cardio vascular system 2

Calcium Channel Blockers Calcium channel blockers reduce myocardial oxygen demands by depression of contractility, HR, and/or decreased arterial BP.7 Myocardial oxygen supply may be improved by dilation of coronary and collateral vessels. Calcium channel blockers are used primarily for symptom control in patients with stable angina pectoris. In an acute ischemic situation, calcium channel blockers (verapamil and diltiazem) may be used for rate control in situations when β-blockers cannot be used. The most important effects of calcium channel blockers, however, may be the treatment of variant angina. These drugs can attenuate ergonovineinduced coronary vasoconstriction in patients with variant angina, suggesting protection via coronary dilation

. Most episodes of silent myocardial ischemia, which may account for 70% of all transient ischemic episodes, are not related to increases in myocardial oxygen demands (HR and BP) but, rather, intermittent obstruction of coronary flow likely caused by coronary vasoconstriction or spasm. All calcium channel blockers are effective at reversing coronary spasm, reducing ischemic episodes, and reducing NTG consumption in patients with variant or Prinzmetal’s angina. Combinations of NTG and calcium channel blockers, which also effectively relieve and possibly prevent coronary spasm, are at present rational therapy for variant angina. β-Blockers may aggravate anginal episodes in some patients with vasospastic angina and should be used with caution. Preservation of CBF with calcium channel blockers is a significant difference from the predominant β-blocker anti-ischemic effects of reducing myocardial oxygen consumption. Calcium channel blockers have proven effective in controlled trials of stable angina. However, rapid-acting dihydropyridines such as nifedipine may cause a reflex tachycardia, especially during initial therapy, and exacerbate anginalsymptoms. Such proischemic effects probably explain why the short-acting dihydropyridine

 nifedipine in high doses produced adverse effects in patients with unstable angina. The introduction of long-acting dihydropyridines such as extended-release nifedipine, amlodipine, felodipine, isradipine, nicardipine, and nisoldipine has led to fewer adverse events. These agents should be used in combination with β-blockers. Some patients may have symptomatic relief improved more with calcium channel blockers than with β-blocker therapy. Calcium Channels Calcium channels are functional pores in membranes through which calcium flows down an electrochemical gradient when the channels are open. Calcium channels exist in cardiac muscle, smooth muscle, and probably many other cellular membranes. These channels are also present in cellular organelle membranes such as the sarcoplasmic reticulum and mitochondria. Calcium functions as a primary generator of the cardiac action potential and an intracellular second messenger to regulate various intracellular events. Calcium enters cellular membranes through voltage-dependent channels orreceptoroperated channels. The voltage-dependent channels depend on a trans­membrane potential for activation (opening). Receptor-operated channels either are linked to a voltage-dependent channel after receptor stimulation or directly allow calcium passage through cell or organelle membranes independent of transmembrane potentials. There are three types of voltage-dependent channels: the T (transient), L (longlasting), and N (neuronal) channels. The T and L channels are located in cardiac and smooth muscle tissue, whereas the N channels are located only in neural tissue. The T channel is activated at low voltages (−50 mV) in cardiac tissue, plays a major role in cardiac depolarization (phase 0), and is not blocked by calcium antagonists. The L channels are the classic “slow” channels, are activated at higher voltages (−30 mV), and are responsible for phase 2 of the cardiac action potential. These channels are blocked by calcium antagonists.

 Calcium channel blockers interact with the L-type calcium channel and are composed of drugs from four different classes: (1) the 1,4-dihydropyridine (DHP) derivatives (nifedipine, nimodipine, nicardipine, isradipine, amlodipine, and felodipine); (2) the phenylalkyl amines (verapamil); (3) the benzothiazepines (diltiazem); and (4) a diarylaminopropylamine ether (bepridil). The L-type calcium channel has specific receptors, which bind to each of the different chemical classes of calcium channel blockers. Physiologic Effects hemodynamic effects Systemic hemodynamic effects of calcium channel blockers represent a complex interaction among myocardial depression, vasodilation, and reflex activation of the autonomic nervous system

Nifedipine, like all dihydropyridines, is a potent arterial dilator with few venodilating effects. Reflex activation of the sympathetic nervous system may increase HR. The intrinsic negative inotropic effect of nifedipine is offset by potent arterial dilation, which results in lowering of BP and increase in CO in patients. Dihydropyridines are excellent antihypertensive agents, owing to their arterial vasodilatory effects. Antianginal effects result from reduced myocardial oxygen requirements secondary to the afterload-reducing effect and to coronary vascular dilation resulting in improved myocardial oxygen delivery. Verapamil is a less potent arterial dilator than the dihydropyridines and results in less reflex sympathetic activation. In vivo, verapamil generally results in

 moderate vasodilation without significant change in HR, CO, or SV. Verapamil can significantly depress myocardial function in patients with preexisting ventricular dysfunction. Diltiazem is a less potent vasodilator and has fewer negative inotropic effects compared with verapamil. Studies in patients reveal reductions in SVR and BP, with increases in CO, pulmonary artery wedge pressure, and ejection fraction. Diltiazem attenuates baroreflex increases in HR secondary to NTG and decreases in HR secondary to phenylephrine. Regional blood flow to the brain and kidney increases, whereas skeletal muscle flow does not change. In contrast to verapamil, diltiazem is not as likely to aggravate congestive heart failure, although it should be used carefully in these patients. Coronary Blood Flow Coronary artery dilation occurs with the calcium channel blockers with increases in total CBF. Nifedipine is the most potent coronary vasodilator, especially in epicardial vessels, which are prone to coronary vasospasm. Diltiazem is effective in blocking coronary artery vasoconstriction caused by a variety of agents, including α-agonists, serotonin, prostaglandin, and acetylcholine. Electrophysiologic Effects Calcium channel blockers exert their primary electrophysiologic effects on tissue of the conducting system that is dependent on calcium for generation of the action potential, primarily at the sinoatrial (SA) and atrioventricular (AV) nodes. They do not alter the effective refractory period of atrial, ventricular, or His-Purkinje tissue. Diltiazem and verapamil exert these electrophysiologic effects in vivo and in vitro, whereas the electrophysiologic depression of the dihydropyridines (nifedipine) is completely attenuated by reflex sympathetic activation. Nifedipine actually can enhance SA and AV node conduction, whereas verapamil and diltiazem slow conduction velocity and prolong refractoriness of nodal tissue.