DAGHTAN

Atenolol is a cardioselective beta-blocker used in a variety of cardiovascular conditions.

Black, a Scottish pharmacologist, pioneered the use of beta-blockers for the management of angina pectoris in for which he received the Nobel Prize.

Beta-blockers quickly became popular in clinical use and where subsequently investigated for use in myocardial infarction, arrhythmias, and hypertension during the 1960s.

Later they continued to be investigated for use in heart failure throughout the 1970-1980s.

Atenolol itself was developed early on in this history by Alvogen Malta under the trade name Tenormin and received FDA approval in September, 1981.

Despite being one of the most widely prescribed beta blockers, evidence suggests atenolol may not significantly reduce mortality, and only modestly reduce the risk of cardiovascular disease in patients with hypertension. 20, 21 A Cochrane review of patients being treated for primary hypertension shows that atenolol shows a risk ratio of 0.88 for cardiovascular disease risk and a risk ratio of 0.99 for mortality. 20, 21 Similar results have been found in other meta-analyses. 22, 23 A meta-analysis of over 145,000 patients showed the risk of stroke in patients taking atenolol may depend on the age of the patient.

The use of atenolol may need to be based on more patient factors than hypertension alone. 20, 21, 22, 23.

Indicated for

Label 1) Management of hypertension alone and in combination with other antihypertensives. 2) Management of angina pectoris associated with coronary atherosclerosis. 3) Management of acute myocardial infarction in hemodynamically stable patients with a heart rate greater than 50 beats per minutes and a systolic blood pressure above 100 mmHg.

Off-label uses include: 1) Secondary prevention of myocardial infarction. 4 2) Management of heart failure. 3 3) Management of atrial fibrillation. 1 4) Management of supraventricular tachycardia. 5 5) Management of ventricular arrythmias such as congenital long-QT and arrhythmogenic right ventricular cardiomyopathy. 6 6) Management of symptomatic thyrotoxicosis in combination with methimazole. 2 7) Prophylaxis of migraine headaches. 7 8) Management of alcohol withdrawal. 8,

Atenolol is a cardio-selective beta-blocker and as such exerts most of its effects on the heart.

It acts as an antagonist to sympathetic innervation and prevents increases in heart rate, electrical conductivity, and contractility in the heart due to increased release of norepinephrine from the peripheral nervous system.

Label, 24, 14 Together the decreases in contractility and rate produce a reduction in cardiac output resulting in a compensatory increase in peripheral vascular resistance in the short-term.

This response later declines to baseline with long-term use of atenolol.

More importantly, this reduction in the work demanded of the myocardium also reduces oxygen demand which provides therapeutic benefit by reducing the mismatch of oxygen supply and demand in settings where coronary blood flow is limited, such as in coronary atherosclerosis.

Reducing oxygen demand, particularly due to exercise, can reduce the frequency of angina pectoris symptoms and potentially improve survival of the remaining myocardium after myocardial infarction.

The decrease in rate of sinoatrial node potentials, electrical conduction, slowing of potentials traveling through the atrioventricular node, and reduced frequency of ectopic potentials due to blockade of adrenergic beta receptors has led to benefit in arrhythmic conditions such as atrial fibrillation by controlling the rate of action potential generation and allowing for more effective coordinated contractions.

Since a degree of sympathetic activity is necessary to maintain cardiac function, the reduced contractility induced by atenolol may precipitate or worsen heart failure, especially during volume overload.

The effects of atenolol on blood pressure have been established, although it is less effective than alternative beta-blockers, but the mechanism has not yet been characterized.

Label, 24 As a β1 selective drug, it does not act via the vasodilation produced by non-selective agents.

Despite this there is a sustained reduction in peripheral vascular resistance, and consequently blood pressure, alongside a decrease in cardiac output.

It is thought that atenolol's antihypertensive activity may be related to action on the central nervous system (CNS) or it's inhibition of the renin-aldosterone-angiotensin system rather than direct effects on the vasculature.

Label Atenolol produces

CNS effects similar to other beta-blockers, but does so to a lesser extent due to reduces ability to cross the blood-brain barrier.

It has the potential to produce fatigue, depression, and sleep disturbances such as nightmares or insomnia.

Label, 24 The exact mechanisms behind these have not been characterized but their occurrence must be considered as they represent clinically relevant adverse effects.

Atenolol exerts some effects on the respiratory system although to a much lesser extent than non-selective beta-blockers.

Interaction with β2 receptors in the airways can produce bronchoconstriction by blocking the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system.

The same action can interfere with β-agonist therapies used in asthma and chronic obstructive pulmonary disease.

Label, 14, 24 Unlike some other beta-blocker drugs, atenolol does not have intrinsic sympathomimetic or membrane stabilizing activity nor does it produce changes in glycemic control.

Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, with the remainder being excreted unchanged in the feces.

Label Administering atenolol with food can decrease the AUC by about 20%.

While atenolol can cross the blood-brain barrier, it does so slowly and to a small extent.

Vd of 63.8-112.5 L.

Distribution takes about 3 hrs for the central compartment, 4 hrs for the shallower peripheral compartment, and 5-6 hrs for the deeper peripheral compartment.

Minimal metabolism in the liver.

The sole non-conjugated metabolite is the product of a hydroxylation reaction at the carbon between the amide and benzene groups.

The only other metabolite to be confirmed is a glucuronide conjugate.

These metabolites make up 5-8% and 2% of the renally excreted dose with 87-90% appearing as unchanged drug.

The hydroxylated metabolite is exerts 1/10th the beta-blocking activity of atenolol.

Hover over products below to view reaction partners Atenolol M1 (Atenolol) Atenolol-glucuronide conjugate.

85% is eliminated by the kidneys following Intravenous administration with 10% appearing in the feces.

Total clearance is estimated at 97.3-176.3 mL/min with a renal clearance of 95-168 mL/min.

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2 g/kg (Oral), 57 mg/kg (Intravenous), 134 mg/kg (IP), 400 mg/kg (Subcutaneous) 26 Rat: 2 g/kg (Oral), 77 mg/kg (Intravenous), 600 mg/kg (Subcutaneous) 26 Rabbit: 50 mg/kg (Intravenous) 26 Carcinogenicity & Mutagenicity Studies in rats and mice at doses of 300 mg/kg/day, equivalent to 150 times maximum recommended human dose, for durations of and 24 months showed no carcinogenicity.

One study in rats at doses of 500-1500 mg/kg/day, 250-750 times maximum human dose, resulted in increases benign adrenal medullary tumors in both sexes and increase mammary fibroadenomas in females.

Atenolol showed no mutagenicity in the Ames test using S. typhinarium, dominant lethal test in mice, or in vivo cytogenetics test in chinese hamster ovary cells.

No adverse effects on fertility were observed in either male or female mice after receiving doses of 200 mg/kg/day, equivalent to 200 times the maximum human dose.

In humans, atenolol is known to cross the placenta and fetuses exposed to the drug have been reported to be smaller than expected considering gestational age.

Embryo-fetal resorption has been observed in rats at doses of 50 mg/kg/day, 50 times the max human dose, but not in rabbits at doses of 25 mg/kg/day. Label Lactation Atenolol appears in breast milk at a ratio of 1.5-6.8 to plasma concentrations.

It has been estimated that infant exposure occurs at 5.7-19.2% maternal weight-adjusted dosage.

Effects in infants include bradycardia, hypothermia, and lethargy.

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 should be withdrawn. See DOSAGE AND ADMINISTRATION. Cessation of Therapy with Atenolol Patients with coronary artery disease, who are being treated with atenolol, 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 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 be promptly reinstituted, at least temporarily.

Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue atenolol therapy abruptly even in patients treated only for hypertension. See DOSAGE AND ADMINISTRATION. 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.

Bronchospastic Diseases PATIENTS WITH BRONCHOSPASTIC DISEASE

Because of its relative beta 1 selectivity, however, atenolol may be used with caution in patients with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive treatment.

Since beta 1 selectivity is not absolute, the lowest possible dose of atenolol should be used with therapy initiated at 50 mg and a beta 2 -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.

Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting).

If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment.

Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism.

Abrupt withdrawal of beta-blockade might precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom atenolol therapy is to be withdrawn should be monitored closely. See DOSAGE AND ADMINISTRATION. Untreated Pheochromocytoma Atenolol should not be given to patients with untreated pheochromocytoma.

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 breastfeeding may be at risk for hypoglycemia and bradycardia.

Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breastfeeding.

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. *Based on the maximum dose of 100 mg/day in a 50 kg patient.

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 any of the drug product’s components.

The initial dose of atenolol is 50 mg given as one tablet a day either alone or added to diuretic therapy.

The full effect of this dose will usually be seen within one to two weeks.

If an optimal response is not achieved, the dosage should be increased to atenolol 100 mg given as one tablet a day. Increasing the dosage beyond 100 mg a day is unlikely to produce any further benefit.

Atenolol may be used alone or concomitantly with other antihypertensive agents including thiazide-type diuretics, hydralazine, prazosin, and alpha-methyldopa.

The initial dose of atenolol is 50 mg given as one tablet a day. If an optimal response is not achieved within one week, the dosage should be increased to atenolol 100 mg given as one tablet a day. Some patients may require a dosage of 200 mg once a day for optimal effect.

Twenty-four hour control with once daily dosing is achieved by giving doses larger than necessary to achieve an immediate maximum effect.

The maximum early effect on exercise tolerance occurs with doses of 50 mg to 100 mg, but at these doses the effect at 24 hours is attenuated, averaging about 50% to 75% of that observed with once a day oral doses of 200 mg. Acute Myocardial Infarction In patients with definite or suspected acute myocardial infarction, treatment with atenolol I.V. injection should be initiated as soon as possible after the patient's arrival in the hospital and after eligibility is established.

Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has stabilized.

Treatment should begin with the intravenous administration of 5 mg atenolol over 5 minutes followed by another 5 mg intravenous injection 10 minutes later.

I.V. injection should be administered under carefully controlled conditions including monitoring of blood pressure, heart rate, and electrocardiogram.

Dilutions of atenolol

I.V. injection in dextrose injection, sodium chloride injection, or sodium chloride and dextrose injection may be used.

These admixtures are stable for 48 hours if they are not used immediately.

In patients who tolerate the full intravenous dose (10 mg), atenolol tablets 50 mg should be initiated 10 minutes after the last intravenous dose followed by another 50 mg oral dose 12 hours later.

Thereafter, atenolol can be given orally either 100 mg once daily or 50 mg twice a day for a further to 9 days or until discharge from the hospital.

If bradycardia or hypotension requiring treatment or any other untoward effects occur, atenolol should be discontinued.

Data from other beta-blocker trials suggest that if there is any question concerning the use of I.V. beta-blocker or clinical estimate that there is a contraindication, the I.V. beta-blocker may be eliminated and patients fulfilling the safety criteria may be given atenolol tablets 50 mg twice daily or 100 mg once a day for at least seven days (if the I.V. dosing is excluded).

Although the demonstration of efficacy of atenolol is based entirely on data from the first seven postinfarction days, data from other beta-blocker trials suggest that treatment with beta-blockers that are effective in the postinfarction setting may be continued for one to three years if there are no contraindications.

Atenolol is an additional treatment to standard coronary care unit therapy.

Elderly Patients or Patients with Renal Impairment Atenolol is excreted by the kidneys; consequently dosage should be adjusted in cases of severe impairment of renal function.

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.

Atenolol excretion would be expected to decrease with advancing age.

No significant accumulation of atenolol occurs until creatinine clearance falls below 35 mL/min/1.73 m 2.

Accumulation of atenolol and prolongation of its half-life were studied in subjects with creatinine clearance between 5 mL/min and 105 mL/min. Peak plasma levels were significantly increased in subjects with creatinine clearances below 30 mL/min. The following maximum oral dosages are recommended for elderly, renally-impaired patients and for patients with renal impairment due to other causes: Creatinine Clearance (mL/min/1.73 m 2 ) Atenolol Elimination Half-Life (h) Maximum Dosage 15-35 16-27 50 mg daily <15 >27 25 mg daily Some renally-impaired or elderly patients being treated for hypertension may require a lower starting dose of atenolol: 25 mg given as one tablet a day. If this 25 mg dose is used, assessment of efficacy must be made carefully.

This should include measurement of blood pressure just prior to the next dose ("trough" blood pressure) to ensure that the treatment effect is present for a full 24 hours.

Although a similar dosage reduction may be considered for elderly and/or renally-impaired patients being treated for indications other than hypertension, data are not available for these patient populations.

Patients on hemodialysis should be given 25 mg or 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.

Cessation of Therapy in Patients with Angina Pectoris If withdrawal of atenolol therapy is planned, it should be achieved gradually and patients should be carefully observed and advised to limit physical activity to a minimum.

USP, 100 mg are round, flat-face, beveled-edge, white to off-white uncoated tablets with “D” debossed on one side and “23” debossed on the other side.

NDC: 71335-2531-7: 10 Tablets in a BOTTLE NDC: 71335-2531-1: 100 Tablets in a BOTTLE NDC: 71335-2531-2: 30 Tablets in a BOTTLE NDC: 71335-2531-3: 60 Tablets in a BOTTLE NDC: 71335-2531-4: 90 Tablets in a BOTTLE NDC: 71335-2531-5: 20 Tablets in a BOTTLE NDC: 71335-2531-6: 180 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Dispense in well-closed, light-resistant containers.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

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 is administered to a nursing woman.

Clinically significant bradycardia has been reported in breastfed 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 at parturition or breastfeeding may be at risk for hypoglycemia and bradycardia.

Caution should be exercised when atenolol is administered during pregnancy or to a woman who is breastfeeding 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 did not include sufficient number of patients aged 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.

Of the 8,037 patients with suspected acute myocardial infarction randomized to atenolol in the ISIS-1 trial, 33% 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.

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.