Action and Clinical Uses:
Oxprenolol is a noncardioselective beta-adrenergic receptor blocking agent which possesses partial agonist activity. It is used in the treatment of hypertension.:
The mechanism of the antihypertensive effect has not been established. Among the factors which may be involved are: a) competitive ability to antagonize catecholamine induced tachycardia at the beta-receptor sites in the heart, thus decreasing cardiac output; b) inhibition of renin release by the kidneys; c) inhibition of the vasomotor centres.
Oxprenolol is rapidly and well absorbed from the gastrointestinal tract. Peak plasma concentrations are reached approximately 0.5 to 1.5 hours after ingestion of the conventional oxprenolol tablet and 2 to 4 hours after the slow-release tablet.
There is a variable hepatic first-pass effect. The systemic bioavailability of oxprenolol hydrochloride ranges from 20 to 70%.
Oxprenolol is 80% bound to plasma proteins, and has a calculated distribution volume of 1.3 L/kg.
The mean plasma half-life for oral doses of the conventional tablet is 1.3 to 1.5 hours. The time taken for mean plasma levels to decrease from the peak value to half that value were approximately 4.5 hours for the 80 mg slow-release tablet and 7 hours for the 160 mg slow-release tablet.
Oxprenolol is primarily excreted in the urine in the form of inactive metabolites. Less than 5% is excreted unchanged and the major metabolite is a glucuronide.
b blocking effects continue for at least 8 hours and up to 12 hours after a conventional tablet and for up to 24 hours after a slow-release tablet.
Indications And Clinical Uses:
In patients with mild or moderate hypertension. It is usually used in combination with other drugs, particularly thiazide or thiazide-related diuretics. However, it may be tried alone as an initial agent in those patients in whom, in the judgment of the physician, treatment should be started with a beta-blocker rather than a diuretic. Therapy should start using Trasicor (regular formulation), and once the maintenance dose has been established, Slow-Trasicor may be substituted (see Dosage).
The combination of oxprenolol with a thiazide-related diuretic and/or peripheral vasodilator has been found to be compatible and generally more effective than oxprenolol alone. Experience with other antihypertensive agents has not shown evidence of incompatibility.
Oxprenolol is not recommended for the emergency treatment of hypertensive crisis.
Bronchospasm (including bronchial asthma); allergic rhinitis during the pollen season; sinus bradycardia and greater than first degree AV block; sick sinus syndrome; right ventricular failure secondary to pulmonary hypertension; congestive heart failure; cardiogenic shock; anesthesia with agents that produce myocardial depression, e.g. ether known hypersensitivity to oxprenolol and related derivatives.
Warnings in Clinical States:
Cardiac Failure: Special caution should be exercised when administering oxprenolol to patients with a history of heart failure. Sympathetic stimulation is a vital component supporting circulatory function in congestive heart failure, and inhibition with beta-blockade always carries the potential hazard of further depressing myocardial contractility and precipitating cardiac failure.
Oxprenolol acts selectively without abolishing the inotropic action of digitalis on the heart muscle. However, the positive inotropic action of digitalis may be reduced by the negative inotropic effect of oxprenolol when the 2 drugs are used concomitantly. The effects of beta-blockers and digitalis are additive in depressing AV conduction.
In patients without a history of cardiac failure, continued depression of the myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic therapy, oxprenolol therapy should be immediately withdrawn.
In rare cases, pre-existing AV conduction disorders may become aggravated (possibly leading to AV block). As a rule, no worsening of peripheral conduction disorders (left and/or right bundle-branch block) occur.
Abrupt Cessation of Therapy with Trasicor: Patients with angina should be warned against abrupt discontinuation of oxprenolol. There have been reports of severe exacerbation of angina and of myocardial infarction or ventricular arrhythmias occurring in patients with angina pectoris following abrupt discontinuation of beta-blocker therapy. The last 2 complications may occur with or without preceding exacerbation of angina pectoris. Therefore, when discontinuation of oxprenolol is planned in patients with angina pectoris, Trasicor should be substituted for Slow-Trasicor and then the dosage should be gradually reduced over a period of about 2 weeks and the patient should be carefully observed. The same frequency of administration should be maintained. In situations of greater urgency, oxprenolol therapy should be discontinued in a stepwise manner and the patient observed closely. If angina markedly worsens or acute coronary insufficiency develops, it is recommended that treatment with oxprenolol be reinstituted promptly, at least temporarily.
Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including oxprenolol. A severe syndrome (oculo-muco-cutaneous syndrome) whose signs include conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with the chronic use of b adrenergic-blocking agent, practolol. This syndrome has not been observed with oxprenolol or any other such agent. However, physicians should be alert to the possibility of such reactions and should discontinue treatment in the event that they occur.
Severe sinus bradycardia due to unopposed vagal activity may occur with the use of oxprenolol; in such cases, dosage should be reduced or withdrawn and the use of atropine and isoproterenol considered.
In patients with thyrotoxicosis, oxprenolol may give a false impression of improvement by masking the clinical signs of continuing hyperthyroidism or its complications. Therefore, abrupt withdrawal of oxprenolol may be followed by an exacerbation of the symptoms of hyperthyroidism, including thyroid storm. Oxprenolol does not alter thyroid function tests.
In patients prone to nonallergic bronchospasm (e.g., chronic bronchitis, emphysema), oxprenolol should be administered with caution since it may block the bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta 2-receptors.
Oxprenolol should be administered with caution to patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycemic agents. b adrenergic blockers may mask the premonitory signs and symptoms of acute hypoglycemia. As b blockade also reduces the release of insulin in response to hyperglycemia, it may be necessary to adjust the dosage of antidiabetic drugs.
Appropriate laboratory tests should be performed at regular intervals during long-term treatment.
There may be increased difficulty in treating an allergic type reaction in patients on b blockers. In these patients, the reaction may be more severe due to pharmacologic effects of the b blockers and problems with fluid changes. Epinephrine should be administered with caution since it may not have its usual effects in the treatment of anaphylaxis. On the one hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the other, these doses can be associated with excessive a adrenergic stimulation with consequent hypertension, reflex bradycardia and heart block and possible potentiation of bronchospasm. Alternatives to the use of large doses of epinephrine include vigorous supportive care such as fluids and the use of b agonists including parenteral salbutamol or isoproterenol to overcome bronchospasm and norepinephrine to overcome hypotension.
In Patients Undergoing Elective or Emergency Surgery: The management of patients being treated with b blockers and undergoing elective or emergency surgery is controversial. Although b adrenergic receptor blockade impairs the ability of the heart to respond to b adrenergically mediated reflex stimuli, abrupt discontinuation of therapy with oxprenolol may be followed by severe complications (see Warnings). Some patients receiving b adrenergic blocking agents have been subject to protracted severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat has also been reported.
For these reasons, in patients with angina undergoing elective surgery, Trasicor should be withdrawn gradually following the recommendation given under Abrupt Cessation of Therapy (see Warnings). According to available evidence, all clinical and physiological effects of b blockade are no longer present 48 hours after cessation of medication.
In emergency surgery, since oxprenolol is a competitive inhibitor of b adrenergic receptor agonists, its effects may be reversed if necessary, by sufficient doses of such agonists as isoproterenol or levarterenol. The anesthetic selected should be one exhibiting as little negative inotropic activity as possible (see Contraindications).
In patients with acute or chronic inflammatory diseases an increase in the plasma levels of oxprenolol has been observed.
Plasma levels may also increase in the presence of severe hepatic insufficiency associated with a reduced metabolic rate.
Impaired renal function generally leads to an increase in the blood levels of oxprenolol, but the area under the concentration-time curve remains within (although at the upper limit of) the range recorded in subjects with healthy kidneys. The apparent elimination half-life for unchanged oxprenolol in patients with renal failure is comparable to the corresponding half-life values determined in subjects with no renal disease. Hence, there is no need to readjust the dosage in the presence of impaired renal function.
In patients with pheochromocytoma, a b blocker should only be given together with an a blocker.
Occupational Hazards: b blockers may adversely affect the patients reactions when driving or operating machinery.
Pregnancy: Oxprenolol crosses the placental barrier. It is not recommended that oxprenolol be given to pregnant women. The use of any drug in patients of childbearing potential requires that the anticipated benefit be weighed against possible hazards. b blockers may possibly cause undesirable side effects (especially bradycardia) in the fetus and newborn infants.
Lactation: Oxprenolol passes into breast milk. If use of the drug is deemed essential the patient should stop nursing.
Children: Although there is limited experience with oxprenolol in children, it is not recommended for pediatric use.
After the active substance has diffused out of the insoluble core of the Slow-Trasicor tablet, the empty matrix is excreted in a softened form and may be found in the feces.
As the antihypertensive effect of oxprenolol is enhanced by concomitant treatment with other antihypertensive agents, dosage should be adjusted appropriately.
Calcium antagonists of the verapamil-type must not be administered i.v. to patients receiving b blocker therapy because of the danger of hypotension, cardiac arrhythmias and cardiac arrest.
b blockers may potentiate the negative-inotropic and negative-dromotropic effect of anti-arrhythmic agents such as quinidine and amiodarone.
Epinephrine or other substances displaying sympathomimetic activity (e.g., antitussives or nose and eye drops) may lead to hypertensive reactions under treatment with oxprenolol and other non-cardioselective b blockers.
The hypertensive crisis which may follow the withdrawal of clonidine may be accentuated in the presence of b blockade. It has been proposed that withdrawal of the b blocker several days before the clonidine may reduce the danger of rebound effects.
The hypoglycemic effect of insulin or oral antidiabetic agents may be potentiated (see above).
Concurrent treatment with indomethacin may decrease the antihypertensive effect of b blockers.
Since cimetidine increases the bioavailability of b blockers which are mainly metabolized in the liver, the effect of oxprenolol may become potentiated during concomitant treatment with cimetidine.
When oxprenolol is used concomitantly with catecholamine-depleting drugs (such as reserpine or guanethidine) or MAO inhibitors, patients should be observed closely. The added b adrenergic blocking action of this drug may produce an excessive reduction of sympathetic activity.
A deterioration in peripheral blood flow has been reported in predisposed patients receiving concomitant treatment with ergot alkaloids and b blockers.
Attention should be paid to the cardiodepressant effect of inhalation anesthetics in patients receiving beta-blocker therapy (see above).
The central depressant effect of alcohol, analgesics, antihistamines, and psycho-active drugs (e.g., tricyclic antidepressants) may be potentiated.
b blockers may diminish liver function and thus affect the metabolism of other drugs.
Cardiovascular congestive heart failure (see Warnings), pulmonary edema, cardiac enlargement, secondary effects of decreased cardiac output which include: syncope, vertigo, lightheadedness and postural hypotension, severe bradycardia, lengthening of PR interval, second and third degree AV block, sinus arrest, palpitations, chest pains, peripheral vascular disorders (cold/tingling extremities) Raynaud’s phenomenon, claudication, hot flushes.
Respiratory: shortness of breath, wheezing, bronchospasm, status asthmaticus.
CNS: headache, dizziness, anxiety, mental depression, nervousness, irritability, hallucinations, sleep disturbances including nightmares and insomnia, tinnitus, weakness, sedation, vivid dreams, vertigo, paresthesia and slurred speech.
Gastrointestinal: diarrhea, constipation, flatulence, heartburn, anorexia, nausea and vomiting, abdominal pain, dryness of mouth.
Allergic/Dermatological: (see Warnings), rash (psoriasiform and exanthematic), dry skin, pruritus, sweating.
Ophthalmological: keratoconjunctivitis, dry eyes, itching eyes, blurred vision.
Miscellaneous: impotence, decreased libido, nasal stuffiness, weight gain, exertional tiredness.
Clinical Laboratory: elevated transaminases, BUN, alkaline phosphatase and bilirubin have occurred in some patients. Thrombocytopenia and leukopenia, and hypoglycemia have also been reported rarely.
Symptoms And Treatment Of Overdose :
Symptoms: The most common signs to be expected with overdosage of a b adrenergic blocking agent are hypotension, bradycardia, congestive heart failure, bronchospasm, and hypoglycemia. Cardiogenic shock and cardiac arrest may develop. Impairment of consciousness and generalized convulsions may occur.
Treatment: If overdosage occurs, in all cases therapy with oxprenolol should be discontinued and the patient observed closely. In addition, if required, the following therapeutic measures are suggested:
Bradycardia and hypotension: Initially 1 to 2 mg atropine sulfate should be given i.v. If a satisfactory effect is not achieved a pressor agent such as norepinephrine may be administered after preceding treatment with atropine. Glucagon in a dose of 1 to 10 mg can also be administered.
Heart block: (second or third degree): isoproterenol or transvenous cardiac pacemaker.
Congestive heart failure: conventional therapy.
Bronchospasm: i.v. aminophylline or a b 2 agonist. (e.g., salbutamol, terbutaline).
Hypoglycemia: i.v. glucose.
Convulsions: i.v. diazepam.
It should be remembered that oxprenolol is a competitive antagonist of isoproterenol and hence large doses of isoproterenol can be expected to reverse many of the effects of excessive doses of oxprenolol. However, the complications of excess isoproterenol should not be overlooked.
Dosage And Administration:
Oxprenolol is usually used in conjunction with other antihypertensive agents, particularly thiazide diuretics, but may be used alone (see Indications).
Dosage must always be adjusted according to the individual requirements of the patient, within the following guidelines:
Initial Dosage: Treatment should be initiated with Trasicor (regular formulation), 20 mg 3 times a day, followed by upward titration of the dose 3 times a day, with increases of 60 mg/day at 1 to 2 week intervals until adequate control of blood pressure is obtained.
Maintenance Dosage: Once the optimal dose has been established, the total daily dose of Trasicor (regular formulation) may be given on a b.i.d. schedule, although no comparison studies between the t.i.d. and b.i.d. regimen have been carried out. Alternatively, an equivalent single daily dose of Slow-Trasicor may be substituted, and should be taken in the morning. Slow-Trasicor tablets should be swallowed whole.
The usual effective dose range is 120 to 320 mg/day, and the daily dosage should not exceed 480 mg.
Availability And Storage:
40 mg: Each white, round, biconvex, film-coated tablet, imprinted CIBA on one side and Al, separated by a score on the other, contains: oxprenolol HCl 40 mg. Nonmedicinal ingredients: calcium phosphate, cellulose compounds, magnesium stearate, polyvinylpyrrolidone, wheat starch, sucrose, talc and titanium dioxide. Energy: 2.8 kJ (0.67 kcal). Also contains gluten. Alcohol-, bisulfite-, lactose-, parabens-, sodium- and tartrazine-free. Bottles of 100.
80 mg: Each light yellow, round, biconvex, film-coated tablet, imprinted “CG” on one side and CG separated by a score on the other, contains: oxprenolol 80 mg. Nonmedicinal ingredients: calcium phosphate, cellulose compounds, colloidal silicon dioxide, iron oxide yellow, magnesium stearate, maize starch, polysorbate, polyvinylpyrrolidone, sodium carboxymethyl starch, talc and titanium dioxide. Energy: 1.2 kJ (0.29 kcal). Sodium: <1 mmol (0.64 mg). Alcohol-, bisulfite-, gluten-, lactose-, parabens- and tartrazine-free. Bottles of 100.
Protect from heat (i.e. store below 30°C.)
TRASICOR® Novartis Pharmaceuticals Oxprenolol HCl Antihypertensive