Published on 07/02/2015 by admin
Filed under Anesthesiology
Last modified 07/02/2015
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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
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