Calcium ion channel blocker

Tisa, L.S., Olivera, B.M. and Adler, J. (1993). Inhibition ofEscherichia coli chemotaxis by (o-conotoxin, a calcium ion channel blocker. / Bacterial. 175, 1235-1238. 

Hansson, K., Ma, X., Eliasson, L., Czerwiec, E., Furie, B., Furie, B.C., Rorsman, P., and Stenflo, J. (2004) The first y-carboxyglutamic acid-containing contryphan - A selective L-type calcium ion channel blocker isolated from the venom of Conus marmoreus. J. Biol. Chem., 279,32453-32463. 

These effects explain how blockers of the p-adrenergic receptors, or blockers of the calcium ion channels in the heart, decrease the force of contraction of the heart and therefore lower blood pressure. 

Tutdibi, O., Brinkmeier, H., Rudel, R., and Fohr, K.J., 1999, Increased calcium entry into dystrophin-deficient muscle fibres of MDX and ADR-MDX mice is reduced by ion channel blockers, J Physiol, 515 ( Pt 3), pp 859-868. 

Similarly, hypothermia has known effects on cardiac rhythm, electrolyte balance, and metabolism, all of which could be enhanced when combined with pharmaceutical agents such as calcium or other ion channel blockers. Thus, as with all possible treatments, there is the potential not only for improvement, but also significant harm if an inappropriate combination is employed. 

Class I calcium channel blockers work preferentially on calcium ion channels in cardiac muscle cells. This results in a delay in electrical conduction in cardiac muscle, reduced contractility and reduction in the heart rate. Because of these effects, class I calcium channel blockers are used to treat ischaemic heart disease and atrial arrhythmia. An example is verapamil. 

Class III calcium channel blockers are intermediate in action affecting calcium ion channels in both cardiac muscle cells and smooth muscle cells in blood vessels. The effect of this is to combine a reduction in heart rate with a fall in blood pressure and they are useful in treating angina and hypertension. An example is diltiazem. 

Calcium channel blockers, also known as calcium antagonists, are a class of hypertension drugs that inhibit the influx of calcium ions through the cell membrane. A decrease in calcium ions results in less contraction of the cardiac and vascular muscles. There is an increase in the diameter of the arteries. This vasodilatation results in a lowering of the blood pressure. Despite their name, calcium channel blockers do not plug the hole and physically block the calcium ion channel. Rather, they bind to specific receptor sites [30]. Examples of calcium channel blockers are nifedipine (Procardia , Pfizer), nicardipine hydrochloride, amlodipine besylate sulfonate (Norvasc , Pfizer) and verapamil hydrochloride (Calan , Pfizer). Verapamil has a chiral carbon but is administered as a racemic mixture. 

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. 

The so-called calcium channel blockers constitute a class of cardiovascular agents that have gained prominence in the past few years. These drugs, which obtund contraction of arterial vessels by preventing the movement of calcium ions needed for those contractions, have proved especially useful in the treatment of angina and hypertension. Dihydropyridines such as nifedipine (30) are par-... 

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. 

FIGURE 41 -1. Calcium channel blockers inhibit the movement of caldum ions across the cell membrane. When calcium channels are blocked by drug molecules, musde contraction is decreased, causing the smooth musdes of the arteries and arterioles to dilate. 

One source of calcium ions, which cause contraction of smooth muscle in arterial walls, is inflow through ion-specific channels. So, the calcium blockers block the channels, limiting inflow of calcium and keeping muscle cells in relaxed states for a longer time. 

Calcium Channel Blockers. The calcium channel blockers work by blocking the influx of calcium, an excitatory ion, into the cell. The first calcium channel blocker, verapamil (Calan), was introduced in the 1960s. Others, including diltiazem, nifedipine, and nimodipine, are now available. The calcium channel blockers have been used to treat a variety of medical conditions including high blood pressure, cardiac pain (angina) and arrhythmias, migraines, seizure disorders, and premature labor. 

Nifedipine is a calcium-channel blocker of the dihydropyridine group. It relaxes smooth muscle and dilates both coronary and peripheral arteries by interfering with the inward displacement of calcium-channel ions through the active cell membrane. Unlike verapamil, nifedipine can be given with beta-blockers. Long-acting formulations of nifedipine are preferred in the long-term treatment of hypertension. 

Calcium-channel blockers interfere with the inward movement of calcium ions through the cell membrane channels. This results in reduction of myocardial contractility (hence negative inotropes), reduction of cardiac output and arteriolar vasodilatation. The dihydropyridine group, such as nifedipine and amlodipine, which may be used in the management of hypertension, are very effective as arterial vasodilators, whereas diltiazem and verapamil are very effective in reducing atrioventricular conduction. 

Amlodipine is a calcium-channel blocker that blocks the intracellular movement of calcium ions and hence slows the contractility of the myocardium and relaxes the vascular smooth muscle. The negative inotropic effects are rarely seen at therapeutic doses since amlodipine has a greater selectivity for vascular smooth muscle than for the myocardium. 

Drugs of this group are calcium channel blockers that inhibit slow transmembrane calcium ion flow in the cell of the conductive system of the heart during depolarization, which causes a slowing of atrioventricular conductivity and increased effective refractive period of atrioventricular ganglia, which eventually leads to the relaxation of smooth muscle of heart musculature and restores normal sinus rhythm during supraventricular tachycardias. 

This can be accomplished either by reducing the load on the heart, or by lowering systemic venous and arterial pressure (nitrates and nitrites), or by partial suppression of adrenergic innervation of the heart (j3-adrenoreceptors), or by suppressing calcium ion transport in myocardial cells since the contraction of smooth muscles vessels is controlled by the concentration of calcinm ions in the cytoplasm (Ca channel blockers). The resulting effect of the aforementioned drngs is that they reduce the need for oxygen in the heart. 

These drugs were developed as coronary vasodilating agents and were used for that purpose for some time, until it was discovered that they inhibit the contractile effect of calcium on smooth musculature and cardiac muscle, and that they affect calcium channels on the cell surface that permit calcium ions to enter. At first, they were called calcium antagonists however, later on this class of compounds was given the preferred name of calcium channel blockers. 

It is now obvious that the contraction of smooth muscle is controlled by the concentration of calcium in the cytoplasm. A basic principle of calcium-channel blocker action is that they disturb diffusion of calcium into muscle cells of the heart and vessels. Reduction of calcium ions entering the cells of the myocardium leads to a reduced use of the energy of phosphate bonds for mechanical heart work. As a result, strength of cardiac contractions and heart work are reduced, which in turn leads to a reduction in the heart s need of oxygen. 

In addition to being used as antianginal and antiarrhythmic agents, calcium channel blockers are used to treat weak and moderate hypertension. These drugs prevent calcium ions from entering into the smooth muscle cells of peripheral vessels, and they cause relaxation of peripheral vessels, which leads to lowering of arterial blood pressure. In clinically used doses, calcium channel blockers relax smooth musculature of arteries and have little effect on veins. In doses that relax smooth musculature, calcium channel blockers have relatively little effect on cardiac contractility. 

Pharmacology The calcium channel blockers share the ability to inhibit movement of calcium ions across the cell membrane. The effects on the cardiovascular system include depression of mechanical contraction of myocardial and smooth muscle and depression of both impulse formation (automaticity) and conduction velocity. 

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. 

---