Benzonatate

Absorption

Following oral administration, benzonatate enters the systemic circulation via gastrointestinal absorption. The Cmax of benzonatate following oral administration of 100 mg in healthy Chinese volunteers was 1063 ± 460 ng/mL.

Toxicity

The lowest published toxic dose (TDLo) from oral administration in man is 51 mg/kg. The oral LD50 is 400 mg/kg and the subcutaneous LD50 is 100 mg/kg in mice.
The signs and symptoms of overdose are typically observed within 15 to 20 minutes and can lead to neurological and cardiovascular toxicity, which is related to blocked sodium channels. Intentional and unintentional death from overdose may occur. The risk of overdose is highest in children and toxicity may result from the ingestion of 1 or 2 capsules in this age group. If capsules are chewed or dissolved in the mouth, oropharyngeal anesthesia will develop rapidly, which may cause choking and a compromised airway function. Symptoms arising from CNS stimulation include restlessness and tremors, which may lead to clonic convulsions followed by profound CNS depression. Within 1 hour following ingestion, convulsions, coma, cerebral edema and cardiac arrest leading to death have been reported.
Evacuation of gastric contents and administration of copious amounts of activated charcoal is advised. It is important to note that cough and gag reflexes may be significantly depressed even in conscious patients with overdose; special attention is needed to protect against aspiration of gastric contents. When intravenously administering short-acting barbiturates to treat convulsions, the dose should be carefully titrated for the smallest effective dose. Overdose should be managed with supportive care with continuous monitoring of neurologic and cardiovascular status. Intensive support of respiration and cardiovascular-renal function should be initiated for severe intoxication. Because benzonatate is structurally similar to local anesthetic agents, the use of intravenous lipid emulsion therapy in response to life-threatening cardiovascular collapse is also suggested.

Description

Benzonatate is a reversible voltage-gated sodium channel blocker. It blocks Na_v1.7 currents in a concentration- and voltage-dependent manner (IC₅₀s = 5.9 and 1.4 μM at holding potentials of -100 and -70 mV, respectively) and inhibits action potential firing in catecholamine A differentiated (CAD) cells. Benzonatate also blocks 80% of Na_v1.3 currents in N1E-115 cells when used at a concentration of 100 μM. In vivo, benzonatate (0.85 mg/min) reduces the frequency, but has no effect on the amplitude, of the cough reflex in anesthetized dogs. Formulations containing benzonatate have been used as antitussive agents for the treatment of coughs.

Originator

Tessalon,Endo (Du Pont),US,1958

The Uses of Benzonatate

Antitussive

Indications

Benzonatate is indicated for the symptomatic relief of cough.

What are the applications of Application

Benzonatate is an anti-tussive chemical used for biochemical research

Background

Benzonatate is an oral antitussive drug used in the relief and suppression of cough in patients older than ten years of age. Currently, benzonatate is the only non-narcotic antitussive available as a prescription drug. It works to reduce the activity of cough reflex by desensitizing the tissues of the lungs and pleura involved in the cough reflex. Benzonatate was approved by the FDA in 1958 under the market name Tessalon Perles. Because its chemical structure resembles that of the anesthetic agents in the para-amino-benzoic acid class (such as procaine and tetracaine), benzonatate exhibits anesthetic or numbing action. Although it not prone to drug misuse or abuse, benzonatate is associated with a risk for severe toxicity and overdose, especially in children.

Definition

ChEBI: The ester obtained by formal condensation of 4-butylaminobenzoic acid with nonaethylene glycol monomethyl ether. Structurally related to procaine and benzocaine, it has an anaesthetic effect on the stretch sensors in the lungs, and is used as a non-narcoti cough suppressant.

Manufacturing Process

4.42 parts of para-butylamino-benzoic acid ethyl ester are put with 16.0 parts of a mixture of polyethylene glycol monomethyl ethers, boiling at 180°-220°C at a pressure of 0.01 mm of mercury, in a closed reaction vessel which is fitted with an adjustable inlet tube for solvents and a connection for distilling off in vacuo. In order to dry the mixture completely, it is heated for an hour at 100°-105°C and absolute xylene is introduced under the surface of the mixture in vacuo at a pressure of 12 mm of mercury. There is thus a constant stream of xylene steam passing through the whole apparatus, which removes the last traces of moisture and any other volatile impurities. The xylene is condensed in a cooler. The whole is cooled to 20°-30°C and 0.06 part of sodium methylate dissolved in 0.6 part of methanol is added.
Thereupon xylene is introduced again in vacuo at a temperature of 100°- 105°C whereby all the methanol and the ethanol formed during reesterification evaporates. The re-esterification is continued under these conditions until a specimen of the reaction mass is clearly soluble in cold water, which occurs after about 2-3 hours. There is now obtained in almost quantitative yield the ester of the formula wherein n stands for approximately 7 to 9, which still contains an excess of polyethylene glycol monomethyl ether. The ester is purified by dissolving in benzene and being washed several times with a sodium carbonate solution of 5% strength. It is advantageous to agitate all the washing solutions with fresh benzene. In this distribution between benzene and sodium carbonate solution the new ester remains in the benzene, the excess polyethylene glycol monomethyl ether and a small amount of brown impurities are taken up by the dilute soda solution. By evaporating the dried and filtered benzene solution there is obtained the new ester in the form of a colorless to very faintly yellow oil which is easily soluble in most organic solvents with the exception of aliphatic hydrocarbons. The new ester is precipitated from aqueous solutions when heated to about 42°C. but it dissolves again readily on cooling.

brand name

Tessalon (Forest).

Therapeutic Function

Antitussive

Biological Functions

Benzonatate (TessaIon) is related to the local anesthetic tetracaine. It anesthetizes the stretch receptors in the lungs, thereby reducing coughing.Adverse reactions include hypersensitivity, sedation, dizziness, and nausea.

Mechanism of action

It is believed that it acts by two mechanisms: selective anesthesia of irritated receptors in the lungs and simultaneous suppression of the cough center.

Pharmacokinetics

Benzonatate suppresses cough associated with both acute and chronic respiratory conditions. Its works by desensitizing the pulmonary stretch receptors involved in the cough reflex. There are limited clinical trials of benzonatate; however, earlier studies demonstrated inhibition of experimentally-induced cough and subjectively-measured pathological cough by benzonatate.
Benzonatate has no inhibitory effects on the respiratory center in recommended dosage. Its onset of action is within 15 to 20 minutes following administration and its duration of effect is about 3 to 8 hours.

Synthesis

Benzonatate, p-butylaminobenzoate 2,5,8,11,14,17,20,23,26-nonaoctacozan- 28-ol (23.2.2), is synthesized by reesterifying the ethyl ester of 4-butylaminobenzoic acid with the monomethyl ether nonaethylenglycol. It is a structural analog of the local anesthetic tetracaine.

Metabolism

Benzonatate is hydrolyzed to the major metabolite 4-(butylamino)benzoic acid (BABA) by plasma butyrylcholinesterase (BChE).