TENORMIN® AstraZeneca Atenolol b-adrenergic Receptor Blocking Agent
Action and Clinical
Atenolol is a b 1-selective, b-adrenergic blocking agent, devoid of membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. It is a racemic mixture and the b 1-properties reside in the S(-) enantiomer. b 1-selectivity decreases with increasing dose.:
The mechanism of the antihypertensive effect has not been established. Among the factors that may be involved are: competitive ability to antagonize catecholamine-induced tachycardia at the b-receptor sites in the heart, thus decreasing cardiac output; inhibition of renin release by the kidneys; inhibition of the vasomotor centres.
The mechanism of the antianginal effect is also uncertain. An important factor may be the reduction of myocardial oxygen requirements by blocking catecholamine-induced increases in heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction.
In man atenolol reduces both isoproterenol- and exercise-induced increases in heart rate over the dose range of 50 to 200 mg. At an oral dose of 100 mg the b 1-blocking effects persist for at least 24 hours; the reduction in exercise-induced heart rate increase being about 32% and 13%, 2 and 24 hours after dosing, respectively. The logarithm of the plasma atenolol level correlates with the degree of b 1-blockade but not with the antihypertensive effect.
Pharmacokinetics: Approximately 40 to 50% of an oral dose of atenolol is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak plasma concentrations occur 2 to 4 hours after dosing and are subject to a 4-fold variability. The plasma levels are proportional to dose over the range 50 to 400 mg and 6 to 16% of atenolol is bound to plasma proteins. The mean peak plasma concentrations of atenolol were approximately 300 and 700 ng/mL following 50 and 100 mg, respectively. The plasma half-life is approximately 6 to 7 hours. Atenolol is extensively distributed to extravascular tissues, but only a small amount is found in the CNS.
There is no significant hepatic metabolism of atenolol in man and more than 90% of the absorbed dose reaches the systemic circulation unaltered. Small quantities of a hydroxy metabolite and a glucuronide are produced but neither has major pharmacological activity. As a consequence no accumulation occurs in patients with liver disease and no dosage adjustment is required. Approximately 47% and 53% of the oral dose is eliminated in the urine and feces, respectively. Recovery is complete after 72 hours.
Atenolol is primarily eliminated by the kidney, predominantly by glomerular filtration. The normal elimination half-life may increase in severe renal impairment but no significant accumulation occurs in patients who have creatinine clearance greater than 35 mL/min. The oral dose should be reduced in patients with a creatinine clearance less than 35 mL/min (see Dosage).
Atenolol is excreted in human breast milk and crosses the placental barrier-the maternal to cord blood ratio being about unity.
Indications And Clinical Uses:
Hypertension: In patients with mild or moderate hypertension. It is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be tried alone as an initial agent in those patients in whom, in the judgement of the physician, treatment should be started with a b-blocker rather than a diuretic. Atenolol may be used in combination with diuretics and/or vasodilators to treat severe hypertension.
The combination of atenolol with a diuretic or peripheral vasodilator has been found to be compatible. Limited experience with other antihypertensive agents has not shown evidence of incompatibility with atenolol.
Atenolol is not recommended for the emergency treatment of hypertensive crises.
Angina Pectoris: In the long-term management of patients with angina pectoris due to ischemic heart disease.
Sinus bradycardia, or bradycardia of other origin; second and third degree AV block; sick sinus syndrome; right ventricular failure secondary to pulmonary hypertension; congestive heart failure; cardiogenic shock; hypotension; severe peripheral arterial disorders; anesthesia with agents that produce myocardial depression; pheochromocytoma, in the absence of a-blockade; metabolic acidosis; known hypersensitivity to the product.
Warnings in Clinical States:
Cardiac Failure: Special caution should be exercised when administering atenolol to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with b-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Atenolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of atenolol when the two drugs are used concomitantly. The effects of b-blockers and digitalis are additive in depressing AV conduction. In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, atenolol therapy should be immediately withdrawn.
Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of atenolol. There have been reports of severe exacerbation of angina and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of b-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of atenolol is planned in patients with angina pectoris, the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed and advised to limit physical activity to a minimum. The same frequency of administration should be maintained. In situations of greater urgency, atenolol should be discontinued stepwise over a shorter time and under closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with atenolol be reinstituted promptly, at least temporarily.
Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with b-blockers, including atenolol. A severe syndrome (oculomucocutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of one b-adrenergic blocking agent (practolol). This syndrome has not been observed with atenolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Prinzmetal’s Angina: Atenolol may increase the number and duration of angina attacks in patients with Prinzmetal’s angina due to unopposed a-receptor mediated coronary artery vasoconstriction. Atenolol, therefore, should only be used in these patients with the utmost care.
Sinus Bradycardia: Severe sinus bradycardia may occur with the use of atenolol from unopposed vagal activity remaining after blockade of b 1-adrenergic receptors; in such cases, dosage should be reduced.
Thyrotoxicosis: In patients with thyrotoxicosis, possible deleterious effects from long-term use of atenolol have not been adequately appraised. b-blockade may mask the clinical signs of continuing hyperthyroidism or its complications and give a false impression of improvement. Therefore, abrupt withdrawal of atenolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
First Degree Heart Block: Due to its negative effect on AV conduction time, atenolol should be used with caution in patients with first degree block.
Peripheral Arterial Circulatory Disorders: Atenolol may aggravate less severe peripheral arterial circulatory disorders (see Contraindications).
Anaphylaxis-Epinephrine and b-blockers: There may be increased difficulty in treating an allergic type reaction in patients on b-blockers. In these patients, the reaction may be more severe due to pharmacologic effects of b-blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive a-adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of b-agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
Diabetes and Patients Subject to Hypoglycemia: Atenolol should be administered with caution to patients subject to spontaneous hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. b-adrenergic blockers may mask the premonitory signs (e.g., tachycardia) and symptoms of acute hypoglycemia.
Impaired Renal Function: Atenolol should be used with caution in patients with impaired renal function (see Dosage).
When renal function is impaired, clearance of atenolol is closely related to the glomerular filtration rate; however, significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73 m
Elective or Emergency Surgery: It is not advisable to withdraw b-adrenoceptor blocking drugs prior to surgery in the majority of patients. However, care should be taken when using atenolol with anesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2 mg i.v.).
Some patients receiving b-adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.
In emergency surgery, since atenolol is a competitive inhibitor of b-adrenergic receptor agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as isoproterenol or norepinephrine.
Ethnic Populations: Atenolol appears to be effective and well-tolerated in most ethnic populations, although the responses may be less in black patients than in Caucasians.
Pregnancy: 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. Although similar effects were not seen in rabbits, the compound was not evaluated in rabbits at doses above 25 mg/kg/day. There are no adequate and well-controlled studies in pregnant women. Studies in humans have shown that transplacental passage of atenolol does occur in pregnant women with fetal drug serum levels equal to those of the mother. In a limited number of patients who were given the drug during the last trimester of pregnancy, low birth weight, neonatal hypoglycemia, bradycardia in the fetus/newborn, and placental insufficiency were observed. Atenolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Lactation: In humans, there is a significant accumulation of atenolol in the breast milk of lactating women. If use of atenolol is considered essential, then mothers should stop nursing.
Children: There is no experience with atenolol in the treatment of pediatric age groups.
Occupational Hazards: Use of atenolol is unlikely to result in any impairment of the ability of patients to drive or operate machinery. However, it should be taken into account that dizziness or fatigue may occur.
Drug Interactions : Clonidine: b-blockers may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two drugs are coadministered, the b-blocker should be withdrawn several days before discontinuing clonidine. If replacing clonidine by b-blocker therapy, the introduction of b-blockers should be delayed for several days after clonidine administration has stopped (see also prescribing information for clonidine).
Reserpine or Guanethidine: Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored because the added b-adrenergic blocking action of atenolol may produce an excessive reduction of sympathetic activity. Atenolol should not be combined with other b-blockers.
Antiarrhythmic Agents: Care should be taken when atenolol is used concomitantly with Class I antiarrhythmic agents since these drugs may potentiate the cardiac depressing activity of atenolol. On rare occasions the concomitant administration of i.v. b-adrenergic blocking agents with i.v. verapamil has resulted in serious adverse effects, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction.
Calcium Channel Blockers: Combined use of b-blockers and calcium channel blockers with negative inotropic effects can lead to prolongation of SA and AV conduction, particularly in patients with impaired ventricular function, conduction abnormalities, or diminished cardiac output. This may result in severe hypotension, bradycardia and cardiac failure. Concomitant therapy with dihydropyridines, e.g., nifedipine, may increase the risk of hypotension, and cardiac failure may occur in patients with latent cardiac insufficiency.
Digitalis Glycosides: Digitalis glycosides may potentiate the bradycardia of b 1-blockade.
Nonsteroidal Anti-inflammatory Agents: The concomitant use of nonsteroidal anti-inflammatory agents may blunt the antihypertensive effects of b-blockers.
Anesthetic Agents: Anesthetics can produce a hypotensive state with associated reflex tachycardia. Since b-blockade will inhibit reflex tachycardia, the hypotensive potential of anesthetic agents is increased with concomitant use of atenolol (see Contraindications and Precautions).
The most serious adverse reactions encountered are congestive heart failure, AV block and bronchospasm.
The most common adverse reactions reported in clinical trials with oral Tenormin in 2 500 patients are bradycardia (3%), dizziness (3%), vertigo (2%), fatigue (3%), diarrhea (2%) and nausea (3%).
Adverse reactions occurring with an incidence of less than 1%, grouped by system, are as follows:
Cardiovascular: congestive heart failure (see Warnings), heart block, palpitations, lengthening of PR interval, chest pain, lightheadedness, postural hypotension which may be associated with syncope, Raynaud’s phenomenon, intermittent claudication, or worsening of pre-existing intermittent claudication, leg pain and cold extremities, edema.
Respiratory: dyspnea, wheeziness, cough, bronchospasm.
CNS: faintness, ataxia, tiredness, lethargy, nervousness, depression, drowsiness, vivid dreams, insommnia, paresthesia, headache, tinnitus, mood changes, visual disturbances, psychoses and hallucinations.
Gastrointestinal: constipation, anorexia, abdominal discomfort, indigestion.
Miscellaneous: skin rash, itchy and/or dry eyes, psoriasiform skin reactions, exacerbation of psoriasis, decreased exercise tolerance, alopecia, epistaxis, flushes, impotence, decreased libido, sweating, general body aches, thrombocytopenia and purpura.
Postmarketing Experience: During the postmarketing experience with Tenormin, the following have been reported in temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, headache, confusion, nightmares, impotence, Peyronie’s disease, psoriasisform rash or exacerbation of psoriasis, purpura, reversible alopecia and thrombocytopenia. Rare cases of hepatic toxicity including intrahepatic cholestasis have been reported. Tenormin, like other b-blockers, has been associated with the development of antinuclear antibodies (ANA) and lupus syndrome.
In a long-term, well-controlled trial of 1 627 elderly patients with systolic hypertension, the incidence of dry mouth was significantly higher in patients taking atenolol (12.2%).
Potential Adverse Reactions: The following adverse reactions have occurred with other b-blockers but have not been reported with atenolol:
Cardiovascular: pulmonary edema, cardiac enlargement, hot flushes and sinus arrest.
CNS: aggressiveness, anxiety, short-term memory loss, and emotional lability with slightly clouded sensorium.
Allergic: laryngospasm, status asthmaticus and fever combined with aching and sore throat.
Dermatological: exfoliative dermatitis.
Ophthalmological: blurred vision, burning, and grittiness.
Gastrointestinal: mesenteric arterial thrombosis and ischemic colitis.
Symptoms And Treatment Of Overdose:
Limited information is available with regard to overdosage with atenolol in humans. Overdosage with atenolol has been reported with patients surviving acute doses as high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely.
The predominant symptoms reported following atenolol overdosage are lethargy, disorder of respiratory drive, wheezing, sinus pause and bradycardia. Additionally, common effects associated with overdosage of any b-adrenergic blocking agent are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.
Treatment should be symptomatic and supportive and directed to the removal of any unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Further consideration should be given to dehydration, electrolyte imbalance and hypotension by established procedures.
Other treatment modalities should be employed at the physician’s discretion and may include:
Bradycardia: Atropine 1 to 2 mg i.v. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated. Glucagon in a 10 mg i.v. bolus has been reported to be useful. If required, this may be repeated or followed by an i.v. infusion of glucagon 1 to 10 mg/h depending on response. If no response to glucagon occurs or if glucagon is unavailable, a b-adrenoceptor stimulant such as dobutamine 2.5 to 10 g/kg/min by i.v. infusion or isoproterenol 10 to 25 g given as an infusion at a rate not exceeding 5 g/min may be given, although larger doses may be required.
Heart Block (second or third degree): Isoproterenol or transvenous pacemaker.
Congestive Heart Failure: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful.
Hypotension: Vasopressors such as dopamine or norepinephrine. Monitor blood pressure continuously.
Bronchospasm: A b 2-stimulant such as isoproterenol or terbutaline and/or i.v. aminophylline.
Hypoglycemia: I.V. glucose.
Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.
Dosage And Administration:
Hypertension: Atenolol is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic, but may be used alone (see Indications).
The dose of atenolol should be administered in accordance with individual patient’s needs.
The following guidelines are recommended: Initial dose: 50 mg administered as 1 tablet a day either added to diuretic therapy or alone. The full effect of this dose will usually be seen within 1 to 2 weeks. If an adequate response is not achieved, the dose should be increased to 100 mg once daily. Increasing the dose beyond 100 mg a day is unlikely to produce any further benefit.
If further lowering of the blood pressure is required, another antihypertensive agent should be added to the regimen.
Angina Pectoris: Initial dose: 50 mg given as 1 tablet a day. The full effect of this dose will usually be seen within 1 or 2 weeks. If an optimal response is not achieved within 1 week, the dosage should be increased to 100 mg given as 1 tablet a day. Some patients may require a dosage of 200 mg a day for optimal effect.
Renal Impairment: Since atenolol is eliminated predominantly via the kidneys, dosage should be adjusted in patients with severe renal impairment. Significant accumulation of atenolol occurs when creatinine clearance falls below 35 mL/min/1.73 m
Patients on hemodialysis should be given 50 mg after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.
Availability And Storage:
50 mg: Each scored, white to off-white biconvex, film-coated tablet embossed with TENORMIN 50 on one face, contains: atenolol 50 mg. Nonmedicinal ingredients: gelatin, glycerol, heavy magnesium carbonate, hydroxypropyl methylcellulose, magnesium stearate, maize starch, sodium lauryl sulfate and titanium dioxide. Energy: 1.26 kJ (0.3 kcal). Sodium: <1 mmol (0.3 mg). Calendar packs of 28.
100 mg: Each scored, white to off-white biconvex, film-coated tablet embossed with TENORMIN on one face, contains: atenolol 100 mg. Nonmedicinal ingredients: gelatin, glycerol, heavy magnesium carbonate, hydroxypropyl methylcellulose, magnesium stearate, maize starch, sodium lauryl sulfate and titanium dioxide. Energy: 2.1 kJ (0.5 kcal). Sodium: <1 mmol (0.6 mg). Calendar packs of 28.
Store at room temperature. Protect from light and moisture.
TENORMIN® AstraZeneca Atenolol b-adrenergic Receptor Blocking Agent