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

not promote the release of NE from sympathetic nerve endings in
the heart. In addition, prazosin decreases cardiac preload and thus
has little tendency to increase cardiac output and rate, in contrast to
vasodilators such as hydralazine that have minimal dilatory effects
on veins. Although the combination of reduced preload and selective
α 1
receptor blockade might be sufficient to account for the relative
absence of reflex tachycardia, prazosin also may act in the CNS to
suppress sympathetic outflow. Prazosin appears to depress baroreflex
function in hypertensive patients. Prazosin and related drugs in this
class tend to have favorable effects on serum lipids in humans,
decreasing low-density lipoproteins (LDL) and triglycerides while
increasing concentrations of high-density lipoproteins (HDL).
Prazosin and related drugs may have effects on cell growth unrelated
to antagonism of α 1
receptors (Hu et al., 1998).
Prazosin (MINIPRESS, others) is well absorbed after oral administration,
and bioavailability is ~ 50-70%. Peak concentrations of prazosin
in plasma generally are reached 1-3 hours after an oral dose.
The drug is tightly bound to plasma proteins (primarily α 1
-acid glycoprotein),
and only 5% of the drug is free in the circulation; diseases
that modify the concentration of this protein (e.g., inflammatory
processes) may change the free fraction. Prazosin is extensively
metabolized in the liver, and little unchanged drug is excreted by the
kidneys. The plasma t 1/2
is ~3 hours (may be prolonged to 6-8 hours
in congestive heart failure). The duration of action of the drug typically
is 7-10 hours in the treatment of hypertension.
The initial dose should be 1 mg, usually given at bedtime so
that the patient will remain recumbent for at least several hours to
reduce the risk of syncopal reactions that may follow the first dose
of prazosin. Therapy is begun with 1 mg given two or three times
daily, and the dose is titrated upward depending on the blood pressure.
A maximal effect generally is observed with a total daily dose
of 20 mg in patients with hypertension. In the off-label treatment of
benign prostatic hyperplasia (BPH), doses from 1-5 mg twice daily
typically are used.
Terazosin. Terazosin (HYTRIN, others) is a close structural analog of
prazosin. It is less potent than prazosin but retains high specificity for
α 1
receptors; terazosin does not discriminate among α 1A
, α 1B
, and
α 1D
receptors. The major distinction between the two drugs is in their
pharmacokinetic properties.
Terazosin is more soluble in water than is prazosin, and its
bioavailability is high (>90%). The t 1/2
of elimination of terazosin
is ~12 hours, and its duration of action usually extends beyond 18 hours.
Consequently, the drug may be taken once daily to treat hypertension
and BPH in most patients. Terazosin has been found more effective
than finasteride in treatment of BPH (Lepor et al., 1996). An interesting
aspect of the action of terazosin and doxazosin in the treatment
of lower urinary tract problems in men with BPH is the
induction of apoptosis in prostate smooth muscle cells. This apoptosis
may lessen the symptoms associated with chronic BPH by limiting
cell proliferation. The apoptotic effect of terazosin and
doxazosin appears to be related to the quinazoline moiety rather than
α 1
receptor antagonism; tamsulosin, a non-quinazoline α 1
receptor
antagonist, does not produce apoptosis (Kyprianou, 2003). Only
~10% of terazosin is excreted unchanged in the urine. An initial first
dose of 1 mg is recommended. Doses are slowly titrated upward
depending on the therapeutic response. Doses of 10 mg/day may be
required for maximal effect in BPH.
Doxazosin. Doxazosin (CARDURA, others) is another structural analog
of prazosin and a highly selective antagonist at α 1
receptors. It
is non-selective among α 1
receptor subtypes, and differs from prazosin
in its pharmacokinetic profile.
The t 1/2
of doxazosin is ~20 hours, and its duration of action
may extend to 36 hours. The bioavailability and extent of metabolism
of doxazosin and prazosin are similar. Most doxazosin metabolites
are eliminated in the feces. The hemodynamic effects of
doxazosin appear to be similar to those of prazosin. As in the cases
of prazosin and terazosin, doxazosin should be given initially as a
1-mg dose in the treatment of hypertension or BPH. Doxazosin also
may have beneficial actions in the long-term management of BPH
related to apoptosis that are independent of α 1
receptor antagonism.
Doxazosin is typically administered once daily. An extended-release
formulation marketed for BPH is not recommended for the treatment
of hypertension.
Alfuzosin. Alfuzosin (UROXATRAL) is a quinazoline-based α 1
receptor
antagonist with similar affinity at all of the α 1
receptor subtypes.
It has been used extensively in treating BPH; it is not approved for
treatment of hypertension. Its bioavailability is ~64%; it has a t 1/2
of
3-5 hours. Alfuzosin is a substrate of CYP3A4 and the concomitant
administration of CPY3A4 inhibitors (e.g., ketoconazole, clarithromycin,
itraconazole, ritonavir) is contraindicated. Alfuzosin
should be avoided in patients at risk for prolonged QT syndrome.
The recommended dosage is one 10-mg extended-release tablet daily
to be taken after the same meal each day.
Tamsulosin. Tamsulosin (FLOMAX), a benzenesulfonamide, is an α 1
receptor antagonist with some selectivity for α 1A
(and α 1D
) subtypes
compared to the α 1B
subtype (Kenny et al., 1996). This selectivity
may favor blockade of α 1A
receptors in prostate. Tamsulosin is efficacious
in the treatment of BPH with little effect on blood pressure
(Beduschi et al., 1998); tamsulosin is not approved for the treatment
of hypertension. Tamsulosin is well absorbed and has a t 1/2
of
5-10 hours. It is extensively metabolized by CYPs. Tamsulosin may
be administered at a 0.4-mg starting dose; a dose of 0.8 mg ultimately
will be more efficacious in some patients. Abnormal ejaculation
is an adverse effect of tamsulosin, experienced by ~18% of
patients receiving the higher dose.
Silodosin. Silidosin (RAPAFLO) also exhibits selectivity for the α 1A
,
over the α 1B
adrenergic receptor. The drug is metabolized by several
pathways; the main metabolite is a glucuronide formed by UGT2B7;
co-administration with inhibitors of this enzyme (e.g., probenecid,
valproic acid, fluconazole) increases systemic exposure to silodosin.
The drug is approved for the treatment of BPH and is reported, as is
tamsulosin, to have lesser effects on blood pressure than the non-α 1
subtype selective antagonists. Nevertheless, dizziness and orthostatic
hypotension can occur. The chief side effect of silodosin is retrograde
ejaculation (in 28% of those treated). Silodosin is available as
4-mg and 8-mg capsules.
Adverse Effects. A major potential adverse effect of
prazosin and its congeners is the first-dose effect;
marked postural hypotension and syncope sometimes
are seen 30-90 minutes after an initial dose of prazosin
and 2-6 hours after an initial dose of doxazosin.
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS