Calcium channel blocker

Overview
Calcium channel blockers are a class of drugs and natural substances with effects on many excitable cells of the body, like the muscle of the heart, smooth muscles of the vessels or neuron cells. The latter are used as antiepileptics and are not covered in this article.

The main action of calcium channel blockers is to decrease the blood pressure. It is for this action that it is used in individuals with hypertension.

Explanation
Most calcium channel blockers decrease the force of contraction of the myocardium (muscle of the heart). This is known as the negative inotropic effect of calcium channel blockers. It is because of the negative inotropic effects of most calcium channel blockers that they are avoided (or used with caution) in individuals with cardiomyopathy.

Many calcium channel blockers also slow down the conduction of electrical activity within the heart, by blocking the calcium channel during the plateau phase of the action potential of the heart (see: cardiac action potential). This is known as a negative dromotropic effect. It causes a lowering of the heart rate and may cause heart blocks, which is known as the negative chronotropic effect of calcium channel blockers. The negative chronotropic effects of calcium channel blockers make them a commonly used class of agents in individuals with atrial fibrillation or flutter in whom control of the heart rate is an issue.

Mechanism of action
Calcium channel blockers work by blocking L-type voltage-gated calcium channels (VGCCs) in muscle cells of the heart and blood vessels. This prevents calcium levels from increasing as much in the cells when stimulated, leading to less muscle contraction. In the heart, a decrease in calcium available for each beat results in a decrease in cardiac contractility. In blood vessels, a decrease in calcium results in less contraction of the vascular smooth muscle and therefore an increase in blood vessel diameter, a phenomenon called vasodilation. Vasodilation decreases total peripheral resistance, while a decrease in cardiac contractility decreases cardiac output. Since blood pressure is in part determined by cardiac output and peripheral resistance, blood pressure drops.

With a relatively low blood pressure, the afterload on the heart decreases; this decreases the amount of oxygen required by the heart. This can help ameliorate symptoms of ischemic heart disease such as angina pectoris.

Unlike β-blockers, calcium channel blockers do not decrease the responsiveness of the heart to input from the sympathetic nervous system. Since moment-to-moment blood pressure regulation is carried out by the sympathetic nervous system (via the baroreceptor reflex), calcium channel blockers allow blood pressure to be maintained more effectively than do β-blockers.

However, because calcium channel blockers result in a decrease in blood pressure, the baroreceptor reflex often initiates a reflexive increase in sympathetic activity leading to increased heart rate and contractility. A β-blocker may be combined with a calcium channel blocker to minimize these effects.

Dihydropyridine
Dihydropyridine calcium channel blockers are often used to reduce systemic vascular resistance and arterial pressure, but are not used to treat angina (with the exception of amlodipine, which carries an indication to treat chronic stable angina as well as vasospastic angina) because the vasodilation and hypotension can lead to reflex tachycardia. This CCB class is easily identified by the suffix "-pine".
 * Amlodipine (Norvasc)
 * Felodipine (Plendil)
 * Nicardipine (Cardene, Carden SR)
 * Nifedipine (Procardia, Adalat)
 * Nimodipine (Nimotop)
 * Nisoldipine (Sular)
 * Nitrendipine (Cardif, Nitrepin)
 * Lacidipine (Motens)
 * Lercanidipine (Zanidip)

Side effects of these synthetic drugs may include but are not limited to:
 * Dizziness
 * Headache
 * Edema, particularly of the lower extremeties
 * Bradycardia
 * Constipation

Phenylalkylamine
Phenylalkylamine calcium channel blockers are relatively selective for myocardium, reduce myocardial oxygen demand and reverse coronary vasospasm, and are often used to treat angina. They have minimal vasodilatory effects compared with dihydropyridines. Action is intracellular.
 * Verapamil (Calan, Isoptin)
 * Gallopamil (D600)

Benzothiazepine
Benzothiazepine calcium channel blockers are an intermediate class between phenylalkylamine and dihydropyridines in their selectivity for vascular calcium channels. By having both cardiac depressant and vasodilator actions, benzothiazepines are able to reduce arterial pressure without producing the same degree of reflex cardiac stimulation caused by dihydropyridines.
 * Diltiazem (Cardizem)

Other

 * Menthol (mint oil)

Drug-drug interactions
An October 2008 Austrian study demonstrates that calcium-channel blockers (CCBs) reduce the antiplatelet effect of clopidogrel. The study examined the interaction by comparing the platelet reactivity index (PRI) (as determined by vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay) for 200 patients with coronary artery disease who were undergoing percutaneous coronary intervention. Patients taking concomitant CCBs and clopidogrel had displayed a PRI of 61%, while patients receiving clopidogrel alone demonstrated a PRI of 48% (absolute difference 13%; 95% CI: 6% to 20%; p = 0.001). The relative difference between the two sets of patients was approximately 21%. An in vitro experiment involving the incubation of blood from 10 additional patients, who received clopidogrel alone, with CCBs showed no difference in the PRI. This finding led the research team to hypothesize that the CCBs block the in vivo bioactivation of clopidogrel by the cytochrome P450 isoform 3A4. The majority of patients in the CCB subset received amlodipine, so additional studies are required to help establish a class effect.

Other drugs with similar uses
Other classes of pharmaceutical agents that have overlapping effects as calcium channel blockers include ACE inhibitors, beta-blockers, and nitrates.

Related Chapter

 * Voltage-dependent calcium channel

Resources

 * Official Adalat® (Nifedipine) site, Bayer
 * Official Adalat® (Nifedipine) site, Bayer