Hypertension 3 adrenergic receptor antagonists

The major circulating hormones that influence vascular smooth muscle tone are the catecholamines epinephrine and norepinephrine. These hormones are released from the adrenal medulla in response to sympathetic nervous stimulation. In humans, 80% of catecholamine secretion is epinephrine and 20% is norepinephrine. Stimulation of cy-adrenergic receptors causes vasoconstriction. The selective a,-adrenergic receptor antagonist, prazosin, is effective in management of hypertension because it causes arterial and venous smooth muscle to relax. 

Prazosin Is a selective tti-adrenergic receptor antagonist that, at therapeutic doses, has little activity at a2-adrenergic receptors and clinically insignificant direct vasodilating activity. The drug does not cause the other effects attributed to phentolamine. Most important, it produces less tachycardia than does phentolamine and, therefore, is useful in the treatment of essential hypertension. 

Beta adrenergic receptor antagonists reduce cardiac output (caused by negative chronotropic and inotropic effects), decrease renin release from the kidneys, and cause smooth muscle relaxation. However, blockage may also decrease secretion of insulin from pancreatic P-cells, which limits its use in T2D. Calcium channel antagonists act on L-type voltage gated channels in the heart and blood vessels to reduce vascular resistance and arterial pressure. Diuretics are also widely used to decrease blood pressure, particularly in the elderly and hypertensive black populations. 

P-adrenergic receptor antagonists may also provide less benefit than other classes of antihypertensive drugs (45). Nevertheless, P-adrenergic receptor antagonists remain a widely accepted choice for the first-line treatment of hypertension. 

Celiprolol is a potent beta -adrenergic receptor antagonist. It has intrinsic sympathomimetic action, possesses some alpha2-adrenoreceptor antagonistic properties, is a direct vasodilator, and a direct bronchodilator. Celiprolol is incompletely and variably absorbed, eliminated both in bile and urine, and has a half-life of 4 to 5 hours. Celiprolol (200 to 400 mg/day) has efficacy similar to atenolol or propranolol in reducing blood pressure and is useful in hypertensive patients with asthma or bronchitis. Furthermore, celiprolol is as effective as atenolol in treating patients with stable angina. 

There is increasing evidence that ACE inhibitors are superior to many other antihypertensive drugs in hypertensive patients with diabetes, in whom they improve endothelial function and reduce cardiovascular events more so than do Ca + channel blockers or diuretics and /3 adrenergic receptor antagonists. 

Epinephrine can produce severe hypertension when used with a nonselective P receptor antagonist due to the unopposed stimulation of a receptors when vascular receptors are blocked. Such paradoxical hypertensive responses to p adrenergic receptor antagonists have been observed in patients with hypoglycemia or pheochromocytoma, during withdrawal from clonidine, following administration of Epi as a therapeutic agent, or in association with the iUicit use of cocaine. 

P receptor antagonists do not usually cause salt and water retention, and diuretic administration is not necessary to avoid edema or the development of tolerance. However, diuretics do have additive antihypertensive effects when combined with /5 blockers. The combination of a /5 receptor antagonist, a diuretic, and a vasodilator is effective for patients who require a third drug. /5 Adrenergic receptor antagonists are preferred drugs for hypertensive patients with conditions such as myocardial infarction, ischemic heart disease, or congestive heart failure. 

ADVERSE EFFECTS The use of doxazosin as monotherapy for hypertension increases the risk of developing congestive heart failure. This may be an adverse effect of all of the adrenergic receptor antagonists. 

Bufuralol is a nonselective (3-adrenoreceptor blocking agent of comparable potency to propranolol. It has proven to be effective in treating hypertension and is a potent nonselective p-adrenergic receptor antagonist. Similarly to the method described earlier in Scheme 57.9, an efficient chemoenzymatic synthesis of (/ )-bufuralol has been reported involving a DKR of the chlorohydrin key intermediate rac-44 (Scheme 57.10). ... 

The most frequently used antiadrenergic drugs for hypertension therapy are the fi-adrenoblockers. Despite the fact that they have been used for many years, their mechanism of action is not completely understood. Only one thing is clear—they are competitive antagonists of adrenaline and noradrenaline on cardiac j3-adrenergic receptors. 

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