Mechanism of Action

1. Calcium channel blockers bind to receptors on voltage-gated calcium ion channels (L, long-lasting; N, neural; and T, transient opening subtypes) resulting in maintenance of these channels in an inactive (closed) state (Fig. 19-4). As a result, calcium influx is decreased and there is a reduction in intracellular calcium.

2. Blockade of slow calcium channels by calcium channel blockers predictably results in slowing of the heart rate, reduction in myocardial contractility, decreased speed of conduction of cardiac impulses through the atrioventricular node, and vascular smooth muscle relaxation.

Pharmacologic Effects (see Table 19-6)

Phenylalkylamines (Fig. 19-5)

Dihydropyridines prevent calcium entry into the vascular smooth cells by extracellular allosteric modulation of the L-type voltage-gated calcium ion channels (see Fig. 19-5).

1. Nifedipine is a dihydropyridine derivative with greater coronary and peripheral arterial vasodilator properties than verapamil. Unlike verapamil, nifedipine has little or no direct depressant effect on sinoatrial or atrioventricular node activity. Peripheral vasodilation and the resulting decrease in systemic blood pressure produced by nifedipine activates baroreceptors, leading to increased peripheral sympathetic nervous system activity most often manifesting as an increased heart rate. The presence of aortic stenosis may also exaggerate the cardiac depressant effects of nifedipine.

   1. Clinical Uses. Nifedipine is administered orally to treat patients with angina pectoris, especially that due to coronary artery vasospasm.

   2. Pharmacokinetics (see Table 19-7)

   3. Side effects of nifedipine include flushing, vertigo, and headache. Nifedipine may induce renal dysfunction. Abrupt discontinuation of nifedipine has been associated with coronary artery vasospasm.

2. Nicardipine lacks effects on the sinoatrial node and atrioventricular node and has minimal myocardial depressant effects. This drug has the greatest vasodilating effects of all the calcium entry blockers, with vasodilation being particularly prominent in the coronary arteries.

   1. Clinical Uses. Nicardipine is used as a tocolytic drug having a similar tocolytic effect as salbutamol but with fewer side effects.

3. Nimodipine is a highly lipid-soluble analogue of nifedipine (lipid solubility facilitates its entrance into the central nervous system).

   1. Clinical Uses. The lipid solubility of nimodipine and its ability to cross the blood-brain barrier is responsible for the potential value of this drug in treating patients with subarachnoid hemorrhage.

   2. Cerebral Vasospasm. The vasodilating effect of nimodipine on cerebral arteries is uniquely valuable in preventing or attenuating cerebral vasospasm that often accompanies subarachnoid hemorrhage.

4. Amlodipine has minimal detrimental effects on myocardial contractility and provides antiischemic effects comparable to blockers in patients with acute coronary syndrome.

Benzothiazepines

1. Diltiazem like verapamil, blocks predominantly the calcium channels of the atrioventricular node and is therefore a first-line medication for the treatment of supraventricular tachydysrhythmias. It may also be used for the chronic control of essential hypertension. Diltiazem exerts minimal cardiodepressant effects and is unlikely to interact with -adrenergic blocking drugs to decrease myocardial contractility.

Drug Interactions. Verapamil and diltiazem have depressant effects on the generation of cardiac action potentials at the sinoatrial node and slow the movement of cardiac impulses through the atrioventricular node (patients with preexisting cardiac conduction abnormalities may experience greater degrees of atrioventricular heart block with concurrent administration of blockers or digoxin). Treatment with calcium channel blockers can be continued until the time of surgery without risk of significant drug interactions, especially with respect to conduction of cardiac impulses. Toxicity reflecting an overdose of calcium channel blockers may be partially reversed with IV administration of calcium or dopamine.

1. Anesthetic Drugs

   1. Calcium channel blockers must be administered with caution to patients with impaired left ventricular function or hypovolemia.

   2. Treatment of cardiac dysrhythmias with calcium channel blockers in anesthetized patients produces only transient decreases in systemic blood pressure and infrequent prolongation of the P-R interval on the electrocardiogram.

   3. Because of the tendency to produce atrioventricular heart block, verapamil should be used cautiously in patients being treated with digitalis or -adrenergic blocking drugs (Table 19-8).

   4. There is no evidence that patients being treated chronically with calcium channel blockers are at increased risk for anesthesia.

2. Neuromuscular blocking drugs potentiate the effects of depolarizing and nondepolarizing neuromuscular blocking drugs. This potentiation resembles that produced by mycin antibiotics in the presence of neuromuscular blocking drugs.

   1. The neuromuscular effects of verapamil may be more likely to manifest in patients with a compromised margin of safety of neuromuscular transmission.

   2. Antagonism of neuromuscular blockade may be impaired because of diminished presynaptic release of acetylcholine in the presence of a calcium channel blocker.

3. Local Anesthetics. Verapamil and diltiazem have potent local anesthetic activity, which may increase the risk of local anesthetic toxicity when regional anesthesia is administered to patients being treated with this drug.

4. Potassium-Containing Solutions. Calcium channel blockers slow the inward movement of potassium ions such that hyperkalemia may occur after much smaller amounts of exogenous potassium infusion (potassium chloride to treat hypokalemia, administration of stored whole blood).

5. Dantrolene. Whenever calcium channel blockers, especially verapamil or diltiazem, and dantrolene must be administered concurrently, invasive hemodynamic monitoring and frequent measurement of the plasma potassium concentration are recommended.

Risks of Chronic Treatment. Despite the popularity of calcium channel blockers in the treatment of cardiovascular diseases (essential hypertension, angina pectoris), there is increasing concern about the long-term safety of these drugs, especially the short-acting dihydropyridine derivatives (risk of developing cardiovascular complications). Treatment with calcium channel blockers, especially short-acting dihydropyridine derivatives, should generally be reserved for second-step rather than initial therapy.

Cytoprotection

1. Drug-induced calcium channel blockade may provide cytoprotection against ischemic reperfusion injury by limiting the accumulation of oxygen free radicals.

2. Calcium channel blockers may attenuate renal injury from nephrotoxic drugs such as cisplatinum and iodinated radiographic contrast media.