involved, propranolol is used, it should be given intravenously in low dosage and very slowly, as the failing heart requires some sympathetic drive for maintenance of myocardial tone (see dosage & administration ). some patients may respond with complete reversion to normal sinus rhythm, but reduction in ventricular rate is more likely. ventricular arrhythmias do not respond to propranolol as predictably as do the supraventricular arrhythmias. intravenous propranolol is indicated for the treatment of persistent premature ventricular extrasystoles that impair the well‑being of the patient and do not respond to conventional measures. 3. tachyarrhythmias of digitalis intoxication intravenous propranolol is indicated to control ventricular rate in life-threatening digitalis-induced arrhythmias. severe bradycardia may occur (see overdosage ). 4. resistant tachyarrhythmias due to excessive catecholamine action during anesthesia intravenous propranolol is indicated to abolish tachyarrhythmias due to excessive catecholamine action during anesthesia when other measures fail. these arrhythmias may arise because of release of endogenous catecholamines or administration of catecholamines. all general inhalation anesthetics produce some degree of myocardial depression. therefore, when propranolol is used to treat arrhythmias during anesthesia, it should be used with extreme caution, usually with constant monitoring of the ecg and central venous pressure (see warnings ).

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 in propranolol-treated patients might augment the risks of general anesthesia and surgical procedures. 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. however, such patients may be subject to protracted severe hypotension. 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 in infants and children, diabetic or not, has been associated with hypoglycemia especially during fasting, as in preparation for surgery. hypoglycemia has been reported 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 t4 and reverse t3, and decreasing t3. wolff-parkinson-white syndrome beta-adrenergic blockade in patients with wolff-parkinson-white syndrome and tachycardia has been associated with severe bradycardia requiring treatment with a pacemaker. in one case this resulted after an initial 5 mg dose of intravenous propranolol.

ivid dreams; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. for immediate‑release formulations, fatigue, lethargy, and vivid dreams appear dose-related. gastrointestinal nausea, vomiting, epigastric distress, abdominal cramping, diarrhea, constipation, mesenteric arterial thrombosis, ischemic colitis. allergic pharyngitis and agranulocytosis; erythematous rash, fever combined with aching and sore throat; laryngospasm, and respiratory distress. respiratory bronchospasm. hematologic agranulocytosis, nonthrombocytopenic purpura, thrombocytopenic purpura. autoimmune in extremely rare instances, systemic lupus erythematosus has been reported. miscellaneous alopecia, le-like reactions, psoriaform rashes, dry eyes, male impotence, and peyronie’s disease have been reported rarely. oculomucocutaneous reactions involving the skin, serous membranes and conjunctivae reported for a beta-blocker (practolol) have not been associated with propranolol. to report suspected adverse reactions, contact west-ward pharmaceuticals corp. at 1-877-233-2001 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

s are found primarily in the heart. blockade of cardiac beta1-adrenergic receptors leads to a decrease in the activity of both normal and ectopic pacemaker cells and a decrease in a-v nodal conduction velocity. all of these actions can contribute to antiarrhythmic activity and control of ventricular rate during arrhythmias. blockade of cardiac beta1‑adrenergic receptors also decreases the myocardial force of contraction and may provoke cardiac decompensation in patients with minimal cardiac reserve. beta2-adrenergic receptors are found predominantly in smooth muscle–vascular, bronchial, gastrointestinal and genitourinary. blockade of these receptors results in constriction. clinically, propranolol may exacerbate respiratory symptoms in patients with obstructive pulmonary diseases such as asthma and emphysema (see contraindications and warnings ). propranolol’s beta blocking effects are attributable to its s(-) enantiomer. pharmacokinetics and drug metabolism distribution propranolol has a distribution half-life (t½ alpha) of 5-10 minutes and a volume of distribution of about 4 to 5 l/kg. approximately 90% of circulating propranolol is bound to plasma proteins. the binding is enantiomer-selective. the s-isomer is preferentially bound to alpha1 glycoprotein and the r-isomer is preferentially bound to albumin. metabolism and elimination the elimination half-life (t½ beta) is between 2 and 5.5 hours. propranolol is extensively metabolized with most metabolites appearing in the urine. the major metabolites include propranolol glucuronide, naphthyloxylactic acid, and glucuronic acid and sulfate conjugates of 4-hydroxy propranolol. following single-dose intravenous administration, side-chain oxidative products account for approximately 40% of the metabolites, direct conjugation products account for approximately 45-50% of metabolites, and ring oxidative products account for approximately 10-15% of metabolites. of these, only the primary ring oxidative product (4-hydroxypropranolol) possesses beta-adrenergic receptor blocking activity. in vitro studies have indicated that the aromatic hydroxylation of propranolol is catalyzed mainly by polymorphic cyp2d6. side‑chain oxidation is mediated mainly by cyp1a2 and to some extent by cyp2d6. 4-hydroxy propranolol is a weak inhibitor of cyp2d6. pharmacodynamics as propranolol concentration increases, so does its beta-blocking effect, as evidenced by a reduction in exercise-induced tachycardia (n = 6 normal volunteers). special populations pediatric the pharmacokinetics of propranolol have not been investigated in patients under 18 years of age. propranolol injection is not recommended for treatment of cardiac arrhythmias in pediatric patients. geriatric elevated propranolol plasma concentrations, a longer mean elimination half-life (254 vs. 152 minutes), and decreased systemic clearance (8 vs. 13 ml/kg/min) have been observed in elderly subjects when compared to young subjects. however, the apparent volume of distribution seems to be similar in elderly and young subjects. these findings suggest that dose adjustment of propranolol injection may be required for elderly patients (see precautions ). gender intravenously administered propranolol was evaluated in 5 women and 6 men. when adjusted for weight, there were no gender-related differences in elimination half-life, volume of distribution, protein binding, or systemic clearance. obesity in a study of intravenously administered propranolol, obese subjects had a higher auc (161 versus 109 hr·mcg/l) and lower total clearance than did non-obese subjects. propranolol plasma protein binding was similar in both groups. renal insufficiency the pharmacokinetics of propranolol and its metabolites were evaluated in 15 subjects with varying degrees of renal function after propranolol administration via the intravenous and oral routes. when compared with normal subjects, an increase in fecal excretion of propranolol conjugates was observed in patients with increased renal impairment. propranolol was also evaluated in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, following a single oral dose of 40 mg of propranolol. the peak plasma concentrations (cmax) of propranolol in the chronic renal failure group were 2- to 3-fold higher (161 ng/ml) than those observed in the dialysis patients (47 ng/‌ml) and in the healthy subjects (26 ng/ml). propranolol plasma clearance was also reduced in the patients with chronic renal failure. chronic renal failure has been associated with a decrease in drug metabolism via downregulation of hepatic cytochrome p-450 activity. hepatic insufficiency propranolol is extensively metabolized by the liver. in a study conducted in 6 normal subjects and 20 patients with chronic liver disease, including hepatic cirrhosis, 40 mg of r-propranolol was administered intravenously. compared to normal subjects, patients with chronic liver disease had decreased clearance of propranolol, increased volume of distribution, decreased protein-binding, and considerable variation in half-life. caution should be exercised when propranolol is used in this population. consideration should be given to lowering the dose of intravenous propranolol in patients with hepatic insufficiency (see precautions ). thyroid dysfunction no pharmacokinetic changes were observed in hyperthyroid or hypothyroid patients when compared to their corresponding euthyroid state. dosage adjustment does not seem necessary in either patient population based on pharmacokinetic findings. drug interactions interactions with substrates, inhibitors or inducers of cytochrome p-450 enzymes because propranolol’s metabolism involves multiple pathways in the cytochrome p-450 system (cyp2d6, 1a2, 2c19), administration of propranolol with drugs that are metabolized by, or affect the activity (induction or inhibition) of one or more of these pathways may lead to clinically relevant drug interactions (see precautions , drug interactions). substrates or inhibitors of cyp2d6 blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of cyp2d6, such as amiodarone, cimetidine, delavirdine, fluoxetine, paroxetine, quinidine, and ritonavir. no interactions were observed with either ranitidine or lansoprazole. substrates or inhibitors of cyp1a2 blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of cyp1a2, such as imipramine, cimetidine, ciprofloxacin, fluvoxamine, isoniazid, ritonavir, theophylline, zileuton, zolmitriptan, and rizatriptan. substrates or inhibitors of cyp2c19 blood levels of propranolol may be increased by administration of propranolol with substrates or inhibitors of cyp2c19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, teniposide, and tolbutamide. no interaction was observed with omeprazole. inducers of hepatic drug metabolism blood levels of propranolol may be decreased by administration of propranolol with inducers such as rifampin and ethanol. cigarette smoking also induces hepatic metabolism and has been shown to increase up to 100% the clearance of propranolol, resulting in decreased plasma concentrations. cardiovascular drugs antiarrhythmics the auc of propafenone is increased by more than 200% with co-administration of propranolol. the metabolism of propranolol is reduced by co-administration of quinidine, leading to a 2- to 3-fold increased blood concentrations and greater beta-blockade. the metabolism of lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. calcium channel blockers the mean cmax and auc of propranolol are increased respectively, by 50% and 30% by co-administration of nisoldipine and by 80% and 47%, by co-administration of nicardipine. the mean values of cmax and auc of nifedipine are increased by 64% and 79%, respectively, by co-administration of propranolol. propranolol does not affect the pharmacokinetics of verapamil and norverapamil. verapamil does not affect the pharmacokinetics of propranolol. non-cardiovascular drugs migraine drugs administration of zolmitriptan or rizatriptan with propranolol resulted in increased concentrations of zolmitriptan (auc increased by 56% and cmax by 37%) or rizatriptan (the auc and cmax were increased by 67% and 75%, respectively). theophylline co-administration of theophylline with propranolol decreases theophylline clearance by 33% to 52%. benzodiazepines propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. diazepam does not alter the pharmacokinetics of propranolol. the pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. neuroleptic drugs co-administration of propranolol at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 50% to 370% and increased thioridazine metabolites concentrations ranging from 33% to 210%. co-administration of chlorpromazine with propranolol resulted in increased plasma levels of both drugs (70% increase in propranolol concentrations). anti-ulcer drugs co-administration of propranolol with cimetidine, a non-specific cyp450 inhibitor, increased propranolol concentrations by about 40%. co‑administration with aluminum hydroxide gel (1200 mg) resulted in a 50% decrease in propranolol concentrations. co-administration of metoclopramide with propranolol did not have a significant effect on propranolol’s pharmacokinetics. lipid lowering drugs co-administration of cholesteramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations. co-administration of propranolol with lovastatin or pravastatin decreased 20% to 25% the auc of both, but did not alter their pharmacodynamics. propranolol did not have an effect on the pharmacokinetics of fluvastatin. warfarin concomitant administration of propranolol and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.

te decreases after intravenous propranolol. similarly limited clinical experience has shown that intravenous propranolol will slow the ventricular rate in patients with wolff-parkinson-white syndrome or with tachycardia associated with thyrotoxicosis. onset of activity is usually within five minutes.