PINDOLOL- pindolol tablet
Sun Pharmaceutical Industries, Inc.
Pindolol, a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity is 1-(Indol-4-yloxy)-3-(isopropylamino)-2-propanol.
C14H20N2O2 M.W. 248.32
Pindolol, USP is a white to off-white, crystalline powder having a faint odor which is practically insoluble in water; slightly soluble in methanol; and very slightly soluble in chloroform.
Each tablet for oral administration contains pindolol and the following inactive ingredients: crospovidone, lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
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.
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 certain clinical situations, (e.g., cardiac failure, heart block, bronchospasm), the preservation of an adequate sympathetic tone may be necessary to maintain vital functions. Although a beta-antagonist with ISA such as pindolol does not eliminate sympathetic tone entirely, there is no controlled evidence that it is safer than other beta-blockers in such conditions as heart failure, heart block, or bronchospasm or is less likely to cause those conditions. In single-dose studies of the effects of beta-blockers on FEV1 , pindolol was indistinguishable from other non-cardioselective agents in its reduction of FEV1 , and its reduction in the effectiveness of an exogenous beta-agonist.
Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors.
Pindolol is rapidly and reproducibly absorbed (greater than 95%), achieving peak plasma concentrations within 1 hour of drug administration. Pindolol has no significant first-pass effect. The blood concentrations are proportional in a linear manner to the administered dose in the range of 5 mg to 20 mg. Upon repeated administration to the same subject, variation is minimal. After a single dose, intersubject variation for peak plasma concentrations was about 4-fold (e.g., 45 to 167 ng/mL for a 20 mg dose). Upon multiple dosing, intersubject variation decreased to 2- to 2.5-fold. Pindolol is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells. The volume of distribution in healthy subjects is about 2 L/kg.
Pindolol undergoes extensive metabolism in animals and man. In man, 35% to 40% is excreted unchanged in the urine and 60% to 65% is metabolized primarily to hydroxy-metabolites which are excreted as glucuronides and ethereal sulfates. The polar metabolites are excreted with a half-life of approximately 8 hours and thus multiple dosing therapy (q.8H) results in a less than 50% accumulation in plasma. About 6% to 9% of an administered intravenous dose is excreted by the bile into the feces.
The disposition of pindolol after oral administration is monophasic with a half-life in healthy subjects or hypertensive patients with normal renal function of approximately 3 to 4 hours. Following t.i.d. administration (q.8H), no significant accumulation of pindolol is observed.
In elderly hypertensive patients with normal renal function, the half-life of pindolol is more variable, averaging about 7 hours, but with values as high as 15 hours.
In hypertensive patients with renal diseases, the half-life is within the range expected for healthy subjects. However, a significant decrease (50%) in volume of distribution (VD ) is observed in uremic patients and VD appears to be directly correlated to creatinine clearance. Therefore, renal drug clearance is significantly reduced in uremic patients, resulting in a significant decrease in urinary excretion of unchanged drug. Uremic patients with a creatinine clearance of less than 20 mL/min generally excreted less than 15% of the administered dose unchanged in the urine.
In patients with histologically diagnosed cirrhosis of the liver, the elimination of pindolol was more variable in rate and generally significantly slower than in healthy subjects. The total body clearance of pindolol in cirrhotic patients ranged from about 50 to 300 mL/min and was directly correlated to antipyrine clearance. The half-life ranges from 2.5 hours to greater than 30 hours. These findings strongly suggest that caution should be exercised in dosage adjustments of pindolol in such patients.
The bioavailability of pindolol is not significantly affected by coadministration of food, hydralazine, hydrochlorothiazide or aspirin. Pindolol has no effect on warfarin activity or the clinical effectiveness of digoxin, although small transient decreases in plasma digoxin concentrations were noted.
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.
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.)
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.
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