Calcium channel blocker

Calcium antagonists or calcium channel blockers in the strict sense are a group of drugs ( medicines ), which are mainly used to treat high blood pressure, coronary heart disease and cardiac arrhythmias. They owe their name to their mechanism of action: they reduce the influx of calcium ions into the interior of the muscle cell. This especially the contractility of vascular smooth muscle is reduced, which dilates the blood vessels. In a broad sense is one of the calcium antagonists of the calcium overload blocker flunarizine, which is mainly used in migraine prophylaxis.

Mechanism of Action

The concentration of calcium ions ( Ca2 ) in the interior of the cell is usually about ten thousand times smaller than in the extracellular space ( 10-7 mol / l in the cytoplasm vs. 10-3 mol / l). By external stimuli calcium channels can be opened, which causes the influx of calcium ions into the cell. The change in membrane potential of the muscle cell causes a muscle contraction (electromechanical coupling). This leads to a narrowing and thus a higher pressure in the vessels or the heart to an increase in impact strength (positive inotropic effect). In the specialized cells that are responsible for the spread of excitation in the heart ( see conduction system ), this causes a faster transition of the stimulus.

The basic principle of calcium antagonists based on the inhibition of voltage-dependent calcium channels of L-type ( long lasting ) and T-type ( transient). The L-type calcium channels, which have the greatest significance for the therapeutic effect, are primarily responsible for the control of vascular tone in smooth muscle cells and cardiac myocytes. The T-type calcium channels are involved in the pacemaker function of the sinus and AV node.

The binding of calcium antagonists on the calcium channels causes a decrease of the calcium influx. Hereby they decrease (depending on the type to varying degrees) the above effects. A reduced calcium ion influx leads therefore to the heart muscle to a reduction in impact force ( negative inotropic effect ) and the stroke rate (negative chronotropic effect). Wherein the core is released, the oxygen demand of the heart and the blood pressure decrease. In the vessel wall, the reduced influx of calcium causes vasodilation (blood vessel dilation ). A larger lumen allows the blood less resistance ( lowering of peripheral vascular resistance ) and it comes to blood pressure. By vessel dilation in the coronary arteries is the heart muscle more oxygen-rich blood for his work available.

Verapamil ( only one enantiomer of the racemate shown)

Diltiazem

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

Structure types

According to specific binding sites on the calcium channel one divides the data used as antihypertensive and antiarrhythmic calcium antagonists in three types. You have characteristic chemical structures:

• Dihydropyridines ( nifedipine - type)
• Phenylalkylamines ( verapamil type )
• Benzothiazepines ( diltiazem type )

Impact and applications

All calcium antagonists lower blood pressure, and this is happening on two different means: in the dihydropyridines ( nifedipine - type) by the vasodilation of arterioles ( afterload reduction ) in the phenylalkylamines ( verapamil type ) by slowing and weakening of the heartbeat in the benzothiazepines ( diltiazem type ) by a combination of both mechanisms. The extent of the reduction in blood pressure is higher the greater the initial blood pressure is at the calcium channel blockers.

Most often, the dihydropyridines be used. These act mainly lowers blood pressure by direct relaxation of vascular smooth muscle of the arterioles and only slightly on the conduction of the heart. Important representatives of this type are nifedipine, nitrendipine, felodipine and amlodipine.

The phenylalkylamines have only a low on blood vessels but provide a strong effect on the impact strength and the spread of excitation of the heart. They are therefore used especially for the treatment of cardiac arrhythmias ( tachycardic atrial fibrillation). The most important representative of this type is verapamil.

An intermediate position is occupied the benzothiazepines which act both vasodilator and thus lowering blood pressure as well as an inhibitory effect on impulse conduction in the heart. The lead compound of this type is diltiazem. The benzothiazepines have a very favorable side effect profile.

In addition to the treatment of hypertension, chronic coronary heart disease (stable angina) and heart rhythm disorders of calcium antagonists are also used in:

• Vasospastic angina ( Prinzmetal's angina )
• Vasospasm after aneurysmal subarachnoid hemorrhage
• Pulmonary arterial hypertension ( pulmonary hypertension)
• Raynaud's syndrome
• Achalasia ( spasm of the lower esophagus sphincter )

Uptake and distribution in the body ( pharmacokinetics )

In most cases, calcium antagonists are administered as a tablet and absorbed in the small intestine ( enteral or oral administration ). Intravenous ( parenteral ) administration is also applied.

The individual active ingredients are absorbed into the blood in varying degrees in the absorption from the intestine. This is a problem (changing and overall low oral bioavailability) especially with verapamil.

The drugs have varying half-lives. In the treatment of high blood pressure, a long half-life is beneficial because a dose per day is then sufficient. This is especially true for amlodipine, nitrendipine and felodipine in constrained. The decomposition of calcium antagonists happens predominantly in the liver.

Adverse effects (side effects)

Frequent and important side effects of calcium antagonists:

• Swelling of the legs (edema, especially in dihydropyridines )
• Slow heartbeat (bradycardia in phenylalkylamines and benzothiazepines )
• Fast heart rate ( reflex tachycardia, with dihydropyridines )
• Allergic reactions
• Facial flushing (reddening) and a general feeling of warmth
• Dizziness
• Headache
• Impotence
• Constipation ( constipation, especially in phenylalkylamines and benzothiazepines )
• Gingival hyperplasia with subsequent severe inflammation

Interactions with other drugs

Calcium antagonists of the Phenylalkylamintyp and from Benzothiazepintyp may not or only with extreme caution be administered with beta-blockers, as this can lead to a life-threatening heart slowing ( bradycardia, AV block ).

The blood pressure lowering effect of other medicines is enhanced.

Since all calcium channel blockers of the degradation by the liver enzyme cytochrome P450 3A4 in common is, the level of action of many other drugs that are metabolized by the same enzyme are affected.

Consuming grapefruit juice inhibits the breakdown of nifedipine, so that there is an effect of amplification. It is not recommended to drink grapefruit juice prolonged treatment with nifedipine.

Contraindications ( contraindications)

• Low blood pressure ( hypotension)
• Advanced heart failure ( NYHA class III -IV)
• Unstable angina pectoris and acute myocardial infarction
• Pregnancy
• For phenylalkylamines and benzothiazepines ( verapamil and diltiazem ) also: AV - block II ° and III ° and atrial fibrillation in Wolff- Parkinson -White syndrome (WPW syndrome)

Clinical Significance

Previously nifedipine was a very popular drug used to treat high blood pressure. It has in its immediate-release form of this meaning, however, largely lost because the duration is too short, there may be rapid and life-threatening drop in blood pressure and the counter- regulatory mechanisms (eg reflex ) of the body especially undesirable in structural heart disease to the same extent.

Nowadays, mainly long-acting calcium antagonist for hypertension be used only once must be taken daily (prototype amlodipine). In this form, the once very popular in the 1990s and then downright demonized calcium antagonists have experienced in recent years a small renaissance. Studies have shown a positive effect, particularly in combination with ACE inhibitors in patients with kidney damage due to diabetes mellitus (diabetic nephropathy). In addition, the incidence of stroke in the elderly can be significantly reduced, while clearly superior in the prevention of heart attacks other medicines ( beta blockers, ACE inhibitors).

The main disadvantage is a higher incidence of heart attacks and heart failure in comparison to high-pressure treatment with other drugs (especially beta-blockers and ACE inhibitors).

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

Verapamil and diltiazem are still used for the treatment of tachycardic atrial fibrillation, although their importance has resigned over beta-blockers. Also in the treatment of chronic coronary artery disease ( stable angina) have been partially displaces the calcium antagonists of other drugs ( beta-blockers, retarded nitrate preparations and molsidomine ).

Pharmacoepidemiological studies

To pharmacoepidemiology the Calcium antagonists are only a few population-representative study or large groups before relevant studies. Here mention two studies for the Federal Republic of Germany and the Kingdom of Bahrain.

Approved individual substances

Phenylalkylamintyp

• Verapamil ( A, CH, D, eg Isoptin ®)
• Gallopamil ( A, D, for example Procorum ®)
• Fendiline (A, D, non- selective)

Benzothiazepintyp

• Diltiazem (A, CH, D, eg Dilzem ®)

Dihydropyridine

• Nitrendipine (CH, D, eg Bayotensin ®)
• Felodipine (A, CH, D, for example, Plendil ®, Modip ®, Munobal ®)
• Amlodipine ( A, CH, D, such as Norvasc ®)
• Nifedipine (A, CH, D, such as Adalat ®)
• Lercanidipine (A, CH, D, eg Carmen ®, Corifeo ®)
• Nimodipine (A, CH, D, eg Nimotop ®)
• Nicardipine ( A, D, for example Antagonil ®)
• Lacidipine (A, CH, D, eg Moten ®)
• Isradipine (A, CH, D, eg Lomir ®, Vascal ®)
• Nisoldipine ( A, D, for example Baymycard ®)
• Nilvadipine ( A, D, for example, Escor ®, Nivadil ®)
• Manidipin (D eg Manyper ®)

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