Calcium compounds Verapamil

An isolated report describes antagonism of the antiarrhythmic effects of oral verapamil due to the use of oral calcium and calcifer-oL Note that intravenous calcium compounds may be used prior to intravenous verapamil where the hypotensive effects of verapamil would be detrimental. 

An elderly woman with atrial fibrillation, successfully treated for over a year with verapamil, developed atrial fibrillation within a week of starting to take an oral calcium compound 1.2 g with calciferol (vitamin D) 3000 units daily for difluse osteoporosis. Her serum calcium levels had risen from 2.45 to 2.7 mmol/L. Normal sinus rhythm was restored by giving 500 mL of saline and repeated doses of furosemide 20 mg and verapamil 5 mg by intravenous injection. ... 

Note that intravenous calcium compounds are sometimes given prior to intravenous verapamil for the treatment of ventricular arrhythmias to prevent verapamil-induced hypotension in situations where a reduction in blood pressure could be detrimental. This use does not affect the antiarrhythmic efficacy. Calcium, usually in the form of intravenous calcium gluconate, is used as an antidote in cases of overdose of calcium-channel blockers. 

Despite the growth in interest in calcium blockers, there are comparatively few calcium channel blocking agents currently in clinical use. These drugs are characterised by the fact that they belong to classes of compounds which are chemically unrelated like Diltiazem , Nifedipine , Verapamil , Fluspirilene and some others (Scheme 1). 

An additional example of a bioavailability-predicted absorption plot is shown for a series of calcium antagonists (Fig. 19.8). Again there is considerable scatter in the data, and the four compounds - felodipine, nisoldipine, diltiazem, and verapamil -are predicted to be much better absorbed than was actually observed. Some of these compounds are known to undergo rapid first-pass metabolic clearance, and are also P-gp inhibitors or substrates (diltiazem and felodipine are P-gp substrates nicardipine and nitrendipine are P-gp inhibitors [25] verapamil is a P-gp inhibitor), and this might contribute to the scatter obtained in the graph. 

Chemically, calcium channel blockers are synthesized up of a fairly diverse group of compounds, which testifies of the diverse receptive regions both on the cell membrane surface as well as within the cell. Verapamil, which can be viewed as a benzylcyanide derivative, is one of the oldest and most actively used compounds of this class up to the present day. Diltiazem is a thiodiazepine, while nifedipin and nicardipine are derivatives of dihydropyridine. 

However, the reverse is not necessarily true all compounds that block the hERG channels do not prolong action potentials. Part of the reason lies in the fact that many compounds have a mixed effect on ion channels, particularly due to the blocking effect on both hERG and the L-type calcium channel [21], which is responsible for phase 2 of the cardiac action potential (Figure 16.1). Examples for such dual-blockers include bepridil, verapamil and mibefradil [22], all blocking hERG and L-type calcium channels at the therapeutic concentrations. However, only verapamil has nearly no cardiac liabilities. 

Mibefradil is a verapamil-like agent with a potentially attractive haemodynamic profile. It is a vasodilator, which also causes a reduction in heart rate, whereas it is devoid of negative inotropic activity. Some of its properties are attributed to its influence of calcium channels of the T- and N-types. Unfortunately, the compound has been withdrawn because of multiple interactions with various other drugs. 

The class IV-antiarrhythmics are the calcium antagonists, but remain limited to verapamil and possibly also diltiazem. The dihydropyridines (nifedipine and related compounds) are unsuitable for antiarrhythmic therapy. The antiarrhythmic activity of verapamil and diltiazem is based upon the impairment of AV conduction and heart rate. A few compounds may be considered to act as antiarrhyth-mics, but they are not included in the Vaughan-Williams classification. 

The effects of the prototypical calcium channel blockers are seen most prominently in the cardiovascular system (Table 19.1), although calcium channels are widely distributed among excitable cells. The following calcium channel-blocking drugs are clinically the most widely used compounds in this very extensive class of pharmacological agents amlodipine, diltiazem, isradipine, nifedipine, nicardipine, nimodipine, and verapamil. 

The studied molecules include such diverse compounds as volatile anesthetics (halothane), local anesthetics of the cocaine type, calcium channel-blocking agents such as verapamil, antidepressants (chlorpromazine), and anti cancer drugs such as adriamycin. It is argued that the factor of interest to the physiological effect may not... 

During the last decades several drugs and compounds have been identified that to different degrees are able to overcome MDR so that the cells resemble sensitive cells in their chemosensitivity. These drugs mainly include catamphiphilic, membrane-active compounds and belong to various classes of drugs such as calcium channel blockers (verapamil), neuroleptics (flupentixol), anesthetics, antimalarial drugs (quinidine), antiarrhythmics (amiodarone), and many other compounds. Reviews were recently published [61, 157]. 

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