Salbutamol

Absorption

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).

Toxicity

The expected signs and symptoms with overdosage of albuterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). In particular, the signs of salbutamol overdosage are significant tachycardia and/or significant muscle tremor.

Hypokalaemia may occur following overdosage with salbutamol. Serum potassium levels should be monitored.

Description

Albuterol is a widely used bronchodilator. It is one of a series of compounds that were patented in 1972 by L. H. C. Lunts and co-inventors and assigned to Allen and Hanburys, a British pharmaceutical company that dated back to the early 18th century. (It eventually became part of the GlaxoSmithKline conglomerate.)
The patent describes the compounds of the invention as stimulants or blockers of ?2-adrenergic receptors. It is now known that albuterol is a short-acting ?22-adrenergic receptor agonist. It is prescribed for treating pulmonary conditions such as bronchitis, asthma, and chronic obstructive pulmonary disease.
Albuterol is a racemic mixture. The pharmaceutical literature contains conflicting accounts of the mechanisms of action of the two enantiomers. What is clear is that (R)-albuterol has 100a??150 times greater affinity for ?22-receptors than the (S) enantiomer and is likely responsible for bronchodilation. In some accounts, (S)-albuterol is said to increase bronchial activity, but in others it is described as inactive.

Description

Albuterol is a β2-adrenergic sympathomimetic amine with pharmacological similarities to terbutaline. It has almost no effect on β1-adrenoreceptors of the heart. It has expressed broncholytic effects—prevention or relief of bronchi spasms, lowering respiratory tract resistance, and increasing the vital capacity of the lungs.

Chemical properties

solid

Originator

Ventolin ,Allen and Hanburys ,UK ,1969

The Uses of Salbutamol

immune suppressant, antineoplastic, antiviral

The Uses of Salbutamol

short-acting b2-adrenergic agonist, asthma therapeutic

The Uses of Salbutamol

Albuterol is widely used for severe and chronic bronchial asthma and other illnesses of the respiratory tract that result in a spastic condition of the bronchi.

Background

Salbutamol is a short-acting, selective beta2-adrenergic receptor agonist used in the treatment of asthma and COPD. It is 29 times more selective for beta2 receptors than beta1 receptors giving it higher specificity for pulmonary beta receptors versus beta1-adrenergic receptors located in the heart. Salbutamol is formulated as a racemic mixture of the R- and S-isomers. The R-isomer has 150 times greater affinity for the beta2-receptor than the S-isomer and the S-isomer has been associated with toxicity. This lead to the development of levalbuterol, the single R-isomer of salbutamol. However, the high cost of levalbuterol compared to salbutamol has deterred wide-spread use of this enantiomerically pure version of the drug. Salbutamol is generally used for acute episodes of bronchospasm caused by bronchial asthma, chronic bronchitis and other chronic bronchopulmonary disorders such as chronic obstructive pulmonary disorder (COPD). It is also used prophylactically for exercise-induced asthma.

Indications

Salbutamol is indicated for (i) the symptomatic relief and prevention of bronchospasm due to bronchial asthma, chronic bronchitis, reversible obstructive airway disease, and other chronic bronchopulmonary disorders in which bronchospasm is a complicating factor, and/or (ii) the acute prophylaxis against exercise-induced bronchospasm and other stimuli known to induce bronchospasm.

Definition

ChEBI: A member of the class of phenylethanolamines that is 4-(2-amino-1-hydroxyethyl)-2-(hydroxymethyl)phenol having a tert-butyl group attached to the nirogen atom. It acts as a beta-adrenergic agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD).

Manufacturing Process

(a) α1-Benzyl-tert-butylaminomethyl-4-hydroxym-xylene-α1,α3-diol: 3.0 g of 5-(N-benzyl-N-tert-butylglycyl)-salicylic acid methyl ester hydrochloride in 40 ml of water was basified with sodium bicarbonate solution and extracted into ether. The ethereal solution was dried over MgSO4 and evaporated and the basic residue in 20 ml of dry tetrahydrofuran was added with stirring to 1.0 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran, over a period of 5 minutes. The light gelatinous precipitate that formed was stirred and refluxed for 8 hours after which time 7 ml of water was carefully added and the solvents were removed under reduced pressure.
The residue was acidified with dilute hydrochloric acid and brought to pH 8 with sodium hydroxide and sodium bicarbonate. The mixture was filtered and the filtrate and orange solid were separately extracted with chloroform. The combined, dried, chloroform solutions were evaporated to give 22 g of the crude basic triol as an orange solid, when triturated with ether. A portion of the material was recrystallized from ether/light petroleum (BP 40-60°C) to give a white solid, MP 109-111°C.
In an alternative process, sodium borohydride was used as the reducing agent, as follows:
36 g of 2-(benzyl-tert-butylamino)-4'-hydroxy-3'-hydroxymethyl acetophenone, hydrochloride was shaken with 100 ml of 10% sodium carbonate solution and 100 ml of ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuum.
The residual gum was dissolved in 360 ml of ethanol and cooled to 15°C in an ice/water bath, 8 g of sodium borohydride was then added in portions over 30 minutes while maintaining the temperature at 15-20°C. After a further 30 minutes at 20°C the solution was stirred at room temperature for 2 hours. The solution was again cooled in ice and 250 ml of 2 N sulfuric acid were slowly added, then the solution was evaporated in vacuum until the ethanol had been removed. The clear aqueous solution was then treated with 250 ml of 10% sodium carbonate solution and the oil which precipitated was extracted into ethyl acetate. The ethyl acetate layer was washed with sodium carbonate solution, then with water, and was dried over anhydrous sodium sulfate and evaporated in vacuum, to a small volume. Petroleum ether (BP 40-60°C) was added, and after standing overnight a white solid was obtained. This was filtered off to give 23 g of the product, MP 110-114°C.
(b) α1-tert-Butylaminomethyl-4-hydroxy-m-xylene-α1,α3-diol: 0.8 g of α1- benzyl-tert-butyl-aminomethyl-4-hydroxy-m-xylene-α1,α3-diol in 20 ml of ethanol and 2 ml of water was shaken with hydrogen in presence of 0.50 g of pre-reduced 10% palladium on charcoal catalyst. When uptake of hydrogen was complete, the solution was filtered and evaporated under reduced pressure to give 0,4 g of the base as a colorless oil which yielded a white solid, MP 144-145°C when triturated with ether/cyclohexane. Recrystallization from ethyl acetate-cyclohexane gave a white solid, MP 147-149°C.

brand name

Proventil (Schering); Ventolin (GlaxoSmithKline).

Therapeutic Function

Bronchodilator

Biological Functions

Levalbuterol is the R-(–)-isomer of albuterol and is available only in solution to be administered via nebulizer. Because it is the active isomer, the dose is fourfold less than that of albuterol. Pirbuterol is the pyridine isostere of albuterol. It has pharmacokinetics similar to albuterol but is half as potent at the β2-receptor. Pirbuterol is only available as an inhaler, whereas albuterol comes in tablet, syrup, solution, and aerosol formulations.

Synthesis Reference(s)

Synthesis, p. 966, 1988 DOI: 10.1055/s-1988-27768

General Description

Standard for Supelco MIP SPE cartridges. For more information request Supelco Literature T407075, T706019, T706030, T706020. Salbutamol is classified under the β-agonist group of chemicals which are known to possess powerful pharmacological activities.

Biochem/physiol Actions

β2-adrenoceptor agonist

Pharmacokinetics

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.

Clinical Use

Albuterol has the N-t-butyl and a salicyl alcohol phenyl ring, which gives it optimal β2-selectivity. It is resistant to COMT and slowly metabolized by MAO, giving it good oral bioavailability. Its onset by inhalation is within 5 minutes, with a duration of action between 4 and 8 hours. It currently is the drug of choice for relief of the acute bronchospasm of an asthmatic attack.

Side Effects

Adverse effects of pirbuterol are nervousness, tremor, and headache, which is less than the profile for albuterol, which adds nausea, vomiting, dizziness, hypertension, insomnia, tachycardia, and palpitations.

Synthesis

Albuterol, 2-tert-butylamino-1-(4-hydroxy-3-hydroxymethylphenyl)ethanol (11.1.26), basically differs from all of the aforementioned sympathomimetics in that the hydroxyl group at C3 of the aromatic ring is replaced with a hydroxymethyl group. It is synthesized in two ways. According to the first, it is prepared from 4-hydroxyacetophenone, the chloromethylation of which gives 4-hydroxy-3-hydroxymethylacetophenone (11.1.20). This is acetylated into a diacetyl derivative (11.1.21), which is further brominated into the corresponding bromoacetophenone (11.1.22). Reacting this with N-benzylN-tert-butylamine gives a derivative of aminoacetophenone (11.1.23), the acetyl group of which is hydrolyzed by hydrochloric acid, and the resulting product (11.1.24) undergoes a reduction?afirst by sodium borohydride for transforming the keto group into a hydroxyl group to give 11.1.25, and then by hydrogenation over a palladium catalyst for removing the benzyl-protecting group, giving albuterol (11.1.26) [26¨C30].

Environmental Fate

Tachycardia occurs as a reflex to the drop in mean arterial pressure (MAP) or as a result of b-1 stimulus. b-Adrenergic receptors in the locus coeruleus also regulate norepinephrineinduced inhibitory effects, resulting in agitation, restlessness, and hand tremor. Stimulation of nonpulmonary b2 receptors may lead to an increase in heart rate, QTc interval prolongation, nonspecific T-wave changes, skeletal muscle tremor, and slight increases in blood glucose and nonesterified fatty acids. Hypokalemia is more pronounced in patients receiving intravenous albuterol. Hypotension is also known to occur mostly in overdose. The buildup of cyclic AMP in the liver stimulates glycogenolysis and an increase in serum glucose.
In skeletal muscle, this process results in increased lactate production. Direct stimulus of sodium/potassium ATPase in skeletal muscle produces a shift of potassium from the extracellular space to the intracellular space. Relaxation of smooth muscle produces a dilation of the vasculature supplying skeletal muscle, which results in a drop in diastolic and MAP.Myocardial ischemia and infarction have been associated with excessive tachycardia in elderly patients. The skin may be warm and pink with evidence of diaphoresis.

Metabolism

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.

Toxicity evaluation

Albuterol’s production and use as a bronchodilator may result in its release to the environment through various waste streams.