ALPHA+BLOCKERS


 * Alpha-blockers**
 * Background:** Systemic alpha-blockers include alfuzosin, doxazosin, phenoxybenzamine, phentolamine, prazosin, tamsulosin, terazosin, tolazoline, and yohimbine. In clinical practice, doxazosin, terazosin, and, less commonly, prazosin are used as oral agents in the treatment of hypertension and prostatic hypertrophy. Alfuzosin and tamsulosin are used exclusively for the treatment of prostatic hypertrophy, since compared to other oral alpha-blockers, they have less antihypertensive effects and are relatively more selective as antagonists at the alpha-1a subtype, the primary subtype located in the prostate. Phenoxybenzamine and tolazoline are seldom used. Phentolamine is used to diagnose pheochromocytoma, to treat hypertension associated with pheochromocytoma, and to prevent tissue necrosis after norepinephrine or dopamine extravasation. Phentolamine has also been used in the treatment of hypertensive crisis associated with monoamine oxidase inhibitor (MAOI) therapy as well as in the treatment of male impotence. Yohimbine is an oral alpha2-blocker which is used for the treatment of erectile impotence.


 * History:** Prazosin originally was evaluated as an agent for treating heart failure but now is no longer used for this condition. It also can be used in the treatment of hypertension. Terazosin originally was approved for the treatment of hypertension and was approved for the treatment of benign prostatic hypertrophy. Tamsulosin was approved by the FDA in 1997 exclusively for the treatment of prostatic hypertrophy. Alfuzosin has been marketed in France since 1987, is widely used in Europeand is expected to be approved in the United States in 2002. Although initially frequently used for hypertension, doxazosin use for hypertension has significantly declined following release of the findings of the ALLHAT trial in 2000.[2857] This clinical trial compared doxazosin to chlorthalidone in the treatment of high-risk hypertensive patients. In this study, only the diuretic significantly reduced the risk of combined cardiovascular disease events, especially heart failure; in comparison to doxazosin. These results led to discontinuation of the doxazosin treatment arm of the study.

Yohimbine is an oral alpha2-blocker that is chemically related to reserpine. It is an alkaloid found in the bark of Rubiaceae and related trees, but can also be found in //Rauwolfia serpentina//. Yohimbine may have a therapeutic role in the treatment of erectile dysfunction.


 * Mechanism of Action:** Phentolamine is an alpha-adrenergic receptor antagonist similar to, but more potent than, tolazoline. Phentolamine and phenoxybenzamine are short-acting, noncompetitive antagonists at alpha-adrenergic receptors. They antagonize both alpha1- and alpha2-receptors, thus blocking the actions of circulating epinephrine and norepinephrine, but phentolamine has a weaker effect on mediators released from adrenergic nerve endings than on circulating catecholamines. Antagonism at alpha2-receptors increases circulating levels of norepinephrine due to loss of negative feedback, which may result in reflex tachycardia and attenuation of hypotensive effects. [Clonidine also works at alpha2-receptors but differs from the alpha-blockers discussed here in its ability to stimulate alpha2-receptors centrally.] Phentolamine also stimulates beta-adrenergic receptors in the heart and lungs. Both of these agents have limited clinical applications.

Unlike phentolamine and phenoxybenzamine, doxazosin, prazosin, tamsulosin, and terazosin are selective for the alpha1-receptor. Because of this alpha1-selectivity, reflex tachycardia and attenuation of the hypotensive effect are less of a problem than with either phentolamine or phenoxybenzamine. Alpha1-receptors are involved in contraction of smooth muscle and are abundant in the prostate, prostatic capsule, prostatic urethra, and bladder neck. Three subtypes of alpha1-receptors have been identified: Alpha-1a, alpha-1b, and alpha-1d. Alpha-1a receptors mediate human prostatic smooth muscle contraction whereas alpha-1b and alpha-1d-receptors are involved in vascular smooth muscle contraction. Both alpha-1a and alpha-1b-receptors exist in the prostate, however, approximately 70% of the alpha-receptors in the human prostate are of the alpha-1a subtype. Blockade of these receptors can cause smooth muscles in the bladder neck and prostate to relax, thereby improving urine flow rate and reducing symptoms of benign prostatic hypertrophy (BPH). Tamsulosin has 7—38-fold greater affinity for alpha-1a-receptors than for alpha-1b-receptors. Alfuzosin is also more specific for alpha-1a receptors than other alpha1-receptor antagonists.

Unlike other antihypertensives, alpha1-receptor blockers exert a favorable effect on lipid metabolism, although individual agents may differ slightly in their effect. These agents have been shown to decrease serum total cholesterol, LDL-cholesterol, and triglycerides. The effect of alpha1-blockers on the lipid profile, in general, are more significant in patients with higher baseline lipid levels.[995]


 * Distinguishing Features:** Phentolamine is similar in action to phenoxybenzamine, but phentolamine is administered parenterally and has a shorter duration of action. As indicated above, phentolamine and phenoxybenzamine are poor antihypertensives due to drug-induced reflex tachycardia, renin release, and attenuation of receptor-blockade potency.

Among prazosin, terazosin, and doxazosin, doxazosin is the longest acting. Doxazosin can be dosed once daily, even at the maximum therapeutic dosage. Due to the unfavorable results of the ALLHAT trial with doxazosin compared to diuretic therapy (see History), alpha-blockers are less frequently used to treat patients with hypertension alone. Because of their favorable effects in BPH, doxazosin, terazosin, or prazosin are useful for men with both hypertension and BPH. Alfuzosin and tamsulosin are used exclusively for the treatment of prostatic hypertrophy, since compared to other oral alpha-blockers, they have less antihypertensive effects and are relatively more selective as antagonists at the alpha-1a subtype, the primary subtype located in the prostate. Preliminary data from the first head-to-head comparison of terazosin with the 5-alpha-reductase inhibitor finasteride show that terazosin showed that terazosin was superior in the treatment of BPH. Finasteride has an advantage for use in men with larger prostates since it reduces the size of the prostate, and has been used as an alternative agent in men with significant adverse effects to alpha-blockers.


 * Adverse Reactions:** Aside from orthostatic hypotension, which is a major effect of alpha-blockade, alpha-blockers cause relatively few adverse reactions. Prazosin has been associated with significant orthostatic hypotension after administration of the initial dose. Orthostatic hypotension also occurs frequently with terazosin and doxazosin (9—10%), but at a lower incidence relative to prazosin, perhaps due to a slower onset of action. The orthostatic and hypotensive effects due to alpha-blockers are dose-related. Alfuzosin and tamsulosin have a low incidence of orthostatic hypotension. Other adverse effects associated with hypotensive effects of alpha-blockers include reflex dizziness, sinus tachycardia (angina, palpitations), syncope, and vertigo.

Other adverse effects associated with the alpha-blockers include abdominal pain, constipation or diarrhea, dyspnea, fatigue/malaise, nasal congestion, nausea/vomiting, peripheral edema, somnolence (drowsiness), and weight gain. Priapism has been very rarely been associated with alpha-blocker therapy. Libido decrease and impotence have also been rarely reported.