BKK (or slow-moving calcium channel blockers) – drugs with a heterogeneous framework. They were created on the basis of the 4 courses of compounds suggested over. Medicinal compounds, which were identified by less adverse effects as well as had vital restorative worth, were separated beforehand as well as ended up being the progenitors of the team of drugs (initial generation). Other representatives that transcend to first-generation BCC in medically vital results were categorized in the II as well as III generation of BCC in the category.
Below is a category of phenylalkylamines, diphenylpiperazines as well as benzodiazepines by generation, where the first medical compounds are designated to a details course. They are shown in the type of global nonproprietary names.
Diphenylpiperazines as well as benzodiazepines are various in framework, however these slow-moving calcium channel blockers have an usual disadvantage – they are rapidly gotten rid of from the blood as well as have a little breadth of restorative impact. About 3 hrs later on, half the whole dosage of the medication is eliminated, consequently, to develop a steady restorative focus, it was called for to recommend 3- as well as 4-fold dosages throughout the day.
Due to the tiny distinctions in restorative as well as poisonous doses, an increase in the frequency of administration of 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 prescribed in such doses. For this reason, their administration is limited to a weakening of therapeutic effects, which is why they are not suitable for monotherapy.
They replaced as well as synthesized and tested calcium channel blockers of the 3rd generation, which are presented only in the dihydroperidine group. These are drugs that can remain in the blood longer and exert their restorative effect. They are more effective and safer, 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 allow you to assign them to 2-fold and single dose during the day. Also, drugs of a number of dihydropyridines are characterized by tissue specificity with respect to the heart and vessels of the peripheral bed.
Among 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 able to dilate blood vessels, significantly enhancing antihypertensive treatment. More often they are combined with diuretics and traditional ACE inhibitors.
|Calcium Antagonist Group||First generation||The second generation||Third Generation|
|II A||II B|
|Dihydropyridines||Nifedipine||Nifedipine SR and GITS, Nicardipine SR, Felodipine SR||Benidipine, Isradipine, Manidipine, Nicardipine, Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine, Felodipine||Amlodipine, Lacidipine, Lekarnididin|
First-generation drugs – verapamil, diltiazem and nifedipine – have a number of properties that limit their effective use. They have low bioavailability because they undergo significant metabolism during the initial passage through the liver. They act for a short time and often cause side effects: tachycardia, headache, redness of the skin. Verapamil and diltiazem reduce heart rate and strength.
Second-generation calcium antagonists are more effective, but many of them also do not last long; their effectiveness for patients often cannot be predicted in advance. The peak concentration in the blood of these drugs in patients is reached at different times.
When creating third-generation calcium antagonists, the disadvantages of the precursors were taken into account. These drugs are characterized by high bioavailability, a long half-life from the body (amlodipine – up to 40-50 hours), and high tissue selectivity. This gives them significant advantages in the treatment of hypertension.
Side effects of calcium antagonists and contraindications to their use
|Side Effects of Calcium Antagonists||Contraindications for use|
|Common to dihydropyridine and non-dihydropyridine calcium antagonists|
|For dihydropyridine calcium antagonists|
|Reflex tachycardia (especially for nifedipine short-acting, to a lesser extent for nifedipine retard, felodipine)|
|For non-dihydropyridine calcium antagonists|
Animal studies have shown that calcium antagonists inhibit the excessive secretion of insulin by blocking the entry of calcium ions into the beta cells of the pancreas. Insulin is involved in the development of arterial hypertension, stimulating the release of “stimulating” hormones, thickening of the vascular wall and salt retention in the body.
- 3. Beta-blockers
- BKK phenylalkylamine series
- A number of dihydropyridines
- 4. Means acting on the renin-angiotensin system
- Classification of Non-Specific BCC
- 5. Neurotropic agents of central action
- Scopes of BKK
- The main therapeutic effects of calcium antagonists
- Concomitant therapeutic effects
- Tissue selectivity of calcium antagonists
- Side effects
Your doctor may prescribe calcium channel blockers to treat high blood pressure.
Calcium is needed to contract muscles throughout the body. This mineral penetrates muscle cells through ion channels, which are tiny pores on the surface of the cell. This process is necessary for the normal functioning of the body.
Calcium channel blockers reduce the amount of calcium that can penetrate through these channels into the muscle cells of the heart and blood vessel walls.
At the same time, they reduce pressure in the blood vessels and on the heart.
Calcium channel blockers (calcium antagonists) are a heterogeneous group of drugs that have the same mechanism of action, but differ in a number of properties, including pharmacokinetics, tissue selectivity, and the effect on heart rate. Another name for this group is calcium ion antagonists.
There are three main subgroups of AK: dihydropyridine (the main representative is nifedipine), phenylalkylamines (the main representative is verapamil) and benzothiazepines (the main representative is diltiazem). Recently, they began to be divided into two large groups depending on the effect on heart rate.
Diltiazem and verapamil are referred to as the so-called “rhythm-reducing” calcium antagonists (non-dihydropyridine). The other group (dihydropyridine) includes amlodipine, nifedipine and all other derivatives of dihydropyridine, increasing or not changing the heart rate. Calcium channel blockers are used for arterial hypertension, coronary heart disease (contraindicated in acute forms!) And arrhythmias. With arrhythmias, not all calcium channel blockers are used, but only pulsating.
- Verapamil 40mg, 80mg (prolonged: Isoptin SR, Verogalid EP) – dosage 240mg;
- Diltiazem 90mg (Altiazem PP) – dosage 180mg;
The following representatives (dihydropyridine derivatives) are not used for arrhythmias: Contraindicated in acute myocardial infarction and unstable angina.
- Nifedipine (Adalat, Cordaflex, Kordafen, Cordipin, Corinfar, Nifecard, Phenigidin) – dosage of 10 mg, 20 mg; Nifecard XL 30mg, 60mg.
- Amlodipine (Norvask, Normodipine, Tenox, Cordy Kor, Es Cordy Kor, Cardilopin, Kulchek,
- Amlotop, Omelarkardio, Amlovas) – dosage of 5 mg, 10 mg;
- Felodipine (Plendil, Felodip) – 2,5 mg, 5 mg, 10 mg;
- Nimodipine (Nimotop) – 30 mg;
- Lacidipine (Lacipil, Sakur) – 2 mg, 4 mg;
- Lercanidipine (Lerkamen) – 20mg.
Of the side effects of dihydropyridine derivatives, one can indicate edema, mainly lower extremities, headache, redness of the face, increased heart rate, increased regularity of urination. If the swelling persists, the drug must be replaced. Lerkamen, who is a representative of the third generation of calcium antagonists, due to the higher selectivity to slow calcium channels, causes swelling to a lesser extent than other representatives of this group.
There are drugs that do not selectively block receptors – non-selective action, they are contraindicated in bronchial asthma, chronic obstructive pulmonary disease (COPD). Other drugs selectively block only beta-receptors of the heart – a selective effect. All beta-blockers interfere with the synthesis of prorenin in the kidneys, thereby blocking the renin-angiotensin system. In this regard, the vessels expand, blood pressure decreases.
- Metoprolol (Betalok ZOK 25mg, 50mg, 100mg, Egilok retard 25mg, 50mg, 100mg, 200mg, Egilok C, Vazokardinretard 200 mg, Metokardretard 100 mg) ;;
- Bisoprolol (Concor, Coronal, Biol, Bisogamma, Cordinorm, Niperten, Biprol, Bidop, Aritel) – most often the dosage is 5 mg, 10 mg;
- Nebivolol (Nebilet, Binelol) – 5 mg, 10 mg;
- Betaxolol (Lokren) – 20 mg;
- Carvedilol (Carvetrend, Coriol, Talliton, Dilatrend, Akridiol) – basically a dosage of 6,25 mg, 12,5 mg, 25 mg.
Drugs of this group are used for hypertension, combined with coronary heart disease and arrhythmias. Short-acting drugs whose use is not rational for hypertension: anaprilin (obzidan), atenolol, propranolol.
The main contraindications to beta blockers:
- bronchial asthma;
- low pressure;
- sick sinus syndrome;
- pathology of peripheral arteries;
- cardiogenic shock;
- atrioventricular block of the second or third degree.
These agents attach to alpha-adrenergic receptors and block them for the irritating effect of norepinephrine. As a result, blood pressure decreases. The applicable representative – Doxazosin (Kardura, Tonocardin) – is more often produced in dosages of 1 mg, 2 mg. It is used for relief of attacks and long-term therapy. Many alpha-blocker drugs have been discontinued.
BKK phenylalkylamine series
This section contains calcium channel blockers, the preparations of which have been used for about 30 years. The first is verapamil, which is presented in the pharmacy market in the form of the following drugs: Isoptin, Finoptin, Verogolid. Verapamil in combination with trandolapril is also present in the “Tarka” preparation.
Substances such as anipamil, falipamil, gallopamil and tiapamil are not available and are not registered in the pharmacopeia. For some, trials have yet to be completed to allow them to be clinically used. Therefore, so far from the number of BCC phenylalkylamines, verapamil, which is used as an antiarrhythmic, is the safest and most affordable.
A number of dihydropyridines
Among the dihydropyridines 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 safest are now considered dihydropyridines of the third generation. 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 trade names for drugs are more common, although with the expansion of the evidence base, lacidipine will become more firmly established in therapeutic practice.
Among the representatives of the second generation of dihydropyridines, calcium channel blockers are presented, 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: “Amlodipin-Pharma”, “Tenox”, “Norvask”, “Amlokordin”, “Asomex”, “Vaskopin”, “Kalchek”, “Cardiolopin”, “ Stamlo, Normodipin, Amlotop.
Isradipine does not have a list of generics, since this drug is presented only by one trade name – Lomir and its modification Lomir SRO. Felodipine, riodipine, nitrendipine, and nisoldipine also characterize poor distribution. 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 seek a replacement among other representatives of the dihydropyridine class.
The medicinal substance riodipine is represented on the market by the drug “Foridon”, and nitrendipine – “Octidipine”. Felodipine in the pharmacy network has two generics – this is Felodip 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 decreasing importance of the first generations, calcium channel blockers, the medicines of which were used earlier, are widely represented on the market. Nifedipine is the most common of all short-acting BCCs, as it has the maximum number of generics: Adalat, Vero-nifedipine, Calcigard, Zanifed, Cordaflex, Corinfar, Cordipin, Nicardia , “Nifadil”, “Nifedex”, “Nifedicor”, “Nifecard”, “Osmo”, “Nifelat”, “Phenigidin.” These drugs are affordable, but their prevalence is gradually decreasing due to the emergence of more effective drugs.
4. Means acting on the renin-angiotensin system
The drugs act at different stages of the formation of angiotensin II. Some inhibit (suppress) the angiotensin-converting enzyme, others block the receptors that are affected by angiotensin II. The third group inhibits renin; it is represented by only one drug (aliskiren).
These drugs inhibit the transition of angiotensin I to active angiotensin II. As a result, the concentration of angiotensin II in the blood decreases, the vessels dilate, the pressure decreases. Representatives (synonyms are indicated in brackets – substances with the same chemical composition):
- Captopril (Kapoten) – dosage of 25 mg, 50 mg;
- Enalapril (Renitek, Burlipril, Renipril, Ednit, Enap, Enarenal, Enam) – dosage most often is 5 mg, 10 mg, 20 mg;
- Lisinopril (Diroton, Dapril, Lysigamma, Lisinoton) – the dosage is most often 5 mg, 10 mg, 20 mg;
- Perindopril (Prestarium A, Perineva) – Perindopril – dosage 2,5mg, 5mg, 10mg. Perineva – dosage of 4 mg, 8 mg .;
- Ramipril (Tritace, Amprilan, Hartil, Pyramil) – dosage of 2,5 mg, 5 mg, 10 mg;
- Hinapril (Akkupro) – 5 mg, 10 mg, 20 mg, 40 mg;
- Fosinopril (Fosicard, Monopril) – in a dosage of 10 mg, 20 mg;
- Trandolapril (Gopten) – 2 mg;
- Zofenopril (Zokardis) – dosage of 7,5 mg, 30 mg.
The drugs are available in different dosages for therapy with varying degrees of increase in blood pressure.
The peculiarity of Captopril (Kapoten) is that because of its short duration of action, it is rational only for hypertensive crises.
Bright representative of the group Enalapril and its synonyms are used very often. This drug does not differ in duration of action, therefore, take 2 times a day. In general, the full effect of ACE inhibitors can be observed after 1-2 weeks of drug use. In pharmacies, you can find a variety of generics (analogues) of enalapril, i.e.
ACE inhibitors cause a side effect – a dry cough. In cases of cough development, ACE inhibitors are replaced with drugs of another group. This group of drugs is contraindicated in pregnancy, has a teratogenic effect in the fetus!
These agents block angiotensin receptors. As a result, angiotensin II does not interact with them, the vessels dilate, blood pressure decreases
- Lozartan (Kozaar 50mg, 100mg; Lozap 12.5mg, 50mg, 100mg; Lorista 12,5mg, 25mg, 50mg, 100mg; Vazotens 50mg, 100mg);
- Eprosartan (Teveten) – 400 mg, 600 mg;
- Valsartan (Diovan 40mg, 80mg, 160mg, 320mg; Valsacor 80mg, 160mg, 320mg, Valz 40mg, 80mg, 160mg; Nortian 40mg, 80mg, 160mg; Valsafors 80mg, 160mg);
- Irbesartan (Aprovel) – 150mg, 300mg;
Candesartan (Atakand) – 8mg, 16mg, 32mg;
Telmisartan (Mikardis) – 40 mg, 80 mg;
Olmesartan (Kardosal) – 10mg, 20mg, 40mg.
Just like their predecessors, they allow you to evaluate the full effect 1-2 weeks after the start of management. Do not cause dry cough. Should not be used during pregnancy! If pregnancy is detected during treatment, antihypertensive therapy with drugs of this group should be discontinued!
If hypertension is caused by prolonged stress, then drugs that act on the central nervous system (sedatives (Novopassit, Persen, Valerian, Pustyrnik, tranquilizers, sleeping pills) are used.
Classification of Non-Specific BCC
This group of drugs contains calcium channel blockers, the list of drugs is limited to 5 substances. These are mibefradil, pergexilin, lidoflazin, caroverin and bepridil. The latter belongs to the class of benzodiazepines, but differs by receptor. It selectively limits the passage of calcium ions through the T-channels of pacemakers and is able to block the sodium channels of the conduction system of the heart. In connection with this mechanism of action, bepridil is used as an antiarrhythmic.
An even more promising drug is Mefefradil, which is tested as an antianginal drug. At the moment, there are a number of publications by the authors, proving its effectiveness in myocardial infarction and angina pectoris. Therefore, it will be assigned to the category of substances in which slow calcium channel blockers are present that can prolong the life of a patient with acute coronary pathology. In this group, there are very few affordable and highly effective drugs.
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 stimulate the growth of new vessels. The development of collateral circulation in the heart is of great importance.
5. Neurotropic agents of central action
Neurotropic drugs of central action affect the vasomotor center in the brain, reducing its tone.
- Moxonidine (Physiotens, Moxonitex, Moxogamma) – 0,2 mg, 0,4 mg;
- Rilmenidine (Albarel (1 mg) – 1 mg;
- Methyldopa (Dopegit) – 250 mg.
The first representative of this group is clonidine, widely used earlier in hypertension. Now this drug is dispensed strictly according to the prescription. Currently, moxonidine is used both for emergency care for hypertensive crisis, and for planned therapy. Dosage 0,2 mg, 0,4 mg. The maximum daily dosage is 0,6 mg / day.
Scopes of BKK
“Lidoflazin” is a representative of the category of drugs that have a mild blocking ability against calcium channels. The therapeutic effect of Lidoflazin is similar to that of flunarizine, however, it differs in the expansion of the coronary arteries of the heart, and therefore it is used for acute myocardial ischemia.
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 caroverin and perhexylin preparations do not have them. These substances are being studied for clinical efficacy and toxicity.
Modern calcium channel blockers, the list of preparations of which is replenished with new substances, are used in therapeutic practice in order to achieve several types of effects: antihypertensive, antianginal, antiischemic and antiarrhythmic. To this end, BCC are applied in the following cases:
- with angina pectoris to expand the vessels of the heart (dihydroperidins, mainly amlodipine);
- with vasospastic angina (amlodipine);
- with Raynaud’s syndrome (dihydropiperidines, mainly amlodipine);
- with arterial hypertension (dihydroperidins, 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 shown. The only exception is the diphenylpiperazine group represented by Cinnarizine and Flunarizine. These drugs can be used for hypertension in adolescents and pregnant women, as well as for the prevention of vascular disorders in the brain provoked by hypertensive crises.
The main therapeutic effects of calcium antagonists
In connection with 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 together with a number of auxiliary drugs of other classes.
With angina pectoris, due to calcium antagonists, myocardial arterial vessels expand and useful suppression of contractility of the heart muscle occurs. This improves the nutrition of myocardial cells with a simultaneous decrease in their oxygen demand. With therapy, anginal attacks develop less frequently and are less prolonged.
The drugs of the group contribute to increased endocardial-epicardial blood flow, improving blood supply to the myocardium against the background of its hypertrophy. AK have the property of reducing preload due to a significant reduction in the amount of blood flowing to the heart. Medicinal substances of the calcium channel blocker group also reduce cardiac afterload, helping to stabilize 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 muscle walls of the arteries and is accompanied by a decrease in systolic and diastolic blood pressure. Also, calcium blockers weaken the effects of angiotensin on the vascular wall, inhibiting the growth of blood pressure. They are second-line drugs necessary for the treatment of hypertension in pregnant women.
Concomitant therapeutic effects
Any blockers of calcium channels, the mechanism of action of which has not been studied enough, 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 drug 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 the activity of RAAS and a drop in blood pressure.
Nimodipine is selective for cerebral vessels, and therefore reduces the likelihood of secondary vasospasm in case of subarachnoid hemorrhage. But with CHF, BCC are undesirable, as they worsen the prognosis for life. Only admission of amlodipine and felodipine is allowed if there is severe arterial hypertension or angina pectoris that are not corrected by beta-blockers, ACE inhibitors, and diuretics. For the same purpose, lercanidipine and lacidipine can be used.
Tissue selectivity of calcium antagonists
The property of tissue selectivity is inherent in all drugs related to calcium antagonists. This means that they do not affect the muscles of the skeleton, smooth muscles of the bronchi, trachea, tissue of the nervous system and digestive tract. Therefore, calcium antagonists do not have such side effects as fatigue and muscle weakness characteristic of beta-blockers. They practically do not affect the central nervous system and therefore do not cause depression or lethargy.
Calcium antagonists also differ in the ratio of their activity against blood vessels and cells of the heart muscle. For verapamil, diltiazem and nifedipine, this ratio is 3: 1, 3: 1 and 10: 1, respectively. Amlodipine, felodipine, nitrendipine, nicardipine, isradipine 100 times, and nizolidipin 1000 times more active on blood vessels than on the heart, i.e., have high vascular selectivity.
Calcium antagonists with high vascular selectivity can be used in patients with heart failure, since their significant vasodilating effect compensates for the small effect of reducing the strength of heart beats. But high vascular selectivity, such as that of nizolidipine, may be excessive.
Regular intake of short-acting BCC (nifedipine) is unacceptable, as it triggers reflex activation of the sympathetic nervous system and is able to develop postural hypotension, increasing the risk of ischemic stroke and myocardial infarction. They are also able to cause a repeated hypertensive crisis or angina pectoris due to withdrawal syndrome.
Short-acting BKK preparations are suitable only for stopping crises and an attack of angina pectoris, but then long-acting ACE inhibitors and beta-blockers should be added. The combined use of BCC with nitrates and ACE inhibitors leads to the appearance of edema of the extremities, redness of the skin and face. Without nitrates, the side effect is weaker.
Dihydropyridines cause gingival hyperplasia with prolonged use. The very 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 myocardial infarction and with unstable angina (robbery syndrome), and their effectiveness in secondary prevention of myocardial infarction has also not been proven.
Fatigue is a possible side effect of calcium channel blockers.
Less commonly, these medications can cause:
- heartbeat that is too fast or too slow
- tingling or numbness in arms and legs
- stomach upset
- difficulty swallowing
If a person experiences any of these side results from taking calcium channel blockers, he should consult a doctor. If side effects create serious problems, the doctor may change the prescription or minimize the dose.
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