1-(1H-indol-4-yloxy)-3-((1-methyl-ethyl)amino)-2-propanol

log Kow = 1.75

1.9

Crystals from ethanol

White to off-white crystalline powder

Practically Insoluble

Practically insoluble in water and slightly soluble in alcohol

8.61e-01 g/L

>37.2 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Adrenergic Beta-Antagonists; Antiarrhythmics

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

171-173 °C

167 - 171 °C

9.54

9.54

9.25

159.1 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

152.36 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

157.6 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Warning

H302 (90.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 43 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H301: Toxic if swallowed [Danger Acute toxicity, oral]

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pindolol, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Acute Tox. 4 (90.7%)

Acute toxicity (Oral) - Category 3

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Concomitant administration of pindolol with reserpine may increase the incidence of hypotension and bradycardia as compared with pindolol alone, because of reserpine's catecholamine-depleting activity. Pindolol also is additive with and may potentiate the hypotensive actions of other hypotensive agents (e.g., hydralazine, hydrochlorothiazide).

Slight transient decreases in serum digoxin concentrations have occurred when pindolol and digoxin were used concurrently; however, this effect is not considered clinically important.

Pindolol has been shown to increase serum thioridazine levels when both drugs are co-administered. Pindolol levels may also be increased with this combination.

Mild-to-moderate elevations in serum aminotransferase levels occur in less than 2% of patients on pindolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its wide spread use, pindolol has not been convincingly linked to instances of clinically apparent liver injury. Other beta-blockers have been implicated in rare instances of clinically apparent liver injury with a latency to onset ranging from 4 to 24 weeks, a hepatocellular pattern of serum enzyme elevations, and a mild, self-limiting course without evidence of hypersensitivity or autoimmune reactions.

/HUMAN EXPOSURE STUDIES/ A 250 mg overdose /of pindolol/ resulted in coma without hypotension ... No deaths were reported before 1985. The partial agonist activity of pindolol may contribute to the relative safety of this drug in overdose.

/HUMAN EXPOSURE STUDIES/ Limited information is available on acute pindolol toxicity. In general, overdosage of pindolol may be expected to produce effects that are mainly extensions of pharmacologic effects, including symptomatic bradycardia, hypotension, bronchospasm, and acute cardiac failure. In one hypertensive patient who ingested 500 mg of pindolol, blood pressure increased and heart rate was at least 80 beats/min; recovery was uneventful. In another individual, 250 mg of pindolol was ingested with 150 mg of diazepam and 50 mg of nitrazepam, resulting in coma and hypotension; the patient recovered in 24 hr.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Pindolol

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In chronic oral toxicologic studies (1-2 years) in mice, rats, and dogs, Pindolol did not produce any significant toxic effects. In 2-year oral carcinogenicity studies in rats and mice in doses as high as 59 mg/kg/day and 124 mg/kg/day ...Pindolol did not produce any neoplastic, preneoplastic, or nonneoplastic pathologic lesions.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In fertility and general reproductive performance studies in rats, Pindolol caused no adverse effects at a dose of 10 mg/kg. In the male fertility and general reproductive performance test in rats, definite toxicity characterized by mortality and decreased weight gain was observed in the group given 100 mg/kg/day. At 30 mg/kg/day, decreased mating was associated with testicular atrophy and/or decreased spermatogenesis ... There appeared to be an increase in prenatal mortality in males given 100 mg/kg but development of offspring was not impaired. If females administered Pindolol prior to mating through day 21 of lactation, mating behavior was decreased at 100 mg/kg and 30 mg/kg. At these dosages there also was increased mortality of offspring. Prenatal mortality was increased at 10 mg/kg but there was not a clear response relationship in this experiment. There was an increased resorption rate at 100 mg/kg observed in females necropsied on the 15th day of gestation.

Glucagon increases cAMP levels via noncatecholamine mechanisms and can exert potent chronotropic and inotropic effects. This likely explains its use as an antidote in beta-blocker and calcium channel blocker overdose. /Class II drugs: Beta Blockers/

Most overdoses are mild and respond to supportive care. Observe mild overdose cases at least 4 hours for the development of signs of poisoning. Hypotension: Multiple intravenous boluses of adrenaline may lead to a rise in blood pressure after dopamine, glucagon, sodium bicarbonate, and calcium have not been successful. Amrinone ... is a positive inotropic agent with intrinsic vasodilator activity that may be as effective as glucagon in reversing depressed myocardial function. /Class II drugs: Beta Blockers/

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma, seizures, hypotension, hyperkalemia, and hypoglycemia if they occur. 3. Treat bradycardia with atropine, ... IV; isoproterenol ... ; or cardiac pacing. 4. Treat bronchospasm with nebulized bronchodilators. 5. Continuously monitor the vital signs and ECG for at least 6 hours after ingestion. /Beta-adrenergic blockers/

Specific drugs and antidotes. 1. Bradycardia and hypotension resistant to... /normal/ measures should be treated with glucagon, ... . Epinephrine (intravenous) infusion ... and titrating to effect. 2. Wide complex conduction defects caused by membrane-depressant poisoning may respond to sodium bicarbonate, ... , as given for tricyclic antidepressant overdose. 3. Torsades de pointes polymorphous ventricular tachycardia associated with QT prolongation resulting from sotalol poisoning can be treated with isoproterenol infusion, magnesium, or overdrive pacing. Correction of hypokalemia may also be useful. /Beta-adrenergic blockers/

For more Antidote and Emergency Treatment (Complete) data for PINDOLOL (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl pindolol, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

C - Cardiovascular system

QC - Cardiovascular system

Pindolol is 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 counselled regarding the risk of cardiac failure, exacerbating ischemic heart disease with sudden withdrawal, nonallergic bronchospasm, masking hypoglycemia in diabetics, and masking hyperthyroidism.

The beta-1 adrenoceptor is a G-protein-coupled receptor. Agonism of the beta-1 adrenoceptor allows the Gs subunit to upregulate adenylyl cyclase, converting ATP to cyclic AMP (cAMP). Increased concentrations of cAMP activate cAMP-dependant kinase A, phosphorylating calcium channels, raising intracellular calcium, increasing calcium exchange through the sarcoplasmic reticulum, and increasing cardiac inotropy. cAMP-dependant kinase A also phosphorylates myosin light chains, increasing smooth muscle contractility. Increased smooth muscle contractility in the kidney releases renin. Pindolol is a non-selective beta blocker. Blocking beta-1 adrenergic receptors in the heart results in decreased heart rate and blood pressure. By blocking beta-1 receptors in the juxtaglomerular apparatus, pindolol inhibits the release of renin, which inhibits angiotensin II and aldosterone release. Reduced angiotensin II inhibits vasoconstriction and reduced aldosterone inhibits water retention. Beta-2 adrenoceptors located in the kidneys and peripheral blood vessels use a similar mechanism to activate cAMP-dependant kinase A to increase smooth muscle contractility. Blocking of the beta-2 adrenoceptor relaxes smooth muscle, leading to vasodilation.

Class II antiarrhythmic, beta-adrenoceptor-blocking agents are membrane- depressant drugs that decrease the influx of sodium and calcium ions by reducing membrane-bound adenylate cyclase and cAMP. The reduction in cation transport lengthens depolarization by decreasing the amplitude and slope of the transmembrane potential. Beta-adrenoceptor-blocking agents also reduce myocardial contractility by decreasing calcium release from the sarcoplasmic reticulum (the influx of calcium couples excitation and contraction by initiating the release of calcium from the sarcoplasmic reticulum). Membrane-stabilizing activity enhances the reduction in myocardial contractility in overdose with these drugs in addition to producing a quinidinelike effect of QRS widening. A direct myocardial effect also leads to myocardial depression independent of beta-adrenergic blockade and membrane stabilization. /Class II beta-Blockers/

The principal physiologic action of pindolol is to competitively block beta-adrenergic receptors within the myocardium (beta1-receptors) and within bronchial and vascular smooth muscle (beta2-receptors). In addition to inhibiting access of physiologic or synthetic catecholamines to the beta-adrenergic receptors, pindolol causes slight activation of the beta-receptors, making the drug a partial beta-agonist. This intrinsic sympathomimetic activity of pindolol differs from the beta-agonist activity of epinephrine and isoproterenol in that the maximum beta-adrenergic stimulation that can be obtained with pindolol is less. Other beta-adrenergic blocking agents can block pindolol's intrinsic sympathomimetic activity. Pindolol also has been shown to possess membrane-stabilizing activity or a quinidine-like effect, but this occurs only at plasma concentrations well above those obtained therapeutically. Unlike atenolol and metoprolol, pindolol is not a beta1-selective adrenergic blocking agent; pindolol is a nonselective beta-adrenergic blocking agent, inhibiting both beta1- and beta2-adrenergic receptors.

By inhibiting myocardial beta1-adrenergic receptors, pindolol produces negative chronotropic and inotropic activity. Both of these actions are reversed somewhat, but not entirely, by the drug's partial agonist activity. The negative chronotropic action of pindolol on the sinoatrial node results in a decrease in sinoatrial node discharge and recovery time, thereby decreasing stress- and exercise-stimulated heart rate. Pindolol has a lesser effect on resting heart rate than do beta-adrenergic blocking agents that do not possess intrinsic sympathomimetic activity, usually decreasing resting heart rate only by about 4-8 beats/min or not at all ... Pindolol has a lesser effect on resting cardiac output than on that stimulated by exercise. The decrease in myocardial contractility, blood pressure, and heart rate produced by pindolol during stress and exercise leads to a reduction in myocardial oxygen consumption which accounts for the effectiveness of the drug in chronic stable angina pectoris. Pindolol is probably not effective in patients who develop angina at rest or at low exercise levels.

Unlike other beta-adrenergic blocking agents, pindolol does not consistently suppress plasma renin activity. In some studies, the drug has increased plasma renin concentrations and reversed the suppression of plasma renin induced by other beta-adrenergic blocking agents. Pindolol has not been shown to cause sodium retention.

For more Mechanism of Action (Complete) data for PINDOLOL (7 total), please visit the HSDB record page.

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

The drug has a plasma half-life of 3-4 hr in healthy adults. Plasma half-life increases to 3-11.5 hr in patients with renal failure, to 7-15 hr in geriatric patients, and varies from 2.5-30 hr in patients with hepatic cirrhosis

30-40% of a dose of pindolol is not metabolized. The remainder is hydroxylated and subsequently undergoes glucuronidation or sulfate conjugation.

Pindolol reportedly does not undergo substantial metabolism on first pass through the liver; ... only about 20% of an oral dose is metabolized on first pass.

Approximately 60-65% of pindolol is metabolized in the liver to hydroxylated metabolites which are then excreted in urine as glucuronides and ethereal sulfates.

BJ4HF6IU1D

PINDOLOL

Mechanisms of Action [MoA] - Adrenergic beta-Antagonists

Established Pharmacologic Class [EPC] - beta-Adrenergic Blocker

Pindolol is a beta-Adrenergic Blocker. The mechanism of action of pindolol is as an Adrenergic beta-Antagonist.

PINDOLOL

Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety.

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS.

Drugs used to cause dilation of the blood vessels.

The mean oral bioavailability of pindolol is 87-92%. A 5 mg oral dose reaches a Cmax of 33.1 ± 5.2 ng/mL, with a Tmax of 1-2 hours.

80% of an oral dose is eliminated in the urine, with 25-40% of the dose as the unchanged parent compound. 6-9% of an intravenous dose is eliminated in the feces. Overall, 60-65% of a dose is eliminated as glucuronide and sulfate metabolites.

The volume of distribution of pindolol is approximately 2-3 L/kg.

In otherwise healthy patients, the systemic clearance of pindolol is 400-500 mL/min. In patients with cirrhosis, the clearance of pindolol varies from 50-300 mL/min.

Pindolol is rapidly absorbed from the GI tract. Reported bioavailability ranges from 50-95%; bioavailability in uremic patients may be at the lower end of this range. Food does not reduce bioavailability but may increase the rate of GI absorption. Pindolol reportedly does not undergo substantial metabolism on first pass through the liver; ... only about 20% of an oral dose is metabolized on first pass. Peak plasma concentrations of 45-167 ng/ml are reached within 1-2 hr after administration of a single 20-mg dose. The extent of absorption may be decreased in patients with impaired renal function. The effect of pindolol on heart rate usually is seen within 3 hr and acute hemodynamic effects persist for 24 hr after administration of the drug.

Approximately 40-60% of pindolol is bound to plasma proteins. In healthy adults, the drug has an apparent volume of distribution of 1.2-2 l/kg; volume of distribution may be decreased by 50% in uremic patients. Pindolol is distributed into milk.

MEDICATION

Use (kg; approx.) in Germany (2009): >10

Tablets, 5 and 10 mg

Oral Tablets, 5 mg, Pindolol Tablets, Visken (scored), Novartis; 10 mg, Pindolol Tablets, Visken (scored), Novartis.

Betapindol, Blocklin L, Decreten, Pectobloc, Pinbetol, Pindoptan, Visken

Calvisken, Durapindol, Glauco-Viskin, Pynastin