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Atenolol and Chlorthalidone (Atenolol / Chlorthalidone) - Description and Clinical Pharmacology

 
 



Atenolol and
Chlorthalidone
Tablets USP
Revised: June 2006
Rx only

DESCRIPTION

Atenolol and chlorthalidone tablets are for the treatment of hypertension. It combines the antihypertensive activity of two agents: a beta1-selective (cardioselective) hydrophilic blocking agent (atenolol), and a monosulfonamyl diuretic (chlorthalidone). Atenolol is Benzeneacetamide, 4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]-. It has the following structural formula:

C<sub>14</sub>H<sub>22</sub>N<sub>2</sub>O<sub>3</sub>            M.W. 266.34

C14H22N2O3            M.W. 266.34

Atenolol (free base) is a relatively polar hydrophilic compound with a water solubility of 26.5 mg/mL at 37°C. It is freely soluble in 1N HCl (300 mg/mL at 25°C) and less soluble in chloroform (3 mg/mL at 25°C).

Chlorthalidone is 2-Chloro-5-(1-hydroxy-3-oxo-1-isoindolinyl)benzenesulfonamide. Chlorthalidone has a water solubility of 12 mg/100 mL at 20°C. It has the following structural formula:

C<sub>14</sub>H<sub>11</sub>ClN<sub>2</sub>O<sub>4</sub>S            M.W. 338.77

C14H11ClN2O4S            M.W. 338.77

Each atenolol and chlorthalidone tablet 50 mg-25 mg for oral administration contains: atenolol USP, 50 mg and chlorthalidone USP, 25 mg.

Each atenolol and chlorthalidone tablet 100 mg-25 mg for oral administration contains: atenolol USP, 100 mg and chlorthalidone USP, 25 mg.

Atenolol and Chlorthalidone Tablets USP, 50 mg-25 mg and 100 mg-25 mg, contain the following inactive ingredients: magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate.

CLINICAL PHARMACOLOGY

Atenolol and Chlorthalidone

Atenolol and chlorthalidone have been used singly and concomitantly for the treatment of hypertension. The antihypertensive effects of these agents are additive, and studies have shown that there is no interference with bioavailability when these agents are given together in the single combination tablet. Therefore, this combination provides a convenient formulation for the concomitant administration of these two entities. In patients with more severe hypertension, atenolol and chlorthalidone may be administered with other antihypertensives such as vasodilators.

Atenolol

Atenolol is a beta1-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 beta2-adrenoreceptors, chiefly located in the bronchial and vascular musculature.

Pharmacodynamics

In standard animal or human pharmacological tests, beta-adrenoreceptor blocking activity of atenolol has been demonstrated by: 1) reduction in resting and exercise heart rates 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. The effect at 24 hours is dose related and also bears a linear relationship to the logarithm of plasma atenolol concentration. 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 beta1-selectivity of atenolol has been shown by its reduced ability to reverse the beta2-mediated vasodilating effect of isoproterenol as compared to equivalent beta-blocking doses of propranolol. In asthmatic patients, a dose of atenolol producing 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 FEV1 than nonselective beta blockers, such as propranolol and unlike those agents did not inhibit bronchodilation in response to isoproterenol.

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 exercise.

In controlled clinical trials, atenolol given as a single daily dose, was an effective antihypertensive agent providing 24-hour reduction of blood pressure. Atenolol has been studied in combination with thiazide-type diuretics and the blood pressure effects of the combination are approximately additive. Atenolol is also compatible with methyldopa, hydralazine and prazosin, the 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 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 with prolonged use.

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 2 and 4 hours after ingestion. Unlike propranolol or metoprolol, but like nadolol, hydrophilic atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. 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. There is no information as to the pharmacokinetic effect of atenolol on chlorthalidone.

The elimination half-life of atenolol is approximately 6 to 7 hours and there is no alteration of the kinetic profile of the drug by chronic administration. Following 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; but significant accumulation does not occur until the creatinine clearance falls below 35 mL/min/1.73 m2 (see prescribing information for atenolol).

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 of atenolol clearance follows the general trend that elimination of renally excreted drugs is decreased with increasing age.

Chlorthalidone

Chlorthalidone is a monosulfonamyl diuretic which differs chemically from thiazide diuretics in that a double ring system is incorporated in its structure. It is an oral diuretic with prolonged action and low toxicity. The diuretic effect of the drug occurs within 2 hours of an oral dose. It produces diuresis with greatly increased excretion of sodium and chloride. At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The site of action appears to be the cortical diluting segment of the ascending limb of Henle’s loop of the nephron.

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