Propranolol Hydrochloride

Propranolol is contraindicated in 1) cardiogenic shock; 2) sinus bradycardia and greater than first degree block; 3) bronchial asthma; and 4) in patients with known hypersensitivity to propranolol hydrochloride.

• Angina Pectoris There have been reports of exacerbation of angina and, in some cases, myocardial infarction, following abrupt discontinuance of propranolol therapy.
• Therefore, when discontinuance of propranolol is planned, the dosage should be gradually reduced over at least a few weeks and 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 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.
• Hypersensitivity and Skin Reactions Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, have been associated with the administration of propranolol (see ADVERSE REACTIONS ).
• 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 ).
• Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure.
• Although beta blockers should be avoided in overt congestive heart failure, some have been shown to be highly beneficial when used with close follow-up in patients with a history of failure who are well compensated and are receiving additional therapies, including diuretics as needed.
• Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle.
• In Patients without a History of Heart Failure, Continued use of beta blockers can, in some cases, lead to cardiac failure.
• Nonallergic Bronchospasm (e.g., Chronic Bronchitis, Emphysema) In general, patients with bronchospastic lung disease should not receive beta blockers.
• Propranolol should be administered with caution in this setting since it may provoke a bronchial asthmatic attack by blocking bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-receptors.
• Major Surgery 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.
• Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of certain premonitory signs and symptoms (pulse rate and pressure changes) of acute hypoglycemia, especially in labile insulin-dependent diabetics.
• In these patients, it may be more difficult to adjust the dosage of insulin.
• Propranolol therapy, particularly when given to infants and children, diabetic or not, has been associated with hypoglycemia, especially during fasting as in preparation for surgery.
• Hypoglycemia has been reported in patients taking propranolol after prolonged physical exertion and in patients with renal insufficiency.
• Thyrotoxicosis Beta-adrenergic 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 T 4 and reverse T 3 and decreasing T 3 .
• Wolff-Parkinson-White Syndrome Beta-adrenergic blockade in patients with Wolf-Parkinson-White Syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker.
• In one case, this result was reported after an initial dose of 5 mg propranolol.
• Pheochromocytoma Blocking only the peripheral dilator (beta) action of epinephrine with propranolol leaves its constrictor (alpha) action unopposed.
• In the event of hemorrhage or shock, there is a disadvantage in having both beta and alpha blockade since the combination prevents the increase in heart rate and peripheral vasoconstriction needed to maintain blood pressure.
• General Propranolol should be used with caution in patients with impaired hepatic or renal function.
• Propranolol is not indicated for the treatment of hypertensive emergencies.
• Beta-adrenergic receptor blockade can cause reduction of intraocular pressure.
• Patients should be told that propranolol may interfere with the glaucoma screening test.
• Withdrawal may lead to a return of increased intraocular pressure.
• While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.
• Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
• Clinical Laboratory Tests In patients with hypertension, use of propranolol has been associated with elevated levels of serum potassium, serum transaminases and alkaline phosphatase.
• In severe heart failure, the use of propranolol has been associated with increases in Blood Urea Nitrogen.
• Drug Interactions Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways.
• Carcinogenesis, Mutagenesis, Impairment of Fertility In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis.
• On a body surface area basis, this dose in the mouse and rat is, respectively, about equal to and about twice the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride.
• In a study in which both male and female rats were exposed to propranolol hydrochloride in their diets at concentrations of up to 0.05% (about 50 mg/kg body weight and less than the MRHD), 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 hydrochloride in bacteria ( S . typhimurium strain TA 1538).
• Pregnancy In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation.
• Nursing Mothers Propranolol is excreted in human milk.
• Pediatric Use Safety and effectiveness of propranolol in pediatric patients have not been established.
• Geriatric Use Clinical studies of propranolol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
• Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
• In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
• General Propranolol should be used with caution in patients with impaired hepatic or renal function.
• Propranolol is not indicated for the treatment of hypertensive emergencies.
• Beta-adrenergic receptor blockade can cause reduction of intraocular pressure.
• Patients should be told that propranolol may interfere with the glaucoma screening test.
• Withdrawal may lead to a return of increased intraocular pressure.
• While taking beta blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic.
• Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.

• In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation.
• At doses of 150 mg/kg/day, but not at doses of 80 mg/kg/day (equivalent to the MRHD on a body surface area basis), treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths).
• Propranolol hydrochloride also was administered (in the feed) to rabbits (throughout pregnancy and lactation) at doses as high as 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose).
• No evidence of embryo or neonatal toxicity was noted.
• There are no adequate and well-controlled studies in pregnant women.
• Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy.
• Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and/or respiratory depression.
• Adequate facilities for monitoring such infants at birth should be available.
• Propranolol 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 is administered to a nursing woman.

• Caution should be exercised when propranolol is administered with drugs that have an effect on CYP2D6, 1A2, or 2C19 metabolic pathways.
• Co-administration of such drugs with propranolol may lead to clinically relevant drug interactions and changes on its efficacy and/or toxicity (see Drug Interactions in PHARMACOKINETICS AND DRUG METABOLISM ).
• Cardiovascular Drugs Antiarrhythmics Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol.
• Quinidine increases the concentration of propranolol and produces greater degrees of clinical beta-blockade and may cause postural hypotension.
• Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol.
• The clearance of lidocaine is reduced with administration of propranolol.
• Lidocaine toxicity has been reported following co-administration with propranolol.
• Caution should be exercised when administering propranolol with drugs that slow A-V nodal conduction, e.g. digitalis, lidocaine and calcium channel blockers.
• Digitalis Glycosides Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate.
• Concomitant use can increase the risk of bradycardia.
• Calcium Channel Blockers Caution should be exercised when patients receiving a beta blocker are administered a calcium-channel-blocking drug with negative inotropic and/or chronotropic effects.
• Both agents may depress myocardial contractility or atrioventricular conduction.
• There have been reports of significant bradycardia, heart failure, and cardiovascular collapse with concurrent use of verapamil and beta-blockers.
• Co-administration of propranolol and diltiazem in patients with cardiac disease has been associated with bradycardia, hypotension, high-degree heart block, and heart failure.
• ACE Inhibitors When combined with beta-blockers, ACE inhibitors can cause hypotension, particularly in the setting of acute myocardial infarction.
• The antihypertensive effects of clonidine may be antagonized by beta-blockers.
• Propranolol should be administered cautiously to patients withdrawing from clonidine.
• Alpha Blockers Prazosin has been associated with prolongation of first dose hypotension in the presence of beta-blockers.
• Postural hypotension has been reported in patients taking both beta-blockers and terazosin or doxazosin.
• Reserpine Patients receiving catecholamine-depleting drugs, such as reserpine, should be closely observed for excessive reduction of resting sympathetic nervous activity, which may result in hypotension, marked bradycardia, vertigo, syncopal attacks, or orthostatic hypotension.
• Inotropic Agents Patients on long-term therapy with propranolol may experience uncontrolled hypertension if administered epinephrine as a consequence of unopposed alpha-receptor stimulation.
• Epinephrine is therefore not indicated in the treatment of propranolol overdose (see OVERDOSAGE ).
• Isoproterenol and Dobutamine Propranolol is a competitive inhibitor of beta-receptor agonists, and its effects can be reversed by administration of such agents, e.g., dobutamine or isoproterenol.
• Also, propranolol may reduce sensitivity to dobutamine stress echocardiography in patients undergoing evaluation for myocardial ischemia.
• Non-Cardiovascular Drugs Nonsteroidal Anti-Inflammatory Drugs Nonsteroidal anti-inflammatory drugs (NSAIDS) have been reported to blunt the antihypertensive effect of beta-adrenoreceptor blocking agents.
• Administration of indomethacin with propranolol may reduce the efficacy of propranolol in reducing blood pressure and heart rate.
• Antidepressants The hypotensive effects of MAO inhibitors or tricyclic antidepressants may be exacerbated when administered with beta-blockers by interfering with the beta blocking activity of propranolol.
• Anesthetic Agents Methoxyflurane and trichloroethylene may depress myocardial contractility when administered with propranolol.
• Warfarin Propranolol when administered with warfarin increases the concentration of warfarin.
• Prothrombin time, therefore, should be monitored.
• Neuroleptic Drugs Hypotension and cardiac arrest have been reported with the concomitant use of propranolol and haloperidol.
• Thyroxine Thyroxine may result in a lower than expected T 3 concentration when used concomitantly with propranolol.
• Alcohol Alcohol, when used concomitantly with propranolol, may increase plasma levels of propranolol.

• Propranolol is not significantly dialyzable.
• In the event of overdosage or exaggerated response, the following measures should be employed:
• General:
• If ingestion is or may have been recent, evacuate gastric contents, taking care to prevent pulmonary aspiration.
• Supportive Therapy:
• Hypotension and bradycardia have been reported following propranolol overdose and should be treated appropriately.
• Glucagon can exert potent inotropic and chronotropic effects and may be particularly useful for the treatment of hypotension or depressed myocardial function after a propranolol overdose.
• Glucagon should be administered as 50 mcg/kg to 150 mcg/kg intravenously followed by continuous drip of 1 mg/hour to 5 mg/hour for positive chronotropic effect.
• Isoproterenol, dopamine or phosphodiesterase inhibitors may also be useful.
• Epinephrine, however, may provoke uncontrolled hypertension.
• Bradycardia can be treated with atropine or isoproterenol.
• Serious bradycardia may require temporary cardiac pacing.
• The electrocardiogram, pulse, blood pressure, neurobehavioral status and intake and output balance must be monitored.
• Isoproterenol and aminophylline may be used for bronchospasm.