Calcium Channel Blockers

·        Cellular calcium homeostasis.

·        Role of calcium in excitable tissues.

Cellular calcium homeostasis

1.       Calcium plays a crucial role as a messenger linking extracellular stimuli to the response mechanism within auto-rhythmic (nodal tissue) and excitable tissues (myocardium and smooth muscle).

2.       These cells at rest are relatively impermeable to Ca²⁺ which prevents the high cellular free Ca²⁺ from entering the cytosol.

3.       During excitation, the intracellular free Ca²⁺ concentration increases about 100-fold through the entry of extracellular Ca²⁺which trigger off the release of bound calcium from intracellular binding sites.

4.    The elevated intracellular Ca²⁺ is restored to pre-excitation levels via:

a.       Ca²⁺-ATPase pump in plasma membrane: extrudes Ca²⁺ from cell.

b.       Ca²⁺-ATPase pump in sarcoplasmic reticulum: catalyzes uptake of Ca²⁺.

c.       Na⁺/Ca²⁺ exchange system: 3 Na⁺ move in for each Ca²⁺ extruded.

5.       Inhibition of Na⁺-K⁺-ATPase results in less Ca²⁺ being extruded through the Na⁺/Ca²⁺ exchange system.

Role of Calcium in excitable tissues

1.       Calcium plays a vita role in stimulus-contraction coupling in cardiac and smooth muscle.

2.    The cytoplasmic free Ca²⁺ concentration influences the force of contraction of myocardium and the tone of smooth muscle.

3.    The intracellular receptor proteins for calcium in cardiac and smooth muscle are troponin-C and calmodulin respectively.

4.    Both receptor proteins have four distinct Ca²⁺ binding sites, the occupation of which leads to a new conformational state.

5.    In troponin-C this change removes another protein, troponin-I, from an inhibitory site on actin which allows the actin-myosin interaction to take place.

6.    The conformational change produced by Ca²⁺ in calmodulin causes calmodulin to bind to and activate myosin light chain kinases which phosphorylates myosin, allowing it to interact with actin.

Pharmacodynamics

1.    The calcium channel blockers inhibit the passage of Ca²⁺ through voltage-gated L-type membrane channels of smooth and cardiac muscle, reduce available intracellular Ca²⁺  and cause the muscle to relax.

2.       There are 3 structurally different classes of calcium blocker:

a.       Dihydropyridines: nifedipine.

b.       Phenylalkylamines: verapamil.

c.       Benzothiazepine: diltiazem.

3.    All members of the group are vasodilators, and some have weakly negative cardiac inotropic action and negative chronotropic effect via pacemaker cells and depress conducting tissue.

4.       Effects on vasculature:

a.    All three drugs dilate coronary and peripheral arteries with nifedipine having the most potent effect.

b.    This action has application in angina pectoris, hypertension and congestive heart failure.

5.       Effects on nodal/conducting tissue:

a.       Reduce rate of sinus node discharge.

b.    Slow conduction velocity through AV node.

c.       Prolong AV nodal refractory period.

Therapeutic indications

1.       Hypertension: vasodilation of peripheral vessels reduce total peripheral resistance thereby reducing blood pressure.

2.       Angina pectoris: dilatation of the coronary vascular bed improves myocardial perfusion and increases oxygen supply whilst systemic arterial vasodilatation reduces left ventricular afterload thereby decreasing myocardial demand for oxygen.

3.       Congestive heart failure: their arterial vasodilator effect reduces ventricular afterload thereby increasing cardiac output and lowering oxygen demand by myocardium.

4.       Raynaud’s disease.

5.       Supraventricular tachycardias: verapamil slows conduction through AV node and also prolong the refractory period.

Adverse effects:

1.       CNS: headache, nausea, nervousness.

2.    CVS: flushing, palpitations, hypotension, bradycardia, asystole.

3.    GI: constipation, vomiting.

4.       Pruritus.

5.       Ankle edema.

6.    Drug interactions:

a.       Amiodarone and digoxin increases AV block.

b.    Non-depolarizing neuromuscular agents: potentiate effect, prolonged respiratory depression and apnoea.

c.       Inhibit metabolism of quinidine, carbamazepine, cycloserine, lovastatin or simvastatin.

Individual drugs

1.       Verapamil:

a.       Undergoes substantial first-pass in the liver with a bioavailability of 65 – 80%.

b.    90% protein-bound and is widely distributed in the body tissues including the CNS, breast milk and across the placenta.

c.    Half-life of 4 – 6h and is rapidly and almost completely metabolized by the liver.

d.    An arterial vasodilator with some venodilator effect; also has marked negative myocardial inotropic and chronotropic actions.

e.       Should not be given to patients with bradycardia, second or third degree heart block, or patients with Wolff-Parkinson-White syndrome who have atrial flutter or fibrillation.

2.       Nifedipine:

a.    Half-life: 2h.

b.    Most potent dilator of peripheral as well as coronary arterioles amongst the calcium channel blockers.

c.    Drug of choice in angina induced by coronary artery spasms.

d.    Can be taken sublingually, by crushing a capsule and squeezing the contents under the tongue.

3.       Diltiazem:

a.    Half-life: 5h.

b.       Similar but less potent effects on CVS then verapamil.

c.       Lower incidence of unwanted effects.

4.       Nimodipine:

a.       Moderate cerebral vasodilator.

b.       Clinical trial evidence indicates that nimodipine given after subarachnoid haemorrhage reduces cerebral infarction.