Cardiovascular system calcium channels

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. 

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. 

NS-8 and ZD-0947 are calcium sensitive potassium channel openers, that have no effects on the cardiovascular system. They are currently being developed for the treatment of bladder hyperactivity (Phase II) (Figure 8.81). 

The cardiovascular effects of local anesthetics result in part from direct effects of these drugs on the cardiac and smooth muscle membranes and from indirect effects on the autonomic nervous system. As described in Chapter 14, local anesthetics block cardiac sodium channels and thus depress abnormal cardiac pacemaker activity, excitability, and conduction. At extremely high concentrations, local anesthetics can also block calcium channels. With the notable exception of cocaine, local anesthetics also depress myocardial contractility and produce direct arteriolar dilation, leading to systemic hypotension. Cardiovascular collapse is rare, but has been reported after large doses of bupivacaine and ropivacaine have been inadvertently administered into the intravascular space. 

For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures the body s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, 13 blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and any other drugs that may be given. 

Antihypertensive Agents. Hypertension (high blood pressure) is a significant risk factor for cardiovascular diseases such as angina heart attacks, and strokes. /(-Adrenoceptor (adrenergic nervous system receptors of the /(-type) antagonists (/(-blockers), calcium channel blockers, angiotensinconverting enzyme (ACE) inhibitors, and potassium channel activators... 

In clinical practice, there Is further selectivity of drug action at the L-channels, in part originating from the fact that there seem to be separate, but adjacent, binding sites for different chemical classes of calcium antagonists. Of the L-channel blockers, some chemical families are more active on the smooth muscle of the cardiovascular system (e.g. nifedipine and most other DHPs), whereas others are more cardioactive (e.g. verapamii). Some further details of these... 

When calcium channel blockers are used clinically it is assumed that the major effects are limited to the cardiovascular system, and indeed, few side effects have been reported for these agents. However, calcium channels in the cardiovascular system... 

These results raise an interesting question. Are calcium channels in different tissues sufficiently distinct to allow development of calcium channel blocking drugs relatively specific for given tissues other than the cardiovascular system Such drugs may have novel tranquilizing or smooth muscle relaxant properties useful clinically as well as experimentally. 

This pharmacological class is one of the most complex since its members act on a variety of newly discovered calcium channels within the central nervous system with either synaptic or somatic localization and numerous functions. Little is known about the impact of calcium antagonists on chemical neurotransmission, neuronal functions and intracellular calcium homeostasis, particularly in neurones and glial cells. This wide area of research and the action of these drugs on cerebral vascularization have been the subject of a number of recent reviews [95, 128-130]. For dihydropyridines, it is also important to note the peripheral (cardiovascular) effects which in turn affect the central nervous system. 

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