Zebeta (bisoprolol fumarate) is a synthetic, beta1-selective (cardioselective)

adrenoceptor blocking agent.

Zebeta (bisoprolol fumarate) is available as 5 and 10 mg tablets for oral administration.

INDICATIONS
Zebeta (bisoprolol fumarate) is indicated in the management of hypertension. It may be used alone or in
combination with other antihypertensive agents.

DOSAGE AND ADMINISTRATION

The dose of Zebeta (bisoprolol fumarate) must be individualized to the needs of the patient. The usual
starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose. If the
antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to
20 mg once daily.
Patients with Renal or Hepatic Impairment
In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less
than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since
limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in
patients undergoing dialysis.
Geriatric Patients
It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic
dysfunction

SIDE EFFECT
Bisoprolol is generally well-tolerated, and side effects are mild and transient. Side effects include
abdominal cramps, diarrhea,dizziness, fatigue, depression, headache, nausea,, impotence, slow heart
rate, low blood pressure,, numbness, tingling, cold extremities, sore throat, and shortness of
breath or wheezing. Patients with asthma may have symptoms increase.

OVERDOSE
The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension,
congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum:
2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted.
Sympathomimetic agents were given in some cases, and all patients recovered.
In general, if overdose occurs, Zebeta (bisoprolol fumarate) therapy should be stopped and supportive and
symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable.
Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following
general measures should be considered when clinically warranted:

CONTRAINDICATIONS
Zebeta (bisoprolol fumarate) is contraindicated in patients with cardiogenic shock, overt cardiac failure,
second or third degree AV block, and marked sinus bradycardia.

CLINICAL PHARMACOLOGY
Zebeta (bisoprolol fumarate) is a beta1-selective (cardioselective) adrenoceptor blocking agent without
significant membrane stabilizing activity or intrinsic sympathomimetic activity in its therapeutic dosage

range. Cardioselectivity is not absolute, however, and at higher doses ( 20 mg) bisoprolol fumarate also
inhibits beta2-adrenoceptors, chiefly located in the bronchial and vascular musculature; to retain selectivity
it is therefore important to use the lowest effective dose.
Pharmacokinetics and Metabolism
The absolute bioavailability after a 10 mg oral dose of bisoprolol fumarate is about 80%. Absorption is not
affected by the presence of food. The first pass metabolism of bisoprolol fumarate is about 20%.
Binding to serum proteins is approximately 30%. Peak plasma concentrations occur within 2-4 hours of
dosing with 5 to 20 mg, and mean peak values range from 16 ng/mL at 5 mg to 70 ng/mL at 20 mg. Once
daily dosing with bisoprolol fumarate results in less than twofold intersubject variation in peak plasma
levels. The plasma elimination half-life is 9-12 hours and is slightly longer in elderly patients, in part
because of decreased renal function in that population. Steady state is attained within 5 days of once daily
dosing. In both young and elderly populations, plasma accumulation is low; the accumulation factor ranges
from 1.1 to 1.3, and is what would be expected from the first order kinetics and once daily dosing. Plasma
concentrations are proportional to the administered dose in the range of 5 to 20 mg. Pharmacokinetic
characteristics of the two enantiomers are similar.
Bisoprolol fumarate is eliminated equally by renal and non-renal pathways with about 50% of the dose
appearing unchanged in the urine and the remainder appearing in the form of inactive metabolites. In
humans, the known metabolites are labile or have no known pharmacologic activity. Less than 2% of the
dose is excreted in the feces. Bisoprolol fumarate is not metabolized by cytochrome P450 II D6
(debrisoquin hydroxylase).
In subjects with creatinine clearance less than 40 mL/min, the plasma half-life is increased approximately
threefold compared to healthy subjects.
In patients with cirrhosis of the liver, the elimination of Zebeta (bisoprolol fumarate) (bisoprolol fumarate)
is more variable in rate and significantly slower than that in healthy subjects, with plasma half-life ranging
from 8.3 to 21.7 hours.
Pharmacodynamics
The most prominent effect of Zebeta (bisoprolol fumarate) is the negative chronotropic effect, resulting in
a reduction in resting and exercise heart rate. There is a fall in resting and exercise cardiac output with little
observed change in stroke volume, and only a small increase in right atrial pressure, or pulmonary
capillary wedge pressure at rest or during exercise.
Findings in short-term clinical hemodynamics studies with Zebeta (bisoprolol fumarate) are similar to
those observed with other beta-blocking agents.
The mechanism of action of its antihypertensive effects has not been completely established. Factors which
may be involved include:
1.
2.
3.

Decreased cardiac output,

Inhibition of renin release by the kidneys,
Diminution of tonic sympathetic outflow from the vasomotor centers in the brain.
In normal volunteers, Zebeta (bisoprolol fumarate) therapy resulted in a reduction of exercise- and
isoproterenol-induced tachycardia. The maximal effect occurred within 1-4 hours post-dosing. Effects
persisted for 24 hours at doses equal to or greater than 5 mg.
Electrophysiology studies in man have demonstrated that Zebeta (bisoprolol fumarate) significantly
decreases heart rate, increases sinus node recovery time, prolongs AV node refractory periods, and, with
rapid atrial stimulation, prolongs AV nodal conduction.
Beta1-selectivity of Zebeta (bisoprolol fumarate) has been demonstrated in both animal and human studies.
No effects at therapeutic doses on beta2-adrenoceptor density have been observed. Pulmonary function

studies have been conducted in healthy volunteers, asthmatics, and patients with chronic obstructive
pulmonary disease (COPD). Doses of Zebeta (bisoprolol fumarate) ranged from 5 to 60 mg, atenolol from
50 to 200 mg, metoprolol from 100 to 200 mg, and propranolol from 40 to 80 mg. In some studies, slight,
asymptomatic increases in airways resistance (AWR) and decreases in forced expiratory volume (FEV1)
were observed with doses of bisoprolol fumarate 20 mg and higher, similar to the small increases in AWR
also noted with the other cardioselective beta-blockers. The changes induced by beta-blockade with all
agents were reversed by bronchodilator therapy.
Zebeta (bisoprolol fumarate) had minimal effect on serum lipids during antihypertensive studies. In U.S.
placebo-controlled trials, changes in totalcholesterol averaged +0.8% for bisoprolol fumarate-treated
patients, and +0.7% for placebo. Changes in triglycerides averaged +19% for bisoprolol fumarate-treated
patients, and +17% for placebo.
Zebeta (bisoprolol fumarate) has also been given concomitantly with thiazide diuretics. Even very low
doses of hydrochlorothiazide (6.25 mg) were found to be additive with bisoprolol fumarate in
lowering blood pressure in patients with mild-to-moderate hypertension.

Dobutamine is an inotropic agent. It works by increasing the strength and force of the
heartbeat, causing more blood to circulate through the body.

INDICATIONS
Dobutamine is indicated when parenteral therapy is necessary for inotropicsupport in the shortterm treatment of adults with cardiac decompensation due to depressed contractility resulting
either from organic heart disease or from cardiac surgical procedures. Experience
with intravenous dobutamine in controlled trials does not extend beyond 48 hours of repeated
boluses and/or continuous infusions.
Whether given orally, continuously intravenously, or intermittently intravenously, neither
dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled trials to
be safe or effective in the long-term treatment of congestive heart failure. In controlled trials
of chronicoral therapy with various such agents, symptoms were not consistently alleviated, and
the cyclic-AMP-dependent inotropes were consistently associated with increased risk of
hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular
risk.

SIDE EFFECTS
Increased Heart Rate, Blood Pressure, and Ventricular Ectopic Activity A 10- to 20-mm
increase in systolic blood pressure and an increase in heartrate of 5 to 15 beats/minute have
been noted in most patients

OVERDOSE
Overdoses of dobutamine have been reported rarely. The following is provided to serve as a
guide if such an overdose is encountered.
Signs and Symptoms Toxicity from dobutamine is usually due to excessivecardiac -receptor
stimulation. The duration of action of dobutamine is generally short (T1/2= 2 minutes) because it is
rapidly metabolized by catechol-0-methyltranferase. The symptoms of toxicity may
include anorexia,nausea, vomiting, tremor, anxiety, palpitations, headache, shortness of breath,
and anginal and nonspecific chest pain. The positive inotropic and chronotropic effects of
dobutamine on the myocardium may causehypertension, tachyarrhythmias, myocardial ischemia,
and ventricular fibrillation. Hypotension may result from vasodilation.

CONTRAINDICATIONS

Dobutamine is contraindicated in patients with idiopathic hypertrophicsubaortic stenosis and in

patients who have shown previous manifestations of hypersensitivity to dobutamine.

CLINICAL PHARMACOLOGY
Dobutamine is a direct-acting inotropic agent whose primary activity results from stimulation of
the receptors of the heart while producing comparatively mild chronotropic, hypertensive,
arrhythmogenic, and vasodilative effects. It does not cause the release
of endogenous norepinephrine, as doesdopamine. In animal studies, dobutamine produces less
increase in heart rate and less decrease in peripheral vascular resistance for a given inotropic
effect than does isoproterenol.
In patients with depressed cardiac function, both dobutamine and isoproterenol increase
the cardiac output to a similar degree. In the case of dobutamine, this increase is usually not
accompanied by marked increases in heart rate (although tachycardia is occasionally observed),
and the cardiac stroke volume is usually increased. In contrast, isoproterenol increases
the cardiac index primarily by increasing the heart rate while strokevolume changes little or
declines.
Facilitation of atrioventricular conduction has been observed in humanelectrophysiologic studies
and in patients with atrial fibrillation.
Systemic vascular resistance is usually decreased with administration of dobutamine.
Occasionally, minimum vasoconstriction has been observed.
Most clinical experience with dobutamine is short-termnot more than several hours in duration.
In the limited number of patients who were studied for 24, 48, and 72 hours, a persistent increase
in cardiac output occurred in some, whereas output returned toward baseline values in others.
The onset of action of dobutamine is within 1 to 2 minutes; however, as much as 10 minutes may
be required to obtain the peak effect of a particular infusion rate.
The plasma half-life of dobutamine in humans is 2 minutes. The principal routes
of metabolism are methylation of the catechol and conjugation. In human urine, the major
excretion products are the conjugates of dobutamine and 3-O-methyl dobutamine. The 3-Omethyl derivative of dobutamine is inactive.
Alteration of synaptic concentrations of catecholamines with either reserpine or tricyclic
antidepressants does not alter the actions of dobutamine in animals, which indicates that the
actions of dobutamine are not dependent on presynaptic mechanisms.
The effective infusion rate of dobutamine varies widely from patient to patient, and titration is
always necessary. At least in pediatric patients, dobutamine-induced increases in cardiac output
and systemic pressure are generally seen, in any given patient, at lower infusion rates than those
that cause substantial tachycardia .