Nadolol

log Kow= 0.71

1.2

1.27

Freely sol in propylene glycol; slightly sol in chloroform; insol in acetone, benzene, ether, hexane.

Practically insoluble in lipids.

It is freely soluble in ethanol, soluble in hydrochloric acid, slightly soluble in water, and very slightly soluble in sodium hydroxide.

2.25e+00 g/L

>46.4 [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

124-130

124-136 °C

124 - 136 °C

9.69

9.67

9.67

pKa= 9.67

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

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

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

This chemical does not meet GHS hazard criteria for 33.3% (1 of 3) of reports.

Danger

H302 (33.3%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P264, P270, P301+P317, P319, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Nadolol, used as a beta adrenergic blocking agent, was approved by FDA for marketing in the United States 12/79.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed drug products, incl nadolol, 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).

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.

The beta-adrenergic stimulating effects of sympathomimetic agents are antagonized by nadolol. The interaction is especially pronounced with isoproterenol, and very large doses of isoproterenol may be needed to overcome the beta-adrenergic blocking effects of nadolol.

Antimuscarinic agents, such as atropine, may counteract the bradycardia caused by nadolol by reestablishing the balance between sympathetic and parasympathetic actions on the heart.

When nadolol is administered with diuretics or other hypotensive drugs, the hypotensive effect of nadolol may be increased.

High doses of nadolol may potentiate and prolong the effects of neuromuscular blocking agents such as tubocurarine chloride.

Mild-to-moderate elevations in serum aminotransferase levels occur in less than 1% of patients on nadolol and are usually transient and asymptomatic, resolving even with continuation of therapy. Despite its widespread use, nadolol has not been convincingly linked to instances of clinically apparent liver injury; the few cases reported have generally occurred in patients who were receiving other well known hepatotoxic agents or were associated with serum enzyme elevations only. Other beta-blockers have been implicated in causing rare instances of acute liver injury, with 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.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 60(SRC), determined from a log Kow of 0.71(2) and a regression-derived equation(3), indicates that nadolol is expected to have high mobility in soil(SRC). Volatilization of nadolol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Nadolol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 9.9X10-11 mm Hg(SRC), determined from a fragment constant method(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 60(SRC), determined from a log Kow of 0.71(2) and a regression-derived equation(3), indicates that nadolol is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), nadolol, which has an estimated vapor pressure of 9.9X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase nadolol may be removed from the air by wet and dry deposition(SRC).

Nadolol has been well-tolerated in most clinical studies with minimal adverse effects. The adverse effects of nadolol are mainly because of its impact on the β-2 receptors. No known reports of major organ injury are from using nadolol. However, there is evidence of a mild-to-moderate increase in liver enzymes in certain patient populations, particularly aspartate aminotransferase (AST) and alanine aminotransferase (ALT), due to the first-pass metabolism of nadolol in the liver. Typically, these patients are asymptomatic, and liver functions return to baseline with continued therapy. No evidence of nadolol causing clinically apparent liver injury exists, but this adverse effect can get aggravated when used in combination with other hepatotoxic drugs. Nadolol is safe for use in patients with cirrhosis for primary or secondary prophylaxis of varices without affecting liver function.

Most nadolol poisonings occur via the intentional consumption of the tablet. No reports of significant toxicity are apparent in the literature. Most cases of nadolol poisoning are mild. These patients can be observed in an emergency department for 4 hours and discharged if no signs of poisoning develop. If moderate-to-severe toxicity persists, early decontamination with activated charcoal can be used along with gastric lavage if significant ingestion is suspected. After stabilizing the patient for airway, breathing, and circulation, enhanced elimination with hemodialysis is possible, considering nadolol's low distribution volume and longer half-life.

/HUMAN EXPOSURE STUDIES/ The effects of short-term nadolol administration on the reactive oxygen species (ROS) generation by polymorphonuclear leukocytes and mononuclear cells /was studied/ in 8 normal subjects. At a oral dose of 40 mg/day for 5 days, nadolol produced a decrease in the ROS generation by leukocytes. ROS generation by polymorphonuclear leukocytes decreased by 38% from 134 +/- 44 mV at baseline to 83 +/- 34 mV after 5 days (p = 0.005), and ROS generation by mononuclear cells decreased by 33% from 174 +/- 69 mV at baseline to 117 +/- 55 mV after 5 days (p = 0.015). A significant reduction in linoleic acid oxidation was reflected by the lower levels of 9- and 13- hydroxy-octadecadienoic acid after 5 days. There was no change in the plasma thiobarbituric acid-reacting substances, a less sensitive index of oxidative damage to lipids. There was also no significant change in the levels of metatyrosine and orthotyrosine, which are known indexes of oxidative damage to amino acids and proteins. The absence of a significant change in metatyrosine, orthotyrosine, and thiobarbituric acid-reacting substances may reflect the short duration of nadolol administration and the decreased ROS load.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Nadolol

Ambiguous-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

Nadolol, used as a beta adrenergic blocking agent, was approved by FDA for marketing in the United States 12/79.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed drug products, incl nadolol, 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

Nadolol is a nonselective beta adrenal receptor blocker that is used to lower blood pressure. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as patients start at doses of 40mg daily but may be increased to doses as high as 240mg daily. Patients taking nadolol should not aburptly stop taking it as this may lead to exacerbation of ischemic heart disease.

Although nadolol is described as a non selective beta blocker, it does not interact with beta 3 adrenal receptors. Antagonism of beta-1 and beta-2 adrenoceptors in the heart inhibits cyclic AMP and its signalling pathway, decreasing the strength and speed of contractions as well as the speed of relaxation and conduction. Antagonism of beta-2 adrenoceptors in the smooth muscle cells of the vasculature inhibits their relaxation, leading to an increase in peripheral vascular resistance and reducing the risk of severe hypotension. The increase in peripheral vascular resistance may contribute to the decrease in insulin sensitivity associated with nadolol use. Antagonism of beta-1 adrenoceptors in the juxtaglomerular apparatus of the kidney inhibits the release of renin, and therefore angiotensin II mediated vasoconstriction, aldosterone mediated water retention, and the release of epinephrine. Antagonism of beta-2 adrenoceptors in the liver and skeletal muscle inhibits glycogenolysis, in the lungs prevents bronchodilation, and in the pancrease inhibits insulin release.

Nadolol inhibits response to adrenergic stimuli by competitively blocking beta1-adrenergic receptors within the myocardium and beta2-adrenergic receptors within bronchial and vascular smooth muscle.

In the management of angina pectoris, the mechanism of action of nadolol is thought to be blockade of catecholamine induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure which result in a net decrease in myocardial oxygen consumption. However, nadolol may increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure.

Through its beta-adrenergic blocking action, nadolol increases airway resistance (especially in asthmatic patients) and inhibits the release of free fatty acids and insulin by adrenergic stimulation.

It has been postulated that beta-adrenergic blocking agents reduce blood pressure by blocking peripheral (especially cardiac) adrenergic receptors (decreasing cardiac output), by decreasing sympathetic outflow from the CNS, and/or by suppressing renin release. Nadolol decreases blood pressure in both supine and standing positions.

The half life of nadolol is 20 to 24 hours.

The elimination half-life of nadolol is 18 hr. /From table/

In patients with normal renal function, the plasma half-life of nadolol is 10-24 hr and, with once daily doses, steady state is attained in 6-9 days. In patients with renal impairment, plasma half-life is increased.

Nadolol is not metabolized by the liver in humans.

Nadolol is not metabolized.

FEN504330V

NADOLOL

Mechanisms of Action [MoA] - Adrenergic beta-Antagonists

Established Pharmacologic Class [EPC] - beta-Adrenergic Blocker

Nadolol is a beta-Adrenergic Blocker. The mechanism of action of nadolol is as an Adrenergic beta-Antagonist.

NADOLOL

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.

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.

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 inhibit the actions of the sympathetic nervous system by any mechanism. The most common of these are the ADRENERGIC ANTAGONISTS and drugs that deplete norepinephrine or reduce the release of transmitters from adrenergic postganglionic terminals (see ADRENERGIC AGENTS). Drugs that act in the central nervous system to reduce sympathetic activity (e.g., centrally acting alpha-2 adrenergic agonists, see ADRENERGIC ALPHA-AGONISTS) are included here.

Oral doses of nadolol are approximately 30% absorbed. In healthy subjects, nadolol has a Tmax of 2.7h with a Cmax or 69±15ng/mL following a 60mg oral dose and 132±27ng/mL after a 120mg oral dose. The AUC following a 60mg oral dose was 1021ng\*h/mL and following a 120mg oral dose was 1913±382ng\*h/mL.

Nadolol is not metabolized in the liver and excreted mainly in the urine. In healthy subjects, following intravenous dosing, 60% of a dose is eliminated in the urine and 15% in the feces after 72 hours. The remainder of the dose is expected to be eliminated in the feces afterwards.

In healthy subjects, the volume of distribution of nadolol is 147-157L.

In healthy subjects, the total body clearance of nadolol is 219-250mL/min and the renal clearance is 131-150mL/min.

Following oral administration of nadolol, absorption is variable and averages about 30-40% of a dose. The presence of food in the GI tract does not affect the rate or extent of absorption. After oral administration of 2 mg of nadolol (in a capsule), peak plasma concentrations usually occur in 2-4 hours. In one study in hypertensive adults who received 80 mg, 160 mg, or 320 mg of nadolol daily, mean steady state plasma concentrations were 25.5-35.5 ng/ml, 51.7-74.1 ng/ml, and 154-191.4 ng/ml, respectively. With doses of 40-320 mg daily, the duration of nadolol's antihypertensive and antianginal effects is at least 24 hours.

Following oral administration of 2 mg of radiolabeled nadolol (in a capsule) in one study in patients with normal renal function, about 24.6% and 76.9% of the radioactivity was recovered in urine and feces, respectively, in 4 days.

MEDICATION

Use (kg) in USA (2002): 2770

Oral tablets 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, Corgard (scored), Monarch; Corgard (with povidone; scored), Monarch.

Oral tablets 40 mg with bendroflumethiazide 5 mg, Corzide 40/5 (with providone; scored), Monarch; 80 mg with bendroflumethiazide 5 mg, Corzide 80/5 (with povidone; scored), Monarch.