Calcium Channel Blockers

Introduction:

In the 1970s, calcium channel blockers (CCBs), also known as calcium channel antagonists, were widely used for several indications. CCBs have been approved by the US Food and Drug Administration (FDA) to treat various conditions such as hypertension, coronary heart disease, and chronic stable angina. However, despite their widespread use, this class of cardiovascular drugs is one of the primary contributors to drug-related fatalities.

They stop calcium from entering the cells of the heart and arteries. Calcium causes the heart and arteries to squeeze more strongly. By blocking calcium, calcium channel blockers allow blood vessels to relax and open.

CCBs are often classified into 2 major categories:

non-dihydropyridines or dihydropyridines.

The non-dihydropyridines include verapamil, classified as a phenylalkylamine, and diltiazem, categorized as a benzothiazepine. Dihydropyridines include many other drugs, most of which end in “pine,” such as amlodipine, felodipine, nisoldipine, and nicardipine.

FDA-Approved Indications

Each drug has distinct FDA-approved indications, with some being utilized off-label. Verification is essential for each drug.

Dihydropyridine drugs are used to treat hypertension, coronary artery disease, and chronic stable angina.

Non-dihydropyridine drugs are used to treat hypertension, paroxysmal supraventricular tachycardia (PSVT) conversion, PSVT prophylaxis, atrial fibrillation/flutter, chronic stable angina, and vasospastic angina.

Mechanism of action

CCBs block the inward movement of calcium by binding to the L-type “long-acting” voltage-gated calcium channels in the heart, vascular smooth muscle, and pancreas. Two major categories of CCBs are based on their primary physiological effects. The non-dihydropyridines exert inhibitory effects on the SA and AV nodes, thereby slowing cardiac conduction and contractility.

This property allows for the treatment of hypertension, reduces oxygen demand, and helps to control the rate of tachydysrhythmias.

The dihydropyridines exert minimal direct effects on the myocardium and are primarily peripheral vasodilators at therapeutic doses. This property renders them useful for conditions such as hypertension, post-intracranial hemorrhage-associated vasospasm, and migraines.

Pharmacokinetics

Absorption:

CCBs are readily absorbed orally. However, many exhibit low bioavailability because of hepatic first-pass metabolism, primarily mediated by CYP3A4.

Distribution:

CCBs are highly protein-bound, and many have high volumes of distribution.

Metabolism:

CCBs are extensively hepatically metabolized. In repeated doses or overdose, the hepatic enzymes responsible for metabolism become saturated and reduce first-pass effects, increasing absorption of the active drug. Modified release formulations and saturation of metabolism of these drugs increase the half-life of various CCBs. The potential for drug-drug interactions is because CCBs are metabolized by CYP3A4, which is responsible for the metabolism of many other xenobiotics.

Elimination:

CCBs are primarily excreted renally after metabolism

Examples of calcium channel blockers

Calcium channel blockers are available in short-acting and long-acting forms. Short-acting medicines work quickly, but their effects last only a few hours. Long-acting medicines are slowly released to provide a longer-lasting effect. Which one is best for you depends on your health and the condition being treated.

Examples of calcium channel blockers include:

Amlodipine (Norvasc).

Diltiazem (Cardizem, Tiazac, others).

Felodipine.

Isradipine.

Nicardipine.

Nifedipine (Procardia).

Nisoldipine (Sular).

Verapamil (Verelan).

Uses:

In addition to being used to treat high blood pressure, calcium channel blockers may be prescribed to prevent, treat or improve symptoms of conditions, such as:

Coronary artery disease.

Chest pain, called angina.

Irregular heartbeats, also called arrhythmia.

Blood vessel conditions, such as Raynaud’s disease.

Hypertrophic cardiomyopathy (enlarged heart).

Pulmonary hypertension.

Subarachnoid hemorrhage (bleeding into the space between the brain and the skull).

For Black people, calcium channel blockers might work better than other blood pressure medicines, such as beta blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers.

Available Dosage Forms and Strengths

CCBs are available in oral or injectable formulations. A selection of various agents in each class, along with their dose forms, are mentioned below.

Dihydropyridine agents:

Amlodipine is available as oral tablets.

Felodipine is available as an extended-release (ER) oral tablet.

Nicardipine is available in oral capsules and injectable formulations.

Nisoldipine is available as an ER oral tablet.

Non-dihydropyridine agents:

Diltiazem is available in oral formulations of 12- and 24-hour ER capsules, immediate-release tablets, ER tablets, and injectable formulations.

Verapamil is available in oral formulations such as 24-hour ER capsules (for morning dosing), 24-hour ER capsules (for evening dosing), immediate-release tablets, ER tablets, and injectable formulations.

Adverse Effects:

The 2 classes of CCBs: —dihydropyridines and non-dihydropyridines—have different adverse event profiles.

Dihydropyridines may lead to lightheadedness, flushing, headaches, and peripheral edema. The peripheral edema is likely related to the redistribution of fluid from the intravascular space to the interstitium. More severe adverse events include acute myocardial infarction (AMI), exacerbated angina, acute hypotension, syncope, erythema multiforme, and hepatitis, which can vary slightly depending on the chosen agent.

Non-dihydropyridines may cause constipation, orthostatic hypotension, elevated liver enzymes, dizziness, constipation, and fatigue. More severe adverse reactions with non-dihydropyridine agents include bradycardia, reflex tachycardia, AV block, arrhythmias, severe hypotension, Stevens-Johnson syndrome, paralytic ileus, congestive heart failure, peripheral edema, and hepatotoxicity.

As with dihydropyridine agents, these adverse events can vary somewhat by the specific drug.

What should I do if I take one of these medications and miss a dose?

The dosing of calcium channel blockers is very important for them to be effective and safe. Because of that, if you miss a dose of one of these medications, you should never try to “catch up” by taking an extra dose, as even doubling your dose may be dangerous. This is especially true with verapamil, which strongly affects the timing and strength of your heartbeat, meaning it can be deadly if you take too much.

How long can I stay on calcium channel blockers?

In general, calcium channel blockers taken by mouth are safe for long-term use. In many cases, you can take them indefinitely. However, you should never stop taking them suddenly without talking to your healthcare provider

Can I ever stop taking these medications?

In some cases — depending on why you take these medications — you may be able to improve your health to a point where you don’t need to take them any longer. One example of this is lowering your blood pressure through diet and exercise.

In those cases, you would need to talk to your healthcare provider and they can help plan a way to wean you off of calcium channel blockers. You should never stop these medications suddenly.

However, there are some conditions, such as arrhythmias or enlarged heart, where you would need to remain on calcium channel blockers (or another medication for that condition) indefinitely

Drug-Drug Interactions:

Many drug-drug interactions involving CCBs result from their extensive first-pass metabolism via the CYP450 enzyme system. The following summarizes some of the potential interactions with CCBs. Reduced doses of interacting medications may be needed.

CYP3A isoenzyme inhibition by verapamil and diltiazem:

Ciclosporin

Statins

Benzodiazepines

Buspirone

Sildenafil

Inhibition of CYP3A isoenzyme:

Cimetidine

Erythromycin

Clarithromycin

Azole antifungals

Protease inhibitors