CORGARD (nadolol) is a nonselective beta-adrenergic
receptor blocking agent. Clinical pharmacology studies have demonstrated
beta-blocking activity by showing (1) reduction in heart rate and cardiac
output at rest and on exercise, (2) reduction of systolic and diastolic blood pressure
at rest and on exercise, (3) inhibition of isoproterenol-induced tachycardia,
and (4) reduction of reflex orthostatic tachycardia.
CORGARD (nadolol) specifically competes with
beta-adrenergic receptor agonists for available beta receptor sites; it
inhibits both the beta1 receptors located chiefly in cardiac muscle and the beta2
receptors located chiefly in the bronchial and vascular musculature, inhibiting
the chronotropic, inotropic, and vasodilator responses to beta-adrenergic
stimulation proportionately. CORGARD has no intrinsic sympathomimetic activity
and, unlike some other beta-adrenergic blocking agents, nadolol has little
direct myocardial depressant activity and does not have an anesthetic-like
membrane- stabilizing action. Animal and human studies show that CORGARD slows
the sinus rate and depresses AV conduction. In dogs, only minimal amounts of
nadolol were detected in the brain relative to amounts in blood and other
organs and tissues. CORGARD has low lipophilicity as determined by
octanol/water partition coefficient, a characteristic of certain beta-blocking
agents that has been correlated with the limited extent to which these agents cross
the blood-brain barrier, their low concentration in the brain, and low
incidence of CNS-related side effects.
In controlled clinical studies, CORGARD (nadolol) at
doses of 40 to 320 mg/day has been shown to decrease both standing and supine
blood pressure, the effect persisting for approximately 24 hours after dosing.
The mechanism of the antihypertensive effects of
beta-adrenergic receptor blocking agents has not been established; however,
factors that may be involved include (1) competitive antagonism of
catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially
cardiac) leading to decreased cardiac output, (2) a central effect leading to
reduced tonic-sympathetic nerve outflow to the periphery, and (3) suppression
of renin secretion by blockade of the beta-adrenergic receptors responsible for
renin release from the kidneys.
While cardiac output and arterial pressure are reduced by
nadolol therapy, renal hemodynamics are stable, with preservation of renal
blood flow and glomerular filtration rate. By blocking catecholamine-induced
increases in heart rate, velocity and extent of myocardial contraction, and
blood pressure, CORGARD (nadolol) generally reduces the oxygen requirements of
the heart at any given level of effort, making it useful for many patients in
the long-term management of angina pectoris. On the other hand, nadolol can
increase oxygen requirements by increasing left ventricular fiber length and
end diastolic pressure, particularly in patients with heart failure.
Although beta-adrenergic receptor blockade is useful in
treatment of angina and hypertension, there are also situations in which
sympathetic stimulation is vital. For example, in patients with severely
damaged hearts, adequate ventricular function may depend on sympathetic drive.
Betaadrenergic blockade may worsen AV block by preventing the necessary
facilitating effects of sympathetic activity on conduction. Beta2-adrenergic
blockade results in passive bronchial constriction by interfering with
endogenous adrenergic bronchodilator activity in patients subject to
bronchospasm and may also interfere with exogenous bronchodilators in such
Absorption of nadolol after oral dosing is variable,
averaging about 30 percent. Peak serum concentrations of nadolol usually occur
in three to four hours after oral administration and the presence of food in
the gastrointestinal tract does not affect the rate or extent of nadolol absorption.
Approximately 30 percent of the nadolol present in serum is reversibly bound to
Unlike many other beta-adrenergic blocking agents, nadolol
is not metabolized by the liver and is excreted unchanged, principally by the
The half-life of therapeutic doses of nadolol is about 20
to 24 hours, permitting once-daily dosage. Because nadolol is excreted
predominantly in the urine, its half-life increases in renal failure (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION). Steady-state serum concentrations of
nadolol are attained in six to nine days with once-daily dosage in persons with
normal renal function. Because of variable absorption and different individual
responsiveness, the proper dosage must be determined by titration.
Exacerbation of angina and, in some cases, myocardial
infarction and ventricular dysrhythmias have been reported after abrupt
discontinuation of therapy with beta-adrenergic blocking agents in patients
with coronary artery disease. Abrupt withdrawal of these agents in patients
without coronary artery disease has resulted in transient symptoms, including
tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms
have been proposed to explain these phenomena, among them increased sensitivity
to catecholamines because of increased numbers of beta receptors.