Propranolol Hydrochloride and Hydrochlorothiazide

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.

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a) if cardiac failure continues, despite adequate digitalization and diuretic therapy, propranolol therapy should be withdrawn (gradually, if possible); b) if tachyarrhythmia is being controlled, patients should be maintained on combined therapy and the patient closely followed until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.

(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.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

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.

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 T_3, and decreasing T₃.

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.

Cutaneous reactions, including Stevens-Johnson Syndrome, toxic epidermal necrolysis, exfoliative dermatitis, erythema multiforme, and urticaria, have been reported with use of propranolol (see ADVERSE REACTIONS).

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Propranolol should be used with caution in patients with impaired hepatic or renal function. Propranolol hydrochloride and hydrochlorothiazide tablets are not indicated for the treatment of hypertensive emergencies.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Medication such as digitalis may also influence serum electrolytes. Warning signs, irrespective of cause, are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Hypokalemia may be avoided or treated by use of potassium supplements or foods with a high potassium content.

Any chloride deficit is generally mild, and usually does not require specific treatment except under extraordinary circumstances (as in liver or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.

Diabetes mellitus which has been latent may become manifest during thiazide administration.

The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.

If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

Calcium excretion is decreased by thiazides. Pathologic changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism, such as renal lithiasis, bone resorption, and peptic ulceration, have not been seen.

Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

Elevated blood urea levels in patients with severe heart disease, elevated serum transaminase, alkaline phosphatase, lactate dehydrogenase.

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Patients receiving catecholamine-depleting drugs such as reserpine should be closely observed if propranolol hydrochloride and hydrochlorothiazide is administered. The added catecholamine-blocking action may produce an excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.

Caution should be exercised when patients receiving a beta-blocker are administered a calcium-channel blocking drug, especially intravenous verapamil, for both agents may depress myocardial contractility or atrioventricular conduction. On rare occasions, the concomitant intravenous use of a beta-blocker and verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.

Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.

Aluminum hydroxide gel greatly reduces intestinal absorption of propranolol.

Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.

Phenytoin, phenobarbitone, and rifampin accelerate propranolol clearance.

Chlorpromazine, when used concomitantly with propranolol, results in increased plasma levels of both drugs.

Antipyrine and lidocaine have reduced clearance when used concomitantly with propranolol.

Thyroxine may result in a lower than expected T₃ concentration when used concomitantly with propranolol.

Cimetidine decreases the hepatic metabolism of propranolol, delaying elimination and increasing blood levels.

Theophylline clearance is reduced when used concomitantly with propranolol.

Thiazide drugs may increase the responsiveness to tubocurarine.

Thiazides may decrease arterial responsiveness to norepinephrine. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Hypokalemia may develop during concomitant use of corticosteroids or ACTH.

Thiazides may decrease serum PBI levels without signs of thyroid disturbance.

Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS: General).

In dietary administration studies in which mice and rats were treated with propranolol for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. In a study in which both male and female rats were exposed to propranolol in their diets at concentrations of up to 0.05%, from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. Based on differing results from Ames Tests performed by different laboratories, there is equivocal evidence for a genotoxic effect of propranolol in bacteria (S. typhimurium strain TA 1538).

Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in vitro in the Ames bacterial mutagen assay (S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538) or in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Nor was it genotoxic in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity), Mouse Lymphoma Cell (mutagenicity) and Aspergillus nidulans non-disjunction assays.

Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to mating and throughout gestation.

Combinations of propranolol and hydrochlorothiazide have not been evaluated for effects on pregnancy in animals. Nor are there adequate and well controlled studies of propranolol, hydrochlorothiazide or the combination in pregnant women. Propranolol and hydrochlorothiazide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Propranolol is excreted in human milk. Caution should be exercised when propranolol hydrochloride and hydrochlorothiazide is administered to a nursing woman.

Thiazides appear in breast milk. If the use of the drug is deemed essential, the patient should stop nursing.

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥ 50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.