Calcium – Channel Blockers as Antihypertensive Drugs

Pharmacology 5,865 Views

There are two types of calcium channels:

Voltage gated
Receptor operated

Type of Voltage gated Calcium Channels

Voltage gated channels open and close at a specific voltage. All types are found in neurons.

L Type -Muscle, Neurons ,Heart

T Type -Neurons , Heart, (thalamic neurons)

N Type -Neurons

P Type -Cerebellar purkinje neurons

R Type -Neurons

Mechanism of Action

Blood Vessels

Arterioles are more sensitive to the effects of Ca++ channel blockers. They cause decrease in the entry of Ca++ leading to decreased Ca-calmodulin complex, decreased activation of myosin light chain kinases, resulting in dephosphorylation producing vasodilatation. This decreases blood pressure, preload and after load.

Cardiac Muscles

In cardiac muscles when given, cause decrease in entry of Ca++ into cardiac muscles. Cardiac muscles are dependent on Ca++ for normal activity. Impulse generation in SA node, conduction through AV node, excitation-contraction coupling and ultimately the contractility of heart, all decrease by the action of Ca++ channel blockers. This in turn leads to decreased cardiac output.

Dihydropyridines

Dihydropyridines have more affinity for smooth muscles of blood vessels. However, verapamil and diltiazem have more effects on cardiac muscles

Pharmacokinetics

They are well absorbed after oral administration. However, they have extensive first pass metabolism, this is why their bioavailability is decreased. They are also extensively bound to plasma proteins.

Drug	Bioavailability	Plasma protein binding
Nifedipine	55%	95%
Diltiazem	50%	80-85%
Verapamil	20%	90%

Half life varies between 4-5 hours; however, nifedipine has half life of 1.5 hours.

They are eliminated in urine, except diltiazem which is excreted in faeces.

Other Pharmacological Effects

1. Effect on other smooth muscles- bronchiolar, gastrointestinal , uterine & vascular muscles

Most smooth muscles are dependent on influx of Ca++ for tone and contractility, Ca++ blockers relax them.

2. Cardiac muscles

Effect AV conduction and contractility of heart, which are depressed by Ca++ channel blockers, thus are having cardio depressant effect.

3. Action on Skeletal muscles

Not depressed by Ca++ channel blockers as they use intracellular pools of Ca++ for their contractility, thus are not dependent on transmembrane Ca++ influx.

4. Cerebral vasospasm & infarct following subarachnoid hemorrhage

Among dihydropyridines, Nimodipine has affinity for cerebral blood vessels, so it is used to relieve cerebral vasospasm and infarcts.

5. Decreased release of insulin

Verapamil has been shown to inhibit the release of insulin, but the dose required is much higher.

6. Interfere with platelet aggregation

Due to interfere with platelet aggregation, preventing development of atheromatous lesions. However, this is not utilized in clinical practice.

7. Verapamil blocks transporter p-170 glycoprotein transporter

Can reverse resistance of cancer cells to chemotherapeutic agents.

Uses

Treatment of hypertension
Treatment of angina
Anti-arrhythmic (supraventricular)
Prophylactically in migraine
Subarachnoid hemorrhage
Raynaud’s phenomenon

Dose

10-20 mg depending upon condition of patient

Toxicity/Adverse effects

Most of the adverse cardiac effects are a direct extension of pharmacological actions, these include:

Cardiac depression
Bradycardia
Aggravation of heart blocks
Immediate acting nifedipine as been shown to increase risk of MI in patients with HTN. Thus slow release preparations are given.
Dihydropyridines increase the risk of cardiac events in patients with or without diabetes.
Ca++ channel blockers should never be combined with beta blockers as both have cardiac depressing effects.