Role of calcium and calcium channel have been reveled since decade for its importance in cardiac physiology. Ca++ is been found as most important contractile ion aiming at key role in cardiac function. Changes in intracellular Ca++ regulate contraction through different mechanisms in cardiac and smooth muscle. In cardiac muscle, Ca++ binding to troponin C relieves troponin inhibition of actin-myosin interactions. In smooth muscle, Ca++ binding to calmodulin activates myosin light chain kinase which in turn phosphorylates the P-light chain of myosin. This triggers contraction (i.e.- actin-myosin interactions), but there appear to be additional Ca++ regulatory mechanisms. There are a variety of ion pumps, channels, and exchangers that are directly involved in controlling intracellular Ca++, thus many possible sites for therapeutic agents to act. Through this basic physiology and its role in cardiac related diseases, various agents specifically termed as calcium channel blockers have been designed for therapeutic use.
In classifying agents that inhibit the movement and binding of calcium, the World Health Organization has identified two types of calcium channel blocker that are used in clinical situations: those that are selective for L-type (long-lasting, large-current, or slow), voltage-dependent calcium channels, and those that are nonselective. Each of the three types of selective calcium channel blocker interacts with a specific receptor domain found on a large (about 165 kD) membrane-spanning protein that constitutes a substantial portion of the L-type, voltage-dependent calcium channel. These receptor sites are all located on the alpha1 subunit of the channel. Binding sites for all three types of calcium channel blocker are found in a variety of tissues, including myocardium, smooth muscle, skeletal muscle, and glandular tissue. Yet this range of target tissues is not necessarily reflected in pharmacologic or therapeutic activity.
History of CCB:
1962 - Verapamil reported to possess negative inotropic & chronotropic effects not seen with other vasodilatory agents such as nitroglycerin (Hass & Hartfelder)
1967 - Fleckenstein et al. suggest that verapamil's negative inotropic effect involved reduction of Ca++ movement into cardiac myocytes
1972 - Kohlhardt et al. show that D600, a verapamil derivative, blocks Ca++ flux through the slow channel
1987 - Sales of calcium channel blockers in U.S. approx. $700 million
1992 - Sales of calcium channel blockers in U.S. approx. $3 billion
1992-1993 - Nifedipine (Procardia), diltiazem (Cardizem), and verapamil (Calan) were among the top 20 most widely sold name brand drugs.
Conventional Therapeutic Uses of CCB
The primary indications for the Ca++-channel blockers are angina, arrhythmias, and hypertension.
i) Angina: CCB are effective in treating variant angina due to their effects on coronary dilatation rather than alterations in peripheral hemodynamics. Ca++ channel blockers (especially verapamil) may be particularly effective if underlying mechanism involves vasospasm.
ii) Arrhythmias: I.v. verapamil (followed by oral administration) is a drug of choice for interrupting and controlling paroxysysmal supraventricular tachycardias (i.e. -- originating from ectopic foci in atrial or junctional tissue. Verapamil (i.v.) is useful in the immediate reduction of ventricular response in response to atrial fibrillation and flutter (except when associated with Wolff-Parkinson-White syndrome, a conduction abnormality)
iii) Hypertension: The calcium channel blockers are generally safe and are as effective as beta-adrenergic blockers or diuretics in the treatment of mild to moderate hypertension
CCB are especially effective in treating low-renin hypertension (common in blacks and the elderly) CCB are well-tolerated; minor side-effects include dizziness, headache, flushing, and edema and are most usually associated with the dihydropyridines.
Recent developments in the clinical use of the CCB
The CCB were specifically designed for the treatment of cardiac diseases with the virtue of the role of calcium in the excitation of the cardiac muscles. But, in the recent years, the medical science has explored the rational clinical benefit of these class of drugs for prevention, mitigation or treatment of diseases of wide origin. This article aims to overview the recent developments in the new therapeutic possibilities of the CCB.
1) Novel Approaches to Pain Control:
A calcium channel blocker, verapamil closes the passageways through which calcium enters and exits cells. Manipulating calcium channels with medications can serve a variety of therapeutic purposes. Physicians often prescribe verapamil and other calcium channel blockers to treat high blood pressure, irregular heartbeat, and chest pain caused by heart disease. In animal experiments, calcium channel blockers also have been shown to increase the pain-relieving effect of morphine In their study, which was the first demonstration of this effect in humans, Dr. Vaupel and his colleagues found that individuals who received a combination of morphine and verapamil had a higher pain threshold than individuals who received only morphine. Another potential therapeutic application of the verapamil-morphine combination could be to control pain in patients who do not respond to opiates alone. Such patients might respond to the enhanced analgesia promoted by verapamil. This effect also could help reduce the dependence liability of analgesic or pain-relieving doses of morphine.
2) New Perspectives in Glaucoma:
The last 30 years many publications have attested that (a) ocular blood flow is compromised by glaucoma; (b) the insult responsible can be vasospastic, and therefore reversible and (c) the extent of vasospasm can be correlated with degree of visual defect. It is irrelevant whether ischemia is the primary insult or a result of increased pressure, since improvement of circulation by treatment with vasodilators such as calcium channel blockers has been shown to benefit glaucoma patients.
3) Role in treatment of Migraine headaches:
The first documented records of migraines originate from 3,000 B.C, when a popular treatment involved drilling holes in the skull to release evil spirits. Several scientifically based theories about the cause of migraines have recently developed, although the exact mechanism is still unknown. One of the current, highly supported theories suggests that migraines occur when there is a specific chemical imbalance in the brain, which in turn results in changes in the blood vessels. Understanding the probable biological origins of migraine headaches is necessary when considering the wide spectrum of available treatments for migraine sufferers. Finally, as a buildup of calcium can cause excess constriction of blood vessels, calcium channel blockers control the levels of calcium within the arteries, thereby restoring normal blood flow in the brain and decreasing the frequency of migraines.
4) Applications in Mood stabilizing medication:
In the past decade, lithium's limitations as an acute and prophylactic treatment for patients with several subtypes of manic-depressive illness have been recognized. However, a substantial number of studies have now revealed that about 50% of patients may show only a partial therapeutic response and inadequate prophylactic effect. Certain diagnostic subtypes (dysphoric mania, rapid cycling) have notably poor response rates to lithium therapy, while a significant number of patients cannot tolerate its side effects, or are unable to achieve suitable degrees of compliance at blood levels that are necessary for complete suppression of symptomatology. The foregoing has necessitated the study of both adjunctive and alternative treatment options to lithium. Other modalities being researched for mood stabilizers include calcium channel blockers, and TRH (thyrotropin releasing hormone) plus other endogenous neuropeptides. The calcium channel blockers like verapamil and nimodipine are showing special promise for rapid and ultra rapid cycling. Preliminary findings have suggested that the dihydropyridine class of L-type calcium channel blockers, which includes nimodipine, isradipine etc., compared to the phenylalkalamine verapamil may have greater mood stabilizing effects, and potential as an alternative or adjunct to lithium. Highly preliminary data on TRH have raised the possibility of its possible acute anti-depressant, anti-anxiety, and anti-suicide effects.
5) Treating Viral Infections:
New research demonstrates the inhibition of replication of human cytomegalovirus (HCMV) in cultured human embryo skin muscle cells by two separate subclasses of direct-acting smooth muscle relaxing agents alone or in combination with each other. These two subclasses are characterized mechanistically as calcium influx blockers (or calcium channel blockers) and cyclic nucleotide modulators. More specifically, the class of calcium influx blockers is exemplified by the drugs verapamil (and methoxyverapamil), nifedipine (the prototype drug of 1,4 dihydropyridines), and diltiazem. The class of cyclic nucleotide modulators is exemplified by the drugs isobutylmethylxanthine, papaverine (and its synthetic analog dioxyline), forskolin, and sodium nitroprusside. In addition, the present disclosure demonstrates that agents from one class, e.g., a calcium influx blocker, act synergistically when used in combination with agents from the other class, e.g., cyclic nucleotide modulators. The calcium influx blockers are shown to act synergistically when used in combination with alpha interferon. In further embodiments, papaverine family member agents are shown to exert antiviral activity synergistically with antiviral nucleoside analogs.
6) Novel use in revascularization:
Calcium antagonists slow atherogenesis in animals, perhaps through inhibiting calcium incorporation, lowering heart rate or reducing thrombus formation, although no benefits were shown in prospective clinical studies of stenosis progression. However, it has been possible to attenuate proliferation in in-vitro and in vivo experimental models. These discoveries are leading to novel calcium antagonist applications in revascularization. They have the potential to act synergistically in thrombolysis, but so far there has been very little evaluation of this. During coronary intervention, the myocardial protective action of calcium antagonists could be of benefit against stunning and in the no-reflow phenomenon. Their action on vasomotor tone and thrombus formation might affect acute closure or restenosis, although clinical studies have not yet shown this, perhaps because systemic administration of calcium antagonists does not achieve a high enough local concentration. Local drug delivery into the arterial wall may have potential. Calcium antagonists could be of use in cardiac surgery by preventing spasm or providing myocardial protection.
7) Attenuation of stunning by calcium antagonists:
Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The underlying mechanisms are not clearly understood. Potential mechanisms, which are not mutually exclusive, may include damage to membranes and enzymes by free radicals, an increase in free cytosolic calcium during ischemia and reperfusion, and a lower calcium sensitivity of myofibrils. Pretreatment with calcium antagonists before ischemia attenuates myocardial stunning. This effect is probably related to a lessened myocardial calcium overload during early ischemia. The potential benefit of treatment with calcium antagonists after reperfusion is established remains controversial.
With the lieu of the therapeutic utilities of the CCBs, more and more avenues are to be found to fully explore the therapeutic effectiveness of the CCBs. The various clinical experiments are under trials, which will open the new gate ways for the broad spectrum utility of the CCBs.
The authors are with Pharmacy Group, Birla Institute of technology and science Pilani., Rajasthan.