Calcium antagonist

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Calcium antagonists , calcium antagonists , Ca 2+ antagonists or, in a narrower sense, calcium channel blockers are a group of drugs that reduce the influx of calcium ions into the muscle cell . This reduces the contractility of the vascular smooth muscle cells of peripheral arteries and coronary arteries, which dilates the blood vessels, reduces the calcium-dependent energy supply for the contraction of the heart muscle and inhibits the automatism of the sinus node and the conduction of excitation in the AV node. Accordingly, calcium antagonists are mainly used for the treatment of high blood pressure , coronary artery disease and cardiac arrhythmias .

In a broader sense, one of the calcium antagonists is the calcium overload blocker flunarizine , which is mainly used in migraine prophylaxis .

The calcium antagonists can be divided into two classes: on the one hand dihydropyridines (like nifedipine ) and on the other hand phenylalkylamines ( verapamil type) and benzothiazepines ( diltiazem type).

Mechanism of action

Since the late 1960s, the Freiburg physiologist Albrecht Fleckenstein has been developing the pharmacological active principle of calcium antagonism based on his investigations with the phenylalkylamines verapamil ( Isoptin ), gallopamil ( Procorum ) and 1,4-dihydropyridine , nifedipine ( Adalat , Bay a1040). Later came benzothiazepine d-cis diltiazem ( Dilzem ) added. Fleckenstein was able to show that the three chemically different classes of calcium antagonists (phenylalkylamines, 1,4-dihydropyridines and benzothiazepines) blocked the influx of calcium via voltage-dependent calcium channels in the heart and the smooth muscles of the blood vessels.

1,4-dihydropyridine (1), phenylalkylamine (2) and benzothiazepine (3) receptor domains of the alpha1 subunit interact with each other (shown by reciprocal arrows) and with calcium binding sites. The different tissue-specific subtypes (heart, smooth muscle, CNS and skeletal muscle) of the L-type calcium channels differ in the dissociation constants for z. B. 1,4 dihydropyridines, the binding strength for calcium and interactions with each other.

The concentration of calcium ions (Ca 2+ ) inside the cell is normally around one ten-thousandth of the concentration in the extracellular space (10 −7 mol / l in the cytoplasm vs. 10 −3 mol / l). External stimuli can open calcium channels , which causes calcium ions to flow into the cell. The changed membrane potential of the muscle cell causes muscle contraction (electromechanical coupling). This leads to a constriction and thus a higher pressure in the vessels , or in the heart to an increase in the impact force (positive-inotropic effect). In the specialized cells that are responsible for the spread of excitation in the heart (see excitation conduction system), this causes a faster transfer of the stimulus (positive-dromotropic effect).

The basic principle of calcium antagonists is based on the inhibition of voltage-dependent calcium channels of the L-type (long lasting) and of the T-type (transient). The L-type calcium channels, which are of greatest importance for the therapeutic effect, are mainly responsible for controlling the vascular tone in smooth muscle cells and heart muscle cells. The T-type calcium channels are involved in the pacemaker function of the sinus and AV nodes .

The binding of the calcium antagonists to the calcium channels causes a reduction in the calcium influx. With this they reduce (depending on the type to different degrees) the above-mentioned effects. A reduced influx of calcium ions leads to a reduction in the impact force (negative inotropic effect) and the beat frequency (negative chronotropic effect) on the heart muscle . This relieves the heart, the heart's need for oxygen and blood pressure decrease. In the vessel walls, the reduced calcium influx leads to vasodilation (vasodilation) in the arterial vascular system. A larger lumen offers less resistance to the blood (lowering of peripheral vascular resistance) and blood pressure drops. The widening of the blood vessels in the coronary arteries means that the heart muscle has more oxygen-rich blood available for its work.

  • Nifedipine

  • Diltiazem

  • Verapamil

The mainly vascular effect (effect in the vessels) of the dihydropyridines can be explained by a preferential binding to calcium channels of the L-type. In contrast, the benzothiazepines and phenylalkylamines also attack T-type calcium channels to different degrees, which leads to a low vascular effect.

Structure types

The calcium antagonists used as antihypertensive agents and antiarrhythmics are divided into three types according to the specific binding sites on the calcium channel . They have characteristic chemical structures:

  • Dihydropyridines ( nifedipine type; the names of the active ingredients usually end with "-dipine".)
  • Phenylalkylamines ( Verapamil type)
  • Benzothiazepines ( diltiazem type)

Effect and areas of application

All calcium antagonists lower the blood pressure (in arterial hypertension), but this happens in different ways: with the dihydropyridines (nifedipine type) through the vasodilation of the arterioles ( afterload reduction), with the phenylalkylamines (verapamil type) through slowing down and weakening the heartbeat, with the benzothiazepines (diltiazem type) by a combination of both mechanisms. The extent of blood pressure lowering with calcium channel blockers is higher the higher the initial blood pressure.

The most commonly used are the dihydropyridines. These mainly have a blood pressure lowering effect through direct relaxation of the smooth vascular muscles of the arterioles and only marginally on the conduction of the heart. Important representatives of this type are nifedipine , nitrendipine , felodipine and amlodipine .

The phenylalkylamines have only a slight effect on the blood vessels, but they have a strong effect on the punching power and the spread of excitation in the heart. They are therefore used in particular for the treatment of cardiac arrhythmias ( tachycardial atrial fibrillation ). The most important representative of this type is verapamil .

The benzothiazepines occupy an intermediate position, which both dilate the blood vessels and thus lower blood pressure and inhibit the conduction of excitation in the heart. The lead substance of this type is diltiazem . The benzothiazepines have a very favorable side effect profile.

In addition to the treatment of high blood pressure, chronic coronary heart disease (CHD, stable angina pectoris ) and cardiac arrhythmias, calcium antagonists are also used in:

An exception is nimodipine , which due to its lipophilicity is able to cross the blood-brain barrier . It is therefore used for neurological deficits caused by a circulatory disorder, as well as for the prophylaxis of vascular spasms as a result of subarachnoid hemorrhage.

The substances gabapentin and pregabalin used in epilepsy and neuropathic pain (e.g. in diabetic polyneuropathy) are used as centrally acting calcium channel blockers .

Absorption and distribution in the body (pharmacokinetics)

As a rule, calcium antagonists are administered as tablets and absorbed in the small intestine ( enteral or peroral application). The intravenous ( parenteral ) administration is also applied.

The individual active ingredients are absorbed into the blood to varying degrees during absorption from the intestine . This is particularly problematic with verapamil (changing and overall low oral bioavailability ).

The drugs also have different half-lives. A long half-life is beneficial in the treatment of high blood pressure, as one intake per day is sufficient. This applies in particular to amlodipine , and to a limited extent also to nitrendipine and felodipine. The breakdown of calcium antagonists mainly takes place in the liver .

Adverse effects (side effects)

Common and important side effects of calcium antagonists are:

  • Swelling of the legs ( edema , especially with dihydropyridines)
  • slow heartbeat ( bradycardia , with phenylalkylamines and benzothiazepines)
  • fast heartbeat ( reflex tachycardia , with dihydropyridines)
  • allergic reaction
  • Face flushing and general feeling of warmth
  • dizziness
  • a headache
  • impotence
  • Constipation ( constipation , especially with phenylalkylamines and benzothiazepines)
  • Hyperplasia of the gingiva (gums) with subsequent severe inflammation

Drug interactions

Calcium antagonists of the phenylalkylamine type and of the benzothiazepine type must not be administered at the same time as beta blockers or only with extreme caution , as this can lead to a life-threatening slowdown of the heart rate ( bradycardia , AV block ).

The blood pressure lowering effect of other drugs is increased.

Since all calcium channel blockers have in common the breakdown by the liver enzyme cytochrome P450 3A4 , the effective level of many other drugs, which are broken down by the same enzyme, can be influenced.

The consumption of grapefruit juice inhibits the breakdown of nifedipine, so that the effect is increased. It is not recommended to drink grapefruit juice during long-term treatment with nifedipine.

Contraindications (contraindications)

Clinical significance

Nifedipine used to be a very popular drug used to treat high blood pressure. In its non- retarded form, however, it has largely lost this meaning because the duration of action is too short, rapid and life-threatening drops in blood pressure can occur and the counter-regulatory mechanisms (e.g. reflex tachycardia) of the body are undesirable to this extent, especially in structural heart diseases .

Nowadays, long-acting calcium antagonists are mainly used against high blood pressure, which only have to be taken once a day (prototype amlodipine ). In this form the calcium antagonists, which used to be very popular and then downright demonized in the 1990s, have experienced a small renaissance in recent years. Studies have shown a positive effect, particularly in combination with ACE inhibitors, in patients with kidney damage from diabetes mellitus (diabetic nephropathy). In addition, the frequency of strokes in the elderly can be significantly reduced, while other drugs are clearly superior in terms of preventing heart attacks (beta blockers, ACE inhibitors).

The main disadvantage is the more frequent occurrence of myocardial infarctions and heart failure compared to high-pressure treatment with other drugs (especially beta blockers and ACE inhibitors).

Overall, the use of calcium antagonists as the only drug (monotherapy) against high blood pressure is controversial. However, they have a firm place in combination therapy if treatment with other substances (ACE inhibitors, beta blockers, diuretics ) does not lead to a sufficient reduction in blood pressure.

Verapamil and diltiazem are still used to treat tachycardiac atrial fibrillation, although their relevance to beta-blockers has diminished. In the treatment of chronic coronary heart disease (stable angina pectoris), the calcium antagonists have been partially displaced by other drugs (beta blockers, delayed nitrate preparations and molsidomine).

Pharmacoepidemiological studies

Only a few studies representative of the population or large study groups are available on the pharmacoepidemiology of calcium antagonists. Two studies for the Federal Republic of Germany and the Kingdom of Bahrain should be mentioned here .

Permitted individual substances

Phenylalkylamine type

Benzothiazepine type

Dihydropyridine type

(A = Austria, CH = Switzerland, D = Germany)

See also

literature

  • Stephen F Flaim, Robert Zelis (Eds.): Calcium Blockers - Mechanisms of Action and Clinical Applications. Urban & Schwarzenberg, Baltimore / Munich 1982, ISBN 3-541-70611-2 .
  • German League for Combating High Blood Pressure e. V. (Hrsg.): Prevention, detection, diagnosis and therapy of arterial hypertension . AWMF guideline 11/2003 (046/001)
  • Rote Liste Service GmbH (Hrsg.): Rote Liste Buch 2005. 1st edition. Editio Cantor Verlag, Aulendorf 2005, ISBN 3-87193-306-6 .
  • M. Schubert-Zsilavecz: Medicinal chemistry of the L-type calcium channel blockers: dihydropyridines and non-dihydropyridines. In: Pharmacy in our time . 34, 2005, pp. 374-379.

Individual evidence

  1. ↑ Reinhard Larsen: Anesthesia and intensive medicine in cardiac, thoracic and vascular surgery. (1st edition 1986) 5th edition. Springer, Berlin / Heidelberg / New York et al. 1999, ISBN 3-540-65024-5 , pp. 61-65 and 180 ( calcium antagonists ).
  2. ^ DR Ferry, H. Glossmann : Evidence of multiple receptor sites within the putative calcium channel. In: Naunyn Schmiedebergs Arch Pharmacol. 321 (1), Oct 1982, pp. 80-83.
  3. ↑ H. Glos man, J. Striessnig: calcium channels. In: Vitam Horm. 44, 1988, pp. 155-328.
  4. ^ DR Ferry, H. Glossmann: Evidence of multiple receptor sites within the putative calcium channel. In: Naunyn Schmiedebergs Arch Pharmacol. 321 (1), Oct 1982, pp. 80-83. PMID 6292744
  5. ↑ Hartmut Glossmann , David R. Ferry et al. a .: Calcium channels: direct identification with radioligand binding studies. In: Trends in Pharmacological Sciences. 3, 1982, pp. 431-437, doi: 10.1016 / 0165-6147 (82) 91221-4 .
  6. ↑ Richard Daikeler, idols Use, Sylke Waibel: diabetes. Evidence-based diagnosis and therapy. 10th edition. Kitteltaschenbuch, Sinsheim 2015, ISBN 978-3-00-050903-2 , p. 172 f.
  7. ^ C. Gasse, J. Stieber, A. Döring, U. Keil, HW Hense: Population trends in antihypertensive drug use: results from the MONICA Augsburg Project 1984 to 1995. In: J Clin Epidemiol. 52 (7), Jul 1999, pp. 695-703. PMID 10391663 .
  8. ↑ H. Knopf, HU Melchert, A. Bertelsmann: Consumption of calcium antagonists: results of the German national health surveys. In: Pharmacoepidemiol Drug Saf . 9 (3), May 2000, pp. 221-233. PMID 19025823 .
  9. ^ KA Al Khaja, RP Sequeira: Pharmacoepidemiology of antihypertensive drugs in primary care setting of Bahrain between 1998 and 2000. In: Pharmacoepidemiol Drug Saf. 15 (10), Oct 2006, pp. 741-748. PMID 16342299 .

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