber. This leads to a decrease in the strength and speed of contraction of the heart muscle, an increase in residual systolic volume and diastolic pressure, and expansion of the heart cavities. And since the contraction of vascular smooth muscle cells depends on the concentration of Ca 2+ in the cytoplasm, if you suppress the transmembrane entrance of Ca 2+ and its amount in the cytoplasm of the cell, then its readiness for contraction will decrease. A critical increase in intracellular Ca 2+ can lead to cell damage and death due to its excessive activation with insufficient energy supply.
Calcium channel blockers (CCBs) reduce the supply of Ca 2+ through calcium L-channels. The mechanism of action of calcium channel blockers is based on the fact that they do not enter into any antagonism with calcium ions and do not block them, but affect their modulation by increasing and/or decreasing the duration of different phases of the state (phase 0 - closed channels, N1 and N2 - open channels) , and thus changing calcium current.
As a result, the load on the myocardium decreases and the tone of the smooth muscles of the arteries decreases (vasodilating effect), high blood pressure decreases, the formation of the action potential changes (they affect the conduction system of the heart, normalizing the heart rhythm), platelet aggregation decreases (the risk of thrombosis decreases), the total peripheral vascular resistance (OPSS). Therefore, calcium channel blockers are widely used in modern medicine.
Calcium channel blockers or selective calcium antagonists are a group of drugs that were originally intended for the treatment of angina pectoris. The first drug of this group, verapamil, which is a derivative of the well-known papaverine, was synthesized in Germany in 1962. Since the late 60s - early 70s of the last century, it was found that calcium channel blockers not only have an antianginal effect, but are also able to reduce systemic arterial pressure. Since then, calcium antagonists have become widely used in the treatment of arterial hypertension (persistent high blood pressure). Calcium channel blockers also penetrate the brain tissue well and limit the entry of calcium ions into nerve cells, which leads to the fact that calcium-dependent mechanisms of neuronal death (so-called apoptosis) are blocked during acute cerebral ischemia. In this, the neuroprotective effect of calcium channel blockers is manifested.
The main indications for the use of calcium channel blockers are:
The scope of BCC is not limited to cardiology and angioneurology. There are other, narrower and less known indications for prescribing these drugs. These include the prevention of cold bronchospasm, as well as the treatment of stuttering, since the drugs in question eliminate the spasmodic contraction of the diaphragm. Cinnarizine has antihistamine properties and can be used for immediate allergic reactions - skin itching, urticaria. It should be noted that in recently, CCB in connection with their neuroprotective and psychotropic properties use in complex treatment of Alzheimer's disease, Huntington's chorea, senile dementia, alcoholism.
We list the most important pharmacological effects of these drugs in the field of cardiohemodynamics:
The pharmacological properties of different CCBs are expressed differently. The drugs under consideration are divided into 4 main groups with somewhat different hemodynamic effects:
The subgroup of dihydropyridines is divided into 3 generations of drugs. Each subsequent generation surpasses the previous one in terms of efficacy, safety and pharmacokinetic parameters.
Classification of calcium channel blockers.
| Subgroup | Preparations | a brief description of |
| Dihydropyridines | I generation: Nifedipine short-acting, Nifedipine retard (long-acting) generation: Nifedipine GITS (continuous action), Felodipine generation: Amlodipine, Lacidipine, Nimodipine | These drugs have a predominant effect on vascular smooth muscle, they have less effect on the conduction system of the heart and on myocardial contractility; Nimodipine (Nimotop) differs in that it has a predominantly dilating effect on the vessels of the brain, and is used for cerebrovascular accidents |
| Phenylalkylamines | Verapamil, Verapamil retard | The effect on the conduction system of the heart is strongly pronounced, namely on the sinus node, where the depolarization of cell membranes depends on the entry of calcium ions, and on the atrioventricular node, in which the entry of calcium and sodium ions is important for the development of the action potential. They practically do not affect the conduction system of the ventricles, they clearly reduce myocardial contractility, and their effect on blood vessels is weakly expressed. |
| Benzothiazepines | Diltiazem, Diltiazem retard | These drugs approximately equally affect the heart and blood vessels, but are somewhat weaker than the nifedipine group. |
| flunarizines | Cinnarizine | In therapeutic doses, drugs of this group have an expanding effect mainly on the vessels of the brain, therefore they are used mainly for cerebrovascular accidents, migraine, and vestibular disorders. The effect of the considered CCBs on the vessels of other basins, as well as on the heart, is insignificant and has no significant clinical significance. |
Table 1.
According to the duration of antihypertensive action, calcium antagonists can be divided into the following groups:
The disadvantage of short-acting dosage forms is both a short duration of their action and sharp changes in blood concentration, resulting in an increased risk of stroke or myocardial infarction. All calcium channel blockers are lipophilic, 90-100% absorbed in the digestive tract and excreted from the body through the liver, however, they differ significantly in important pharmacokinetic parameters, such as bioavailability and plasma half-life.
| Duration | A drug | Bioavailability, % | Half-life in blood plasma, h | Time to reach maximum plasma concentration, h |
| short action | Verapamil | 10-30 | 4-10 | 1-2 |
| Diltiazem | 30-40 | 2-7 | 1-2 | |
| Nifedipine | 23-30 | 2-6 | 0,6 | |
| Average duration of action | Felodipine | 12-16 | 3-14 | 1,5 |
| Isradipin | 17-33 | 7-8 | 1,6 | |
| Lacidipine | 3-52 | 7-8 | 1 | |
| Long acting | Felodipine retard | 12-16 | 10-36 | 2-8 |
| Verapamil retard | 10-30 | 12 | 1-2 | |
| Nifedipine retard | 60-75 | 12 | 4 | |
| Extra long acting | Amlodipine | 60-80 | 35-52 | 6-12 |
Source: drug guide.
The drug must be effective, have as few side effects as possible, and deal with the disease in the best possible way. If the drug meets all the requirements that apply to it, then it is considered to be of high quality.
All calcium channel blockers have a sufficient number of side effects, so when choosing this drug, you must be very careful not to have the opposite effect.
Calcium channel blockers should be used systematically, therefore, certain requirements are imposed on them:
Calcium channel blockers do not fully satisfy the requirements, each drug has its own advantages and disadvantages, which must be carefully analyzed before prescribing any drug. Table 3 compares the most common calcium channel blockers used in clinical practice. The basic principles that should be followed when prescribing these drugs are shown in Table 4. However, the treatment must take into account all factors that may have an adverse effect, especially individual intolerance to this drug and all concomitant diseases.
Comparative characteristics of calcium channel blockers.
| A drug | disadvantages | Advantages |
| Nifedipine | There are many more side effects than other calcium channel blockers. Frequent symptoms associated with vasodilation (sensation of flushing, burning sensation; tachycardia, arterial hypotension), chest pain (sometimes like angina pectoris), which requires immediate discontinuation of the drug; |
Increases the excretion of sodium and water from the body. In therapeutic doses, it does not inhibit myocardial conduction. Virtually no antiarrhythmic activity. Able to quickly reduce blood pressure, especially when taken under the tongue. Ambulance for ambulatory relief of hypertensive crises, reduction of transient rises in blood pressure. High efficiency in reducing blood pressure, rapid onset of effect, and low cost have made nifedipine practically a folk remedy for the treatment of certain forms of angina pectoris, arterial hypertension, and a number of cardiovascular diseases. |
| Amlodipine | The maximum effect of amlodipine can be expected in a week from the start of its administration, because. slowly absorbed after oral administration and gradually begins to act, that is, it is unsuitable for a rapid decrease in blood pressure. | High bioavailability. The duration of action due to its slow release from the connection with the receptors. It can be used in patients with diabetes mellitus, as well as bronchial asthma and gout. It has a pronounced hypotensive effect on both systolic and diastolic blood pressure. With the development of the hypotensive effect of amlodipine, there is no change in the heart rate. Has a high selectivity for coronary and cerebral vessels, virtually devoid of inotropic effect and influence on the function of the sinus node and atrioventricular conduction. Well tolerated by patients, safe and effective in patients with hypertension in combination with severe heart failure. |
| Lacidipine | Little bioavailability. Recently on the market, few clinical studies have been conducted. | It has a gradual and prolonged antihypertensive effect. |
| Felodipine | In most cases, adverse reactions are dose-dependent and appear immediately after the start of treatment. These reactions are temporary and disappear with time. There are frequent cases of edema on the background of the use of this drug. |
Effective and well tolerated by elderly patients, regardless of age or comorbidity, does not have a negative effect on blood glucose concentration and lipid profile The main pharmacodynamic feature of the drug is its strong vascular selectivity. Smooth muscle resistance muscles are particularly sensitive to felodipine. |
| Nimodipine | The most common side effects are: hypotension, tachycardia, pastosity, redness of the face; dyspeptic phenomena; sleep disorders, increased psychomotor activity. There is only imported drug on the market. Expensive. Inconvenient to administer (intravenously). Virtually no effect on conduction in the AV and SA nodes and myocardial contractility. Reflexively increases heart rate in response to vasodilation. |
Blocks calcium channels in certain areas of the brain, has a positive effect on learning ability and memory (nootropic effect). Effective in violation of cerebral circulation. |
| Verapamil | When using large doses, especially in predisposed patients, severe bradycardia, AV blockade, arterial hypotension, and symptoms of heart failure are possible. In patients with coronary artery disease or cerebrovascular insufficiency, an excessive decrease in blood pressure during antihypertensive therapy may lead to the development of myocardial infarction or cerebrovascular accident. With rapid on / in the introduction in isolated cases - complete transverse heart block, asystole, collapse. Verapamil can cause asymptomatic first degree atrioventricular block or transient bradycardia. |
The anti-ischemic effect with regular use of verapamil increases. No orthostatic hypotension or reflex tachycardia has been observed to cause changes in systolic cardiac function in patients with normal ventricular function. It has an effective antiarrhythmic effect in supraventricular arrhythmias. The contractility of the ventricles slows down with flutter or atrial fibrillation. Restores sinus rhythm in paroxysmal supraventricular tachycardia The action of Verapamil can rarely lead to atrioventricular block II or III severity, bradycardia, or in rare cases to asystole. |
| Diltiazem | The ability to quickly reach the maximum concentration, the effect of the drug passes just as quickly, the risk of bradycardia. | Diltiazem is one of the most effective and safe drugs of modern cardiology, which does not affect lipid and carbohydrate metabolism. Effective in supraventricular arrhythmias reduces the peripheral and renal effects of angiotensin II. |
| Cinnarizine | Almost no effect on blood pressure. sometimes moderate drowsiness, dry mouth, gastrointestinal disorders are possible; in these cases reduce the dose. With severe arterial hypotension. In some elderly patients, extrapyramidal symptoms appear (or intensify). Enhances the effect of sedatives and alcohol. |
Few side effects. The cheapest drug on the market. Increases the resistance of tissues to hypoxia. It has a direct antispasmodic effect on blood vessels, reduces their response to biogenic vasoconstrictor substances. |
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. Flekenstein. There are also calcium antagonists (CA), whose chemical structure does not allow them to be classified into certain categories.
The full list of calcium channel blockers consists of more than 20 drugs, each of which has its own characteristics of influence on human biological tissues. Due to differences in the 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 BPCs have found use 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 of the cerebral cortex (in the dendrites and dendritic spines of neurons).
In addition to L-channels, there are 4 more types of specific proteins in the body, a change in the structure of which changes the intracellular and membrane-bound calcium concentration. The greatest value, in addition to the previously discussed channels of the L type, are voltage-dependent channels of the T-type. They are located in cells with pacemaker activity. They are atypical cardiomyocytes that automatically generate an impulse for myocardial contraction in 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 the 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 can inhibit the automatism of atypical cardiomyocytes, providing a useful antiarrhythmic effect.
Classification by chemical structure
In the chemical classification, calcium channel blockers, the list of drugs of which is slightly expanding with new studies, 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 group of diphenylalkylamines are the very first of those compounds of the class that began to be used as new-galenic preparations. Benzothiazepines are considered the next branch to which calcium channel blockers have branched off. Now the drugs of the group are widely used in therapeutic and obstetric practice.
The group of dihydropyridines is the most dynamically developing and most promising. It consists of the maximum number of medicinal substances, a number of which are included in the standard protocols for the treatment of diseases. Slightly less important 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 a heterogeneous structure. They were developed on the basis of the 4 above-mentioned classes of substances. Medicinal substances, which had fewer side effects and had an important therapeutic value, were isolated in advance and became the progenitors of the group of drugs (first generation). Other agents that outperform 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 medicinal substances are assigned to a specific class. They are listed as international non-proprietary names.
Diphenylpiperazines and benzodiazepines differ in structure, but these slow calcium channel blockers have a common drawback - they are quickly excreted from the blood and have a small breadth of therapeutic action. In about 3 hours, half of the entire dose of the drug is excreted, therefore, to create a stable therapeutic concentration, it was necessary to prescribe 3- and 4-fold doses during the day.
Due to small differences in therapeutic and toxic doses, an increase in the frequency of taking first-generation drugs causes a risk of intoxication of the body. At the same time, dihydropyridine calcium channel blockers of the first generation are poorly tolerated when administered at such doses. For this reason, their intake is limited with a weakening of therapeutic effects, which is why they are unsuitable for monotherapy.
They were replaced by synthesized and tested calcium channel blockers of the 3rd generation, which are presented only in the group of dihydroperidines. These are drugs that can stay in the blood longer and exert their therapeutic effect. They are more effective and safer, and can be used more widely in a number of pathologies. The classification of these drugs is presented below.
Modern dihydropyridine calcium channel blockers are drugs with an increased 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 blood vessels.
Among the representatives of the III generation there are blockers of slow calcium channels, drugs based on which are already widely used in therapy today. Lercanidipine and lacidipine are able to dilate 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 preparations 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, Verogolid. The composition of the drug "Tarka" also contains verapamil in combination with trandolapril.
Substances such as anipamil, falipamil, gallopamil and thiapamil are not on the list of available drugs and are not registered in the pharmacopoeia. For some, trials have not yet been completed to allow them for clinical use. Therefore, verapamil, which is used as an antiarrhythmic, is the safest and most affordable among the CCA phenylalkylamines.
Series of dihydropyridines
Among the dihydropyridines there are calcium channel blockers, the list of drugs based on which is the widest. These medicinal substances are used very often due to the presence of 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: "Lacipin", "Lacipil" and "Sakur". These brand 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 preparations 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, Norvask, Amlocordin, Asomex, Vascopin, 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 characterizes felodipine, riodipine, nitrendipine and nisoldipine. Basically, this trend is due to the presence of "Amlodipine" - a cheap and effective drug. However, in the presence of allergic reactions to Amlodipine, patients are forced to look for a replacement among other members of the dihydropyridine class.
The medicinal substance rhyodipine is represented on the market by the drug "Foridon", and nitrendipine - by "Octidipine". Felodipine in the pharmacy network has two generics - these are "Felodipine" and "Plendil". Nisoldipine is not yet produced by any of the pharmacological companies, and therefore is not available to patients. Nimodipine is offered in the form of Nimotop and Nitop.
Despite the decrease in the importance of the first generations, calcium channel blockers, the drugs of which were used earlier, are widely represented on the market. Nifedipine is the most massive of all short-acting CCBs, as it has the maximum number of generics: Adalat, Vero-nifedipine, Calcigard, Zanifed, Cordaflex, Corinfar, Kordipin, Nicardia , "Nifadil", "Nifedeks", "Nifedikor", "Nifekard", "Osmo", "Nifelat", "Fenigidin". These drugs are affordable, but their prevalence is slowly declining as more effective drugs become available.
Classification of non-specific CCBs
This group of drugs contains calcium channel blockers, the list of drugs of which is limited to 5 substances. These are mibefradil, perhexilin, lidoflazin, caroverine and bepridil. The latter belongs to the class of benzodiazepines, but differs in receptor. It selectively limits the permeability of calcium ions through the T-channels of the pacemakers and is able to block the sodium channels of the cardiac conduction system. In connection with 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 pectoris. 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 available and highly effective means in this group.
An exception may be the more affordable Lidoflazin. Studies suggest that the latter has the ability not only to expand the arteries of the heart, while lowering 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 lidoflavin 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 with a mild blocking ability in relation to 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 without acute manifestations. Preparations in which the active ingredient is lidoflazin have several trade names: Ordiflazin, Klinium, Claviden, Klintab and Korflazin. They can be used for non-severe angina, not associated with the presence of extended 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 proved by a number of studies, while caroverine and perhexilin preparations do not have them. These substances are under study for clinical efficacy and toxicity.
Areas of application of the BKK
Modern calcium channel blockers, the list of drugs of which is updated with new substances, are used in therapeutic practice to achieve several types of effects: hypotensive, antianginal, antiischemic and antiarrhythmic. For this purpose, the BKK is used in the following cases:
- with angina pectoris to dilate the vessels of the heart (dihydroperidines, mainly amlodipine);
- with vasospastic angina (amlodipine);
- with Raynaud's syndrome (dihydropiperidines, mainly amlodipine);
- with arterial hypertension (dihydroperidines, mainly amlodipine, less often lercanidipine and lacidipine);
- with 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 in the prevention of vascular disorders in the brain, provoked by hypertensive crises.
Main therapeutic effects of calcium antagonists
In connection with the blockade of voltage-dependent 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, together with a number of auxiliary drugs from other classes.
In angina pectoris, due to calcium antagonists, the arterial vessels of the myocardium expand and a beneficial inhibition of the contractility of the heart muscle occurs. This improves the nutrition of myocardial cells while reducing their oxygen demand. With therapy, anginal attacks develop less frequently and are less prolonged. Also, with vasospastic angina, calcium antagonists are considered the most effective drugs for preventing and stopping an attack of anginal pain.
The drugs of the group contribute to the enhancement of endocardial-epicardial blood flow, improving the 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 of the calcium channel blockers group also reduce cardiac afterload, contributing to the stabilization of metabolic processes in ischemic myocardial disease.
In arterial hypertension, calcium channel blockers mediate a decrease in the total peripheral resistance of the vascular bed. The effect is achieved due to the expansion of 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 growth of blood pressure. They are also second-line drugs necessary for the treatment of hypertension in pregnant women.
Concomitant therapeutic effects
Any calcium channel blockers, the mechanism of action of which is not well understood, have secondary effects. Also, their use is limited by the insufficient information content of the available scientific studies designed to prove the appropriateness of the use of this medicinal substance in 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 a weakening of 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 with CHF, BCC is undesirable, as it worsens 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, diuretics. Lercanidipine and lacidipine can be used for the same purpose.
Side effects
Regular intake 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 recurrent hypertensive crisis or angina pectoris due to withdrawal syndrome.
Short-acting CCBs are suitable only for relief of crises and angina, but then long-acting ACE inhibitors and beta-blockers should be added. The combined use of CCB 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 prolonged use. The same drugs are contraindicated in 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 in unstable angina (steal syndrome), and their effectiveness in the secondary prevention of MI has not been proven.
Drugs that lower the amount of calcium ions inside cells are called calcium blockers (slow calcium channels). Three generations of these drugs have been registered. Used to treat coronary disease, high blood pressure and tachycardia, hypertrophic cardiomyopathy.
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General information about calcium channel blockers
Medicines of this group have a different structure, chemical and physical properties, therapeutic and side effects, but they are united by a single mechanism of action. It consists in inhibition of the transfer of calcium ions through the membrane.
Among them are drugs with a predominant effect on the heart, blood vessels, selective (selective) and non-selective action. Often in one drug there is a blocker in combination with a diuretic.
Calcium channel blockers (CCBs) have been used for treatment in cardiology for about 50 years, this is due to the following advantages:
- clinical efficacy in myocardial ischemia;
- treatment and prevention,;
- reducing the risk of complications and mortality from heart disease;
- good tolerability and safety even for long courses;
- lack of addiction;
- there is no negative effect on metabolic processes, accumulation of uric acid;
- can be used in patients with bronchial asthma, diabetes, kidney disease;
- do not reduce mental or physical activity, potency;
- have antidepressant effects.
The mechanism of action of drugs
The main pharmacological action of CCB is the inhibition of the transition of calcium ions from the extracellular space to the muscle fibers of the heart and vascular walls through slow type L channels. With calcium deficiency, these cells lose their ability to actively contract, therefore, relaxation of the coronary and peripheral arteries occurs.
In addition, the use of drugs manifests itself in the following way:
- myocardial oxygen demand decreases;
- improves exercise tolerance;
- low resistance of arterial vessels leads to a decrease in the load on the heart;
- blood flow is activated in ischemic zones, the damaged myocardium is restored;
- the movement of calcium in the nodes and fibers of the conducting system is inhibited, which slows down the rhythm of contractions and the activity of pathological foci of excitation;
- platelet adhesion and thromboxane production slow down, blood fluidity increases;
- there is a gradual regression of left ventricular hypertrophy;
- the peroxidation of fats is significantly reduced, and hence the formation of free radicals that destroy the cells of blood vessels and the heart.
The influence of calcium antagonists on the process of atherosclerotic lesions of arteries and veins allows you to influence the main cause of coronary and hypertension.
Medicines in the initial stages prevent the formation of a plaque that clogs the arteries, prevent the coronary vessels from narrowing and stop the growth of the smooth muscles of the vascular wall.
Use of antianginal or selective blockers
The main indications for the use of BPC are such diseases:
- primary and symptomatic hypertension, including during a crisis (drops or a tablet lowers blood pressure in 10 minutes);
- angina pectoris at rest and exertion (with bradycardia and blockade, hypertension, Nifedipine is used, and - or Diltiazem);
- tachycardia, flickering, treated with Verapamil;
- acute disorders of cerebral blood flow (Nimotop);
- chronic cerebral ischemia, encephalopathy, motion sickness, migraine headache (Cinnarizine);
- (Amlodipine, Nifedipine, Procorum);
- (Corinfar, Lacipil).
No less effective was the use of calcium antagonists for bronchospasm, stuttering, allergies (Cinnarizine), complex treatment of senile dementia, Alzheimer's disease, and chronic alcoholism.
Watch the video about the choice of drugs for hypertension:
Contraindications
There are general restrictions for prescribing calcium channel blockers. These include:
- sinus node depression syndrome,
- , heart attack (risk of complications),
- low blood pressure,
- acute manifestations of heart failure,
- severe renal or hepatic pathology,
- pregnancy, breastfeeding, childhood.
In addition, drugs containing Verapamil or its analogues are contraindicated in case of blockade of impulse conduction, and Nifedipine in case of tachycardia.
For patients with heart failure, heart attack, short-acting drugs such as Nifedipine are of particular danger. Severe circulatory failure is not treated with Verapamil or Diltiazem.
Types of slow calcium channel blockers
Since the BPC group combines heterogeneous drugs, several classification options have been proposed. There are three generations of medicines:
- the first - Isoptin, Corinfar, Diltiazem;
- the second - Gallopamil, Lacipil, Foridon, Klentiazem;
- the third - Lerkamen, Zanidip, Naftopidil.
According to the influence on the main clinical symptoms, the following subgroups are distinguished:
- expanding peripheral arterioles - Nifedipine, Felodipine;
- improving coronary blood flow - Amlodipine, Felodipine;
- lowering myocardial contractility - Verapamil;
- inhibitory conductivity and automatism - Verapamil.
Depending on the chemical structure, BPCs are subdivided into:
- Nifedipine group - Corinfar, Norvasc, Lacipil, Loxen, Nimotop, Foridon. Predominantly expand the peripheral arteries.
- Verapamil group - Isoptin, Veranorm, Prokorum. They act on the myocardium, inhibit the conduction of a heart impulse through the atria, do not affect the vessels.
- Diltiazem group - Cardil, Klentiazem. Equally affect the heart and blood vessels.
- Cinnarizine group - Stugeron, Nomigrain. Expand mainly cerebral vessels.
3rd generation drugs
First-generation calcium blockers are characterized by low bioavailability, insufficient selectivity of action, and rapid elimination from the body. This requires frequent administration and sufficiently high doses. The second generation is devoid of these shortcomings, since the drugs are in the blood for a long time, their absorption is much higher.
The third generation of BKK is represented by Lerkamen. It penetrates well into the cell membrane, accumulates in it and is slowly washed out. Therefore, despite the short circulation in the blood, its effect is long-lasting. Use the drug 1 time per day, which allows you to maintain a constant effect and is convenient for the patient.
The action of Lerkamen is manifested in the relaxation of the walls of blood vessels, it does not reduce the contractility of the myocardium, which makes it the safest remedy for the treatment of hypertension or angina with weakness of the heart muscle.
At the same time, the drug has other positive effects on hemodynamics:
- improves cerebral circulation,
- protects brain cells from destruction
- acts as an antioxidant
- dilates the arteries of the kidneys, inhibits their sclerosis,
- has a pronounced hypotensive effect,
- refers to cardio-nephro- and cerebroprotectors.
Side effects:
- headache,
- edema,
- pressure drop,
- facial redness,
- feelings of hot flashes,
- increased heart rate,
- inhibition of cardiac impulse conduction.
Verapamil inhibits conduction and automatism function, can cause blockade and asystole. Less common: constipation, indigestion, rash, cough, shortness of breath and drowsiness.
Blockers of slow calcium channels effectively lower blood pressure, with a long course of therapy they prevent myocardial hypertrophy, protect the inner lining of blood vessels from the atherosclerotic process, remove sodium and water due to the expansion of the renal arteries. They reduce the mortality rate and the frequency of complications in heart disease, increase exercise tolerance and have no pronounced side effects.
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As a rule, treatment is reduced to the correction of antihypertensive therapy and the appointment of drugs that improve microcirculation in tissues. With the ineffectiveness of these methods, surgical intervention is indicated.
Calcium channel blockers, or calcium antagonists (CA) are medicinal substances that inhibit the entry of calcium ions into cells through calcium channels.
Calcium channels are protein structures through which calcium ions move in and out of the cell. These charged particles are involved in the formation and conduction of an electrical impulse, and also provide contraction of the muscle fibers of the heart and vascular walls.
Calcium antagonists are actively used in therapy, hypertension and.
These drugs slow down the entry of calcium into the cells. This expands the coronary vessels, improves blood flow in the heart muscle. As a result, the supply of oxygen to the myocardium and the removal of metabolic products from it are improved. 
By reducing the heart rate and myocardial contractility, AK reduce the heart's need for oxygen. These drugs improve the diastolic function of the myocardium, that is, its ability to relax.
AKs dilate peripheral arteries, helping to lower blood pressure.
Some drugs from this group (verapamil, diltiazem) have antiarrhythmic properties.
These drugs reduce the aggregation ("gluing") of platelets, preventing the formation of blood clots in the coronary vessels. They exhibit anti-atherogenic properties, improving cholesterol metabolism. AA protect cells by inhibiting lipid peroxidation and slowing down the release of dangerous lysosomal enzymes into the cytoplasm.
Classification depending on the chemical structure
AAs are divided into three groups depending on their chemical structure. In each of the groups, preparations of the 1st and 2nd generations are isolated, differing from each other in their selectivity (“targetedness”) of action and the duration of the effect.
AK classification:
Derivatives of diphenylalkylamine:
- 1st generation: verapamil (isoptin, finoptin);
- 2nd generation: anipamil, gallopamil, falipamil.
Benzothiazepine derivatives:
- 1st generation: diltiazem (cardil, dilzem, tilzem, dilacor);
- 2nd generation: Altiazem.
Derivatives of dihydropyridine:
- 1st generation: nifedipine (corinfar, cordafen, cordipin, fenigidin);
- 2nd generation: amlodipine (Norvasc), isradipine (Lomir), nicardipine (Carden), nimodipine, nisoldipine (Ciscor), nitrendipine (Bypress), riodipine, felodipine (Plendil).
Derivatives of diphenylalkylamine (verapamil) and benzothiazepine (dilthiazem) act on both the heart and blood vessels. They have expressed antianginal, antiarrhythmic, hypotensive action. These drugs decrease the heart rate.
Dihydropyridine derivatives dilate blood vessels, have antihypertensive and antianginal effects. They are not used to treat arrhythmias. These drugs cause an increase in heart rate. Their effect in angina pectoris is more pronounced than in the first two groups.
Currently, second-generation dihydropyridine derivatives, in particular, amlodipine, are widely used. They have a long duration of action and are well tolerated.
Indications for use
angina pectoris
For long-term therapy, verapamil and diltiazem are used. They are most indicated in young patients, with a combination of angina pectoris with sinus bradycardia, arterial hypertension, bronchial obstruction, hyperlipidemia, biliary dyskinesia, and a tendency to diarrhea. Additional indications for the choice of these drugs are cerebrovascular insufficiency.
In many cases, combination therapy is indicated, combining diltiazem and beta-blockers. The combination of AA with nitrates is not always effective. The combination of beta-blockers and verapamil can be used with great care to avoid possible severe bradycardia, arterial hypotension, cardiac conduction disturbances and reduced myocardial contractility.
myocardial infarction
In transmural myocardial infarction (“with a Q wave”), AKs are not indicated.
Hypertonic disease
AAs are able to cause reverse development, protect the kidneys, and do not cause metabolic disorders. Therefore, they are widely used in the treatment of hypertension. Derivatives of nifedipine II generation (amlodipine) are especially shown.
These drugs are especially indicated for the combination of arterial hypertension with exertional angina, lipid metabolism disorders, and obstructive bronchial diseases. 
They help improve kidney function in diabetic nephropathy and chronic renal failure.
The drug "Nimotop" is especially indicated for the combination of hypertension and cerebrovascular insufficiency. In case of rhythm disturbances and hypertension, it is especially recommended to use drugs of the verapamil and diltiazem groups.
Heart rhythm disorders
In the treatment of arrhythmias, drugs from the verapamil and diltiazem groups are used. They slow down the conduction of the heart and reduce the automatism of the sinus node. These drugs inhibit the re-entry mechanism in supraventricular tachycardias.
AK are used to stop and prevent attacks of supraventricular tachycardia. They also help to reduce the heart rate during. These medications are also prescribed for the treatment of supraventricular extrasystole.
With ventricular arrhythmias, AKs are ineffective.
Side effects
AKs cause vasodilation. As a result, dizziness, headache, facial flushing, and heart palpitations may occur. As a result of low vascular tone, edema occurs in the legs, ankles, and feet. This is especially true for nifedipine preparations.
AK worsen the ability of the myocardium to contract (negative inotropic effect), slow down the heart rate (negative chronotropic effect), slow down atrioventricular conduction (negative dromotropic effect). These side effects are more pronounced in derivatives of verapamil and diltiazem.
When using nifedipine preparations, constipation, diarrhea, nausea, and in rare cases vomiting are possible. The use of verapamil in high doses in some patients causes severe constipation.
It is quite rare for skin side effects to occur. They are manifested by redness, rash and itching, dermatitis, vasculitis. In severe cases, the development of Lyell's syndrome is likely.
withdrawal syndrome
After abrupt discontinuation of AC intake, the smooth muscles of the coronary and peripheral arteries become hypersensitive to calcium ions. As a result, a spasm of these vessels develops. It can be manifested by an increase in angina attacks, an increase in blood pressure. Withdrawal is less common in the verapamil group.
Contraindications
Due to the difference in the pharmacological action of drugs, contraindications for different groups differ.
Verapamil and diltiazem derivatives should not be prescribed for atrioventricular block, left ventricular systolic dysfunction, cardiogenic shock. They are contraindicated at systolic blood pressure levels below 90 mm Hg. Art., as well as with anterograde conduction along an additional path.
Drugs from the verapamil and diltiazem groups are relatively contraindicated in digitalis intoxication, severe sinus bradycardia (less than 50 beats per minute), and a tendency to severe constipation. They should not be combined with beta-blockers, nitrates, prazosin, quinidine and disopyramide, because in this case there is a danger of a sharp decrease in blood pressure.
