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

disease (hypertension, heart failure, coronary artery disease),
the advantages of using β 1
receptor antagonists
may outweigh the risk of worsening pulmonary function
(Salpeter et al., 2005).
CNS. The adverse effects of β receptor antagonists that
are referable to the CNS may include fatigue, sleep disturbances
(including insomnia and nightmares), and
depression. The previously ascribed association between
these drugs and depression is unclear (Gerstman et al.,
1996; Ried et al., 1998). Interest has focused on the relationship
between the incidence of the adverse effects of
β receptor antagonists and their lipophilicity; however,
no clear correlation has emerged.
Metabolism. As already described, β adrenergic blockade may blunt
recognition of hypoglycemia by patients; it also may delay recovery
from insulin-induced hypoglycemia. β Receptor antagonists should
be used with great caution in patients with diabetes who are prone to
hypoglycemic reactions; β 1
-selective agents may be preferable for
these patients. The benefits of β receptor antagonists in type 1 diabetes
with myocardial infarction may outweigh the risk in selected patients
(Gottlieb et al., 1998).
Miscellaneous. The incidence of sexual dysfunction in men with
hypertension who are treated with β receptor antagonists is not
clearly defined. Although experience with the use of β adrenergic
receptor antagonists in pregnancy is increasing, information about
the safety of these drugs during pregnancy still is limited.
Overdosage. The manifestations of poisoning with β receptor antagonists
depend on the pharmacological properties of the ingested
drug, particularly its β 1
selectivity, intrinsic sympathomimetic activity,
and membrane-stabilizing properties. Hypotension, bradycardia,
prolonged AV conduction times, and widened QRS complexes are
common manifestations of overdosage. Seizures and depression may
occur. Hypoglycemia and bronchospasm can occur. Significant
bradycardia should be treated initially with atropine, but a cardiac
pacemaker often is required. Large doses of isoproterenol or an α
receptor agonist may be necessary to treat hypotension. Glucagon,
acting through its own GPCR and independently of the β adrenergic
receptor, has positive chronotropic and inotropic effects on the heart,
and the drug has been useful in some patients suffering from an overdose
of a β receptor antagoinst.
Drug Interactions. Both pharmacokinetic and pharmacodynamic
interactions have been noted between β receptor antagonists and
other drugs. Interactions with sympathomimetics, α blockers, and β
agonists are predictable from the pharmacology. Aluminum salts,
cholestyramine, and colestipol may decrease the absorption of β
blockers. Drugs such as phenytoin, rifampin, and phenobarbital, as
well as smoking, induce hepatic biotransformation enzymes and may
decrease plasma concentrations of β receptor antagonists that are
metabolized extensively (e.g., propranolol). Cimetidine and
hydralazine may increase the bioavailability of agents such as propranolol
and metoprolol by affecting hepatic blood flow. β Receptor
antagonists can impair the clearance of lidocaine.
Other drug interactions have pharmacodynamic explanations.
For example, β antagonists and Ca 2+ channel blockers have
additive effects on the cardiac conducting system. Additive effects
on blood pressure between β blockers and other antihypertensive
agents often are employed to clinical advantage. However, the antihypertensive
effects of β receptor antagonists can be opposed by
indomethacin and other nonsteroidal anti-inflammatory drugs
(Chapter 34).
THERAPEUTIC USES
Cardiovascular Diseases
β Receptor antagonists are used extensively in the
treatment of hypertension, angina and acute coronary
syndromes, and congestive heart failure (Chapters 27
and 28). These drugs also are used frequently in the
treatment of supraventricular and ventricular arrhythmias
(Chapter 29).
Myocardial Infarction. A great deal of interest has
focused on the use of β receptor antagonists in the treatment
of acute myocardial infarction and in the prevention
of recurrences for those who have survived an
initial attack. Numerous trials have shown that β receptor
antagonists administered during the early phases of
acute myocardial infarction and continued long-term
may decrease mortality by ~25% (Freemantle et al.,
1999). The precise mechanism is not known, but the
favorable effects of β receptor antagonists may stem
from decreased myocardial oxygen demand, redistribution
of myocardial blood flow, and anti-arrhythmic
actions. There is likely much less benefit if β adrenergic
receptor antagonists are administered for only a short
time. In studies of secondary prevention, the most
extensive, favorable clinical trial data are available for
propranolol, metoprolol, and timolol. In spite of these
proven benefits, many patients with myocardial infarction
do not receive a β adrenergic receptor antagonist.
Congestive Heart Failure. It is a common clinical observation
that acute administration of β receptor antagonists
can worsen markedly or even precipitate
congestive heart failure in compensated patients with
multiple forms of heart disease, such as ischemic or
congestive cardiomyopathy. Consequently, the hypothesis
that β receptor antagonists might be efficacious in
the long-term treatment of heart failure originally
seemed counterintuitive to many physicians. However,
the reflex sympathetic responses to heart failure may
stress the failing heart and exacerbate the progression of
the disease, and blocking those responses could be beneficial.
A number of well-designed randomized clinical
trials involving numerous patients have demonstrated
that certain β receptor antagonists are highly effective
317
CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS