PROPRANOLOL HYDROCHLORIDE- propranolol hydrochloride capsule, extended release
Propranolol hydrochloride is a synthetic beta-adrenergic receptor-blocking agent chemically described as 2-Propanol, 1-[(1-methylethyl)amino]-3-(1-naphthalenyloxy)-, hydrochloride,(±)-. It’s molecular and structural formulae are:
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Its molecular weight is 295.80.
Propranolol Hydrochloride Extended-Release Capsules, USP, are formulated to provide a sustained release of propranolol hydrochloride.
Propranolol Hydrochloride Extended-Release Capsules, USP, are available as 60 mg, 80 mg, 120 mg, and 160 mg capsules for oral administration.
Each capsule for oral administration contains sugar spheres, ethylcellulose, hypromellose phthalate, povidone, diethyl phthalate, polyethylene glycol, titanium dioxide, ammonium hydroxide, potassium hydroxide, black iron oxide, and gelatin. The 80 mg, 120 mg, and 160 mg capsules contain red and yellow iron oxide. In addition, the 160 mg capsules contain FD&C Blue No. 2.
These capsules comply with USP Dissolution Test 1.
Propranolol is a nonselective, 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. At dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action, which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
Propranolol Hydrochloride Extended-Release Capsules, USP, should not be considered a simple mg-for-mg substitute for conventional propranolol and the blood levels achieved do not match (are lower than) those of two to four times daily dosing with the same dose (see DOSAGE AND ADMINISTRATION). When changing to Propranolol Hydrochloride Extended-Release Capsules, USP, from conventional propranolol, a possible need for retitration upwards should be considered, especially to maintain effectiveness at the end of the dosing interval. In most clinical settings, however, such as hypertension or angina where there is little correlation between plasma levels and clinical effect, Propranolol Hydrochloride Extended-Release Capsules, USP, have been therapeutically equivalent to the same mg dose of conventional propranolol as assessed by 24-hour effects on blood pressure and on 24-hour exercise responses of heart rate, systolic pressure, and rate pressure product.
Mechanism of Action
The mechanism of the antihypertensive effect of propranolol has not been established. Among the factors that may be involved in contributing to the antihypertensive action include: (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 of propranolol.
Effects of propranolol on plasma volume appear to be minor and somewhat variable.
In angina pectoris, propranolol generally reduces the oxygen requirement of the heart at any given level of effort by blocking the catecholamine-induced increases in the heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction. Propranolol may increase oxygen requirements by increasing left ventricular fiber length, end diastolic pressure, and systolic ejection period. The net physiologic effect of beta-adrenergic blockade is usually advantageous and is manifested during exercise by delayed onset of pain and increased work capacity.
Propranolol exerts its antiarrhythmic effects in concentrations associated with beta-adrenergic blockade, and this appears to be its principal antiarrhythmic mechanism of action. In dosages greater than required for beta blockade, propranolol also exerts a quinidine-like or anesthetic-like membrane action which affects the cardiac action potential. The significance of the membrane action in the treatment of arrhythmias is uncertain.
The mechanism of the anti-migraine effect of propranolol has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
Propranolol is highly lipophilic and almost completely absorbed after oral administration. However, it undergoes high first pass metabolism by the liver and on average, only about 25% of propranolol reaches the systemic circulation. Propranolol Hydrochloride Extended-Release Capsules, USP, (60, 80, 120, and 160 mg) release propranolol HCl at a controlled and predictable rate. Peak blood levels following dosing with Propranolol Hydrochloride Extended-Release Capsules, USP, occur at about 6 hours.
The effect of food on Propranolol Hydrochloride Extended-Release Capsules, USP, bioavailability has not been investigated.
Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha-1-acid glycoprotein). The binding is enantiomer-selective. The S(–)-enantiomer is preferentially bound to alpha- 1-glycoprotein and the R(+)-enantiomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters/kg.
Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. It has been estimated that the percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol.
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.
Propranolol is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, p-glycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.
In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) with respect to oral clearance or elimination half-life. Partial clearance of 4-hydroxy propranolol was significantly higher and naphthyloxylactic acid was significantly lower in EMs than PMs.
When measured at steady state over a 24-hour period the areas under the propranolol plasma concentration-time curve (AUCs) for the Propranolol Hydrochloride Extended-Release Capsules, USP, are approximately 60% to 65% of the AUCs for a comparable divided daily dose of propranolol hydrochloride extended-release tablets. The lower AUCs for the Propranolol Hydrochloride Extended-Release Capsules, USP, are due to greater hepatic metabolism of propranolol, resulting from the slower rate of absorption of propranolol. Over a twenty-four (24) hour period, blood levels are fairly constant for about twelve (12) hours, then decline exponentially. The apparent plasma half-life is about 10 hours.
Propranolol is a racemic mixture of two enantiomers, R(+) and S(–). The S(–)-enantiomer is approximately 100 times as potent as the R(+)-enantiomer in blocking beta adrenergic receptors. In normal subjects receiving oral doses of racemic propranolol, S(–)-enantiomer concentrations exceeded those of the R(+)-enantiomer by 40-90% as a result of stereoselective hepatic metabolism. Clearance of the pharmacologically active S(–)-propranolol is lower than R(+)-propranolol after intravenous and oral doses.
The pharmacokinetics of Propranolol Hydrochloride Extended-Release Capsules, USP, have not been investigated in patients over 65 years of age.
In a study of 12 elderly (62-79 years old) and 12 young (25-33 years old) healthy subjects, the clearance of S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-life of both the R- and S-propranolol were prolonged in the elderly compared with the young (11 hours vs. 5 hours).
Clearance of propranolol is reduced with aging due to decline in oxidation capacity (ring oxidation and side chain oxidation). Conjugation capacity remains unchanged. In a study of 32 patients age 30 to 84 years given a single 20-mg dose of propranolol, an inverse correlation was found between age and the partial metabolic clearances to 4-hydroxypropranolol (40HP ring oxidation) and to naphthoxylactic acid (NLA-side chain oxidation). No correlation was found between age and the partial metabolic clearance to propranolol glucuronide (PPLG conjugation).
In a study of 9 healthy women and 12 healthy men, neither the administration of testosterone nor the regular course of the menstrual cycle affected the plasma binding of the propranolol enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the binding of propranolol after treatment with ethinyl estradiol. These findings are inconsistent with another study, in which administration of testosterone cypionate confirmed the stimulatory role of this hormone on propranolol metabolism and concluded that the clearance of propranolol in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for propranolol showed any significant association with either estradiol or testosterone.
A study conducted in 12 Caucasian and 13 African-American male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(–)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively.
Chinese subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha-1-acid glycoprotein.
The pharmacokinetics of Propranolol Hydrochloride Extended-Release Capsules, USP, have not been investigated in patients with renal insufficiency.
In a study conducted in 5 patients with chronic renal failure, 6 patients on regular dialysis, and 5 healthy subjects, who received a single oral dose of 40 mg of propranolol, the peak plasma concentrations (C max ) of propranolol in the chronic renal failure group were 2 to 3-fold higher (161±41 ng/mL) than those observed in the dialysis patients (47±9 ng/mL) and in the healthy subjects (26±1 ng/mL). Propranolol plasma clearance was also reduced in the patients with chronic renal failure.
Studies have reported a delayed absorption rate and a reduced half-life of propranolol in patients with renal failure of varying severity. Despite this shorter plasma half-life, propranolol peak plasma levels were 3-4 times higher and total plasma levels of metabolites were up to 3 times higher in these patients than in subjects with normal renal function.
Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity resulting in a lower “first-pass” clearance.
Propranolol is not significantly dialyzable.
The pharmacokinetics of Propranolol Hydrochloride Extended-Release Capsules, USP, have not been investigated in patients with hepatic insufficiency.
Propranolol is extensively metabolized by the liver. In a study conducted in 6 patients with cirrhosis and 7 healthy subjects receiving 160 mg of a long-acting preparation of propranolol once a day for 7 days, the steady-state propranolol concentration in patients with cirrhosis was increased 2.5-fold in comparison to controls. In the patients with cirrhosis, the half-life obtained after a single intravenous dose of 10 mg propranolol increased to 7.2 hours compared to 2.9 hours in control (see PRECAUTIONS).
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