Nadolol

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).

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.