High Blood Pressure / Hypertension

α-Adrenergic receptor antagonists

By Cardiologist on July 7th, 2011

Pharmacology and mechanism of action

Prazosin was developed as a direct-acting vasodilator (structurally related to theophyllines) but was subsequently found to be an α-adrenergic antagonist. With the discovery of α₁- and α₂-adrenergic receptors, it became clear that prazosin was very much more potent in blocking α₁- than α₂-adrenergic receptors. Additional α₁-adrenergic receptor selective antagonists have subsequently been developed with different pharmacokinetic profiles and possibly different effects on α₁-adrenergic receptor subtypes. These drugs are listed in Table α₁-Adrenergic Receptor Antagonists. Doxazosin and terazosin are similar to prazosin, although their duration of action as autohypertensives is longer, allowing once daily dosing in most patients. Tamsulosin is an α₁-adrenergic receptor antagonist that was developed to treat benign prostate hyperplasia rather than hypertension; it has some selectivity for the α₁-adrenergic receptor subtype in the prostate, which may contribute to its efficacy in that disease.

The α-adrenergic blocking agents that are clinically useful to treat hypertension are selective α₁-adrenergic receptor blocking agents. They antagonize the vasoconstrictor actions of norepinephrine and epinephrine. This effect causes arteriolar vasodilatation and lowers peripheral vascular resistance. The action may lead to venodilation and a fall in venous return. The combination of decreased peripheral vascular resistance with decreased venous return impairs the body’s response to upright posture and can result in orthostatic hypotension that can be symptomatic, particularly with initial dosing (the so-called “first-dose effect”). However, the orthostatic effects attenuate over time. There is little evidence of loss of efficacy (tachyphylaxis) in the long-term antihypertensive effects of prazosin and related drugs; however, this is in contrast to effects in refractory congestive heart failure for which prazosin‘s effects quickly wane.

Clinical use and adverse effects of α-adrenergic receptor antagonists

The typical antihypertensive effect of α₁-adrenergic receptor antagonists is similar to the average effects of other major, commonly used antihypertensive drugs. Falls in blood pressure are typically in the range of about 10/10 mm Hg. α-Adrenergic antagonists are antihypertensive agents that actually lower low-density lipoprotein cholesterol and raise high-density lipoprotein cholesterol (in other words, they have potentially favorable effects on plasma lipids). Unfortunately there are no data yet to determine whether this effect translates into a reduction of atherosclerotic disease in humans. Prazosin can be used in asthmatic patients because it has a mild relaxant effect on bronchial smooth muscle and may improve exercise-induced asthma. Because α-adrenergic antagonists decrease symptomatic urinary hesitancy and bladder neck spasm associated with prostatic hyperplasia, these drugs are very attractive for use in hypertensive men with prostatism.

Adverse effects often occur early in therapy using prazosin. Symptomatic orthostatic hypotension is common with initial large doses (10–50% at ≥2 mg) and in patients who are fasting, volume-depleted, salt-restricted, or elderly, or who are taking any other antihypertensive drug. Using an initial dose of 0.5–1.0 mg given at bedtime for a few days minimizes this risk. Similarly, it is important to initiate therapy at analogously low doses with other α₁-adrenergic receptor antagonists. Drugs in this class may have an increased risk of causing orthostatic hypotension in the elderly. It is also important to check upright blood pressure before increasing the daily dose of any of these drugs. Fatigue, nonspecific dizziness (unrelated to postural hypotension), and headaches can be caused by these drugs.

Recommendations

α-Adrenergic antagonists are effective and can be safe antihypertensive drugs. Generally considered to be second-line therapeutic agents in the treatment of hypertension, they may be particularly advantageous in hypertensive patients with prostatism or possibly with vasospasm such as Raynaud’s phenomenon or with aortic or mitral valvular insufficiency. These drugs may be neutral or possibly advantageous in hypertensive patients with associated asthma or dyslipidemia. Because they are much more difficult to titrate, phenoxybenzamine and phentolamine are not indicated for the treatment of primary hypertension; phenoxybenzamine can be useful in treating pheochromocytoma.

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