CALCIUM CHANNEL BLOCKERS

Mechanism of action

Here's a video (7m 50s) detailing the mechanism of action of calcium channel blockers.

Effect of calcium channel blockers on blood vessels

Calcium channels in vascular smooth muscle cells play an important role in determining the tone of blood vessels.

CCBs reduce influx of Ca2+ into vascular smooth muscle cells.
This causes a reduction in intracellular Ca2+, which reduces Ca2+ binding to calmodulin - this normally initiates smooth muscle cell contraction.
This reduces contraction of the vascular smooth muscle cell, causing vasodilatation.

Calcium-channel blockers cause vasodilatation by causing relaxation of vascular smooth muscle cells

Peripheral arteries

Arterial vasodilatation reduces mean arterial pressure.

Coronary arteries

Vasodilatation of coronary arteries relieves vasospasm, which occurs in angina. Resolution of vasospasm reduces myocardial ischaemia (and therefore chest pain) by restoring coronary blood flow to the myocardium.

Vasospasm around an atherothrombotic plaque in the coronary artery causes ischaemic chest pain

CCBs vasodilate coronary arteries leading to restored coronary blood flow and relief of chest pain

Effect of calcium channel blockers on cardiac myocytes

Calcium channels found in cardiac muscle cells play an important role in determining the strength of contractility of the heart.

CCBs reduce influx of Ca2+ into the cardiac myocytes.
This reduces intracellular Ca2+, which reduces Ca2+ binding to troponin - this normally initiates cardiac muscle cell contraction.
This reduces cardiac muscle cell contraction, causing reduced heart contractility (AKA negative inotropy).

Calcium-channel blockers reduce contractility of cardiac myocytes leading to negative inotropy

Effect of calcium channel blockers on cardiac pacemaker cells

Pacemaker cell physiology

Pacemaker cells in the sino-atrial node spontaneously generate action potentials by the movements of Ca2+ through L-type channels.

The action potential is divided into 3 phases:

1st phase: Slow Na+ inflow (via 'funny' channels) and slow Ca2+ inflow (through T-type channels) begin DEPOLARISATION.
2nd phase: Slow Ca2+ inflow (via L-type channels) cause HYPERPOLARISATION.
3rd phase: Fast K+ outflow causes REPOLARISATION.

1st phase of cardiac pacemaker action potential

2nd and 3rd phase of cardiac pacemaker action potential

Effect of CCBs on pacemaker cells

CCBs slow the influx of Ca2+ through L-type channels in the 2nd phase.
At the SA node, this reduces heart rate (AKA negative chronotropy).
At the AV node, this reduces conduction velocity (AKA negative dromotropy).
If there are any aberrant pacemaker sites (e.g. in SVT), CCBs also reduce the firing rate in these pacemaker cells. This gives CCBs anti-arrhythmic properties.

Calcium channel blockers slow the 2nd phase of the cardiac pacemaker action potential (leading to negative chronotropy)

Classes of calcium channel blocker

Classes of CCB differ in their chemical structure AND more importantly, in their selectivity for cardiac vs. vascular calcium channels.

Dihydropyridines (the '-pine's)

Examples: Amlodipine, Felodipine, Nifedipine, Nimodipine (note: all of them end in '-pine'!)

Dihydropyridines (DHPs) are more selective for vascular calcium channels, meaning they cause vasodilation.

However this vasodilatation causes a reflex tachycardia - in response to hypotension the baroreceptors detect this and increase sympathetic drive which increases heart rate in order to maintain cardiac output. This increase in cardiac work increases the O2 demand of the myocardium and can exacerbate angina. To combat this, DHPs are sometimes given in slow-release form for the treatment of HTN, so not to cause a reflex tachycardia.

Dihydropyridines

Verapamil

Verapamil

Verapamil is more selective for cardiac calcium channels, meaning it has cardiac depressing effects, which include reducing heart rate (negative chronotropy), reducing heart contractility (negative inotropy) and reducing the speed of conduction in the heart (negative dromotropy). Verapamil is a less potent vasodilator than dihydropyridines due to its decreased selectivity for vascular calcium channels.

Diltiazem

Diltiazem is intermediate between dihydropyridines and verapimil in its calcium channel selectivity. Therefore, it has both vasodilating and cardiac depressing effects. Diltiazem can reduce blood pressure without producing the same degree of reflex tachycardia as dihydropyridines which is beneficial in managing hypertension in patients with angina.

Diltiazem

Table comparing the effects of the 3 classes of calcium channel blockers

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