United States - English - NLM (National Library of Medicine)
ATENOLOL - atenolol tablet
A-S Medication Solutions
Atenolol Tablets, USP
Atenolol, a synthetic, beta -selective (cardioselective) adrenoreceptor blocking agent,
may be chemically described as 4 - [2-hydroxy-3-[(1- methylethyl) amino] propoxy]-
benzeneacetamide. The molecular and structural formulas are:
H N O
Atenolol (free base) has a molecular weight of 266.34. It is a relatively polar hydrophilic
compound with a water solubility of 26.5 mg/mL at 37°C and a log partition coefficient
(octanol/water) of 0.23. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less
soluble in chloroform (3 mg/mL at 25°C).
Atenolol tabletsare available as 25, 50 and 100 mg tablets for oral administration.
Inactive Ingredients:microcrystalline cellulose, povidone, sodium starch glycolate,
colloidal silicon dioxide and magnesium stearate
Atenolol is a beta -selective (cardioselective) beta-adrenergic receptor blocking agent
without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities.
This preferential effect is not absolute, however, and at higher doses, atenolol inhibits
beta -adrenoreceptors, chieflylocated in the bronchial and vascular musculature.
Pharmacokinetics and Metabolism
In man, absorption of an oral dose is rapid and consistent but incomplete.
Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the
remainder being excreted unchanged in the feces. Peak blood levels are reached
between two (2) and four (4) hours after ingestion. Unlike propranolol or metoprolol, but
like nadolol, atenolol undergoes little or no metabolism by the liver, and the absorbed
portion is eliminated primarily by renal excretion. Over 85% of an intravenous dose is
excreted in urine within 24 hours compared with approximately 50% for an oral dose.
Atenolol also differs from propranolol in that only a small amount (6%-16%) is bound to
proteins in the plasma. This kinetic profile results in relatively consistent plasma drug
levels with about a fourfold interpatient variation.
The elimination half- life of oral atenolol is approximately 6 to 7 hours, and there is no
alteration of the kinetic profile of the drug by chronic administration. Following
intravenous administration, peak plasma levels are reached within 5 minutes. Declines
from peak levels are rapid (5- to 10-fold) during the first 7 hours; thereafter, plasma
levels decay with a half-life similar to that of orally administered drug. Following oral
doses of 50 mg or 100 mg, both beta-blocking and antihypertensive effects persist for
at least 24 hours. When renal function is impaired, elimination of atenolol is closely
related to the glomerular filtration rate; significant accumulation occurs when the
creatinine clearance falls below 35 mL/min/1.73m . (See DOSAGE AND
In standard animal or human pharmacological tests, beta- adrenoreceptor blocking
activity of Atenolol has been demonstrated by: (1) reduction in resting and exercise
heart rate and cardiac output, (2) reduction of systolic and diastolic blood pressure at
rest and on exercise, (3) inhibition of isoproterenol induced tachycardia, and (4)
reduction in reflex orthostatic tachycardia.
A significant beta-blocking effect of atenolol, as measured by reduction of exercise
tachycardia, is apparent within one hour following oral administration of a single dose.
This effect is maximal at about 2 to 4 hours, and persists for at least 24 hours.
Maximum reduction in exercise tachycardia occurs within 5 minutes of an intravenous
dose. For both orally and intravenously administered drug, the duration of action is dose
related and also bears a linear relationship to the logarithm of plasma atenolol
concentration. The effect on exercise tachycardia of a single 10 mg intravenous dose is
largely dissipated by 12 hours, whereas beta-blocking activity of single oral doses of 50
mg and 100 mg is still evident beyond 24 hours following administration. However, as
has been shown for all beta-blocking agents, the antihypertensive effect does not
appear to be related to plasma level.
In normal subjects, the beta selectivity of atenolol has been shown by its reduced ability
to reverse the beta -mediated vasodilating effect of isoproterenol as compared to
equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of
atenololproducing a greater effect on resting heart rate than propranolol resulted in
much less increase in airway resistance. In a placebo controlled comparison of
approximately equipotent oral doses of several beta blockers, atenolol produced a
significantly smaller decrease of FEV than nonselective beta blockers such as
propranolol and, unlike those agents, did not inhibit bronchodilation in response to
Consistent with its negative chronotropic effect due to beta blockade of the SA node,
atenolol increases sinus cycle length and sinus node recovery time. Conduction in the
AV node is also prolonged. Atenolol is devoid of membrane stabilizing activity, and
increasing the dose well beyond that producing beta blockade does not further depress
myocardial contractility. Several studies have demonstrated a moderate (approximately
10%) increase in stroke volume at rest and during exercise.
In controlled clinical trials, atenolol tablets, given as a single daily oral dose, was an
effective antihypertensive agent providing 24-hour reduction of blood pressure. Atenolol
tablets have been studied incombination with thiazide type diuretics, and the blood
pressure effects of the combination are approximately additive. Atenolol tabletsare also
compatible with methyldopa, hydralazine, and prazosin, each combination resulting in a
larger fall in blood pressure than with the single agents. The dose range of atenolol is
narrow and increasing the dose beyond 100 mg once daily is not associated with
increased antihypertensive effect. The mechanisms of the antihypertensive effects of
beta-blocking agents have not been established. Several possible mechanisms have
been proposed and include: (1) competitive antagonism of catecholamines at peripheral
(especially cardiac) adrenergic neuron sites, leading to decreased cardiac output, (2) a
central effect leading to reduced sympathetic outflow to the periphery, and (3)
suppression of renin activity. The results from long-term studies have not shown any
diminution of the antihypertensive efficacy of atenolol tabletswith prolonged use.
By blocking the positive chronotropic and inotropic effects of catecholamines and by
decreasing blood pressure, atenolol 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, atenolol can increase oxygen
requirements by increasing left ventricular fiber length and end diastolic pressure,
particularly in patients with heart failure.
In a multicenter clinical trial (ISIS-1) conducted in 16,027 patients with suspected
myocardial infarction, patients presenting within 12 hours (mean = 5 hours) after the
onset of pain were randomized to either conventional therapy plus atenolol tablets(n =
8,037), or conventional therapy alone (n = 7,990). Patients with a heart rate of < 50
bpm or systolic blood pressure < 100 mm Hg or with other contraindications to beta
blockade were excluded. Thirty- eight percent of each group were treated within 4 hours
of onset of pain. The mean time from onset of pain to entry was 5.0 ± 2.7 hours in both
groups. Patients in the atenololgroup were to receive Atenolol I.V. Injection 5-10 mg
given over 5 minutes plus atenolol tablets 50 mg every 12 hours orally on the first study
day (the first oral dose administered about 15 minutes after the IV dose) followed by
either atenolol tablets 100 mg once daily or atenololtablets 50 mg twice daily on days 2-
7. The groups were similar in demographic and medical history characteristics and in
electrocardiographic evidence of myocardial infarction, bundle branch block, and first
degree atrioventricular block at entry.
During the treatment period (days 0- 7), the vascular mortality rates were 3.89% in the
atenolol tablets group (313 deaths) and 4.57% in the control group (365 deaths). This
absolute difference in rates, 0.68%, is statistically significant at the P < 0.05 level. The
absolute difference translates into a proportional reduction of 15% (3.89-4.57/4.57 = -
0.15). The 95% confidence limits are 1%- 27%. Most of the difference was attributed to
mortality in days 0-1 (Atenolol - 121 deaths; control - 171 deaths).
Despite the large size of the ISIS-1 trial, it is not possible to identify clearly subgroups of
patients most likely or least likely to benefit from early treatment with atenolol. Good
clinical judgment suggests, however, that patients who are dependent on sympathetic
stimulation for maintenance of adequate cardiac output and blood pressure are not
good candidates for beta blockade. Indeed, the trial protocol reflected that judgment by
excluding patients with blood pressure consistently below 100 mm Hg systolic. The
overall results of the study are compatible with the possibility that patients with
borderline blood pressure (less than 120 mm Hg systolic), especially if over 60 years of
age, are less likely to benefit.
The mechanism through which atenolol improves survival in patients with definite or
suspected acute myocardial infarction is unknown, as is the case for other beta blockers
in the postinfarction setting. Atenolol, in addition to its effects on survival, has shown
other clinical benefits including reduced frequency of ventricular premature beats,
reduced chest pain, and reduced enzyme elevation.
Atenolol Geriatric Pharmacology:
In general, elderly patients present higher atenolol plasma levels with total clearance
values about 50% lower than younger subjects. The half-life is markedly longer in the
elderly compared to younger subjects. The reduction in atenolol clearance follows the
general trend that the elimination of renallyexcreted drugs is decreased with increasing
INDICATIONS AND USAGE
Atenolol tablets are indicated for the treatment of hypertension, to lower blood
pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular
events, primarily strokes and myocardial infarctions. These benefits have been seen in
controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes
Control of high blood pressure should be part of comprehensive cardiovascular risk
management, including, as appropriate, lipid control, diabetes management,
antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many
patients will require more than 1 drug to achieve blood pressure goals. For specific
advice on goals and management, see published guidelines, such as those of the
National High Blood Pressure Education Program's Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with
different mechanisms of action, have been shown in randomized controlled trials to
reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood
pressure reduction, and not some other pharmacologic property of the drugs, that is
largely responsible for those benefits. The largest and most consistent cardiovascular
outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial
infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the
absolute risk increase per mmHg is greater at higher blood pressures, so that even
modest reductions of severe hypertension can provide substantial benefit. Relative risk
reduction from blood pressure reduction is similar across populations with varying
absolute risk, so the absolute benefit is greater in patients who are at higher risk
independent of their hypertension (for example, patients with diabetes or
hyperlipidemia), and such patients would be expected to benefit from more aggressive
treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in
black patients, and many antihypertensive drugs have additional approved indications
and effects (eg, on angina, heart failure, or diabetic kidney disease). These
considerations may guide selection of therapy.
Atenolol tablets may be administered with other antihypertensive agents.
Angina Pectoris Due to Coronary Atherosclerosis
Atenolol tablets are indicated for the long-term management of patients with angina
Acute Myocardial Infarction
Atenolol tablets are indicated in the management of hemodynamically stable patients
with definite or suspected acute myocardial infarction to reduce cardiovascular
mortality. Treatment can be initiated as soon as the patient's clinical condition allows.
(See DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS.)
In general, there is no basis for treating patients like those who were excluded from the
ISIS -1 trial (blood pressure less than 100 mm Hg systolic, heart rate less than 50 bpm)
or have other reasons to avoid beta blockade. As noted above, some subgroups (eg,
elderly patients with systolic blood pressure below 120 mm Hg) seemed less likely to
Atenolol tablets are contraindicated in sinus bradycardia, heart block greater than first
degree, cardiogenic shock, and overt cardiac failure. (See WARNINGS.)
Atenolol tablets are contraindicated in those patients with a history of hypersensitivity to
the atenolol or anyof the drug product's components.
Sympathetic stimulation is necessary in supporting circulatory function in congestive
heart failure, and beta blockade carries the potential hazard of further depressing
myocardial contractility and precipitating more severe failure.
In patients with acute myocardial infarction, cardiac failure which is not promptly and
effectively controlled by 80 mg of intravenous furosemide or equivalent therapy is a
contraindication to beta-blocker treatment.
In Patients without a History of Cardiac Failure
Continued depression of the myocardium with beta-blocking agents over a period of
time can, in some cases, lead to cardiac failure. At the first sign or symptom of
impending cardiac failure, patients should be treated appropriately according to
currently recommended guidelines, and the response observed closely. If cardiac failure
continues despite adequate treatment, atenolol tablets should be withdrawn. (See
DOSAGE AND ADMINISTRATION)
Cessation of Therapy with Atenolol Tablets
Patients with coronary artery disease, who are being treated with Atenolol tablets, should be advised
against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of
myocardial infarction and ventricular arrhythmias have been reported in angina patients following the
abrupt discontinuation of therapy with beta blockers. The last two complications may occur with or
without preceding exacerbation of the angina pectoris. As with other beta blockers, when
discontinuation of atenolol tablets is planned, the patients should be carefully observed and advised to
limit physical activity to a minimum. If the angina worsens or acute coronary insufficiency develops, it is
recommended that atenolol tablets be promptly reinstituted, at least temporarily. Because coronary
artery disease is common and may be unrecognized, it may be prudent not to discontinue atenolol
tablets therapy abruptly even in patients treated only for hypertension. (See DOSAGE AND
Concomitant Use of Calcium Channel Blockers
Bradycardia and heart block can occur and the left ventricular end diastolic pressure can
rise when beta-blockers are administered with verapamil or diltiazem. Patients with pre-
existing conduction abnormalities or left ventricular dysfunction are particularly
susceptible. (See PRECAUTIONS.)
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT
RECEIVE BETA BLOCKERS. Because of its relative beta selectivity, however,
Atenolol tablets may be used with caution in patients with bronchospastic
disease who do not respond to, or cannot tolerate, other antihypertensive
treatment. Since beta selectivity is not absolute, the lowest possible dose
of atenolol tablets should be used with therapy initiated at 50 mg and a
beta -stimulating agent (bronchodilator) should be made available. If dosage
must be increased, dividing the dose should be considered in order to
achieve lower peak blood levels.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior
to major surgery, however the impaired ability of the heart to respond to reflex
adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Diabetes and Hypoglycemia
Atenolol tablets should be used with caution in diabetic patients if a beta-blocking agent
is required. Beta blockers may mask tachycardia occurring with hypoglycemia, but other
manifestations such as dizziness and sweating may not be significantly affected. At
recommended doses atenolol does not potentiate insulin-induced hypoglycemia and,
unlike nonselective beta blockers, does not delay recovery of blood glucose to normal
Beta-adrenergic blockade may mask certain clinical signs (eg, tachycardia) of
hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm;
therefore, patients suspected of developing thyrotoxicosis from whom atenolol tablets
therapy is to be withdrawn should be monitored closely. (See DOSAGE AND
Atenolol tablets should not be given to patients with untreated pheochromocytoma.
Pregnancy and Fetal Injury
Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol
crosses the placental barrier and appears in cord blood. Administration of atenolol,
starting in the second trimester of pregnancy, has been associated with the birth of
infants that are small for gestational age. No studies have been performed on the use of
atenolol in the first trimester and the possibility of fetal injury cannot be excluded. If this
drug is used during pregnancy, or if the patient becomes pregnant while taking this
drug, the patient should be apprised of the potential hazard to the fetus.
Neonates born to mothers who are receiving Atenolol at parturition or breast-feeding
may be at risk for hypoglycemia and bradycardia. Caution should be exercised when
atenolol tablets is administered during pregnancy or to a woman who is breast-feeding.
(See PRECAUTIONS, Nursing Mothers.)
Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions
in rats at doses equal to or greater than 50 mg/kg/day or 25 or more times the
maximum recommended human antihypertensive dose.* Although similar effects were
not seen in rabbits, the compound was not evaluated in rabbits at doses above 25
mg/kg/day or 12.5 times the maximum recommended human antihypertensive dose.*
Patients already on a beta blocker must be evaluated carefully before Atenolol tabletsare
administered Initial and subsequent Atenolol tablet dosages can be adjusted downward
depending on clinical observations including pulse and blood pressure. Atenolol may
aggravate peripheral arterial circulatory disorders.
Impaired Renal Function
The drug should be used with caution in patients with impaired renal function. (See
DOSAGE AND ADMINISTRATION.)
*Based on the maximum dose of 100 mg/day in a 50 kg patient.
Catecholamine-depleting drugs (eg, reserpine) may have an additive effect when given
with beta-blocking agents. Patients treated with atenolol tablets plus a catecholamine
depletor should therefore beclosely observed for evidence of hypotension and/or
marked bradycardia which may produce vertigo, syncope, or postural hypotension.
Calcium channel blockers may also have an additive effect when given with atenolol
tablets (See WARNINGS).
Disopyramide is a Type I antiarrhythmic drug with potent negative inotropic and
chronotropic effects. Disopyramide has been associated with severe bradycardia,
asystole and heart failure when administered with beta blockers.
Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may
be additive to those seen with beta blockers.
Beta blockers may exacerbate the rebound hypertension which can follow the
withdrawal of clonidine. If the two drugs are coadministered, the beta blocker should be
withdrawn several days before the gradual withdrawal of clonidine. If replacing clonidine
by beta-blocker therapy, the introduction of beta blockers should be delayed for several
days after clonidine administration has stopped.
Concomitant use of prostaglandin synthase inhibiting drugs, eg, indomethacin, may
decrease the hypotensive effects of beta blockers.
Information on concurrent usage of atenolol and aspirin is limited. Data from several
studies, ie, TIMI-II, ISIS-2, currently do not suggest any clinical interaction between
aspirin and beta blockers in the acute myocardial infarction setting.
While taking beta blockers, patients with a history of anaphylactic reaction to a variety of
allergens may have a more severe reaction on repeated challenge, either accidental,
diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of
epinephrine used to treat the allergic reaction.
Both digitalis glycosides and beta-blockers slow atrioventricular conduction and
decrease heart rate.
Concomitant use can increase the risk of bradycardia.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two long-term (maximum dosing duration of 18 or 24 months) rat studies and one
long- term (maximum dosing duration of 18 months) mouse study, each employing
dose levels as high as 300 mg/kg/day or 150 times the maximum recommended human
antihypertensive dose,* did not indicate a carcinogenic potential of atenolol. A third (24
month) rat study, employing doses of 500 and 1,500 mg/kg/day (250 and 750 times the
maximum recommended human antihypertensive dose*) resulted in increased
incidences of benign adrenal medullary tumors in males and females, mammary
fibroadenomas in females, and anterior pituitary adenomas and thyroid parafollicular cell
carcinomas in males. No evidence of a mutagenic potential of atenolol was uncovered in
the dominant lethal test (mouse), in vivo cytogenetics test (Chinese hamster) or Ames
Fertility of male or female rats (evaluated at dose levels as high as 200 mg/kg/day or 100
times the maximum recommended human dose*) was unaffected by atenolol
Chronic studies employing oral atenolol performed in animals have revealed the
occurrence of vacuolation of epithelial cells of Brunner's glands in the duodenum of both
male and female dogs at all tested dose levels of atenolol (starting at 15 mg/kg/day or
7.5 times the maximum recommended human antihypertensive dose*) and increased
incidence of atrial degeneration of hearts of male rats at 300 but not 150 mg
atenolol/kg/day (150 and 75 times the maximum recommended human antihypertensive
Usage in Pregnancy
Pregnancy Category D
See WARNINGS - Pregnancy and Fetal Injury.
*Based on the maximum dose of 100 mg/day in a 50 kg patient.
Atenolol is excreted in human breast milk at a ratio of 1.5 to 6.8 when compared to the
concentration in plasma. Caution should be exercised when Atenolol tablets is
administered to a nursing woman. Clinically significant bradycardia has been reported in
breast-fed infants. Premature infants, or infants with impaired renal function, may be
more likely to develop adverse effects.
Neonates born to mothers who are receiving atenolol tabletsat parturition or breast-
feeding may be at risk for hypoglycemia and bradycardia. Caution should be exercised
when Atenolol tabletsare administered during pregnancy or to a woman who is breast-
feeding (See WARNINGS, Pregnancy and Fetal Injury).
Safety and effectiveness in pediatric patients have not been established.
Hypertension and Angina Pectoris Due to Coronary Atherosclerosis:
Clinical studies of atenolol tabletsdid not include sufficient number of patients aged 65
and over to determine whether they respond differently from younger subjects. Other
reported clinical experience has not identified differences in responses between the
elderly and younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the greater
frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease
or other drug therapy.
Acute Myocardial Infarction:
Of the 8,037 patients with suspected acute myocardial infarction randomized to atenolol
in the ISIS-1 trial (See CLINICAL PHARMACOLOGY), 33% (2,644) were 65 years of
age and older. It was not possible to identify significant differences in efficacy and safety
between older and younger patients; however, elderly patients with systolic blood
pressure < 120 mmHg seemed less likely to benefit (See INDICATIONS AND USAGE).
In general, dose selection for an elderly patient should be cautious, usually starting at
the low end of the dosing range, reflecting greater frequency of decreased hepatic,
renal, or cardiac function, and of concomitant disease or other drug therapy. Evaluation
of patients with hypertension or myocardial infarction should always include assessment
of renal function.
Most adverse effects have been mild and transient.
The frequency estimates in the following table were derived from controlled studies in
hypertensive patients in which adverse reactions were either volunteered by the patient
(US studies) or elicited, eg, by checklist (foreign studies). The reported frequency of
elicited adverse effects was higher for both atenolol tabletsand placebo-treated patients
than when these reactions were volunteered. Where frequency of adverse effects of
atenolol tabletsand placebo is similar, causal relationship to atenolol tabletsis uncertain.
Total volunteered and
(Foreign + US studies)
CENTRAL NERVOUS SYSTEM/
RESPIRATOR (See WARNINGS )
Acute Myocardial Infarction
In a series of investigations in the treatment of acute myocardial infarction, bradycardia
and hypotension occurred more commonly, as expected for any beta blocker, in
atenolol-treated patients than in control patients. However, these usually responded to
atropine and/or to withholding further dosage of atenolol. The incidence of heart failure
was not increased by atenolol. Inotropic agents were infrequently used. The reported
frequency of these and other events occurring during these investigations is given in the
In a study of 477 patients, the following adverse events were reported during either
intravenous and/or oral atenolol administration:
BBB + Major Axis Deviation
Total Cardiac Arrests
Nonfatal Cardiac Arrests
Development of Ventricular
Development of Mitral
In the subsequent International Study of Infarct Survival (ISIS-1) including over 16,000
patients of whom 8,037 were randomized to receive atenolol tabletstreatment, the
dosage of intravenous and subsequent oral atenolol tabletswas either discontinued or
reduced for the following reasons:
Reasons for reduced Dosage
Oral Partial Dose
Heart Block (> first
During postmarketing experience with atenolol tablets, the following have been reported
in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin,
hallucinations, headache, impotence, Peyronie's disease, postural hypotension which
may be associated with syncope, psoriasiform rash or exacerbation of psoriasis,
psychoses, purpura, reversible alopecia, thrombocytopenia, visual disturbance, sick
sinus syndrome, and dry mouth. Atenolol tablets, like other beta blockers, have been
associated with the development of antinuclear antibodies (ANA), lupus syndrome, and
POTENTIAL ADVERSE EFFECTS
In addition, a variety of adverse effects have been reported with other beta-adrenergic
blocking agents, and may be considered potential adverse effects of atenolol tablets.
Full dosage was 10 mg and some patients received less than 10 mg but more than 5 mg.