DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

308 Syncopal episodes also have occurred with a rapid increase in
dosage or with the addition of a second antihypertensive drug to the
regimen of a patient who already is taking a large dose of prazosin.
The mechanisms responsible for such exaggerated hypotensive
responses or for the development of tolerance to these effects are not
clear. An action in the CNS to reduce sympathetic outflow may contribute
(described earlier). The risk of the first-dose phenomenon is
minimized by limiting the initial dose (e.g., 1 mg at bedtime), by
increasing the dosage slowly, and by introducing additional antihypertensive
drugs cautiously.
Since orthostatic hypotension may be a problem during longterm
treatment with prazosin or its congeners, it is essential to check
standing as well as recumbent blood pressure. Nonspecific adverse
effects such as headache, dizziness, and asthenia rarely limit treatment
with prazosin. The nonspecific complaint of dizziness generally
is not due to orthostatic hypotension. Although not extensively
documented, the adverse effects of the structural analogs of prazosin
appear to be similar to those of the parent compound. For tamsulosin,
at a dose of 0.4 mg daily, effects on blood pressure are not
expected, although impaired ejaculation may occur.
SECTION II
NEUROPHARMACOLOGY
Therapeutic Uses
Hypertension. Prazosin and its congeners have been
used successfully in the treatment of essential hypertension
(Chapter 28). Considerable interest has also
focused on the tendency of these drugs to improve
rather than worsen lipid profiles and glucose-insulin
metabolism in patients with hypertension who are at
risk for atherosclerotic disease (Grimm, 1991).
Catecholamines are also powerful stimulators of vascular
smooth muscle hypertrophy, acting by α 1
receptors.
To what extent these effects of α 1
antagonists have
clinical significance in diminishing the risk of atherosclerosis
is not known.
Congestive Heart Failure. α receptor antagonists have
been used in the treatment of congestive heart failure, as
have other vasodilating drugs. The short-term effects of
prazosin in these patients are due to dilation of both
arteries and veins, resulting in a reduction of preload
and afterload, which increases cardiac output and
reduces pulmonary congestion. In contrast to results
obtained with inhibitors of angiotensin-converting
enzyme or a combination of hydralazine and an organic
nitrate, prazosin has not been found to prolong life in
patients with congestive heart failure.
Benign Prostatic Hyperplasia (BPH). In a significant percentage
of older men, BPH produces symptomatic urethral
obstruction that leads to weak stream, urinary
frequency, and nocturia. These symptoms are due to a
combination of mechanical pressure on the urethra due
to the increase in smooth muscle mass and the α 1
receptor–mediated increase in smooth muscle tone in
the prostate and neck of the bladder (Kyprianou, 2003).
α 1
receptors in the trigone muscle of the bladder and urethra
contribute to the resistance to outflow of urine. Prazosin reduces this
resistance in some patients with impaired bladder emptying caused
by prostatic obstruction or parasympathetic decentralization from
spinal injury. The efficacy and importance of α receptor antagonists
in the medical treatment of benign prostatic hyperplasia have been
demonstrated in multiple controlled clinical trials. Transurethral
resection of the prostate is the accepted surgical treatment for symptoms
of urinary obstruction in men with BPH; however, there are
some serious potential complications (e.g., risk of impotence), and
improvement may not be permanent. Other, less invasive procedures
also are available.
Medical therapy has utilized α receptor antagonists for many
years. Finasteride (PROPECIA, PROSCAR, others) and dutasteride (AVO-
DART), two drugs that inhibit conversion of testosterone to dihydrotestosterone
(Chapter 41) and can reduce prostate volume in some
patients, are approved as monotherapy and in combination with
α receptor antagonists. α 1
-Selective antagonists have efficacy in
BPH owing to relaxation of smooth muscle in the bladder neck,
prostate capsule, and prostatic urethra. These drugs rapidly improve
urinary flow, whereas the actions of finasteride are typically delayed
for months. Combination therapy with doxazosin and finasteride
reduces the risk of overall clinical progression of BPH significantly
more than treatment with either drug alone (McConnell et al., 2003).
Tamsulosin at the recommended dose of 0.4 mg daily and silodosin
at 0.8 mg are less likely to cause orthostatic hypotension than are
the other drugs. There is growing evidence that the predominant α 1
receptor subtype expressed in the human prostate is the α 1A
receptor
(Michel and Vrydag, 2006). Developments in this area will provide
the basis for the selection of α receptor antagonists with
specificity for the relevant subtype of α 1
receptor. However, the possibility
remains that some of the symptoms of BPH are due to α 1
receptors in other sites, such as bladder, spinal cord, or brain.
Other Disorders. Though anecdotal evidence suggested that prazosin
might be useful in the treatment of patients with variant angina
(Prinzmetal’s angina) due to coronary vasospasm, several small controlled
trials have failed to demonstrate a clear benefit. Some studies
have indicated that prazosin can decrease the incidence of digital
vasospasm in patients with Raynaud’s disease; however, its relative
efficacy as compared with other vasodilators (e.g., Ca 2+ channel
blockers) is not known. Prazosin may have some benefit in patients
with other vasospastic disorders. Prazosin decreases ventricular
arrhythmias induced by coronary artery ligation or reperfusion in
laboratory animals; the therapeutic potential for this use in humans
is not known. Prazosin also may be useful for the treatment of
patients with mitral or aortic valvular insufficiency, presumably
because of reduction of afterload.
α 2
ADRENERGIC RECEPTOR
ANTAGONISTS
The α 2
receptors have an important role in regulation of
the activity of the sympathetic nervous system, both
peripherally and centrally. As mentioned earlier, activation
of presynaptic α 2
receptors inhibits the release
of NE and other co-transmitters from peripheral