Calcium channel blockers

Calcium channel blockers are one of the most commonly prescribed drugs in the treatment of cardiovascular diseases. They were discovered by a German pharmacologist and physiologist Albrecht Fleckenstein in 1964. when he was researching the actions of verapamil and prenylamine, but the term calcium channel blocker was introduced later, in 1969. Since then, many other drugs of this type have been synthesized in the 20^th century.

Calcium

Calcium ions (Ca2+) play a significant role in human organism, acting as second messengers in signal transduction pathways, playing a role in all muscle contractions, stabilization of potential difference on cell membranes, coagulation processes, exocytosis, cell division and growth, milk synthesis, as well as being a crucial part of bones. The concentration of Ca2+ in the blood is physiologically being kept in narrow limits, between 8.6 – 10.2 mg / dL for adults, and around 1 kg or 99% total organism’s Ca2+ is stored in bones.

Calcium channel

As the Ca²⁺ concentration in the cytoplasm of cells is 10000 times lower than the concentration outside of them, and even greater gradient exist compared to Ca²⁺deposits, it is normal that many mechanisms are required to keep this gradient possible. Calcium channels are responsible for the entrance of Ca²⁺into the cells, and they can be voltage-gated or ligand-gated. The voltage-gated channels are more significant than the ligand-gated channels. There are many types of voltage-gated calcium channels, but the most important one for the cardiovascular system is the L-type, where L stands for long-lasting. Beside for contraction of the heart muscle, L-type calcium channels are involved in skeletal and smooth muscle contractions, as well as in secretion of aldosterone from adrenal glands.

Types of calcium channel blockers

Calcium channel blockers are divided into three classes, depending on their chemical structures. Those classes include dihydropyridines, phenylalkylamines, and benzothiazepines.

Dihydropyridines

This type of calcium channel blockers is derivative from an organic compound dihydropyridine. They act predominantly on calcium channels of the arteries. Some of the famous drugs from this class include amlodipine, clevidipine, felodipine, lercanidipine, nicardipine, nifedipine, nimodipine, nitrendipine, and others.

Phenylalkylamines

Phenylalkylamines include verapamil, gallopamil, and tiapamil. They act mainly on calcium channels located in the heart.

Benzothiazepines

Diltiazem is the representative of this group. It blocks the calcium channels of both heart and blood vessels.

Mechanism of action

Calcium channel blockers don’t obstruct the channel pores, they have a special place for reversible binding on the α₁subunit of the channels. When the drug binds to its target, calcium channel changes its conformation, thus blocks the entrance of Ca²⁺ions in cells of the heart and blood vessels. By blocking of Ca²⁺channels on blood vessels they reduce their contraction, widening them, and that process is called the vasodilation. Their effect on the heart include negative inotropic (reducing in force of heart muscle contractions), negative chronotropic (decreased heart rate), and lowered dromotropic (lowered conductivity) effects. Calcium channel blockers, reduce the release of aldosterone, a hormone responsible for the conservation of sodium and water in the organism.

Indications

Calcium channel blockers are part of the treatment of various heart and blood vessel related diseases. These include hypertension, angina (stable and vasospastic), supraventricular arrhythmia, Raynaud’s disease, and other non-heart related such as cluster headache and achalasia.

Hypertension

Hypertension represents high blood pressure, higher than 140 / 90 mm Hg. It is recommended that calcium channel blockers should be used as the first line of drugs that are prescribed in the therapy of people older than 55 years or those of African-American descent. All types of calcium channel blockers are indicated in high blood pressure. They are effective in hypertension on its own, and different types are effective on hypertension associated with angina, atrial fibrillation, and peripheral vascular diseases. Dihydropyridines dominantly block calcium channels on arteries, therefore reducing vascular resistance and blood pressure, while phenylalkylamines dominantly block calcium channels in the heart, decreasing the heart rate and the strength of the heart contractions, reducing blood pressure. Diltiazem works both as a cardiac depressant and vasodilator, reducing cardiac output, as well as vascular resistance.

Angina

Angina is chest pain or discomfort, caused by ischemic heart disease. Beside beta blockers, calcium channel blockers are often in the therapy in stable angina, especially if a patient doesn’t respond well to beta blockers; beta blockers cause significant side effects, or asthma / COPD is present along with angina. Phenylalkylamines lower contractility and heart rate, thus reducing the blood pressure and the heart’s needs for oxygen. Dihydropyridines are widening the arteries, lowering the blood pressure, improving the blood flow, and they can be given in Prinzmetal’s (variant angina). This condition is not triggered by physical activity like stable angina, but in rest, due to vasospasms (narrowing of arteries).

Arrhythmia

The term arrhythmia describes a group of diseases, which include heart rhythm abnormalities. Non-dihydropyridine calcium channel blockers represent the IV group of antiarrhythmic drugs. They are used in supraventricular tachycardias, including the atrial fibrillation. Calcium channel blockers are used to slow down the contraction rate of ventricles, and to prevent the arrhythmia recurrence. They are decreasing the conduction of electrical impulses through the atrioventricular node while lowering the heart rate.

Raynaud’s disease

Raynaud’s disease is a condition in which some body parts such as fingers and toes have reduced blood circulation due to vasospasms (narrowing of arteries). That limited blood flow is causing them to feel numb and cold. Episodes can be triggered by cold or by emotional stress. Raynaud’s disease is manifested by discoloration of the affected area, which becomes white, then blue, and lastly red when the circulation recovers. Severe cases of Raynaud’s disease may require the use of medications. Dihydropyridines can help in the management of the vasospasms, as they relax arteries, causing their widening, and improving the blood flow.

Contraindications of calcium channel blockers

Depending on type of calcium channel blockers, where they act on blood vessels or the heart, conditions where Non-dihydropyridines shouldn’t be used are bradycardia, hypotension, acute coronary syndorme, second and third degree AV block, congestive heart failure, sick sinus syndrome, and Wolff-Parkinson-White syndrome. Dihydropyridines shouldn’t be in therapy of hypotension, acute coronary syndrome, hypertrophic obstructive cardiomyopathy, and aortic valve stenosis.

Bradycardia

Bradycardia is a heart rate slower than normal. In this condition the heart beats less than 60 times per minute, but the symptoms mainly shown, when the heart rate drops bellow 50 bpm. Symptoms include dizziness, fatigue, lightheadedness, and fainting. As calcium channel blockers slow down the heart rate, they may additionally decrease it, inducing a life threatening condition.

Hypotension

Calcium channel blockers are antihypertensives, meaning that they lower the blood pressure. Hypotension is a state of low blood pressure, under 90 / 60 mm Hg. Critically low blood pressure may lead to state of shock, which can be very dangerous.

Second and third degree AC block

Second degree atriventricular block is a condition where some electrical impulses can’t pass from the atria to ventricles, while the third degree atrioventricular block represents the completely stopped intermission between atria and ventricles, so ventricles need to create a abnormal rhythm, called escape rhythm. Heart rate is very low, as well as the blood pressure. Calcium channel blockers can additionally worsen the symptoms, and lead to dangerous complications.

Acute coronary syndrome

Acute coronary syndrome may be caused by thrombotic obstruction of the coronary arteries. ST elevation myocardial infarction (total obstruction which leads to death of heart muscle cells), and unstable angina or non ST elevation myocardial infarction (when the obstruction isn’t completely blocked the blood flow, or when It doesn’t last long) are caused by atherosclerotic plaque rupture. Calcium channel blockers don’t help in these conditions, moreover they can increase mortality rate if used. At the other hand they can be alternative to beta blockers if those are not part of therapy of (Asthma, COPD), and the left heart function is normal.

Congestive heart failure

Heart failure is an inability of heart to provide enough nutrient and oxygen rich blood to organs and peripheral tissues. If the left ventricular ejection fraction is weakened, calcium channel blockers can increase a progress of this disease, lowering the contractility, and heart’s blood pumping ability.

Sick sinus syndrome

Sick sinus syndrome is a group of arrhythmias caused by abnormal work of sinus node, the pacemaker of the heart. Heart rhythm may be increased, decreased, or represent a combination of these two conditions. Calcium channel blockers can worsen those rhythms.

Wolff-Parkinson-White syndrome

WPWS is heart rhythm disorder characterized by abnormality of the electrical pathways. Accessory pathway, known as bundle of Kent is present, it connects the atria and ventricles, bypassing the atrioventricular node. Often without any symptoms when the heart rate is not rapid, but episodes of supraventricular tachycardia manifest symptoms such as palpitation, dizziness, and fainting. Calcium channel blockers, and other AV blockers can increase the tachycardia, because they block the conduction via the AV node, forcing the usage of accessory pathway.

Hypertrophic obstructive cardiomyopathy

In this condition, a part of the heart is thicker, and it has limited ability to pump blood. Dihydropyridines can worsen the symptoms of this condition, causing fainting, and even a sudden cardiac death.

Aortic valve stenosis

A condition which occurs when the aortic valve of the heart is narrower, preventing it to manage the blood flow normally. Dihydropyridines can cause myocardial ischemia, and induce dangerous complications.

Side effects

As all other medications, calcium channel blockers can cause side effects, but they are mostly mild and not dangerous.

bradycardia – hearth rhythm can drop bellow the normal levels
hypotension – blood pressure can go lower
lightheadedness, drowsiness, headache – these effects can be induced by vasodilation effect of calcium channel blockers
facial flushing – also caused by vasodilation
edema – swelling in lower legs and ankles; this effect can be explained by increasement of hydrostatic pressure in blood vessels by vasodilation that is provoking the fluid transition outside the blood vessels
tachycardia – reflex tachycardia may occur in use of vasodilation agents, as they widen the blood vessels, reducing the blood pressure, which may induce the response from heart in a way of increased heart rate
constipation – gut motility can work less, leading to constipation
upset stomach – a potential side effect of many drugs
heart failure – calcium channel blockers that reduce the heart contractility can worsen the symptoms or even promote heart failure
AV block – calcium channel blockers that act on heart’s electrical conductivity can invoke a dangerous event of atrioventricular block
erectile dysfunction, loss of sex drive – these are potential side effects of many drugs that reduce blood pressure

Interactions

Calcium channel blockers can interact with other drugs, so it’s important to note your current therapy to your doctor or pharmacist.

Beta blockers

Patients should not simultaneous use of beta blockers and verapamil, as both these drugs lower the contractility, electrical conductivity, and heart rate. A risk for development of dangerous AV block, hypotension, and heart failure is significantly higher. Dihydropyridines may be combined with beta blockers, as they are primarly vasodilators, and they don’t affect the heart directly, but due to increased lowering of blood pressure, a hypotension may occur.

Digoxin

Digoxin is the drug that is sometimes combined with calcium channel blockers in more serious cases of atrial fibrillation. The calcium channel blockers may lead to increased concentration of digoxin due to their inhibitory effect on P-glycoprotein (protein responsible for ejection of substances out of cells). The concentration of digoxin should be monitored, and its dose lowered accordingly.

Statins

Verapamil may increase the concentration of lipid lowering medications, called statins. Hepatic enzymes should be monitored, and the dose of a statin should be lowered, as the statins can induce a muscle pain and, rarely rhabdomyolysis (destruction of muscle cells) in high concentrations.