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Overview of Calcium Channel Blockers

The different types

Calcium channel blockers are subdivided into two categories: the dihydropyridines and the non-dihydropyridines. There is no variation in their chemical compositions, but they differ in their relative selectivity towards the L type calcium channels.

Calcium channel blockers are subdivided into two categories: the dihydropyridines and the non-dihydropyridines. Their main difference is the area at which their effects can be seen.

Dihydropyridines: mainly target system vasculature, producing systemic vasodilation -> decreasing afterload on the heart. This can develop into reflex tachycardia (due to the drop in blood pressure [from the systemic vasodilation, especially in arteries and the heart’s work to maintain pulse pressure. These drugs include (brand name):

  • Amlodipine (Norvasc)
  • Nicardipine (Cardene)
  • Nifedipine (Nivadil)
  • Felodipine (Plendil)
  • Nimodipine
  • Nitrendipine
  • Isradipine

Note: Dihydropyridines have names that end in –dipine.

Non-dihydropyridines: these are further divided into other groups:

  • Phenylalkylamines – Classic example is Verapamil. These CaCh blockers mainly act on (selective for) the myocardium itself. They have minimal vasodilatory effects (systemic). They are, therefore, mainly used to treat angina (where tachycardia would be a bad thing) by reducing the myocardium’s oxygen demand and reversing vasopasm of coronary vessels. It can be also be used to cure arrhythmias.
  • Benzothiazepines – Classic example is Diltiazem (Cardizem). These are a mix between dihydropyridines and phenylalkylamines. They act as cardiac depressant and vasodilators. They are used to decrease the arterial pressure without causing reflex cardiac stimulation as done by dihydropyridines.
  • Nonselective – these mainly relate to the drugs that are nonselective and can cross the blood-brain barrier.

Verapamil predominantly has a direct effect on the heart. Diltiazem has an effect on the myocardium as well as peripheral vessels.

Notice: Dihydropyridines affect the peripheral vessels, while verapamil acts predominantly on the heart.

Mechanism of Action

The effect on the L-type calcium channel

Calcium channel blockers inhibit the voltage-dependent L-type calcium channel of cardiac and vascular smooth muscle cells. Inhibiting calcium influx into the cell creates a negative inotropic effect, and the smooth muscle cells relax and vasodilate.

Dihydropyridines mainly act on the vessels (arteries and arterioles), but will also act on the heart at high doses. Therefore, they can reduce coronary and vascular resistance more than verapamil and diltiazem. Verapamil and diltiazem also have a vasodilating effect, but they mainly have a negative chronotropic and inotropic (it slows it down) effect on the heart.

The dihydropyridines create a counter-regulation through the sympathetic nervous system, meaning they can cause an overall increase in heart rate. By decreasing peripheral resistance and blood pressure, the sympathetic nervous system compensates by increasing the heart rate.

This effect is rare with diltiazem or verapamil (because they work mainly on the heart); instead, they have a negative chronotropic effect, slowing down the transition of action potentials at the AV node. Therefore, they are used in antiarrhythmic therapy of atrial fibrillation to slow down the ventricular rate.

Metabolism

Calcium channel blockers are metabolized by CYP3A4. Rifampicin accelerates the breakdown of calcium channel blockers. However, antihistamines, protease inhibitors, immunosuppressants, antifungals, and grapefruit juice inhibit the breakdown.

Adverse Effects

Dihydropyridines

The most common adverse effects include headaches, peripheral edemas, excessive hypotension, and flushing. An important adverse effect is reflex tachycardia, which is mainly associated with nifedipine. This effect may aggravate existing heart conditions from increased cardiac work. Long-acting dihydropyridines are safer as anti-hypertensive drugs and more effective for angina than short-acting ones.

Diltiazem and verapamil

The most common adverse effects are bradycardia and type I AV block. It can also cause depressed contractility and interfere with the action of beta-blockers.

Indications

Indications for dihydropyridines

Dihydropyridines are used to treat arterial hypertension as well as vasospastic angina (Prinzmetal angina). They are also used to treat coronary spasms, migraine headaches,  Raynaud’s phenomenon, cerebral vasospasm, and cerebrovascular insufficiencies. Substances with a long half-life period, like amlodipine (35-50 hours), are preferred for regular use. In contrast, nifedipine has a half-life period of about two hours and, hence, a short effect duration.

Indications for diltiazem and verapamil

Diltiazem and verapamil are used to treat arterial hypertension, stable angina, and hypertrophic obstructive cardiomyopathy. They are also used as a treatment for supraventricular tachycardia (they are a type IV antiarrhythmic) and cardiac infarction.

Verapamil has a distinctive first-pass effect. Its bioavailability is only 10–20% and can also only be increased to 35–40% during constant use. It is effective in the treatment of supraventricular arrhythmias.

Contraindications

Dihydropyridines

Caution should be used in patients with cardiac insufficiency. Contraindications include an acute coronary syndrome (up to four weeks after myocardial infarction), persistent bradycardia hypotension, aortic stenosis, or pregnancy.

Diltiazem and verapamil

Contraindications include AV block (grade II and III), sick sinus syndrome, conduction defects, and decompensated cardiac insufficiency. Pre-excitation syndromes are also contraindications, especially verapamil because it promotes the occurrence of re-entries. They also interfere with the action of beta-blockers. Diltiazem and verapamil must not be prescribed during pregnancy or nursing periods.

Review Questions

The correct answers can be found below the references.

1. What is the advantage of therapy with amlodipine compared to the application of other dihydropyridines?

  1. Fast onset of action
  2. Longer duration of action
  3. Stronger effects on the AV node
  4. Has an additional effect on the sinus node
  5. Enhanced affinity to L-type calcium channels

2. What is a contraindication for the application of verapamil?

  1. Arterial hypertension
  2. Hypertrophic obstructive cardiomyopathy
  3. Angina pectoris
  4. Atrial fibrillation
  5. AV block

3. What belongs least to the adverse effects of dihydropyridines?

  1. Flush
  2. Headache
  3. Reflective tachycardia
  4. Re-entry
  5. Peripheral edema
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