CLINICAL PHARMACOLOGY
Mechanism of Action
The mechanism of the antihypertensive effect of propranolol has not been established. Among factors that contribute to the antihypertensive action are: (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. Effects of propranolol on plasma volume appear to be minor and somewhat variable.
Pharmacodynamics
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. Of the 2 enantiomers of propranolol, the S-enantiomer blocks beta-adrenergic receptors. When access to beta-receptor sites is blocked by propranolol, 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.
Pharmacokinetics
Absorption: Propranolol is highly lipophilic and is 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.
A single-dose, food-effect study in 36 healthy subjects showed that a high fat meal administered with INNOPRAN XL at 10 p.m., increased the lag time from 3 to 5 hours and the time to reach the maximum concentration from 11.5 to 15.4 hours, with no effect on the AUC.
Following multiple-dose administration of INNOPRAN XL at 10 p.m. under fasting conditions, the steady state lag time was between 4 and 5 hours and propranolol peak plasma concentrations were reached approximately 12 to 14 hours after dosing. Propranolol trough levels were achieved 24 to 27 hours after dosing, and persisted for 3 to 5 hours after the next dose.
The plasma levels of propranolol showed dose-proportional increases after single and multiple administration of 80, 120, and 160mg of INNOPRAN XL.
At steady state, the bioavailability of a 160-mg dose of INNOPRAN XL and propranolol hydrochloride long-acting capsules did not differ significantly.
Distribution: Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The binding is enantiomer-selective. The S-isomer is preferentially bound to alpha1 glycoprotein and the R-isomer preferentially bound to albumin. The volume of distribution of propranolol is approximately 4 liters.
Metabolism and Elimination: Propranolol is extensively metabolized with most metabolites appearing in the urine. Propranolol is metabolized through 3 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 4 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 for 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 to 4-hydroxy propranolol was significantly higher and to naphthyloxylactic acid was significantly lower in EMs than PMs.
In normal subjects receiving oral doses of racemic propranolol, S-enantiomer concentrations exceeded those of the R-enantiomer by 40 to 90% as a result of stereoselective hepatic metabolism.
The elimination half-life of propranolol was approximately 8 hours.
Specific Populations
Pediatric: The pharmacokinetics of INNOPRAN XL have not been investigated in patients younger than 18 years of age.
Geriatric: The pharmacokinetics of INNOPRAN XL have not been investigated in patients older than 65 years. In a study of 12 elderly (62 to 79 years old) and 12 young (25 to 33 years old) healthy subjects administered immediate-release propranolol, the clearance of the S-enantiomer of propranolol was decreased in the elderly. Additionally, the half-lives of both R- and S-propranolol were prolonged in the elderly compared with the young (11 hours versus 5 hours).
Gender: In a dose-proportionality study, the pharmacokinetics of INNOPRAN XL were evaluated in 22 male and 14 female healthy volunteers. Following single doses under fasting conditions, the mean AUC and Cmax were about 49% and 16% higher for females across the dosage range. The mean elimination half-life was longer in females than in males (11 hours versus 7.5 hours).
Race: A study conducted in 12 white and 13 African-American male subjects taking immediate-release propranolol showed, that at steady state, the clearance of R- and S-propranolol were about 76% and 53% higher in African-Americans than in whites, respectively.
Renal Impairment:
The pharmacokinetics of propranolol after administration of INNOPRAN XL have not been evaluated in patients with renal impairment. 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 (Cmax) of propranolol in the chronic renal failure group were 3- to 5-fold (161±41 ng/mL) 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.
Chronic renal failure has been associated with a decrease in drug metabolism via down regulation of hepatic cytochrome P450 activity.
Propranolol is not significantly dialyzable.
Hepatic Impairment:
The pharmacokinetics of propranolol after administration of INNOPRAN XL have not been evaluated in patients with hepatic impairment. However, propranolol is extensively metabolized by the liver. In a study conducted in 7 patients with cirrhosis and 9 healthy subjects receiving 80 mg oral propranolol every 8 hours for 7 doses, the steady-state unbound propranolol concentration in patients with cirrhosis was 3-fold that of controls. In cirrhosis, the half-life increased to 11 hours compared to 4 hours.
Drug-Drug Interactions
Impact of Propranolol on Other Drugs
The effect of propranolol on exposure to other drugs is shown in Table 2.
Table 2 Impact of propranolol on other drugs
| Other drug
|
Effect on their exposure
|
| Amide anesthetics (lidocaine, bupivacaine, mepivicaine) |
Increased |
| Warfarin |
Increased |
| Propafenone |
Increased >200% |
| Nifedipine |
Increased 80% |
| Verapamil |
None |
| Pravastatin, lovastatin |
Decreased 20% |
| Fluvastatin |
None |
| Zolmitriptan |
Increased 60% |
| Rizatriptan |
Increased 80% |
| Thioridazine |
Increased 370% |
| Diazepam |
Increased |
| Oxazepam, triazolam, lorazepam, alprazolam |
None |
| Theophylline |
Increased 70% |
Impact of Other Drugs on Propranolol
The effect of propranolol on exposure to other drugs is shown in Table 3.
Table 3 Impact of other drugs on exposure to propranolol
| Other drug
|
Effect on propranolol exposure
|
| Inhibitors of CYP2D6, CYP1A2, or CYP2C19 |
Increased |
| Inducers of CYP1A2 or CYP2C19 |
Decreased |
| Quinidine |
Increased >200% |
| Nisoldipine |
Increased 50% |
| Nicardipine |
Increased 80% |
| Chlorpromazine |
Increased 70% |
| Cimetidine |
Increased 50% |
| Cholestyramine, colestipol |
Decreased 50% |
| Alcohol |
Increased |
| Diazepam |
None |
| Verapamil |
None |
| Metochlopramide |
None |
| Ranitidine |
None |
| Lansoprazole |
None |
| Omeprazole |
None |
| Alcohol |
Increase acutely or decrease chronically |
| Propafenone |
Increased 200% |
| Quinidine |
Increased 200% |
| Cimetidine |
Increased 40% |
| Aluminum hydroxide |
Decreased 50% |
| Diazepam |
None |
| Nisoldipine, nicardipine, nifedipine |
Increased 50-80% |
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In dietary administration studies in which mice and rats were treated with propranolol HCl 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 MRHD of 640 mg propranolol HCl. In a study in which both male and female rats were exposed to propranolol HCl 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 2 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 HCl in bacteria (S. typhimurium strain TA 1538).
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