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

metoprolol tartrate is available. Oral dosing is initiated as soon as
the clinical situation permits. Metoprolol generally is contraindicated
for the treatment of acute myocardial infarction in patients
with heart rates of < 45 beats per minute, heart block greater than
first-degree (PR interval ≥ 0.24 second), systolic blood pressure
<100 mm Hg, or moderate to severe heart failure. Metoprolol also
has been proven to be effective in chronic heart failure. Its use is
associated with a striking reduction in all-cause mortality and hospitalization
for worsening heart failure and a modest reduction in
all-cause hospitalization (MERIT-HF Study Group, 1999; Prakash
and Markham, 2000).
Atenolol
Atenolol (TENORMIN, others) is a β 1
-selective antagonist
that is devoid of intrinsic sympathomimetic and membrane
stabilizing activity. Atenolol is very hydrophilic
and appears to penetrate the CNS only to a limited extent.
Its t 1/2
is somewhat longer than that of metoprolol.
Absorption, Fate, and Excretion. Atenolol is incompletely
absorbed (~50%), but most of the absorbed dose reaches the systemic
circulation. There is relatively little interindividual variation in
the plasma concentrations of atenolol; peak concentrations in different
patients vary over only a 4-fold range. The drug is
excreted largely unchanged in the urine, and the elimination t 1/2
is 5-8 hours. The drug accumulates in patients with renal failure,
and dosage should be adjusted for patients whose creatinine clearance
is < 35 mL/min.
Therapeutic Uses. Atenol can be used to treat hypertension, coronary
heart disease, arrhythmias, and angina pectoris, and to treat or
reduce the risk of heart complications following myocardial infarction.
It is also used to treat Graves disease until anti-thyroid medication
can take effect. The initial dose of atenolol for the treatment
of hypertension usually is 50 mg/day, given once daily. If an adequate
therapeutic response is not evident within several weeks, the
daily dose may be increased to 100 mg; higher doses are unlikely to
provide any greater antihypertensive effect. Atenolol has been shown
to be efficacious, in combination with a diuretic, in elderly patients
with isolated systolic hypertension. Atenolol causes fewer CNS side
effects (depression, nightmares) than most β blockers and few bronchospatic
reactions due to its pharmacological and pharmacokinetic
profile (Varon, 2008).
Esmolol
Esmolol (BREVIBLOC, others) is a β 1
-selective antagonist
with a rapid onset and a very short duration of
action. It has little if any intrinsic sympathomimetic
activity and lacks membrane-stabilizing actions.
Esmolol is administered intravenously and is used when
β blockade of short duration is desired or in critically ill
patients in whom adverse effects of bradycardia, heart
failure, or hypotension may necessitate rapid withdrawal
of the drug. It is a class II anti-arrhythmic agent
(Chapter 29).
Absorption, Fate, and Excretion. Esmolol is given by slow IV
injection and has a t 1/2
of ~8 minutes and an apparent volume of distribution
of ~2 L/kg. The drug contains an ester linkage, and it is
hydrolyzed rapidly by esterases in erythrocytes. The t 1/2
of the carboxylic
acid metabolite of esmolol is far longer (4 hours), and it
accumulates during prolonged infusion of esmolol. However, this
metabolite has very low potency as a β receptor antagonist (1/500 of
the potency of esmolol); it is excreted in the urine.
Esmolol is commonly used in patients during surgery to prevent
or treat tachycardia and in the treatment of supraventricular
tachycardia. The onset and cessation of β receptor blockade with
esmolol are rapid; peak hemodynamic effects occur within 6-10 minutes
of administration of a loading dose, and there is substantial attenuation
of β blockade within 20 minutes of stopping an infusion.
Esmolol may have striking hypotensive effects in normal subjects,
although the mechanism of this effect is unclear.
Because esmolol is used in urgent settings where immediate
onset of β blockade is warranted, a partial loading dose typically is
administered, followed by a continuous infusion of the drug. If an
adequate therapeutic effect is not observed within 5 minutes, the
same loading dose is repeated, followed by a maintenance infusion
at a higher rate. This process, including progressively greater infusion
rates, may need to be repeated until the desired end point (e.g.,
lowered heart rate or blood pressure) is approached. Esmolol is particularly
useful in severe postoperative hypertension and is a suitable
agent in situations where cardiac output, heart rate, and blood
pressure are increased. The American Heart Association/American
College of Cardiology guidelines recommend against using esmolol
in patients already on β blocker therapy, bradycardiac patients, and
decompensated heart failure patients, as the drug may compromise
their myocardial function (Varon, 2008).
Acebutolol
Acebutolol (SECTRAL, others) is a β 1
-selective antagonist
with some intrinsic sympathomimetic and membranestabilizing
activity.
Absorption, Fate, and Excretion. Acebutolol is well absorbed, and
undergoes significant first-pass metabolism to an active metabolite,
diacetolol, which accounts for most of the drug’s activity. Overall
bioavailability is 35-50%. The elimination t 1/2
of acebutolol typically
is ~3 hours, but the t 1/2
of diacetolol is 8-12 hours; it is excreted
largely in the urine. Acebutolol has lipophilic properties and crosses
the blood-brain barrier. It has no negative impact on serum lipids
(cholesterol, triglycerides, or HDL).
Therapeutic Uses. Acebutol has been used to treat hypertension,
ventricular and atrial cardiac arrhythmias, acute myocardial infarction
in high-risk patients, and Smith-Magenis syndrome. The initial
dose of acebutolol in hypertension usually is 400 mg/day; it may be
given as a single dose, but two divided doses may be required for
adequate control of blood pressure. Optimal responses usually occur
with doses of 400-800 mg per day (range, 200-1200 mg).
Bisoprolol
Bisoprolol (ZEBETA) is a highly selective β 1
receptor
antagonist that does not have intrinsic sympathomimetic
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CHAPTER 12
ADRENERGIC AGONISTS AND ANTAGONISTS