Propranolol Hydrochloride and Hydrochlorothiazide

PROPRANOLOL HYDROCHLORIDE AND HYDROCHLOROTHIAZIDE- propranolol hydrochloride and hydrochlorothiazide tablet
Actavis Elizabeth LLC

DESCRIPTION

Propranolol hydrochloride and hydrochlorothiazide tablets for oral administration combine two antihypertensive agents: propranolol hydrochloride, a beta-adrenergic blocking agent, and hydrochlorothiazide, a thiazide diuretic-antihypertensive.

Propranolol hydrochloride and hydrochlorothiazide tablets are available in 40 mg/25 mg and 80 mg/25 mg strengths. The 40 mg/25 mg tablets contain 40 mg propranolol hydrochloride and 25 mg hydrochlorothiazide; the 80 mg/25 mg tablets contain 80 mg propranolol hydrochloride and 25 mg hydrochlorothiazide.

Propranolol hydrochloride is a stable, white to off-white crystalline powder which is soluble in water and in alcohol. Its molecular weight is 295.81. Propranolol hydrochloride is a synthetic beta-adrenergic receptorblocking agent chemically described as 1-(Isopropylamino)-3 -(1- naphthyloxy)-2-propanol hydrochloride, which may be represented by the following structural formula:

Image from Drug Label Content

Hydrochlorothiazide is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution; sparingly soluble in methanol; insoluble in ether, chloroform, benzene, and dilute mineral acids. Its chemical name is 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide, which may be represented by the following structural formula:

Image from Drug Label Content

The following inactive ingredients are contained in propranolol hydrochloride and hydrochlorothiazide tablets: Colloidal Silicon Dioxide, Corn Starch, Lactose Monohydrate and Magnesium Stearate.

CLINICAL PHARMACOLOGY

Propranolol Hydrochloride: Propranolol hydrochloride is a non-selective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.

Propranolol is almost completely absorbed from the gastrointestinal tract, but a portion is immediately metabolized by the liver on its first pass through the portal circulation.

Peak effect occurs in one to one and one-half hours. The biologic half-life is approximately four hours. Propranolol is not significantly dialyzable. There is no simple correlation between dose or plasma level and therapeutic effect, and the dose-sensitivity range, as observed in clinical practice, is wide. The principal reason for this is that sympathetic tone varies widely between individuals. Since there is no reliable test to estimate sympathetic tone or to determine whether total beta blockade has been achieved, proper dosage requires titration.

The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to antihypertensive action are: (1) decreased cardiac output, (2) inhibition of renin release by the kidneys, and (3) diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain. Although total peripheral resistance may increase initially, it readjusts to, or below, the pretreatment level with chronic use. Effects on plasma volume appear to be minor and somewhat variable. Propranolol has been shown to cause a small increase in serum potassium concentration when used in the treatment of hypertensive patients. Propranolol hydrochloride decreases heart rate, cardiac output, and blood pressure.

Beta-receptor blockade can be useful in conditions in which, because of pathologic or functional changes, sympathetic activity is detrimental to the patient. But there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function is maintained by virtue of sympathetic drive, which should be preserved. In the presence of AV block, greater than first degree, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta blockade results in bronchial constriction by interfering with adrenergic bronchodilator activity, which should be preserved in patients subject to bronchospasm.

The proper objective of beta-blockade therapy is to decrease adverse sympathetic stimulation, but not to the degree that may impair necessary sympathetic support.

Hydrochlorothiazide: Hydrochlorothiazide is a benzothiadiazine (thiazide) diuretic closely related to chlorothiazide. The mechanism of the antihypertensive effect of the thiazides is unknown. Thiazides do not affect normal blood pressure.

Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency.

Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate. Onset of diuretic action of hydrochlorothiazide occurs in two hours, and the peak effect in about four hours. Its action persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.

Propranolol Hydrochloride and Hydrochlorothiazide Indications and Usage

Propranolol hydrochloride and hydrochlorothiazide tablets are indicated in the management of hypertension. This fixed combination is not indicated for initial therapy of hypertension. Hypertension requires therapy titrated to the individual patient. If the fixed combination represents the dosage so determined, its use may be more convenient in patient management.

CONTRAINDICATIONS

Propranolol Hydrochloride: Propranolol is contraindicated in: 1) cardiogenic shock; 2) sinus bradycardia and greater than first-degree block; 3) bronchial asthma; 4) congestive heart failure (see WARNINGS) unless the failure is secondary to a tachyarrhythmia treatable with propranolol.

Hydrochlorothiazide: Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs.

WARNINGS

Propranolol Hydrochloride: Cardiac Failure: Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure. Propranolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle (i.e., that of supporting the strength of myocardial contractions). In patients already receiving digitalis, the positive inotropic action of digitalis may be reduced by propranolol’s negative inotropic effect. The effects of propranolol and digitalis are additive in depressing AV conduction.

Patients Without a History of Heart Failure: Continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. In rare instances, this has been observed during propranolol therapy. 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: a) if cardiac failure continues, despite adequate digitalization and diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the patient closely followed until threat of cardiac failure is over.

Angina Pectoris: There have been reports of exacerbation of angina and, in some cases, myocardial infarction following abrupt discontinuation of propranolol therapy. Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced and the patient should be carefully monitored. In addition, when propranolol is prescribed for angina pectoris, the patient should be cautioned against interruption or cessation of therapy without the physician’s advice. If propranolol therapy is interrupted and exacerbation of angina occurs, it usually is advisable to reinstitute propranolol therapy and take other measures appropriate for the management of unstable angina pectoris. Since coronary artery disease may be unrecognized, it may be prudent to follow the above advice in patients considered at risk of having occult atherosclerotic heart disease, who are given propranolol for other indications.

Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema): PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS. Propranolol should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta receptors.

Major Surgery:The necessity or desirability of withdrawal of beta-blocking therapy prior to major surgery is controversial. It should be noted, however, that the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Propranolol, like other beta blockers, is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents; e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Difficulty in starting and maintaining the heartbeat has also been reported with beta blockers.

Diabetes and Hypoglycemia:Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia in labile insulin-dependent diabetes. In these patients, it may be more difficult to adjust the dosage of insulin. Hypoglycemic attack may be accompanied by a precipitous elevation of blood pressure in patients on propranolol.

Propranolol therapy, particularly in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting as in preparation for surgery. Hypoglycemia also has been found after this type of drug therapy and prolonged physical exertion and has occurred in renal insufficiency, both during dialysis, and sporadically, in patients on propranolol.

Acute increases in blood pressure have occurred after insulin-induced hypoglycemia in patients on propranolol.

Thyrotoxicosis:Beta blockade may mask certain clinical signs of hyperthyroidism. Therefore, abrupt withdrawal of propranolol may be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. Propranolol may change thyroid-function tests, increasing T4 , and reverse T3 , and decreasing T3 .

Wolff-Parkinson-White Syndrome:Several cases have been reported in which, after propranolol, the tachycardia was replaced by a severe bradycardia requiring a demand pacemaker. In one case this resulted after an initial dose of 5 mg propranolol.

Hydrochlorothiazide: Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. In patients with impaired renal function, cumulative effects of the drug may develop.

Thiazides should also be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic-blocking drugs.

Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma. The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

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