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Calcium Channel Blockers (Class IV Antiarrhythmics)

Calcium channel blockers are used in the treatment of arrhythmias and hypertension. Verapamil and Diltiazim have antiarrhythmic property.

Calcium channel blockers have various groups:

1. Diphydropyridine derivatives (only used in HTN, no antiarrhythmic property)

Nifedipine

Amlodipine

Nitrendipine

2. Phenylalkylamines

Verapamil has both antiarrhythmic and antihypertensive effects

Benzothiazepines              

Diltiazem has both antiarrhythmic and antihypertensive effects

Diphenyl Piperazine   (used only in HTN, effect blood vessels)

Depridil

 Mechanism of Action

These drugs block the voltage gated Ca++ channels. There are two main types of Ca++ channels:

  1. Potential dependent/Voltage gated channels
  2. Receptor operated channels (ROC)

Potential dependent channels (PDC) are divided into:

L, T and N types.

a. Out of these L type are mainly present in the blood vessels and myocardium and are the long Ca++ channels or larger Ca++ channels.

b. T type are the transient channels, present in the thalamus, CNS and are responsible for propagation at particular voltage (antiepileptic)

c. N stands for neuron. These are neuronal in distribution.

In the CVS, L type are present in the heart and smooth muscles of blood vessels.

The binding sites of these groups are different, so have different effects.

Antihypertensive Effect:

Ca++ channel blockers have different effects on the blood vessels and heart:

  1. They cause vasodilatation of coronary and systemic blood vessels.
  2. Block Ca++ channels in the blood vessels
  3. Diltiazin and Verapamil act at SA and AV node causing decrease in cardiac contractility.

So a decrease in blood pressure and cardiac contractility occurs.

By causing vasodilatation in systemic blood vessels due to decrease in entry of Ca++ into blood vessels leading to decrease in formation of calcium-calmodulin complex. This causes inhibition and decrease in activity of myosin kinase enzyme, leading to dephosphorylation of myosin light chain.

Dilatation of arteries and veins cause decrease in preload and after load, being effective in angina.

Antiarrhythmic Effect

Blockage of Ca++ channels in SA and AV node cause a decrease in entry of Ca++ into cardiac cells, causing decrease in force of contraction, which inhibits the troponin bridge causing decrease in force of contraction and decrease in oxygen consumption by heart. This produces antiarrhythmic effect.

As these drugs depress the rate of discharge of SA and AV node, they cause a decrease in AV conduction, decrease in force of contraction and heart block in over dosage.

Since these drugs block SA and AV nodal conduction, they are effective in supraventricular arrhythmias.

Pharmacokinetics

They are well absorbed after oral route of administration.

They undergo extensive first pass metabolism, due to which their bioavailability is low.

Drug Bioavailability Protein binding Half Life
Verapamil 20% 90% 4 hours
Diltiazem 50% 80% 5 hours
Nifedipine 55% 95% 1.5 hours
Therapeutic Uses
    1. Treatment of hypertension
    2. Treatment of supraventricular arrhythmias
    3. Anti anginal
    4. Nifedipine and Amlodipine are used in treatment of peripheral vascular disease (raynaud’s disease) involving the contraction of digital arteries, producing pain.
Adverse Effects

Most adverse effects are due to vasodilatation

  1. Headache
  2. Flushing
  3. Ankle edema (peripheral edema)
  4. Constipation (esp. Verapamil)
  5. May also cause AV block
Contraindications
  1. Bradycardia
  2. AV block (2nd and 3rd degree heart block)
  3. Heart failure
  4. Sick sinus syndrome

Excessive and low discharge from SA node alternates (sometimes increasing, sometimes     decreasing), contraindicated because may lead to severe bradycardia and cardiac arrest.

Drug Interactions
  1. Beta blockers –dose is reduced or given very carefully, normally contraindicated
  2. Digoxin as:
  1. Bradycardia may increase (negative ionotropic)
  2. May rise plasma levels of digoxin
Dose

Verapamil dose is 40-240 mg, depending on the condition, twice or thrice daily, it has high therapeutic index.

Diltiazem dose is 60-340 mg in a day in divided doses.

Nifedipine is given 10-20 mg daily.

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