アルブテロール

log Kow = 0.64 /Estimated/

1.4

White to off-white crystalline solid

Crystalline powder from ethanol-ethyl acetate or ethyl acetate-cyclohexane

Soluble in ethanol, sparingly soluble in water, and very soluble in chlorform.

Soluble in most organic solvents.

In water, 1.43X10+4 mg/L, temp not specified

2.15e+00 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Asthmatic Agents; Bronchodilator Agents; Beta Adrenergic Agonists

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Antiasthmatic and medicines for chronic obstructive pulmonary disease

147-149

151 °C (Lunts); 157-158 °C (Collins)

157 - 158 °C

10.3

pKa1 = 9.2 (amine nitrogen); pKa2 = 10.7 (phenolic -OH) /Estimated/

Warning

H302 (98%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P270, P272, P280, P301+P317, P302+P352, P321, P330, P333+P317, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 51 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Status: Active Update: 28-11-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/21548

1,3-Benzenedimethanol, .alpha.1-(1,1-dimethylethyl)aminomethyl-4-hydroxy-: Does not have an individual approval but may be used under an appropriate group standard

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

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

Certain other dosage form new animal drugs. Albuterol. Indications for use: for the immediate relief of bronchospasm and bronchoconstriction associated with reversible airway obstruction in horses. Limitations: Not for use in horses intended for food.

Albuterol sulfate tablets, extended-release tablets, and the oral solution should be stored at 2-30 °C, unit-dose packages of the extended-release tablets should be protected from excessive moisture. /Albuterol sulfate/

Preparations containing albuterol or albuterol sulfate should be stored in well-closed, light resistant containers. Commercially available metered-dose albuterol and albuterol sulfate inhalers should be stored at 15-30 adn 15-25 °C, respectively.

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.

Following single-dose IV or oral administration of albuterol to healthy individuals who had received digoxin for 10 days, a 16-22% decrease in serum digoxin concentration was observed.

Epinephrin, other orally inhaled sympathomimetic amines: May increase sympathomimetic effects and risk of toxicity. Avoid use together /with albuterol/.

MAO inhibitors, tricyclic antidepressants: Serious cardiovascular effects and risk of toxicity. Avoid use together /with albuterol/.

Propanolol, other beta blockers: May antagonize effects of albuterol. Use together cautiously.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 23(SRC), determined from a water solubility of 1.41X10+4 mg/L(2) and a regression-derived equation(3), indicates that albuterol is expected to have very high mobility in soil(SRC). However, the estimated pKa of albuterol is 10(4), indicating that this compound may partially exist in the protonated form in the environment. Cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5), suggesting that mobility may be much lower in some soils(SRC). Volatilization of albuterol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.4X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(6). Albuterol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 8.9X10-9 mm Hg(SRC), determined from a fragment constant method(7).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 23(SRC), determined from a water solubility of 1.41X10+4 mg/L(2) and a regression-derived equation(3), indicates that albuterol 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 6.4X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The pKa1 and pKa2 of albuterol are 9.2 and 10.7(5), respectively, indicating that this compound will partially exist in the protonated in the environment and cations generally adsorb more strongly to suspended solids and sediment than their neutral counterparts(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from its water solubility(2) and a regression-derived equation(3), 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), albuterol, which has an estimated vapor pressure of 8.9X10-9 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 albuterol may be removed from the air by wet and dry deposition(SRC).

The primary adverse effects of albuterol therapy are tremors and nervousness, and although they can occur at any age, they are predominantly observed in children aged 2 to 6. Tremors result from the activation of β2-receptors found on motor nerve terminals, leading to an increase in intracellular cAMP. These adverse effects occur in approximately 1 in every 5 patients. Additional adverse effects include insomnia and nausea, which occur in approximately 1 in every 10 patients. Less common adverse effects may include fever, bronchospasm, vomiting, headache, dizziness, cough, allergic reactions, otitis media, epistaxis, increased appetite, urinary tract infections, dry mouth, gas, hyperhidrosis, pain, dyspepsia, hyperactivity, chills, lymphadenopathy, ocular pruritus, sweating, conjunctivitis, and dysphonia. Albuterol also has been shown to increase blood pressure levels and may cause hypokalemia. Although rare, occurrences of increased blood glucose concentrations, prolonged QTc interval, and ST-segment depression have been reported.

Signs and Symptoms of Overdose

Salbutamol is a beta(2)-adrenergic agonist and thus it stimulates beta(2)-adrenergic receptors. Binding of albuterol to beta(2)-receptors in the lungs results in relaxation of bronchial smooth muscles. It is believed that salbutamol increases cAMP production by activating adenylate cyclase, and the actions of salbutamol are mediated by cAMP. Increased intracellular cyclic AMP increases the activity of cAMP-dependent protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular calcium concentrations. A lowered intracellular calcium concentration leads to a smooth muscle relaxation and bronchodilation. In addition to bronchodilation, salbutamol inhibits the release of bronchoconstricting agents from mast cells, inhibits microvascular leakage, and enhances mucociliary clearance.

The Koc of albuterol is estimated as 23(SRC), using a water solubility of 1.41X10+4 mg/L(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that albuterol is expected to have very high mobility in soil. However, the estimated pKa1 and pKa2 values for albuterol are 9.2 and 10.7, respectively(4), indicating that this compound may partially exist in the protonated form in the environment. Cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(5), suggesting that mobility may be much lower in some soils(SRC).

/HUMAN EXPOSURE STUDIES/ During worldwide marketing experience, various congenital anomalies, including cleft palate and limb defects, have been reported in the offspring of patients being treated with albuterol. Some of the mothers were taking multiple medication during their pregnancies. No consistent pattern of defects can be discerned, and a relationship between albuterol use and congenital anomalies has not been established.

/HUMAN EXPOSURE STUDIES/ This study was designed to determine the threshold dose for toxicity, the potential for serious medical complications, and the medical care required after unintentional albuterol ingestion in children. This study was prospective and descriptive. Data were obtained on pediatric albuterol ingestions evaluated emergently as reported to three regional poison control centers. Data elements included dose ingested, physical findings, medical treatment, and outcome. During 18 months, 78 patients who ingested albuterol and who received urgent medical evaluation were identified. Mean age was 2.8 years. The amount ingested ranged from 0.2 to 8.8 mg/kg. The most commonly reported signs of toxicity were tachycardia (57%, 44/78), widened pulse pressure (50%, 27/54), hyperglycemia (50%, 12/24), agitation (45%, 35/78), low serum carbon dioxide (42%, 10/24), vomiting (26%, 20/78), and hypokalemia (26%, 9/35). We found a threshold dose of 1 mg/kg for three or more signs of toxicity (P < 0.01). No patient required any specific treatment for toxicity. Seventy-two percent of patients were discharged from medical care within six hours of ingestion. Albuterol overdose in children causes a variety of cardiovascular, neuromuscular, and metabolic effects that are usually benign. The threshold dose for the development of three or more signs of toxicity is 1 mg/kg or three to 10 times the recommended daily dose. Toxicity is short-lived and does not require specific therapy or hospital admission in most cases.

/SIGNS AND SYMPTOMS/ signs and symptoms of overdose including exaggeration of common adverse reactions, particularly angina, hypertension, hypokalemia, and seizures. Cardiac arrest may occur.

/SIGNS AND SYMPTOMS/ Albuterol also has been reported to cause maternal and fetal tachycardia and hyperglycemia (especially in patients with diabetes), as well as maternal hypotension, acute congestive heart failure, pulmonary edema, and death.

/CASE REPORTS/ Albuterol overdose can lead to tachycardia, hypotension, tremor, hypokalemia, and hyperglycemia in children. Hypoglycemia had been previously reported in only one child. A 3-year-old boy who ingested high-dose albuterol in this report /is described/. On arrival to the emergency department, the child was agitated and had noticeable restlessness, sinus tachycardia, mild hypokalemia (3.2 mEq/L), and hyperglycemia (187 mg/dL). Activated charcoal and intravenous hydration were given, and electrocardiogram monitoring was performed. Sinus tachycardia resolved within 4 to 6 hours. Hypoglycemia (45 mg/dL) was identified 4 hours after admission. The child recovered uneventfully within 24 hours with glucose replacement. This case suggests that hypoglycemia could be a late complication of acute albuterol overdose; thus, the period of observation should be extended in these cases.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Albuterol

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 3 was calculated for albuterol(SRC), using a water solubility of 1.41X10+4 mg/L(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

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

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

Certain other dosage form new animal drugs. Albuterol. Indications for use: for the immediate relief of bronchospasm and bronchoconstriction associated with reversible airway obstruction in horses. Limitations: Not for use in horses intended for food.

R03AC02

R - Respiratory system

R - Respiratory system

QR - Respiratory system

QR - Respiratory system

R03AC02

Salbutamol (INN) or albuterol (USAN), a moderately selective beta(2)-receptor agonist similar in structure to terbutaline, is widely used as a bronchodilator to manage asthma and other chronic obstructive airway diseases. The R-isomer, levalbuterol, is responsible for bronchodilation while the S-isomer increases bronchial reactivity. The R-enantiomer is available and sold in its pure form as levalbuterol and subsequently may produce fewer side-effects with only the R-enantiomer present - although this has not been formally demonstrated. After oral and parenteral administration, stimulation of the beta receptors in the body, both beta-1 and beta-2, occurs because (a) beta-2 selectivity is not absolute, and (b) higher concentrations of salbutamol occur in the regions of these receptors with these modes of administration. This results in the beta-1 effect of cardiac stimulation, though not so much as with isoprenaline, and beta-2 effects of peripheral vasodilatation and hypotension, skeletal muscle tremor, and uterine muscle relaxation. Metabolic effects such as hyperinsulinemia and hyperglycemia also may occur, although it is not known whether these effects are mediated by beta-1 or beta-2 receptors. The serum potassium levels have a tendency to fall.

In vitro studies and in vivo pharmacologic studies have shown that salbutamol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. Although beta2­ adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1 adrenoceptors are the predominant receptors in the heart, there are also beta2-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but their presence raises the possibility that even selective beta2-agonists may have cardiac effects. Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenyl cyclase and to an increase in the intracellular concentration of cyclic-3′,5′-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Salbutamol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Salbutamol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Salbutamol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes. A measurable decrease in airway resistance is typically observed within 5 to 15 minutes after inhalation of salbutamol. The maximum improvement in pulmonary function usually occurs 60 to 90 minutes after salbutamol treatment, and significant bronchodilator activity has been observed to persist for 3 to 6 hours.

Adrenergic bronchodilators act by stimulating beta2-adrenergic receptors in the lungs to relax bronchial smooth muscle, thereby relieving bronchospasm. /Adrenergic bronchodilators/

Primarily stimulates beta2-adrenergic receptors, with some minor beta1-adrenergic activity.

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, date indicate that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors has not been established.

Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylcyclase and to an increase in the intracellular concentration of cyclic-3',5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, this protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from most cells in the airway.

The elimination half-life of inhaled or oral salbutamol has been recorded as being between 2.7 and 5 hours while the apparent terminal plasma half-life of albuterol has been documented as being approximately 4.6 hours.

Elimination: 3.8 to 6 hours.

Salbutamol is not metabolized in the lung but is converted in the liver to the 4'-o-sulphate (salbutamol 4'-O-sulfate) ester, which has negligible pharmacologic activity. It may also be metabolized by oxidative deamination and/or conjugation with glucuronide. Salbutamol is ultimately excreted in the urine as free drug and as the metabolite.

Metabolized through sulfate conjugation to its inactive 4'-O-sulfate ester by phenol sulphotransferase (PST). The (R)-enantiomer of albuterol is preferentially metabolized (ten fold) by PST compared to the (S)-enantiomer of albuterol.

Hydrolyzed by esterases in tissue and blood to the active compound colterol. The drug is also conjugatively metabolized to salbutamol 4'-O-sulfate. Route of Elimination: Approximately 72% of the inhaled dose is excreted in the urine within 24 hours, 28% as unchanged drug and 44% as metabolite. Half Life: 1.6 hours

QF8SVZ843E

ALBUTEROL

Mechanisms of Action [MoA] - Adrenergic beta2-Agonists

Established Pharmacologic Class [EPC] - beta2-Adrenergic Agonist

Albuterol is a beta2-Adrenergic Agonist. The mechanism of action of albuterol is as an Adrenergic beta2-Agonist.

ALBUTEROL

Agents that cause an increase in the expansion of a bronchus or bronchial tubes.

Drugs that prevent preterm labor and immature birth by suppressing uterine contractions (TOCOLYSIS). Agents used to delay premature uterine activity include magnesium sulfate, beta-mimetics, oxytocin antagonists, calcium channel inhibitors, and adrenergic beta-receptor agonists. The use of intravenous alcohol as a tocolytic is now obsolete.

Compounds bind to and activate ADRENERGIC BETA-2 RECEPTORS.

Following inhalation, salbutamol acts topically on bronchial smooth muscle and the drug is initially undetectable in the blood. After 2 to 3 hours low concentrations are seen, due presumably to the portion of the dose which is swallowed and absorbed in the gut. In particular, the systemic levels of salbutamol are low after inhalation of recommended doses. A trial conducted in 12 healthy male and female subjects using a higher dose (1,080 mcg of albuterol base) showed that mean peak plasma concentrations of approximately 3 ng/mL occurred after dosing when salbutamol was delivered using propellant HFA-134a. The mean time to peak concentrations (Tmax) was delayed after administration of VENTOLIN (salbutamol) HFA (Tmax = 0.42 hours) as compared with CFC-propelled salbutamol inhaler (Tmax = 0.17 hours).

After oral administration, 58-78% of the dose is excreted in the urine in 24 hours, approximately 60% as metabolites. A small fraction is excreted in the feces.

The volume of distribution recorded for intravenously administered salbutamol has been recorded as 156 +/- 38 L.

The renal clearance of salbutamol has been documented as 272 +/- 38 ml/min after oral administration and 291 +/- 70 ml/min after intravenous administration. Furthermore, the renal clearance of the predominant sulfate conjugate metabolite was recorded as 98.5 +/- 23.5 ml/min following oral administration.

Elimination: Renal, 69 to 90% (60% as the metabolite). Fecal, 4%.

Extended-release tablets: Availability is approximately 80% of that for tablets after a single dose, regardless of whether or not taken with food, but is 100% of that for immediate-release tablets at steady-state. Food decreases the rate of absorption without affecting bioavailability.

Bronchodilator; tocolytic

Medication

Medication (Vet)

Use (kg; approx.) in Germany (2009): >250

For symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis, and other chronic bronchopulmonary disorders such as COPD.

Oral Inhalation: Aerosol: 90 ug/metered spray Proventil Inhalation Aerosol (with chlorofluorohydrocarbon propellants and oleic acid), (Schering), Ventolin Inhalation Aerosol (with chlorofluorohydrocarbon propellants and oleic acid), (GlaxoSmithKline).

Oral: Solution 2 mg (of albuterol) per 5 mL Proventil Syrup (Schering). Tablets: 2 mg (of albuterol) Proventil (scored), (Schering); 4 mg (of albuterol) Proventil (scored), (Schering), Ventolin (scored), (GlaxoSmithKline). Tablets, extended release: 4 mg (of albuterol) Volmax (with povidone), (Muro), Vospire ER (Odyssey); 8 mg (of albuterol) Volmax (with povidone), (Muro), Vospire ER (Odyssey). Tablets, extended-release core, film-coated: 4 mg (core 2 mg with 2 mg immediate release) (of albuterol) Proventil Repetabs (with butylparaben), (Schering). /Albuterol Sulfate/

Oral Inhalation: Aerosol: 90 ug (of albuterol) per metered spray Proventil HFA (with alcohol, hydrofluoroalkane propellant, and oleic acid), (Schering), Ventolin HFA (with hydrofluoroalkane propellant), (GlaxoSmithKline); Solution, for nebulization: 0.21 mg (of albuterol) per mL (0.63 mg) AccuNeb (preservative-free; available as polyethylene vials), (Dey); 0.42 mg (of albuterol) per mL (1.25 mg) AccuNeb (preservative-free; available as polyethylene vials), (Dey); 0.083% (of albuterol) Albuterol Albuterol Sulfate Inhalation Solution (Dey), Proventil (preservative-free), (Schering). Solution, concentrate, for nebulization: 0.5% (of Albuterol) Albuterol Sulfate Inhalation Solution (with benzalkonium chloride), (Warrick), Proventil (with benzalkonium chloride), (Schering).