CALCIUM CHANNEL BLOCKERS

• Drugs blocking L-type of voltage-gated calcium channels, present in blood vessels & heart.

Drug groups:

• Three groups of drugs:

Phenylalkylamines – 

• Verapamil, nor-verapamil.

Benzothiazepines – 

• Diltiazem.

Dihydropyridines – 

• Nifedipine, nicardipine, nimodipine, nisoldipine, nitrendipine, isradipine, lacidipine, felodipine & amlodipine.

Drug actions of CCB’s:

• Inhibits calcium channels & reduces frequency of Ca⁺ channels opening –> Results in vasodilation.
• Smooth muscle relaxation in blood vessels & extravascular organs (bronchus, GIT, urinary bladder, uterus).

CCB’s & cardiac activity:

Decreased cardiac activity – 

• Decreased heart rate, AV conduction & contractility.

Little direct cardiac activity:

• Dihydropyridine (DHP) group.
• Acts mainly on blood vessels – Hence, called peripherally acting CCBs.

Strong direct cardiac activity:

• Verapamil & diltiazem (verapamil > diltiazem).
• Strong cardiodepressant activity.

Effect of different CCBs on HR & BP:

General indications of CCB’s:

• Used in angina (both classical & variant angina)
  • Mainly Verapamil, diltiazem & long acting DHPs.
• DOC for hypertensive patients with migraine.
  • Eg: Flunarizine (weak CCB) – For prophylaxis of migraine.
• In hypertensive patients with PVD (peripheral vascular diseases – Raynaud’s phenomena).

General contraindications of CCB’s:

In sick sinus syndrome –

• Because of CCB’s reflex tachycardia.

In angina –

• Precipitates acute attack of angina
• Accentuates angina symptoms by causing tachycardia (Except short-acting DHPs like nifedipine).

In Hyperglycemia (mainly Nifedipine):

• By decreasing insulin release.
• CCB’s along with β-blockers.

General adverse effects of CCB’s:

Reflex tachycardia:

• Caused due to vasodilatory action.
• Mainly by DHP’s drugs.
• Nifedipine (short half-life) – More marked tachycardia.
• Amlodipine – Long-acting drugs (maximum half-life) – Less tachycardia.
• This effect nullified by direct cardiodepressant action (except DHPs).

Voiding difficulty in elderly:

• Due to urinary bladder relaxation.
• Constipation & ankle edema (particularly verapamil).
• Increases plasma digoxin concentration –
• By decreasing its excretion.

Individual drug description:

1. Verapamil:

Actions:

• Maximum cardio-depressant action.
• Causes vasodilation – By blocking calcium channel.
• Maximum effect on cardiac conduction.
• Increases PR interval.

Metabolic properties:

• Maximum plasma protein-bound drug.
• CYP3A inhibitor.
• Has racemic mixture of two enantiomers with different pharmacokinetic & pharmacodynamic properties.

Indications:

• Treatment of angina, PSVT, hypertension & hypertrophic obstructive cardiomyopathy (HOCM).

2. Diltiazem:

• Lesser effect on heart than verapamil.

Uses:

• Same indication as verapamil.
• Suitable for elderly patients, low renin hypertension cases, asthma, migraine or peripheral vascular disease & isolated systolic hypertensive cases.

3. Dihydropyridine drug group:

• Safe in pregnancy.

3a.) Nifedipine:

• Predominant peripheral action.
• Increases angina risk.
• Increases heart rate & thus cardiac work.
• Prevented by sustained-release preparation of nifedipine & amlodipine.
• Possesses natriuretic property.
• Interferes with anesthesia.
• Nifedipine & beta-blocker given together – To overcome nifedipine’s increased sympathetic activity.

History:

• Previously used sublingually for hypertensive emergencies.
• Banned due to increased risk of MI & mortality.

Uses:

• For Achalasia cardia.

3b.) Nicardipine:

• Longest acting parenteral CCB.
• DOC for hypertensive emergencies.
• Combined with beta blockers to avoid tachycardia.

3c.) Nimodipine:

• Shortest acting CCB’s
• Relatively Cerebro-selective vasodilator.
• Used for reversal of compensatory vasoconstriction after subarachnoid hemorrhage.

3d.) Clevidipine:

• Ultrashort-acting DHP.
• Recently approved for hypertensive emergencies.