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

heterogeneous. Some of these drugs have markedly different
affinities for α 1
and α 2
receptors. For example,
prazosin is much more potent in blocking α 1
than α 2
receptors (i.e., α 1
selective), whereas yohimbine is α 2
selective; phentolamine has similar affinities for both of
these receptor subtypes. More recently, agents that discriminate
among the various subtypes of a particular
receptor have become available; e.g., tamsulosin has
higher potency at α 1A
than at α 1B
receptors. Figure 12–6
shows the structural formulas of many of these agents.
Prior editions of this textbook contain information about
the chemistry of α receptor antagonists.
Some of the most important effects of α receptor
antagonists observed clinically are on the cardiovascular
system. Actions in both the CNS and the periphery
are involved; the outcome depends on the cardiovascular
status of the patient at the time of drug administration
and the relative selectivity of the agent for α 1
and
α 2
receptors.
Catecholamines increase the output of glucose
from the liver; in humans this effect is mediated predominantly
by β receptors, although α receptors may
contribute. α Receptor antagonists therefore may
reduce glucose release. Receptors of the α 2A
subtype
facilitate platelet aggregation; the effect of blockade of
platelet α 2
receptors in vivo is not clear. Activation of α 2
receptors in the pancreatic islets suppresses insulin
secretion; conversely, blockade of pancreatic α 2
receptors
may facilitate insulin release (Chapter 43).
α 1
Receptor Antagonists
General Pharmacological Properties. Blockade of α 1
adrenergic receptors inhibits vasoconstriction induced
by endogenous catecholamines; vasodilation may
occur in both arteriolar resistance vessels and veins.
The result is a fall in blood pressure due to decreased
peripheral resistance. The magnitude of such effects
depends on the activity of the sympathetic nervous
system at the time the antagonist is administered, and
thus is less in supine than in upright subjects and is
particularly marked if there is hypovolemia. For most
α receptor antagonists, the fall in blood pressure is
opposed by baroreceptor reflexes that cause increases
in heart rate and cardiac output, as well as fluid retention.
These reflexes are exaggerated if the antagonist
also blocks α 2
receptors on peripheral sympathetic
nerve endings, leading to enhanced release of NE and
increased stimulation of postsynaptic β 1
receptors in
the heart and on juxtaglomerular cells (Chapter 8)
(Starke et al., 1989). Although stimulation of α 1
receptors in the heart may cause an increased force
of contraction, the importance of blockade at this site
in humans is uncertain.
Blockade of α 1
receptors also inhibits vasoconstriction
and the increase in blood pressure produced
by the administration of a sympathomimetic amine. The
pattern of effects depends on the adrenergic agonist that
is administered: pressor responses to phenylephrine can
be completely suppressed; those to NE are only incompletely
blocked because of residual stimulation of cardiac
β 1
receptors; and pressor responses to epinephrine
may be transformed to vasodepressor effects because
of residual stimulation of β 2
receptors in the vasculature
with resultant vasodilation.
Blockade of α 1
receptors can alleviate some of
the symptoms of benign prostatic hyperplasia (BPH).
The symptoms of BPH include a resistance to urine outflow.
This results from mechanical pressure on the urethra
due to an increase in smooth muscle mass and an
α adrenergic receptor mediated increase in smooth
muscle tone in the prostate and neck of the bladder.
Antagonism of α 1
receptors permits relaxation of the
smooth muscle and decreases the resistance to the outflow
of urine. The prostate and lower urinary tract tissues
exhibit a high proportion of α 1A
receptors (Michel
and Vrydag, 2006).
Available Agents
Prazosin and Related Drugs. Due in part to its greater α 1
receptor selectivity, this class of α receptor antagonists
exhibits greater clinical utility and has largely replaced
the non-selective haloalkylamine (e.g., phenoxybenzamine)
and imidazoline (e.g., phentolamine) α receptor
antagonists.
Prazosin is the prototypical α 1
-selective antagonist.
The affinity of prazosin for α 1
adrenergic receptors
is ~1000-fold greater than that for α 2
adrenergic
receptors. Prazosin has similar potencies at α 1A
, α 1B
,
and α 1D
subtypes. Interestingly, the drug also is a relatively
potent inhibitor of cyclic nucleotide phosphodiesterases,
and it originally was synthesized for this
purpose. The pharmacological properties of prazosin
have been characterized extensively. Prazosin and the
related α receptor antagonists, doxazosin and tamsulosin,
frequently are used for the treatment of hypertension
(Chapter 27).
Pharmacological Properties. The major effects of prazosin result from
its blockade of α 1
receptors in arterioles and veins. This leads to a fall
in peripheral vascular resistance and in venous return to the heart.
Unlike other vasodilating drugs, administration of prazosin usually
does not increase heart rate. Since prazosin has little or no α 2
receptor–
blocking effect at concentrations achieved clinically, it probably does
305
CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS