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

agents. The pharmacology of these drugs is discussed in
detail in Chapter 12. Prazosin, terazosin, and doxazosin
are the agents that are available for the treatment of
hypertension.
Pharmacological Effects. Initially, α 1
adrenergic receptor
antagonists reduce arteriolar resistance and increase
venous capacitance; this causes a sympathetically
mediated reflex increase in heart rate and plasma renin
activity. During long-term therapy, vasodilation persists,
but cardiac output, heart rate, and plasma renin activity
return to normal. Renal blood flow is unchanged
during therapy with an α 1
receptor antagonist. The
α 1
adrenergic blockers cause a variable amount of postural
hypotension, depending on the plasma volume.
Retention of salt and water occurs in many patients during
continued administration, and this attenuates the
postural hypotension. α 1
Receptor antagonists reduce
plasma concentrations of triglycerides and total LDL
cholesterol and increase HDL cholesterol. These potentially
favorable effects on lipids persist when a thiazidetype
diuretic is given concurrently. The long-term
consequences of these small, drug-induced changes in
lipids are unknown.
Adverse Effects. The use of doxazosin as monotherapy for hypertension
increased the risk for developing congestive heart failure
(ALLHAT Officers, 2002). This may be a class effect that represents
an adverse effect of all of the α 1
receptor antagonists.
However, this interpretation of the outcome of the ALLHAT study
is controversial.
A major precaution regarding the use of the α 1
receptor
antagonists for hypertension is the so-called first-dose phenomenon,
in which symptomatic orthostatic hypotension occurs within 30-90
minutes (or longer) of the initial dose of the drug or after a dosage
increase. This effect may occur in up to 50% of patients, especially
in patients who are already receiving a diuretic or an α receptor antagonist.
After the first few doses, patients develop a tolerance to this
marked hypotensive response.
Therapeutic Uses. α 1
Receptor antagonists are not recommended
as monotherapy for hypertensive patients
primarily as a consequence of the ALLHAT study.
Consequently, they are used primarily in conjunction
with diuretics, β blockers, and other antihypertensive
agents. β Receptor antagonists enhance the efficacy
of the α 1
blockers. α 1
Receptor antagonists are not
the drugs of choice in patients with pheochromocytoma,
because a vasoconstrictor response to epinephrine
can still result from activation of unblocked
vascular α 2
adrenergic receptors. α 1
Receptor antagonists
are attractive drugs for hypertensive patients
with benign prostatic hyperplasia, because they also
improve urinary symptoms.
COMBINED α 1
AND β ADRENERGIC
RECEPTOR ANTAGONISTS
Labetalol (see Chapter 12) is an equimolar mixture of
four stereoisomers. One isomer is an α 1
antagonist (like
prazosin), another is a nonselective β antagonist with
partial agonist activity (like pindolol), and the other two
isomers are inactive. Because of its capacity to block
α 1
adrenergic receptors, labetalol given intravenously
can reduce blood pressure sufficiently rapidly to be
useful for the treatment of hypertensive emergencies.
Labetalol has efficacy and adverse effects that would
be expected with any combination of β and α 1
receptor
antagonists; it also has the disadvantages that are inherent
in fixed-dose combination products: the extent of
α-receptor antagonism compared to β receptor antagonism
is somewhat unpredictable and varies from patient
to patient.
Carvedilol (see Chapters 12) is a β receptor
antagonist with α 1
receptor antagonist activity. The
drug has been approved for the treatment of hypertension
and symptomatic heart failure. The ratio of α 1
to
β receptor antagonist potency for carvedilol is approximately
1:10. Carvedilol undergoes oxidative metabolism
and glucuronidation in the liver; the oxidative
metabolism occurs via CYP2D6. Carvedilol reduces
mortality in patients with congestive heart failure associated
with systolic dysfunction when used as an
adjunct to therapy with diuretics and ACE inhibitors. It
should not be given to those patients with decompensated
heart failure who are dependent on sympathetic
stimulation. As with labetalol, the long-term efficacy
and side effects of carvedilol in hypertension are predictable
based on its properties as a β and α 1
adrenergic
receptor antagonist.
Nebivolol is a β 1
selective adrenergic antagonist
that also promotes vasodilatation; rather than blocking
α 1
receptors, nebivolol augments arterial smooth muscle
relaxation via NO (Veverka et al., 2006). In addition,
nebivolol has agonist activity at β 3
receptors,
although the clinical significance of this effect is not
known.
Methyldopa
Methyldopa is a centrally acting antihypertensive agent.
It is a prodrug that exerts its antihypertensive action via
an active metabolite. Although used frequently as an
antihypertensive agent in the past, methyldopa’s significant
adverse effects limit its current use largely to treatment
of hypertension in pregnancy, where it has a
record for safety.
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CHAPTER 27
TREATMENT OF MYOCARDIAL ISCHEMIA AND HYPERTENSION