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

302 syndrome and idiopathic autonomic failure. Therapeutic approaches
include physical maneuvers and a variety of drugs (fludrocortisone,
prostaglandin synthesis inhibitors, somatostatin analogs, caffeine,
vasopressin analogs, and DA antagonists). A number of sympathomimetic
drugs also have been used in treating this disorder. The
ideal agent would enhance venous constriction prominently and produce
relatively little arterial constriction so as to avoid supine hypertension.
No such agent currently is available. Drugs used in this
disorder to activate α 1
receptors include both direct- and indirectacting
agents. Midodrine shows promise in treating this challenging
disorder.
SECTION II
NEUROPHARMACOLOGY
Hypertension. Centrally acting α 2
receptor agonists such as clonidine
are useful in the treatment of hypertension. Drug therapy of
hypertension is discussed in Chapter 27.
Cardiac Arrhythmias. Cardiopulmonary resuscitation in patients
with cardiac arrest due to ventricular fibrillation, electromechanical
dissociation, or asystole may be facilitated by drug treatment.
Epinephrine is an important therapeutic agent in patients with cardiac
arrest; epinephrine and other α agonists increase diastolic pressure
and improve coronary blood flow. Alpha agonists also help to
preserve cerebral blood flow during resuscitation. Cerebral blood
vessels are relatively insensitive to the vasoconstricting effects of
catecholamines, and perfusion pressure is increased. Consequently,
during external cardiac massage, epinephrine facilitates distribution
of the limited cardiac output to the cerebral and coronary circulations.
Although it had been thought that the β adrenergic effects of
epinephrine on the heart made ventricular fibrillation more susceptible
to conversion with electrical countershock, tests in animal models
have not confirmed this hypothesis. The optimal dose of
epinephrine in patients with cardiac arrest is unclear. Once a cardiac
rhythm has been restored, it may be necessary to treat arrhythmias,
hypotension, or shock.
In patients with paroxysmal supraventricular tachycardias,
particularly those associated with mild hypotension, careful infusion
of an α agonist (e.g., phenylephrine) to raise blood pressure to
~160 mm Hg may end the arrhythmia by increasing vagal tone.
However, this method of treatment has been replaced largely by Ca 2+
channel blockers with clinically significant effects on the AV node,
β antagonists, adenosine, and electrical cardioversion (Chapter 29).
Beta agonists such as isoproterenol may be used as adjunctive or
temporizing therapy with atropine in patients with marked bradycardia
who are compromised hemodynamically; if long-term therapy
is required, a cardiac pacemaker usually is the treatment of choice.
Congestive Heart Failure. Sympathetic stimulation of β receptors
in the heart is an important compensatory mechanism for maintenance
of cardiac function in patients with congestive heart failure.
Responses mediated by β receptors are blunted in the failing human
heart. While β agonists may increase cardiac output in acute emergency
settings such as shock, long-term therapy with β agonists as
inotropic agents is not efficacious. Indeed, interest has grown in the
use of β receptor antagonists in the treatment of patients with congestive
heart failure (Chapter 28).
Local Vascular Effects of α Adrenergic Receptor Agonists.
Epinephrine is used in many surgical procedures in the nose, throat,
and larynx to shrink the mucosa and improve visualization by
limiting hemorrhage. Simultaneous injection of epinephrine with
local anesthetics retards the absorption of the anesthetic and
increases the duration of anesthesia (Chapter 20). Injection of α agonists
into the penis may be useful in reversing priapism, a complication
of the use of α receptor antagonists or PDE5 inhibitors (e.g.,
sildenafil) in the treatment of erectile dysfunction. Both phenylephrine
and oxymetazoline are efficacious vasoconstrictors when
applied locally during sinus surgery.
Nasal Decongestion. α Receptor agonists are used extensively as
nasal decongestants in patients with allergic or vasomotor rhinitis
and in acute rhinitis in patients with upper respiratory infections.
These drugs probably decrease resistance to airflow by decreasing
the volume of the nasal mucosa; this may occur by activation of α
receptors in venous capacitance vessels in nasal tissues that have
erectile characteristics. The receptors that mediate this effect appear
to be α 1
receptors. Interestingly, α 2
receptors may mediate contraction
of arterioles that supply nutrition to the nasal mucosa. Intense
constriction of these vessels may cause structural damage to the
mucosa. A major limitation of therapy with nasal decongestants is
loss of efficacy, “rebound” hyperemia, and worsening of symptoms
with chronic use or when the drug is stopped. Although mechanisms
are uncertain, possibilities include receptor desensitization and damage
to the mucosa. Agonists that are selective for α 1
receptors may
be less likely to induce mucosal damage.
For decongestion, α agonists may be administered either
orally or topically. Oral ephedrine often causes CNS adverse effects.
Pseudoephedrine is a stereoisomer of ephedrine that is less potent
than ephedrine in producing tachycardia, increased blood pressure,
and CNS stimulation. Sympathomimetic decongestants should be
used with great caution in patients with hypertension and in men with
prostatic enlargement, and they are contraindicated in patients who
are taking MAO inhibitors. A variety of compounds (see under
Ephedrine, earlier) are available for topical use in patients with rhinitis.
Topical decongestants are particularly useful in acute rhinitis
because of their more selective site of action, but they are apt to be
used excessively by patients, leading to rebound congestion. Oral
decongestants are much less likely to cause rebound congestion but
carry a greater risk of inducing adverse systemic effects. Indeed,
patients with uncontrolled hypertension or ischemic heart disease
generally should carefully avoid the oral consumption of over-thecounter
products or herbal preparations containing sympathomimetic
drugs.
Asthma. Use of β adrenergic agonists in the treatment of asthma and
chronic obstructive pulmonary disease (COPD) is discussed in
Chapter 36.
Allergic Reactions. Epinephrine is the drug of choice to reverse the
manifestations of serious acute hypersensitivity reactions (e.g., from
food, bee sting, or drug allergy). A subcutaneous injection of epinephrine
rapidly relieves itching, hives, and swelling of lips, eyelids,
and tongue. In some patients, careful intravenous infusion of
epinephrine may be required to ensure prompt pharmacological
effects. This treatment may be life-saving when edema of the glottis
threatens airway patency or when there is hypotension or shock
in patients with anaphylaxis. In addition to its cardiovascular effects,
epinephrine is thought to activate β receptors that suppress the
release from mast cells of mediators such as histamine and