TENORETIC (atenolol/chlorthalidone) combines the antihypertensive activity of two agents, a beta-adrenergic receptor blocking agent (atenolol) and a diuretic (chlorthalidone).
Atenolol is a beta1-selective, beta adrenergic blocking agent, devoid of membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. It is a racemic mixture and the beta1 properties reside in the S(-) enantiomer. Beta1-selectivity decreases with increasing dose.
The mechanism of the antihypertensive effect of atenolol has not been established. Among the factors that may be involved are: a) competitive ability to antagonize catecholamine-induced tachycardia at the beta receptor sites in the heart, thus decreasing cardiac output. b) inhibition of renin release by the kidneys. c) inhibition of the vasomotor centres.
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 beta1 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 beta1 blockade but not with the antihypertensive effect.
Chlorthalidone, a monosulfonamyl diuretic, increases excretion of sodium and chloride. Natriuresis is accompanied by some loss of potassium. The mechanism by which chlorthalidone reduces blood pressure is not fully known but may be related to the excretion and redistribution of body sodium. Chlorthalidone usually does not decrease normal blood pressure.
The combination of atenolol with thiazide-like diuretics has been shown to be compatible and generally more effective than either drug used alone as an antihypertensive agent.
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 plasma half-life is approximately 6 to 7 hours.
Approximately 60% of an oral dose of chlorthalidone is absorbed from the gastrointestinal tract and excreted unchanged in the urine. Following a single dose, the peak blood concentration of chlorthalidone occurs after approximately 12 hours and decreases thereafter according to first-order kinetics; the disposition half-life is approximately 50 hours. Approximately 75% of chlorthalidone is bound in plasma.
Cardiac Failure: Special caution should be exercised when administering TENORETIC to patients with a history of cardiac failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure and inhibition with β-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure.
In patients without a history of cardiac failure, continued depression of the myocardium with β-blocking agents 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 additional diuretic and the response observed closely.
Atenolol acts selectively without blocking 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 β-blockers and digitalis are additive in depressing AV conduction. If cardiac failure continues, despite adequate digitalization, TENORETIC therapy should be withdrawn immediately and diuretic therapy maintained (see below).
Abrupt Cessation of Therapy: Patients with angina should be warned against abrupt discontinuation of TENORETIC. 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 β-blocker therapy. The last two complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of TENORETIC is planned in patients with angina pectoris, the drug should be stopped and immediately replaced with atenolol and a diuretic given separately, so that the dose of atenolol may be gradually reduced over a period of about 2 weeks while the dose of diuretic is maintained. The same frequency of administration of both drugs should be maintained. The patients should be carefully observed.
In situations of greater urgency, TENORETIC 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 TENORETIC be reinstituted promptly, at least temporarily.
Since ischemic heart disease may be unrecognized, the above advice should be followed in patients considered to be at risk of having asymptomatic ischemic heart disease.
Oculomucocutaneous Syndrome: Various skin rashes and conjunctival xerosis have been reported with β-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 β-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 with TENORETIC 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 α-receptor mediated coronary artery vasoconstriction. TENORETIC, 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 β1-adrenergic receptors; in such cases, the dose should be reduced.
Thyrotoxicosis: In patients with thyrotoxicosis, possible deleterious effects from long-term use of atenolol have not been adequately appraised. β-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. Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Impaired Renal Function: TENORETIC should be used with caution since chlorthalidone may precipitate or increase azotemia. Cumulative effects may develop since both components of TENORETIC are excreted by the kidney. If progressive renal impairment becomes evident, TENORETIC should be discontinued.
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 m2.
Impaired Hepatic Function: In patients with impaired hepatic function or progressive liver disease, even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Hepatic encephalopathy, manifested by tremors, confusion and coma, has been reported in association with diuretic therapy, including chlorthalidone.
Hypersensitivity Reactions: In patients receiving chlorthalidone, sensitivity reactions may occur with or without a history of allergy or bronchial asthma.
Systemic Lupus Erythematosus: Possible exacerbation of systemic lupus erythematosus has been reported with thiazide-like diuretics.
