Propranolol
PROPRANOLOL- propranolol hydrochloride injection, solution
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Rx only
DESCRIPTION
Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as (+)- 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride. Its structural formula is:
C
16 H
21 NO
2 • HCl
M.W. 295.80
Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol.
Propranolol Hydrochloride Injection, USP is available as a 1 mg/mL sterile injectable solution for intravenous administration. Each mL contains 1 mg of propranolol hydrochloride in Water for Injection. The pH is adjusted to 2.8 to 4.0 with citric acid monohydrate.
CLINICAL PHARMACOLOGY
General
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, chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately.
At doses 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.
Mechanism of Action
The effects of propranolol are due to selective blockade of beta-adrenergic receptors, leaving alpha-adrenergic responses intact. There are two well-characterized subtypes of beta receptors (beta 1 and beta 2 ); propranolol interacts with both subtypes equally. Beta 1 -adrenergic receptors are found primarily in the heart. Blockade of cardiac beta 1 -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 beta 1 -adrenergic receptors also decreases the myocardial force of contraction and may provoke cardiac decompensation in patients with minimal cardiac reserve.
Beta 2 -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 Mechanism
Distribution
Propranolol has a distribution half-life (T 1/2 alpha) of 5 to 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 (T 1/2 alpha) 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 to 50% of metabolites, and ring oxidative products account for approximately 10 to 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 (C max ) 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 P450 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.
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