Pindolol

INDICATIONS AND USAGE Pindolol tablets are indicated in the management of hypertension. It may be used alone or concomitantly with other antihypertensive agents, particularly with a thiazide-type diuretic.

CLINICAL PHARMACOLOGY Pindolol is a nonselective beta-adrenergic antagonist (beta-blocker) which possesses intrinsic sympathomimetic activity (ISA) in therapeutic dosage ranges but does not possess quinidine-like membrane stabilizing activity. PHARMACODYNAMICS In standard pharmacologic tests in man and animals, pindolol attenuates increases in heart rate, systolic blood pressure, and cardiac output resulting from exercise and isoproterenol administration, thus confirming its beta-blocking properties. The ISA or partial agonist activity of pindolol is mediated directly at the adrenergic receptor sites and may be blocked by other beta-blockers. In catecholamine depleted animal experiments, ISA is manifested as an increase in the inotropic and chronotropic activity of the myocardium. In man, ISA is manifested by a smaller reduction in the resting heart rate (4 to 8 beats/min) than is seen with drugs lacking ISA. There is also a smaller reduction in resting cardiac output. The clinical significance of this observation has not been evaluated and there is no evidence, or reason to believe, that exercise cardiac output is less affected by pindolol. Pindolol has been shown in controlled, double-blind clinical studies to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. Divided dosages in the range of 10 mg to 60 mg daily have been shown to be effective. As monotherapy, pindolol is as effective as propranolol, α-methyldopa, hydrochlorothiazide, and chlorthalidone in reducing systolic and diastolic blood pressure. The effect on blood pressure is not orthostatic, i.e., pindolol was equally effective in reducing the supine and standing blood pressure. In open, long-term studies up to 4 years, no evidence of diminution of the blood pressure lowering response was observed. An average 3-pound increase in body weight has been noted in patients treated with pindolol alone, a larger increase than was observed with propranolol or placebo. The weight gain appeared unrelated to blood pressure response and was not associated with an increased risk of heart failure, although edema was more common than in control patients. Pindolol does not have a consistent effect on plasma renin activity. The mechanism of the antihypertensive effects of beta-blocking agents has not been established, but several mechanisms have been postulated: 1) an effect on the central nervous system resulting in a reduced sympathetic outflow to the periphery, 2) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic receptor sites, leading to decreased cardiac output, 3) an inhibition of renin release. These mechanisms appear less likely for pindolol than other beta-blockers in view of the modest effect on resting cardiac output and renin. Beta-blockade therapy is useful when it is necessary to suppress the effects of beta-adrenergic agonists in order to achieve therapeutic goals. However, in certa

DOSAGE AND ADMINISTRATION The dosage of pindolol tablets should be individualized. The recommended initial dose of pindolol tablets is 5 mg b.i.d. alone or in combination with other antihypertensive agents. An antihypertensive response usually occurs within the first week of treatment. Maximal response, however, may take as long as or occasionally longer than 2 weeks. If a satisfactory reduction in blood pressure does not occur within 3 to 4 weeks, the dose may be adjusted in increments of 10 mg/day at these intervals up to a maximum of 60 mg/day.

ADVERSE REACTIONS Most adverse reactions have been mild. The incidences listed in the following table are derived from 12-week comparative double-blind, parallel design trials in hypertensive patients given pindolol as monotherapy, given various active control drugs as monotherapy, or given placebo. Data for pindolol and the positive controls were pooled from several trials because no striking differences were seen in the individual studies, with one exception. When considering all adverse reactions reported, the frequency of edema was noticeably higher in positive control trials (16% pindolol vs. 9% positive control) than in placebo controlled trials (6% pindolol vs. 3% placebo). The table includes adverse reactions either volunteered or elicited, and at least possibly drug-related, which were reported in greater than 2% of pindolol patients and other selected important reactions. ADVERSE REACTIONS WHICH WERE VOLUNTEERED OR ELICITED (and at least possibly drug-related) Body System/ Adverse Reactions Pindolol (N = 322) % Central Nervous System Bizarre or Many Dreams 5 Dizziness 9 Fatigue 8 Hallucinations < 1 Insomnia 10 Nervousness 7 Weakness 4 Autonomic Nervous System Paresthesia 3 Cardiovascular Dyspnea 5 Edema 6 Heart Failure < 1 Palpitations < 1 Musculoskeletal Chest Pain 3 Joint Pain 7 Muscle Cramps 3 Muscle Pain 10 Gastrointestinal Abdominal Discomfort 4 Nausea 5 Skin Pruritus 1 Rash < 1 Body System/ Adverse Reactions Active Controls Active Controls: Patients received either propranolol, α-methyldopa or a diuretic (hydrochlorothiazide or chlorthalidone). (N = 188) % Central Nervous System Bizarre or Many Dreams 0 Dizziness 11 Fatigue 4 Hallucinations 0 Insomnia 3 Nervousness 3 Weakness 2 Autonomic Nervous System Paresthesia 1 Cardiovascular Dyspnea 4 Edema 3 Heart Failure < 1 Palpitations 1 Musculoskeletal Chest Pain 1 Joint Pain 4 Muscle Cramps 1 Muscle Pain 9 Gastrointestinal Abdominal Discomfort 4 Nausea 2 Skin Pruritus < 1 Rash < 1 Body System/ Adverse Reactions Placebo (N = 78) % Central Nervous System Bizarre or Many Dreams 6 Dizziness 1 Fatigue 4 Hallucinations 0 Insomnia 10 Nervousness 5 Weakness 1 Autonomic Nervous System Paresthesia 6 Cardiovascular Dyspnea 6 Edema 1 Heart Failure 0 Palpitations 0 Musculoskeletal Chest Pain 3 Joint Pain 4 Muscle Cramps 0 Muscle Pain 8 Gastrointestinal Abdominal Discomfort 5 Nausea 1 Skin Pruritus 0 Rash 1 The following selected (potentially important) adverse reactions were seen in 2% or fewer patients and their relationship to pindolol is uncertain. CENTRAL NERVOUS SYSTEM: anxiety, lethargy; AUTONOMIC NERVOUS SYSTEM: visual disturbances, hyperhidrosis; CARDIOVASCULAR: bradycardia, claudication, cold extremities, heart block, hypotension, syncope, tachycardia, weight gain; GASTROINTESTINAL: diarrhea, vomiting; RESPIRATORY: wheezing; UROGENITAL: impotence, pollakiuria; MISCELLANEOUS: eye discomfort or burning eyes.

POTENTIAL ADVERSE EFFECTS In addition, other adverse effects not aforementioned have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of pindolol. Central Nervous System: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation for time and place, short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance on neuropsychometrics. Cardiovascular: Intensification of AV block. (See CONTRAINDICATIONS. ) Allergic: Erythematous rash; fever combined with aching and sore throat; laryngospasm; respiratory distress. Hematologic: Agranulocytosis; thrombocytopenic and nonthrombocytopenic purpura. Gastrointestinal: Mesenteric arterial thrombosis; ischemic colitis. Miscellaneous: Reversible alopecia; Peyronie's disease. The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with pindolol during investigational use and extensive foreign experience amounting to over 4 million patient-years

WARNINGS Cardiac Failure Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta-blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt congestive heart failure, if necessary, pindolol can be used with caution in patients with a history of failure who are well-compensated, usually with digitalis and diuretics. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase risk of bradycardia. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on heart muscle. In Patients Without A History of Cardiac Failure In patients with latent cardiac insufficiency, continued depression of the myocardium with beta-blocking agents over a period of time can in some cases lead to cardiac failure. At the first sign or symptom of impending cardiac failure, patients should be fully digitalized and/or be given a diuretic, and the response observed closely. If cardiac failure continues, despite adequate digitalization and diuretic, pindolol therapy should be withdrawn (gradually, if possible). Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy; exacerbation of angina and, in some cases, myocardial infarction have occurred after abrupt discontinuation of such therapy. When discontinuing chronically administered pindolol, particularly in patients with ischemic heart disease, the dosage should be gradually reduced over a period of 1 to 2 weeks and the patient should be carefully monitored. If angina markedly worsens or acute coronary insufficiency develops, pindolol administration should be reinstituted promptly, at least temporarily, and other measures appropriate for the management of unstable angina should be taken. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue pindolol therapy abruptly even in patients treated only for hypertension. Nonallergic Bronchospasm (e.g., chronic bronchitis, emphysema) - Patients with Bronchospastic Diseases Should in General Not Receive Beta-Blockers Pindolol should be administered with caution since it may block bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta 2 receptors. Major Surgery Because beta-blockade impairs the ability of the heart to respond to reflex stimuli and may increase the risks of general anesthesia and surgical procedures, resulting in protracted hypotension or low cardiac output, it has generally been suggested that such therapy should be gradually withdrawn several days prior to surgery. Recognition of the increased sensitivity to catecholamines of patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn well before surgery takes place. In the event of emergency surgery, the anesthesiologist should be informed that the patient is on beta-blocker therapy. The effects of pindolol can be reversed by administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or norepinephrine. Difficulty in restarting and maintaining the heart beat has also been reported with beta-adrenergic receptor blocking agents. Diabetes and Hypoglycemia Beta-adrenergic blockade may prevent the appearance of premonitory signs and symptoms (e.g., tachycardia and blood pressure changes) of acute hypoglycemia. This is especially important with labile diabetics. Beta-blockade also reduces the release of insulin in response to hyperglycemia; therefore, it may be necessary to adjust the dose of antidiabetic drugs. Thyrotoxicosis Beta-adrenergic blockade may mask certain

CONTRAINDICATIONS Pindolol tablets are contraindicated in: 1) bronchial asthma; 2) overt cardiac failure; 3) cardiogenic shock; 4) second and third degree heart block; 5) severe bradycardia. (See WARNINGS. )

OVERDOSAGE No specific information on emergency treatment of overdosage is available. Therefore, on the basis of the pharmacologic actions of pindolol, the following general measures should be employed as appropriate in addition to gastric lavage: Excessive Bradycardia: administer atropine; if there is no response to vagal blockade, administer isoproterenol cautiously. Cardiac Failure: digitalize the patient and/or administer diuretic. It has been reported that glucagon may be useful in this situation. Hypotension: administer vasopressors, e.g., epinephrine or norepinephrine, with serial monitoring of blood pressure. (There is evidence that epinephrine may be the drug of choice.) Bronchospasm: administer a beta 2 stimulating agent such as isoproterenol and/or a theophylline derivative. A case of an acute overdosage has been reported with an intake of 500 mg of pindolol by a hypertensive patient. Blood pressure increased and heart rate was ≥ 80 beats/min. Recovery was uneventful. In another case, 250 mg of pindolol was taken with 150 mg diazepam and 50 mg nitrazepam, producing coma and hypotension. The patient recovered in 24 hours.