Slow channel blockers

Systemic and coronary arteries are influenced by movement of calcium across cell membranes of vascular smooth muscle. The contractions of cardiac and vascular smooth muscle depend on movement of extracellular calcium ions into these walls through specific ion channels. Calcium channel blockers, such as amlodipine (Norvasc), diltiazem (Cardizem), nicardipine (Cardene), nifedipine (Procardia), and verapamil (Calan), inhibit die movement of calcium ions across cell membranes. This results in less calcium available for the transmission of nerve impulses (Fig. 41-1). This drug action of the calcium channel blockers (also known as slow channel blockers) has several effects on die heart, including an effect on die smooth muscle of arteries and arterioles. These drug dilate coronary arteries and arterioles, which in turn deliver more oxygen to cardiac muscle. Dilation of peripheral arteries reduces die workload of die heart. The end effect of these drug is the same as that of die nitrates. 

The concept of calcium antagonism as a specific mechanism of drug action was pioneered by Albrecht Fleckenstein and his colleagues, who observed that verapamil and subsequently other drugs of this class mimicked in reversible fashion the effects of Ca++ withdrawal on cardiac excitability. These drugs inhibited the Ca" + component of the ionic currents carried in the cardiac action potential. Because of this activity, these drugs are also referred to as slow channel blockers, calcium channel antagonists, and calcium entry blockers. 

Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). It has generally been indicated for the treatment of angina and, more recently (2), hypertension. Diltiazem hydrochloride is a potent dilator of coronary arteries and has been shown to increase exercise tolerance in man. It is available for dosing as immediate release tablets and as extended or sustained release capsules and is usually well-tolerated. While some adverse reactions have been reported during diltiazem hydrochloride therapy, it is generally considered to be well-tolerated. In most cases, no causal relationship between the events and diltiazem hydrochloride use has yet to be established (1). 

Calcium antagonists (slow channel blockers, slow Ca2+ antagonists) are a heterogeneous group of substances with widely differing tissue specificities, potency and properties. Some of them exhibit other properties in addition to that of Ca + antagonism. 

Why the various organic inhibitors differ with respect to their preferred site of action is unknown. Is it because of their different chemical structure Or are the slow Ca + channels themselves tissue specific Some substances - eg. pentobarbitone and adenosine, which are relatively weak slow channel blockers do not display tissue specificity with respect to their Ca2+ antagonism. Indeed in these substances it is questionable... 

Theoretically it should be possible to classify the slow channel blockers according to whether or not they affect the kinetics of slow channel transport. In this way we could readily separate the nifedipine type of drugs from those that are more like verapamil. Alternatively can these drugs be subgrouped according to their chemistry This possibility seems to be remote. Thus diltiazem is a benzothiazepine derivative (Figure 1 nifedipine is derived from dihydropyridine whilst verapamil has some structural features in common with papaverine. 

As far as the circulation is concerned, however, these other properties of the slow channel blockers are probably insignificant when compared with their inhibitory effect on slow channel and possibly on calmodulin-Ca + binding activity. 

Calcium-entry blockers include those agents that are selective for slow calcium channels in the myocardium (slow-channel blockers), and consist of the following categories of substances ... 

Calcium-entry blockers include those agents that are selective for slow calcium channels in the myocardium (slow channel blockers) and consist of the following categories of substances benzothiazepines (diltiazem and dihydropy-ridines)—nifedipine, nicardipine, niludipine, nimodipine, nisoldipine, nitrendipine, ryosidine, amlodipine, azodipine, dazodipine, felodipine, flordipine, iodipine, isradipine, mesu-dipine, oxodipine, and riodipine and, phenylalkylamines— verapamil, gallopamil, anipamil, desmethoxyverapamil, emopamil, falipamil, and ronipamil. 

Known as calcium channel blockers or slow channel blockers. Examples ... 

The electrophysiological effects of amiodarone may be a composite of several properties. In addition to prolonging action potential duration and refractory period in ad tissues of the heart, the compound is an effective sodium channel blocker (49), calcium channel blocker (50), and a weak noncompetitive -adrenoceptor blocking agent (51). Amiodarone slows the sinus rate, markedly prolongs the QT interval, and slightly prolongs the QRS duration (1,2). 

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

Verapamil (Table 1), the first slow channel calcium blocker synthesized to selectively inhibit the transmembrane influx of calcium ions into cells, lowers blood pressure in hypertensive patients having good organ perfusion particularly with increased renal blood flow. Sustained-release verapamil for once a day dosing is available for the treatment of hypertension. Constipation is a prominent side effect. Headache, dizziness, and edema are frequent and verapamil can sometimes cause AV conduction disturbances and AV block. Verapamil should not be used in combination with -adrenoceptor blockers because of the synergistic negative effects on heart rate and contractile force. 

Class IV antiarrhythmic drugs are Ca2+ channel blockers, which predominantly slow sinus rate and atrioventricular conduction and thus are used in the treatment of supraventricular tachyarrhythmias. These drugs exert a pronounced negative inotropic effect. 

Channel blockers are often classified as slow, intermediate, or fast blockers, based on the very wide range of values that have been found for the microscopic dissociation rate constant of different... 

Verapamil (Class IV antiarrhythmic drug) is an effective agent for atrial or supraventricular tachycardia. A Ca++ channel blocker, it is most potent in tissues where the action potentials depend on calcium currents, including slow-response tissues such as the SA node and the AV node. The effects of verapamil include a decrease in heart rate and in conduction velocity of the electrical impulse through the AV node. The resulting increase in duration of the AV nodal delay, which is illustrated by a lengthening of the PR segment in the ECG, reduces the number of impulses permitted to penetrate to the ventricles to cause contraction. 

The answer is d. (Hardman, pp 767—775.) Ca channel blockers, of which nifedipine is a prime example, are now considered to be more effective than nitrates in relieving variant angina This is because this type of angina is believed to be caused by vasospasm, which is best antagonized by slow-channel Ca blockers. Such blockers appear to have a relative selectivity for coronary arteries. 

L The answer is d. (Hardman, p 906.) Cimetidine slows the metabolism of Ca channel blockers, which are substrates for hepatic mixed-function oxidases. Inhibition of cytochrome P450 activity is peculiar to cimetidine and is not a mechanism of action of other histamine 2 (Hz) blockers. 

Slow-channel syndrome. Abnormally long-lived openings of mutant AChR channels result in prolonged endplate currents and potentials, which in turn elicit one or more repetitive muscle action potentials of lower amplitude that decrement. The morphologic consequences stem from prolonged activation of the AChR channel that causes cationic overload of the postsynaptic region - the endplate myopathy - with Ca2+ accumulation, destruction of the junctional folds, nuclear apoptosis, and vacuolar degeneration of the terminal. Some slow-channel mutations in the transmembrane domain of the AChR render the channel leaky by stabilization of the open state, which is populated even in the absence of ACh. Curiously, some slow-channel mutants can be opened by choline even at the concentrations that are normally present in serum. Quinidine, an open-channel blocker of the AchR, is used for therapy. 

Some idea of the rate of absorption can be obtained from examination of the plasma concentration-time profile. It should be remembered, however, that the time to maximum plasma concentration Y ) is not when absorption is complete but when the rates of drug absorption and elimination are equal. Thus two drugs with the same absorption rate will differ in /max if elimination rates differ. Assessment of the rate of absorption can also be confounded by complex or slow drug distribution. For example, the calcium-channel blocker amlodipine has a much later /max than other similar drugs. This is not due to slow absorption but to partitioning in the liver membrane with slow redistribution. A quantitative assessment of the rate of absorption can be obtained by deconvolution of plasma profiles following IV and oral administration. 

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