Actions of Proral in details
Pharmacology: Pharmacodynamics: Proral is a competitive antagonist at both the beta-1 and beta-2 adrenoceptors. It has no agonist activity at the beta-adrenoceptor, but has membrane stabilising activity at concentrations exceeding 1-3 mg/litre, though such concentrations are rarely achieved during oral therapy. Competitive beta-adrenoceptor blockade has been demonstrated in man by a parallel shift to the right in the dose-heart rate response curve to beta agonists such as isoprenaline.
Proral, as with other beta-blockers, has negative inotropic effects, and is therefore contraindicated in uncontrolled heart failure.
Proral is a racemic mixture and the active form is the S(-) isomer, of Proral. With the exception of inhibition of the conversion of thyroxine to triiodothyronine it is unlikely that any additional ancillary properties possessed by R(+) Proral, in comparison with the racemic mixture will give rise to different therapeutic effects.
Proral is effective and well-tolerated in most ethnic populations, although the response may be less in black patients.
Pharmacokinetics: Proral is completely absorbed after oral administration and peak plasma concentrations occur 1-2 hours after dosing in fasting patients. The liver removes up to 90% of an oral dose with an elimination half-life of 3 to 6 hours. Proral is widely and rapidly distributed throughout the body with highest levels occurring in the lungs, liver, kidney, brain and heart. Proral is highly protein bound (80-95%).
How should I take Proral?
Take Proral exactly as prescribed by your doctor. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not take this medicine in larger or smaller amounts or for longer than recommended.
Adults may take Proral with or without food, but take it the same way each time.
Take this medicine at the same time each day.
Do not crush, chew, break, or open an extended-release capsule. Swallow it whole.
Your blood pressure will need to be checked often.
If you need surgery, tell the surgeon ahead of time that you are using Proral. You may need to stop using Proral for a short time.
Do not skip doses or stop using Proral suddenly. Stopping suddenly may make your condition worse. Follow your doctor's instructions about tapering your dose.
This medicine can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using Proral.
If you are being treated for high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.
Proral is only part of a complete program of treatment for hypertension that may also include diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely if you are being treated for hypertension.
Store at room temperature away from moisture and heat.
Proral administration
Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.
You may take Proral with or without food, but take it the same way each time.
Take the medicine at the same time each day.
Do not crush, chew, break, or open an extended-release capsule. Swallow it whole. Breaking or opening the pill may cause too much of the drug to be released at one time.
To be sure you get the correct dose, measure the liquid with a marked measuring spoon or medicine cup, not with a regular table spoon. If you do not have a dose-measuring device, ask your pharmacist for one.
Do not skip doses or stop using Proral without first talking to your doctor. You may need to use less and less before you stop the medication completely.
Your blood pressure will need to be checked often. Visit your doctor regularly.
If you need surgery, tell the surgeon ahead of time that you are using Proral. You may need to stop using the medicine for a short time.
Proral is only part of a complete program of treatment for hypertension that may also include diet, exercise, and weight control. Follow your diet, medication, and exercise routines very closely if you are being treated for hypertension.
If you are being treated for high blood pressure, keep using this medication even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medication for the rest of your life.
This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using Proral.
Store at room temperature away from moisture and heat.
Proral pharmacology
General
Proral 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 Proral, the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation are decreased proportionately. At dosages greater than required for beta blockade, Proral 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.
Proral should not be considered a simple mg-for-mg substitute for conventional Proral and the blood levels achieved do not match (are lower than) those of two to four times daily dosing with the same dose. When changing to Proral from conventional Proral, 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, Proral has been therapeutically equivalent to the same mg dose of conventional Proral 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 Proral 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 Proral. Effects of Proral on plasma volume appear to be minor and somewhat variable.
In angina pectoris, Proral 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. Proral 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.
Proral 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, Proral 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 Proral has not been established. Beta-adrenergic receptors have been demonstrated in the pial vessels of the brain.
Pharmacolinetics And Drug Metabolism
Absorption
Proral 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 Proral reaches the systemic circulation. Proral Capsules (60, 80, 120, and 160 mg) release Proral at a controlled and predictable rate. Peak blood levels following dosing with Proral occur at about 6 hours.
The effect of food on Proral bioavailability has not been investigated.
Distribution
Approximately 90% of circulating Proral 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 Proral is approximately 4 liters/kg.
Proral crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Metabolism And Elimination
Proral is extensively metabolized with most metabolites appearing in the urine. Proral is metabolized through three primary routes: aromatic hydroxylation (mainly 4-hydroxylation), Ndealkylation 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 Proral glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4- hydroxy Proral.
In-vitro studies have indicated that the aromatic hydroxylation of Proral is catalyzed mainly by polymorphic CYP2D6. Side-chain oxidation is mediated mainly by CYP1A2 and to some extent by CYP2D6. 4-hydroxy Proral is a weak inhibitor of CYP2D6.
Proral is also a substrate of CYP2C19 and a substrate for the intestinal efflux transporter, pglycoprotein (p-gp). Studies suggest however that p-gp is not dose-limiting for intestinal absorption of Proral 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 Proral was significantly higher and naphthyloxyactic acid was significantly lower in EMs than PMs.
When measured at steady state over a 24-hour period the areas under the Proral plasma concentration-time curve (AUCs) for the Proral capsules are approximately 60% to 65% of the AUCs for a comparable divided daily dose of Proral Tablets. The lower AUCs for the Proral capsules are due to greater hepatic metabolism of Proral, resulting from the slower rate of absorption of Proral. 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.
Enantiomers
Proral 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 Proral, 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(–)-Proral is lower than R(+)-Proral after intravenous and oral doses.
Special Population
Geriatric
The pharmacokinetics of Proral 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 Proral was decreased in the elderly. Additionally, the half-life of both the Rand S-Proral were prolonged in the elderly compared with the young (11 hours vs. 5 hours).
Clearance of Proral 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 Proral, 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 Proral glucuronide (PPLG conjugation).
Gender
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 Proral enantiomers. In contrast, there was a significant, although non-enantioselective diminution of the binding of Proral 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 Proral metabolism and concluded that the clearance of Proral in men is dependent on circulating concentrations of testosterone. In women, none of the metabolic clearances for Proral showed any significant association with either estradiol or testosterone.
Race
A study conducted in 12 Caucasian and 13 African-American male subjects taking Proral, showed that at steady state, the clearance of R(+)- and S(–)-Proral 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 Proral in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha-1-acid glycoprotein.
Renal Insufficiency
The pharmacokinetics of Proral 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 Proral, the peak plasma concentrations (Cmax) of Proral 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). Proral 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 Proral in patients with renal failure of varying severity. Despite this shorter plasma half-life, Proral 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. Proral is not significantly dialyzable.
Hepatic Insufficiency
The pharmacokinetics of Proral have not been investigated in patients with hepatic insufficiency. Proral 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 Proral once a day for 7 days, the steady-state Proral 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 Proral increased to 7.2 hours compared to 2.9 hours in control.
Drug Interactions
All drug interaction studies were conducted with Proral. There are no data on drug interactions with Proral capsules.
Interactions with Substrates, Inhibitors or Inducers of Cytochrome P-450 Enzymes
Because Proral’s metabolism involves multiple pathways in the Cytochrome P-450 system (CYP2D6, 1A2, 2C19), co-administration 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.
Substrates Or Inhibitors Of CYP2D6
Blood levels and/or toxicity of Proral may be increased by co-administration with substrates or inhibitors of CYP2D6, such as amiodarone, cimetidine, delavudin, fluoxetine, paroxetine, quinidine, and ritonavir. No interactions were observed with either ranitidine or lansoprazole.
Substrates Or Inhibitors Of CYP1A2
Blood levels and/or toxicity of Proral may be increased by co-administration 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 and/or toxicity of Proral may be increased by co-administration with substrates or inhibitors of CYP2C19, such as fluconazole, cimetidine, fluoxetine, fluvoxamine, tenioposide, and tolbutamide. No interaction was observed with omeprazole.
Inducers Of Hepatic Drug Metabolism
Blood levels of Proral may be decreased by co-administration with inducers such as rifampin, ethanol, phenytoin, and phenobarbital. Cigarette smoking also induces hepatic metabolism and has been shown to increase up to 77% the clearance of Proral, resulting in decreased plasma concentrations.
Cardiovascular Drugs
Antiarrhythmics
The AUC of propafenone is increased by more than 200% by co-administration of Proral.
The metabolism of Proral is reduced by co-administration of quinidine, leading to a two to three fold increased blood concentration and greater degrees of clinical beta-blockade.
The metabolism of lidocaine is inhibited by co-administration of Proral, resulting in a 25% increase in lidocaine concentrations.
Calcium Channel Blockers
The mean C and AUC of Proral are increased respectively, by 50% and 30% by coadministration of nisoldipine and by 80% and 47%, by co-administration of nicardipine.
The mean C and AUC of nifedipine are increased by 64% and 79%, respectively, by coadministration of Proral.
Proral does not affect the pharmacokinetics of verapamil and norverapamil. Verapamil does not affect the pharmacokinetics of Proral.
Non-Cardiovascular Drugs
Migraine Drugs
Administration of zolmitriptan or rizatriptan with Proral 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 Proral decreases theophylline oral clearance by 30% to 52%.
Benzodiazepines
Proral can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of Proral.
The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by coadministration of Proral.
Neuroleptic Drugs
Co-administration of long-acting Proral at doses greater than or equal to 160 mg/day resulted in increased thioridazine plasma concentrations ranging from 55% to 369% and increased thioridazine metabolite (mesoridazine) concentrations ranging from 33% to 209%.
Co-administration of chlorpromazine with Proral resulted in a 70% increase in Proral plasma level.
Anti-Ulcer Drugs
Co-administration of Proral with cimetidine, a non-specific CYP450 inhibitor, increased Proral AUC and Cmax by 46% and 35%, respectively. Co-administration with aluminum hydroxide gel (1200 mg) may result in a decrease in Proral concentrations.
Co-administration of metoclopramide with the long-acting Proral did not have a significant effect on Proral’s pharmacokinetics.
Lipid Lowering Drugs
Co-administration of cholestyramine or colestipol with Proral resulted in up to 50% decrease in Proral concentrations.
Co-administration of Proral with lovastatin or pravastatin, decreased 18% to 23% the AUC of both, but did not alter their pharmacodynamics. Proral did not have an effect on the pharmacokinetics of fluvastatin.
Warfarin
Concomitant administration of Proral and warfarin has been shown to increase warfarin bioavailability and increase prothrombin time.
Pharmacodynamics And Clinical Effects
Hypertension
In a retrospective, uncontrolled study, 107 patients with diastolic blood pressure 110 to 150 mmHg received Proral 120 mg t.i.d. for at least 6 months, in addition to diuretics and potassium, but with no other hypertensive agent. Proral contributed to control of diastolic blood pressure, but the magnitude of the effect of Proral on blood pressure cannot be ascertained.
Four double-blind, randomized, crossover studies were conducted in a total of 74 patients with mild or moderately severe hypertension treated with Proral 160 mg once daily or Proral 160 mg given either once daily or in two 80 mg doses. Three of these studies were conducted over a 4-week treatment period. One study was assessed after a 24-hour period. Proral was as effective as Proral in controlling hypertension (pulse rate, systolic and diastolic blood pressure) in each of these trials.
Angina Pectoris
In a double-blind, placebo-controlled study of 32 patients of both sexes, aged 32 to 69 years, with stable angina, Proral 100 mg t.i.d. was administered for 4 weeks and shown to be more effective than placebo in reducing the rate of angina episodes and in prolonging total exercise time.
Twelve male patients with moderately severe angina pectoris were studied in a double-blind, crossover study. Patients were randomized to either Proral 160 mg daily or conventional Proral 40 mg four times a day for 2 weeks. Nitroglycerine tablets were allowed during the study. Blood pressure, heart rate and ECG's were recorded during serial exercise treadmill testing. Proral was as effective as conventional Proral for exercise heart rate, systolic and diastolic blood pressure, duration of anginal pain and ST-segment depression before or after exercise, exercise duration, angina attack rate and nitroglycerine consumption.
In another double-blind, randomized, crossover trial, the effectiveness of Proral LA 160 mg daily and conventional Proral 40 mg four times a day were evaluated in 13 patients with angina. ECG's were recorded while patients exercised until angina developed. Proral was as effective as conventional Proral for amount of exercise performed, ST-segment depression, number of anginal attacks, amount of nitroglycerine consumed, systolic and diastolic blood pressures and heart rate at rest and after exercise.
Migraine
In a 34-week, placebo-controlled, 4-period, dose-finding crossover study with a double-blind randomized treatment sequence, 62 patients with migraine received Proral 20 to 80 mg 3 or 4 times daily. The headache unit index, a composite of the number of days with headache and the associated severity of the headache, was significantly reduced for patients receiving Proral as compared to those on placebo.
Hypertrophic Subaortic Stenosis
In an uncontrolled series of 13 patients with New York Heart Association (NYHA) class 2 or 3 symptoms and hypertrophic subaortic stenosis diagnosed at cardiac catheterization, oral Proral 40-80 mg t.i.d. was administered and patients were followed for up to 17 months. Proral was associated with improved NYHA class for most patients.
References
- NCIt. "Propranolol: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Propranolol: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
- NCI Cancer Drugs. "propranolol-hydrochloride". https://www.cancer.gov/about-cancer/... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology
