LO-TEN

Atenolol

Presentation

LO-TEN 50mg tablets: white film coated biconvex tablet, 7.9mm in diameter, imprinted "AT" over "50" on one side, with a "D" type breakline on the other side.

LO-TEN 100mg tablets: orange film coated biconvex tablet, 10mm in diameter, imprinted "AT" breakline "100" on one side.

Uses

Actions

LO-TEN (atenolol) is a beta-adrenoreceptor blocking medicine which is beta₁-selective (i.e. acts preferentially on beta₁-adrenergic receptors in the heart). Selectivity decreases with increasing dose. It is without intrinsic sympathomimetic and membrane-stabilising activities. Human studies indicate that it crosses the blood brain barrier only to a negligible extent.

As with other beta-adrenoreceptor blocking medicines, its mode of action in the treatment of hypertension is unclear. It is probably the action of ATENOLOL in reducing cardiac rate and contractility which makes it effective in eliminating or reducing the symptoms of patients with angina.

Pharmacokinetics

Following intravenous administration the blood levels of atenolol decay tri-exponentially with an elimination half-life of about 6 hours. Throughout the intravenous dose range of 5 to 10mg the blood level profile obeys linear pharmacokinetics and beta-blockade is still measurable 24 hours after a 10mg intravenous dose. Absorption of atenolol following oral dosing is consistent but incomplete (approximately 40 to 50%) with peak plasma concentrations occurring 2 to 4 hours after dosing. There is no significant hepatic metabolism of atenolol and more than 90% of that absorbed reaches the systemic circulation unaltered. The plasma half-life is about 6 hours but this may rise in severe renal impairment since the kidney is the major route of elimination. Atenolol penetrates tissues poorly due to its low lipid solubility and its concentration in brain tissue is low. Plasma protein binding is low (approximately 3%).

Indications

Control of hypertension.

Management of angina pectoris.

Control of cardiac dysrhythmias.

Myocardial infarction: early intervention in the acute phase and long term prophylaxis after recovery.

Dosage and Administration

Adults

Hypertension:

Most patients respond to 50 to 100mg daily given orally as a single dose. The effect will be fully established after one to two weeks. A further reduction in blood pressure may be achieved by combining Atenolol with other antihypertensive agents.

Angina:

Most patients with angina pectoris will respond to 100mg daily given orally as a single or divided dose. It is unlikely that additional benefit will be gained by increasing the dose.

Dysrhythmias:

Having controlled the dysrhythmias with intravenous Atenolol, a suitable oral maintenance dosage is 50 to 100mg daily, given as a single dose.

Myocardial Infarction:

Early intervention with Atenolol in acute myocardial infarction reduces infarct size and decreases morbidity and mortality. Fewer patients with a threatened infarction progress to a frank infarction; the incidence of ventricular arrhythmias is decreased and marked pain relief may result in reduced need of opiate analgesics. Early mortality is decreased. Atenolol is an additional treatment to standard coronary care.

For patients suitable for treatment with intravenous beta blockade and presenting within 12 hours of the onset of chest pain, Atenolol (5 to 10mg) should be given immediately by slow intravenous injection (1mg/minute) followed by Atenolol (50mg) orally about 15 minutes later, provided no untoward effects occur from the intravenous dose. This should be followed by 50mg orally 12 hours after the intravenous dose, and then 12 hours later by 100mg orally to be given once daily. If bradycardia and or hypotension, or any other untoward effects requiring treatment occur, Atenolol should be discontinued. For patients who present some days after suffering an acute myocardial infarction, an oral dose of 100mg daily is recommended for long term prophylaxis.

Renal Dysfunction:

Since Atenolol is excreted via the kidneys, dosage should be adjusted in cases of severe impairment of renal function. No significant accumulation of Atenolol occurs in patients who have a creatinine clearance > 35 mL/min/1.73m² (normal range is 100 to 150 mL/min/1.73m²). For patients with a creatinine clearance of 15 to 35mL/min/1.73m² (equivalent to serum creatinine clearance of 300 to 600 mcmol/litre) the oral dose should be 50mg daily and the intravenous dose should be 10mg once every two days. For patients with a creatinine clearance of <15 mL/min/1.73m² (equivalent to serum creatinine of 600mcmol/litre) the oral dose should be 25mg daily or 50mg on alternate days and the intravenous dose should be 10mg once every four days. Patients on haemodialysis should be given 50mg orally after each dialysis; this should be done under hospital supervision as marked falls in blood pressure can occur.

Elderly

Dosage requirements may be reduced, especially in patients with impaired renal function.

Children

There is no experience with Atenolol in children.

Contraindications

Atenolol as with other beta-blockers, should not be used in patients with any of the following: known hypersensitivity to the substance; bradycardia; bronchial asthma or other obstructive lung disorders; cardiogenic shock; hypotension; metabolic acidosis; severe peripheral arterial circulatory disturbances; second or third degree heart block; sick sinus syndrome; untreated phaeochromocytoma; uncontrolled heart failure.

Warnings and Precautions

Special care should be taken with patients whose cardiac reserve is poor. Because of their negative inotropic effects, beta-adrenoreceptor blocking medicines should be avoided in uncontrolled heart failure. However, they may be used in patients whose signs of failure have been controlled.

Atenolol may increase the number and duration of angina attacks in patients with Prinzmetal's angina due to unopposed alpha receptor mediated coronary artery vasoconstriction. Atenolol is a beta₁-selective beta-blocker; consequently, its use may be considered although utmost caution must be exercised.

Atenolol is contraindicated in severe peripheral arterial circulatory disturbances and may also aggravate less severe peripheral arterial circulatory disorders.

Due to its negative effect on conduction time, caution must be exercised if Atenolol is given to patients with first degree heart block.

Atenolol modifies the tachycardia of hypoglycaemia.

Atenolol may mask the signs of thyrotoxicosis.

One of the pharmacological actions of Atenolol is to reduce heart rate. In the rare instances when symptoms may be attributable to the slow heart rate, the dose may be reduced.

Cessation of therapy with a beta-adrenoreceptor blocking medicine should be gradual.

In patients suffering from ischaemic heart disease, as with other beta-adrenoreceptor blocking agents, treatment should not be discontinued abruptly.

Atenolol may cause a more severe reaction to a variety of allergens, when given to patients with a history of anaphylactic reaction to such allergens. Such patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions.

Anaesthesia:

It may not be advisable to withdraw beta-adrenoreceptor blocking medicines prior to surgery in the majority of patients. If Atenolol is withdrawn, 48 hours should elapse between the last dose and anaesthesia. Care should be taken when using anaesthetic agents with Atenolol. If treatment is continued, the anaesthetist should be informed and the choice of anaesthetic should be the agent with as little negative inotropic activity as possible. Use of beta-adrenoreceptor blocking medicines with anaesthetic medicines may result in attenuation of the reflex tachycardia and increase the risk of hypotension. Anaesthetic agents causing myocardial depression are best avoided. Care should also be taken when using anaesthetic agents such as ether, cyclopropane and trichloroethylene. Vagal dominance, if it occurs, may be corrected with atropine (1 to 2mg IV).

Renal failure: (See Dosage and Administration).

Pregnancy:

Atenolol crosses the placental barrier and appears in the cord blood. No studies have been performed on the use of Atenolol in the first trimester, and the possibility of foetal injury cannot be excluded. Atenolol has been used under close supervision for the treatment of hypertension in the third trimester.

Administration of Atenolol for longer periods to pregnant women in the management of mild to moderate hypertension has been associated with intrauterine growth retardation. The use of Atenolol in women who are, or may become, pregnant requires that the anticipated benefit be weighed against the possible risks, particularly in the first and second trimesters.

Lactation:

There is significant accumulation of Atenolol in breast milk. Caution should be exercised when Atenolol is administered to a nursing woman.

Effect on ability to drive or operate machinery:

The use of Atenolol is unlikely to result in any impairment of the patient to drive or operate machinery. However, it should be taken into account that occasionally dizziness or fatigue may occur.

Adverse Effects

Atenolol is well tolerated. In clinical studies, the undesired events reported are usually attributable to the pharmacological actions of Atenolol.

The following undesired events, listed by body system have been reported:

Cardiovascular: bradycardia; heart failure deterioration; postural hypotension which may be associated with syncope; cold extremities.

In susceptible patients: Precipitation of heart block; intermittent claudication; Raynaud's phenomenon.

CNS: confusion; dizziness; headache; mood changes; nightmares; psychoses and hallucinations; sleep disturbances of the type noted with other beta-blockers.

Gastrointestinal: dry mouth; gastrointestinal disturbances.

Haemotological: purpura; thrombocytopenia.

Integumentary: alopecia; dry eyes; psoriasiform skin reactions; exacerbation of psoriasis; skin rashes.

Neurological: paraesthesia

Respiratory: bronchospasm may occur in patients with bronchial asthma or a history of asthmatic complaints.

Special senses: visual disturbances.

Others: fatigue; an increase in ANA (Antinuclear Antibodies) has been observed, however the clinical relevance of this is not clear.

Discontinuance of the drug should be considered if, according to clinical judgement, the well-being of the patient is adversely affected by any of the above reactions.

Interactions

Combined use of beta-blockers and calcium channel blockers with negative inotropic effects e.g. verapamil, diltiazem can lead to an exaggeration of these effects particularly in patients with impaired ventricular function and/or SA or AV conduction abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. Neither the beta-blocker nor the calcium channel blocker should be administered intravenously within 48 hours of discontinuing the other.

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, in association with beta-blockers, may increase atrioventricular conduction time.

Beta-adrenoreceptor blocking medicines may exacerbate the rebound hypertension which can follow the withdrawal of clonidine. If the two medicines are co-administered, the beta-adrenoreceptor blocking medicine should be withdrawn several days before discontinuing clonidine. If replacing clonidine by beta-adrenoreceptor blocking therapy, the introduction of beta-adrenoreceptor blocking medicines should be delayed for several days after clonidine administration has stopped (also see prescribing information for clonidine).

Care should be taken in prescribing a beta-adrenoreceptor blocking medicine with Class I antidysrhythmic agents such as disopyramide.

Concomitant use of sympathomimetic agents, e.g. adrenaline, may counteract the effect of beta-adrenoreceptor blocking medicines.

Concomitant use of prostaglandin synthetase inhibiting drugs (e.g. ibuprofen, indomethacin), may decrease the hypotensive effects of beta adrenoreceptor blocking medicines.

Overdosage

The symptoms of overdosage may include bradycardia, hypotension, acute cardiac insufficiency and bronchospasm.

General treatment should include: close supervision, treatment in an intensive care ward, the use of gastric lavage, activated charcoal and a laxative to prevent absorption of any drug still present in the gastrointestinal tract, the use of plasma or plasma substitutes to treat hypotension and shock. The possible uses of haemodialysis or haemoperfusion may be considered.

Excessive bradycardia can be countered with atropine 1 to 2mg intravenously and or a cardiac pacemaker. If necessary, this may be followed by a bolus dose of glucagon 10mg intravenously. If required, this may be repeated or followed by an intravenous infusion of glucagon 1 to 10mg/hour depending on response. If no response to glucagon occurs or if glucagon is unavailable, a beta-adrenoreceptor stimulant such as dobutamine 2.5 to 10 micrograms/kg/min by intravenous infusion may be given. Dobutamine, because of its positive inotropic effect could also be used to treat hypotension and acute cardiac insufficiency. It is likely that these doses would be inadequate to reverse the cardiac effects of beta-blockade if a large overdose has been taken. The dose of dobutamine should therefore be increased if necessary to achieve the required response according to the clinical condition of the patient.

Bronchospasm can usually be reversed by bronchodilators.

Pharmaceutical Precautions

Atenolol tablets should be stored below 25°C protected from light and moisture.

Package Quantities

Atenolol 50mg AND 100mg Tablets are available in 30 day calendar packs and bottles of 100 and 500 tablets.

Further Information

Atenolol is effective for at least 24 hours after a single oral dose. This facilitates compliance by its acceptability to patients and simplicity of dosing. Atenolol is compatible with diuretics, other antihypertensive agents and antianginals. (See Warnings and Precautions). Atenolol is contraindicated in bronchial asthma or patients with other obstructive lung disorders. However, should adverse respiratory effects occur in susceptible patients, these are usually less severe than those associated with the administration of non-cardioselective blocking agents; this bronchospasm may usually be reversed by commonly used dosage of bronchodilators such as salbutamol or isoprenaline.

Atenolol is effective and well tolerated in most ethnic populations although the response may be less in Afro-Caribbean black patients.

It is unlikely that any additional ancillary properties possessed by S (-) Atenolol, in comparison with the racemic mixture, will give rise to different therapeutic effects