20. Calcium channel blockers

Calcium channels

Many types of calcium channels exist: voltage-gated (L, N, T and R types), ligand gated (IP3 receptor, ryanodine receptor) and store-operated types. However, only the voltage-gated L-type channels are important therapeutically. When we talk about calcium channel blockers we mean those drugs that inhibit the action of L-type calcium channels.

L-type calcium channels are voltage-gated channels that are found on the cardiac pacemakers, smooth (vascular) muscle and cardiac muscle. This channel is the main source of Ca2+ needed for contraction in these types of muscle. The action potential arrives, the membrane is depolarized, the channels open and Ca2+ flows into the cell which causes the contraction.

The channels have 5 subunits: α1, α2, β, γ and δ.

Calcium channel blockers

Also called calcium antagonists or calcium entry blockers, calcium channel blockers (CCBs) bind to a binding site on the α1 subunit. This messes with the “gating” machinery, which reduces the channel’s ability to open correctly.

Three types exist:

• Phenylkylamines like verapamil
• Benzothiazepines like diltiazem
• Dihydropyridines (DHPs) like nifedipine

Verapamil and diltiazem work on both cardiac and vascular muscle, while DHPs work mostly on vascular muscle. Therefore do all three drugs have similar vascular effects, while only verapamil and diltiazem have significant cardiac effects, so we’ll talk about them together.

Vascular effects

All three drug types produce vascular effects.

By inhibiting contraction in vascular smooth muscle these drugs cause vasodilation with resulting decrease in peripheral resistance. The coronaries are also vasodilated.

The vasodilatory effect of these drugs may activate the baroreflex, which causes increased sympathetic tone and tachycardia. This occurs mostly in fast-acting DHPs, like nifedipine. The sympathetic activation of the heart in patients taking verapamil is completely counteracted by the effects of verapamil. Therefore will verapamil cause bradycardia while diltiazem produces no net change in heart rate.

Cardiac effects

Verapamil and diltiazem prevent calcium from entering through L-type channels in the SA node, the AV node and the myocardial fibres, causing negative heart effects:

• Negative chronotropic effect – decreased heart rate
• Negative inotropic effect – decreased contractility
• Negative dromotropic effect – decreased conduction velocity
• Negative bathmotropic effect – decreased excitability

There are also the indirect positive heart effects due to the baroreflex.

Verapamil and diltiazem

These drugs have both vascular and cardiac effects. Verapamil has stronger cardiac effects than diltiazem.

Indications

Angina pectoris, supraventricular arrythmias (Afib, SVT), hypertrophic cardiomyopathy, hypertension.

Mechanism of action

These drugs inhibit calcium channels in vascular smooth muscle and cardiac muscle. This vasodilates the coronaies, which gives more blood to the myocardium. Thanks to the negative chronotropic and inotropic effects, O2 demand of the myocardium decreases.

Contraindications

Their use in patients with heart failure is not recommended, as the negative inotropic effect may worsen it.

They’re also contraindicated in patients with pre-existing cardiac conduction disorders like bradycardia, sick sinus syndrome and AV-block due to the negative heart effects. They are also contraindicated in hypotension due to vasodilatory effects and cardiac depression.

Pharmacokinetics

They have good oral absorption but significant first-pass effect. The administered dose should therefore be reduced in liver failure. They have extensive plasma protein binding and a Vd > 1L/kg, meaning that they accumulate in tissues. They’re eliminated by biotransformation by CYP3A4 and CYP1A2 and can be given orally or IV.

Interactions

They should not be combined with other drugs that give negative heart effects, like beta blockers or digitalis drugs. Verapamil even decreases renal elimination of digoxin, so using those two together would be especially bad.

Side effects

• Negative heart effects
• Constipation

Dihydropyridines

DHPs are classified according to their duration of action:

• Short-and-rapidly acting
  • Nifedipine
  • Nimodipine
  • Nicardipine
• Intermediate-acting
  • Nitredipine
  • Isradipine
• Long-and-slowly acting
  • Amlodipine
  • Lacidipine

These drugs have no cardiac effects in therapeutic dose, only vascular effects. They may cause reflex positive heart effects due to the baroreflex, however this problem doesn’t occur with slower acting DHPs.

Because they have no negative heart effects they can be given with beta blockers.

Indications

Hypertension, angina pectoris and vasospastic diseases. Only slow-acting drugs should be used for angina pectoris to prevent reflex tachycardia.

Nicardipine can be administered IV for hypertensive emergencies.

Nimodipine prevents vasospasm following subarachnoid hemorrhage.

Pharmacokinetics

DHPs have good oral absorption but extensive first-pass effect. They have extensive plasma protein binding and accumulate in tissues (Vd > 1L/kg), are eliminated by biotransformation by CYP3A4 and can be given orally. One type can be given IV as well.

Contraindications

They’re contraindicated in unstable angina and acute myocardial infarction, due to the reflex tachycardia, which may increase the O2 demand of the myocardium.

Side effects

• Peripheral oedema
• Flushing
• Gingival hyperplasia

The short-and-rapidly acting DHPs strongly evoke the baroreflex, causing a strong reflex sympathetic activation. Giving them with beta blockers can prevent the baroreflex-mediated positive heart effects.

The slowly-and-long acting DHPs cause minimal reflex sympathetic activation.