Pindolol

Pindolol is a nonselective beta-adrenergic blocker belonging to the beta-blocker class.

Pindolol is approved for the treatment of Hypertension. It is also used to treat Angina pectoris, Atrial fibrillation, and Depression.

The mean oral bioavailability of pindolol is 87-92%. The volume of distribution of pindolol is approximately 2-3 L/kg. 30-40% of a dose of pindolol is not metabolized. The remainder is hydroxylated and subsequently undergoes glucuronidation or sulfate conjugation. 80% of an oral dose is eliminated in the urine, with 25-40% of the dose as it remains unchanged in the parent compound. 6-9% of an intravenous dose is eliminated through feces. Overall, 60-65% of a dose is eliminated as the glucuronide and sulfate metabolites.

The common side effects associated with Pindolol include insomnia, muscle pain, dizziness, fatigue, elevated liver enzymes, joint pain, abdominal discomfort, paresthesias, bradycardia, cold extremities, and hypotension.

Pindolol is available in the form of dosage forms as tablets.

Pindolol is available in India, France, Japan, and the UK.

Pindolol, belonging to the beta blocker acts as a nonselective beta-adrenergic blocker. Pindolol works by relaxing the blood vessels and slowing heart rate to improve blood flow and decrease blood pressure.

It works by blocking the effects of certain natural substances (such as epinephrine) on the heart and blood vessels. This results in a lowering of heart rate, blood pressure, and strain on the heart. By blocking beta-1 receptors in the juxtaglomerular apparatus, pindolol inhibits the release of renin, which inhibits angiotensin II and aldosterone release.

The onset of action of Pindolol occurs within 3 hours of its administration. The Duration of Action for Pindolol in the body is approximately 24 hours. The Tmax was found within 1-2 hours following the administration of Pindolol Cmax was about 33.1 ± 5.2 ng/mL.

Pindolol is available in the form of tablets

• Pindolol tablets to be swallowed whole with water.
•  It is usually taken two times a day

Pindolol is a nonselective beta-adrenergic blocking agent belonging to the beta-blocker class. It is used in the treatment of various diseases:

• Pindolol is approved for the treatment of Hypertension. It is also used to treat Angina pectoris, Atrial fibrillation, and Depression.

Pindolol possesses partial agonist activity (intrinsic sympathomimetic activity, ISA). This means that apart from blocking beta-adrenoceptors it produces some stimulation. Pindolol therefore only slightly influences normal sympathetic drive at rest but effectively reduces the effects of elevated sympathetic activity.

Pindolol is approved for use in the following clinical indications:

Pindolol is indicated for the treatment of mild to moderate hypertension. Pindolol is usually used in combination with other drugs, particularly a thiazide diuretic. However, it may be used alone as an initial agent in those patients in whom, in the judgment of the physician, treatment should be started with a β blocker rather than a diuretic. The combination of pindolol with a diuretic and/or peripheral vasodilator has been found to be compatible and generally more effective than pindolol alone. Limited experience with other antihypertensive agents, including methyldopa, has not shown evidence of incompatibility with pindolol.

Although not approved, there have been certain off-label uses documented for Pindolol. These include:

Angina Pectoris:

Pindolol is indicated for prophylaxis (prevention) of angina pectoris.

Pindolol is available in the form of tablets.

• Hypertension:

Pindolol is usually used in conjunction with other antihypertensive agents, particularly a thiazide diuretic but may be used alone .pindolol should be taken with meals. The dosage of pindolol must always be adjusted to the individual requirements of the patients in accordance with the following guidelines: pindolol therapy should be initiated with a dose of 5 mg in the morning with breakfast and 5 mg with the evening meal. If an adequate response is not achieved after one to two weeks, the dose should be increased to 10 mg twice a day. If after one to two additional weeks an adequate response is not observed, the dosage may be increased to 15 mg twice a day (30 mg/day). Doses greater than 30 mg daily must be given on a t.i.d. schedule. Patients who show a satisfactory response to pindolol at daily doses of 10 to 20 mg may be maintained by giving the required total dose once daily in the morning with breakfast. The usual maintenance dose is within the range of 15 to 45 mg daily which should not be exceeded. However, during long-term therapy, some patients may be maintained on smaller dose of pindolol.

• Angina Pectoris:

The dosage of pindolol must always be adjusted to the individual requirements of the patient. In angina, pindolol should be administered on a three or four times per day dosing regimen. Pindolol therapy should be initiated with doses of 5 mg three times a day taken with meals. If after one to two weeks an adequate response is not observed, dosage may be increased. The usual maintenance dose is 15 mg up to the maximum of 40 mg per day.

Pindolol can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Pindolol is available in various dosage strengths as 5mg and 10 mg.

Pindolol is available in the form of tablets.

Pindolol is approved for the treatment of Hypertension. It is also used to treat Angina pectoris, Atrial fibrillation, and Depression.

• Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

• Angina Pectoris:  Avoid foods that are high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce your intake of dairy products including cheese, cream, and eggs.

• Atrial Fibrillation: Some foods can negatively affect your heart health and have been shown to increase the risk of heart complications. Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk They can also lead to other negative health outcomes like weight gain, and diabetes, cognitive decline, and certain cancers.

The dietary restriction should be individualized as per patient requirements.

Pindolol may be contraindicated in the following:

• Abrupt discontinuation:

Abrupt discontinuation of any beta-adrenergic-blocking agent, including pindolol, can result in the development of myocardial ischemia, myocardial infarction, ventricular arrhythmias, or severe hypertension, particularly in patients with preexisting cardiac disease.

• Hyperthyroidism, thyroid disease, thyrotoxicosis:

Beta-blockers, such as pindolol, should be used with caution in patients with hyperthyroidism or thyrotoxicosis because the drug can mask tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate a thyroid storm. However, certain beta-blockers are generally useful in the symptomatic treatment of hyperthyroid-related states, like thyrotoxicosis.

• AV block, bradycardia, cardiogenic shock, heart failure, pheochromocytoma, pulmonary edema, sick sinus syndrome, vasospastic angina, ventricular dysfunction:

Because beta blockers, like pindolol, depress conduction through the AV node, these drugs are contraindicated in patients with severe bradycardia or advanced AV block unless a functioning pacemaker is present. Beta-blockers should also be avoided in patients with sick sinus syndrome unless a functioning pacemaker is present. In general, beta-blockers are contraindicated in patients with cardiogenic shock and decompensated systolic congestive heart failure, particularly in those with severely compromised left ventricular dysfunction, and should not be used in patients with acute pulmonary edema because the negative inotropic effect of these drugs can further depress cardiac output. In stable patients with heart failure, however, beta-blockers (e.g., bisoprolol, carvedilol, metoprolol) given in low doses have been documented to be beneficial. Many beta-blockers are used in the treatment of hypertrophic cardiomyopathy. Beta-blocker monotherapy should be used with caution in patients with pheochromocytoma or vasospastic angina (Prinzmetal's angina) because of the risk of hypertension secondary to unopposed alpha-receptor stimulation. In patients with pheochromocytoma, an alpha-blocking agent should be used prior to the initiation of any beta-blocker. In the treatment of myocardial infarction, beta-blockers are contraindicated in patients with hypotension (SBP < 100 mmHg).

• Cerebrovascular disease:

Because of the potential effects of beta-blockade on blood pressure and pulse, beta-blockers, like pindolol, should be used with caution in patients with cerebrovascular insufficiency (cerebrovascular disease) or stroke. If signs or symptoms suggesting reduced cerebral blood flow develop following initiation of beta-blocker, alternative therapy should be considered.

• Diabetes mellitus:

Beta-blockers have been shown to increase the risk of developing diabetes mellitus in hypertensive patients; however, this risk should be evaluated relative to the proven benefits of beta-blockers in reducing cardiovascular events. Pindolol should be used with caution in patients with poorly controlled diabetes mellitus, particularly brittle diabetes. Beta-blockers can prolong or enhance hypoglycemia by interfering with glycogenolysis; this effect may be less pronounced with beta1-selective beta-blockers than with nonselective agents. Beta-blockers can also mask signs of hypoglycemia, especially tachycardia, palpitations, and tremors; in contrast, diaphoresis and the hypertensive response to hypoglycemia are not suppressed with beta-blockade. Beta-blockers can occasionally cause hyperglycemia. This is thought to be due to the blockade of beta2-receptors on pancreatic islet cells, which would inhibit insulin secretion. Thus, blood glucose levels should be monitored closely if a beta-blocker is used in a patient with diabetes mellitus.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

• Cardiac Failure:

Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by the 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 the risk of bradycardia. Beta-adrenergic blocking agents do not abolish the inotropic action of digitalis on the heart muscle.

• In Patients Without 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, dosage should be gradually reduced over a period of 1-2 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 the 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 the bronchodilation produced by endogenous or exogenous catecholamine stimulation of the beta2 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 the surgery. Recognition of increased sensitivity to catecholamines of the patients recently withdrawn from beta-blocker therapy, however, has made this recommendation controversial. If possible, beta-blockers should be withdrawn well before the 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 the administration of beta-receptor agonists such as isoproterenol, dopamine, dobutamine, or levarterenol. Difficulty in restarting and maintaining the heartbeat has also been reported with the 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 clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might precipitate a thyroid crisis.

PRECAUTIONS:

• Impaired Renal or Hepatic Function:

Beta-blocking agents should be used with caution in patients with impaired hepatic or renal function. Poor renal function has only minor effects on pindolol clearance, but poor hepatic function may cause blood levels of pindolol to increase substantially

Drinking alcohol while taking the pindolol can increase drowsiness and dizziness which in turn increase the risk of accidental injury.

Pindolol use in breastfeeding patients is not recommended.

Pregnancy Category (FDA): B

Studies in rats and rabbits exceeding 100 times the maximum recommended human doses revealed no embryotoxicity or teratogenicity. Since there are no adequate and well-controlled studies on pregnant women, and since animal reproduction studies are not always predictive of human response, pindolol, as with any drug, should be employed during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Potassium-Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium when taken along with Pindolol, can be led to an increase in blood potassium levels.

• Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to the molecule Pindolol can be categorized as:

• Common Adverse effects:

Insomnia, Muscle pain, Dizziness, fatigue, etc.

• Less Common adverse effects:

Nervousness, Elevated liver enzymes, joint pain, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesias, bradycardia, cold extremities, hypotension, palpitations, syncope, Tachycardia, Anxiety, lethargy, diarrhea, vomiting, Impotence/reduced libido.

• Rare adverse effects:

Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, Raynaud's phenomenon, etc.

The clinically relevant drug interactions of Pindolol are briefly summarized here:

• Catecholamine-depleting drugs (e.g., reserpine) may have an additive effect when given with beta-blockers. Patients receiving pindolol plus a catecholamine-depleting agent should, therefore, be closely observed for evidence of hypotension and/or marked bradycardia which may produce vertigo, syncope, or orthostatic hypotension.
• Pindolol has been used with a variety of antihypertensive agents, including hydrochlorothiazide, hydralazine, and guanethidine without unexpected adverse interactions.
• Pindolol has been shown to increase serum thioridazine levels when both drugs are coadministered. Pindolol levels may also be increased with this combination.

The common side effects of Pindolol include the following:

Cold hands or feet, Eye irritation, upset stomach, headache, depression, dizziness, nausea, etc.

The use of Pindolol should be prudent in the following group of special populations:

Pregnancy

• Pregnancy Category (FDA): B

Studies in rats and rabbits exceeding 100 times the maximum recommended human doses revealed no embryotoxicity or teratogenicity. Since there are no adequate and well-controlled studies on pregnant women, and since animal reproduction studies are not always predictive of human response, pindolol, as with any drug, should be employed during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Pregnancy Category (AUS):

There is no Australian Drug Evaluation Committee (ADEC) guidance on the usage of Pindolol in women who are pregnant.

• Labor and Delivery:

There is no FDA guidance on the use of Pindolol during labor and delivery.

• Nursing Mothers:

Since pindolol is secreted in human milk, nursing should not be undertaken by mothers receiving the drug.

• Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use:

There is no FDA guidance on the use of Pindolol in geriatric settings.

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 a 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 beta2 stimulating agent such as isoproterenol and/or a theophylline derivative. A case of 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.

Pharmacodynamics:

• Pindolol remains a nonselective beta-blocker indicated in the management of hypertension and prophylaxis of angina. It has a short duration of action as it is given twice daily, and a wide therapeutic window as doses can range from 10-60 mg/day. Patients should be counseled regarding the risk of cardiac failure, exacerbating ischemic heart disease with sudden withdrawal, nonallergic bronchospasm, masking hypoglycemia in diabetics, and masking hyperthyroidism. Both heart rate and cardiac output during rest and exercise decrease in both systolic and diastolic blood pressure.

• 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 the catecholamines at peripheral (especially cardiac) adrenergic receptor sites, leading to decreased cardiac output, 3) inhibition of the 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 its 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, and 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.

Pharmacokinetics:

• Absorption:

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 5-20 mg. Upon repeated administration to the same subject, variation is minimal. After a single dose, intersubject variation for peak plasma concentrations was about 4fold (e.g., 45-167 ng/ml for a 20 mg dose). Upon multiple dosing, intersubject variation decreased to 2-2.5 fold. pindolol is only 40% bound to plasma proteins and is evenly distributed between plasma and red cells.

• Distribution:

The volume of distribution in the healthy subjects is about 2 L/kg. pindolol undergoes extensive metabolism in animals and man. In man, 35%-40% is excreted unchanged in the urine, and 60%-65% is metabolized primarily to hydroxy-metabolites which are excreted as glucuronides and ethereal sulfates.

• Metabolism:

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.

• Elimination:

About 6%-9% of an administered intravenous dose is excreted by the bile into the feces.

The half-life of pindolol varies from 3 hours to 4 hours but can be as high as 30 hours in patients with cirrhosis of the liver.

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