Published on 07/02/2015 by admin
Filed under Anesthesiology
Last modified 22/04/2025
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Ian MacVeigh, MD
Calcium channel blockers (CCBs), also known as calcium entry blockers or calcium channel antagonists, are a heterogeneous group of drugs that selectively inhibit the influx of extracellular calcium through L-type voltage-gated calcium channels (VGCCs). This type of calcium channel plays an important role in signal transduction on excitable cells such as myocytes and neurons. For cells to use adenosine triphosphate as an energy source, the concentration of intracellular Ca2+ must be quite low, otherwise the Ca2+ would precipitate with phosphorus. When an action potential on the cell surface opens VGCCs, the flux of Ca2+ that passes into the cytoplasm is relatively large compared with the tiny amount of intracellular Ca2+; the electrical signal that depolarized the cell membrane is thereby converted to an ion-coded signal. The Ca2+ functions as a secondary messenger—its divalent charge is sufficient to produce conformational change in a number of cytoplasmic proteins, such as actin-myosin, for example. VGCCs close rapidly by a voltage-dependent mechanism, and the intracellular Ca2+ quickly dissipates, allowing for precise intracellular signaling. VGCCs require either a low voltage (T-type) or high voltage to open. High-voltage calcium channels are identified as N-type (present on neurons) or L-type (so named because when investigators studying VGCCs replaced Ca2+ with Ba2+ in organ baths, there was a large unitary conductance to Ba2+).
The currently available CCBs effectively inhibit the opening of L-type VGCCs, and, when inward flux of calcium is inhibited, contraction of smooth muscle cells in peripheral arterial blood vessels decreases, arteries vasodilate, systemic vascular resistance (SVR) decreases, and blood pressure falls. CCBs have no effect on venous blood vessels but are particularly effective in dilating larger more noncompliant arteries, one of the most common causes of systolic hypertension in elderly patients.
Inotropy also decreases because the amount of calcium available for each myocardial contraction is less. The combination of decreased SVR (afterload) and decreased inotropy optimizes myocardial O2 demand-supply, decreasing the incidence and severity of angina pectoris.
In addition, CCBs decrease electrical activity in the conducting system within the heart by inhibiting VGCCs during phase 0 of the slow-response sinoatrial and atrioventricular nodal cells and during phase 2 of the action potential of the fast-response Purkinje fibers, producing a negative chronotropic effect (i.e., decreased heart rate) and dromotropic effect (i.e., decreased conduction). The combination of effects is one of the reasons that CCBs are commonly used to treat atrial fibrillation and atrial flutter in patients for whom heart rate control is a primary goal.
The two main types of CCBs are the dihydropyridine (DHP) and the nondihydropyridine (N-DHP) compounds. The DHPs have a similar chemical structure and have similar pharmacologic effects, different from those that result from administration of the N-DHPs, partly explained by the fact that the two classes of drugs bind to different sites on the L-type VGCCs. There is some rationale, therefore, for using certain drugs (e.g., a DHP and an N-DHP [diltiazem]) in combination.
The DHPs have more vascular selectivity than do the N-DHPs, and because they have little chronotropic effect, a β-adrenergic receptor blocking agent is sometimes used to counteract the reflex tachycardia that can be seen when certain DHPs are administered. As a class, DHPs are not used to treat angina, with the exception of amlodipine, nicardipine, and nifedipine, which are approved to treat stable angina as well as angina caused by vasospasm in the coronary arteries.
The N-DHPs have chronotropic and dromotropic effects for the reasons described above. As a consequence, the N-DHPs increase the potential for heart block and should be used judiciously, if at all, in patients with cardiomyopathies. The N-DHP drugs have either a phenylalkylamine or a benzothiazepine chemical structure. Verapamil, the best-known phenylalkylamine, is relatively selective for the heart and, for the reasons mentioned earlier, reduces myocardial O2 demand and reverses coronary artery spasm; therefore, this drug is used to treat angina. Diltiazem, the best-known benzothiazepine, has cardiac effects that are somewhat similar to those of verapamil but are not as pronounced. Diltiazem has some effects on the peripheral vasculature, similar to those of the DHPs, reducing SVR but without producing the same degree of reflex tachycardia as is seen with the use of the DHPs.
Except for nimodipine, which is only approved to prevent or treat vasospasm associated with subarachnoid hemorrhage, all of the CCBs are approved to treat hypertension either by themselves or in combination with other drugs. CCBs have also been used (off label) to treat some of the sequelae of Raynaud syndrome, migraine and cluster headaches, high-altitude pulmonary edema, and hypertension associated with the use of nonsteroidal anti-inflammatory agents, cyclosporine, and other drugs. Some (see following discussion) have been approved to treat angina and others to treat atrial arrhythmias.
With the exception of sublingual nifedipine, these drugs have a long duration of action. Nifedipine, nicardipine, and felodipine have some negative inotropy, whereas amlodipine and lacidipine have no, or very little, cardiac-depressant activity.
The use of sublingual capsules of nifedipine has been associated with myocardial ischemia and death when given to patients with coronary artery disease. Because sublingual nifedipine may cause a rapid peripheral vasodilation that decreases blood pressure and myocardial O2 supply, along with a reflex tachycardia that results in an increased myocardial O2 demand, the U.S. Food and Drug Administration requires the labeling to include a warning against the use of sublingual nifedipine to treat hypertension. All other formulations of nifedipine are approved for the treatment of hypertension, effort angina, and vasospastic angina. These formulations have approximately 60% bioavailability, are 95% protein bound, have high first-pass hepatic metabolism by CYP-450 enzymes, and have a half-life of 2 to 5 h. Its metabolites are excreted by the kidneys and in feces. Because nifedipine is such a potent vasodilator, its use is contraindicated in patients with aortic stenosis, hypertrophic obstructive cardiomyopathy, and severe left ventricular dysfunction; the vasodilation results in its primary side effects: headaches and ankle edema.
Nicardipine is commonly administered intravenously to treat hypertension in patients in the operating room and intensive care unit. It is injected as a bolus of 0.625 to 2.5 mg followed by a continuous infusion of 0.5 to 5 mg/h. The advantages of nicardipine are its lack of effect on heart rate and preload and the fact that its use is not associated with rebound hypertension upon discontinuation.
Amlodipine has a slow onset of 1 to 2 h and a long duration of action, with an elimination half-life of 35 to 48 h. Its major clinical uses are for the treatment of hypertension and effort angina.
Nimodipine is the only CCB approved for preventing and for treating cerebral vasospasm after subarachnoid hemorrhage or after cerebral aneurysm clipping. This drug is usually administered as a 30-mg to 40-mg oral dose every 4 h.
Verapamil, a phenylalkylamine, is indicated to treat essential hypertension, effort-induced angina, vasospastic angina, and atrial arrhythmias, usually at an oral dose of 180 to 480 mg/day or as an intravenous bolus of 2.5 to 10 mg. When verapamil is administered orally, its bioavailability is only 10% to 20%, and it has a protein binding of approximately 90%. Similar to the other CCBs, it has high first-pass hepatic metabolism by P-450 CYP3A4, an active metabolite (norverapamil), and an elimination half-life of 3 to 7 h. Metabolites are excreted by the kidneys (75%) or in the gastrointestinal tract (25%). Because of its mechanism of action, the use of verapamil is contraindicated in patients with sick sinus syndrome, preexisting atrioventricular nodal disease, severe left ventricular myocardial depression, or digoxin toxicity. Patients with Wolff-Parkinson-White syndrome with concomitant atrial fibrillation are at risk of developing antegrade conduction through the bypass tract, manifested usually within a few minutes of administration as a wide-complex ventricular tachycardia that can rapidly deteriorate into ventricular fibrillation. Patients receiving β-adrenergic receptor blocking agents should not receive verapamil because these patients have a high risk of developing severe bradycardia. The side effects of verapamil include headache, facial flushing, dizziness, and constipation. Verapamil also interacts with several drugs, increasing blood levels of digoxin, atorvastatin, simvastatin, lovastatin, ketoconazole, cyclosporine, carbamazepine, and theophylline.
Verapamil toxicity can be treated with calcium administered intravenously either as the chloride salt or as calcium gluconate. Glucagon and levosimendan have also been successfully used to treat toxicity, as have isoproterenol and atropine. For patients with acute heart block that is unresponsive to pharmacologic therapy, temporary pacing should be considered. Because CCBs can block the effect of insulin, insulin supplementation may be required.
Diltiazem, a benzothiazepine, is often administered intravenously as a bolus dose of 0.25 mg/kg followed by a continuous infusion of 5 to 15 mg/min to treat acute supraventricular tachycardias and to decrease the ventricular response rate in atrial fibrillation or flutter. It is approximately 85% protein bound, metabolized in the liver to an active metabolite, desacetyl diltiazem; metabolites are 35% excreted in urine, with the remainder excreted in the gastrointestinal tract. Diltiazem has a low incidence of side effects, but the same care should be taken when this drug is administered to patients taking β-adrenergic receptor blocking agents, and it should be used with caution, if at all, in patients with cardiomyopathy or atrioventricular nodal disease.
Most of the toxicity associated with CCBs is mild and can be treated by discontinuing the drug. As mentioned earlier, severe toxicity can be treated with intravenous calcium, inotropes, isoproterenol, glucagon, or other drugs. Similar to the toxicity seen when verapamil is used in combination with a β-adrenergic receptor blocking agent, the side effects seen with the CCBs are agent specific. However, because these are all potent vasodilators, headache, lightheadedness or dizziness, flushing, and peripheral edema can be seen in 10% to 20% of patients. One of the adverse side effects of verapamil is constipation, reported in 25% of patients taking the drug. Interestingly, however, peripheral edema is less common with verapamil than it is with the other compounds. As mentioned previously, patients using a short-acting nifedipine are at increased risk of experiencing myocardial infarction and dying; therefore, this drug should not be used in patients with known coronary artery disease. In 1995, a report suggested that the use of even long-acting CCBs is associated with an increased risk of myocardial infarction; however, more recent studies have failed to confirm these findings. Other studies associating the use of CCBs with gastrointestinal bleeding and malignancy in the elderly have likewise been flawed. CCBs can be safely used for most patients with hypertension, angina, Raynaud syndrome, hypertension and asthma, or hypertension in patients that is not controlled with other medications.
Inhalation anesthetic agents decrease the availability of intracellular calcium, which, in turn, increases the negative inotropic, chronotropic, and dromotropic effects of CCBs. The inhibition of calcium influx into myocytes potentiates the effects of all neuromuscular blocking agents. There are reports of patients who were on verapamil preoperatively who developed cardiovascular collapse when they were given dantrolene intraoperatively for presumed malignant hyperthermia. CCBs have also been reported to impair hypoxic pulmonary vasoconstriction and, because of their vasodilating properties, to increase intracranial pressure.
Fausts Anesthesiology Review Expert Consult 4e
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