| Description | Benzonatate is a reversible voltage-gated sodium channel blocker. It blocks Nav1.7 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 Nav1.3 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 |
| History | Benzonatate is used to relieve cough. Benzonatate is in a class of medications called antitussives (cough suppressants). It works by reducing the cough reflex in the lungs and air passages. It was first synthesized in 1956 and was introduced as an antitussive in the United States in 1958.
Availability worldwide is limited, with the drug remaining marketed only in the United States and Mexico. In 2023, it was the 122nd most commonly prescribed medication in the United States, with more than 5 million prescriptions. A 2023 systematic review found that there is inadequate evidence to support the effectiveness and safety of benzonatate for cough and highlighted rising safety concerns. |
| Uses | Antitussive |
| 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 partsof a mixture of polyethylene glycol monomethyl ethers, boiling at 180°-220°Cat a pressure of 0.01 mm of mercury, in a closed reaction vessel which isfitted with an adjustable inlet tube for solvents and a connection for distillingoff in vacuo. In order to dry the mixture completely, it is heated for an hour at100°-105°C and absolute xylene is introduced under the surface of themixture in vacuo at a pressure of 12 mm of mercury. There is thus a constantstream of xylene steam passing through the whole apparatus, which removesthe last traces of moisture and any other volatile impurities. The xylene iscondensed in a cooler. The whole is cooled to 20°-30°C and 0.06 part ofsodium 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 theseconditions until a specimen of the reaction mass is clearly soluble in coldwater, which occurs after about 2-3 hours. There is now obtained in almostquantitative yield the ester of the formula wherein n stands for approximately7 to 9, which still contains an excess of polyethylene glycol monomethyl ether.The ester is purified by dissolving in benzene and being washed several timeswith a sodium carbonate solution of 5% strength. It is advantageous toagitate all the washing solutions with fresh benzene. In this distributionbetween benzene and sodium carbonate solution the new ester remains in thebenzene, the excess polyethylene glycol monomethyl ether and a smallamount of brown impurities are taken up by the dilute soda solution. Byevaporating the dried and filtered benzene solution there is obtained the newester in the form of a colorless to very faintly yellow oil which is easily solublein most organic solvents with the exception of aliphatic hydrocarbons. Thenew 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 anesthetictetracaine. It anesthetizes the stretch receptors inthe lungs, thereby reducing coughing.Adverse reactionsinclude hypersensitivity, sedation, dizziness, and nausea. |
| Mechanism of action | It is believed that it acts by two mechanisms: selective anesthesia of irritated receptors inthe lungs and simultaneous suppression of the cough center. |
| 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-butylaminobenzoicacid with the monomethyl ether nonaethylenglycol. It is a structural analog of thelocal anesthetic tetracaine. |
| References | [1] M. STEVEN EVANS . Benzonatate inhibition of voltage-gated sodium currents[J]. Neuropharmacology, 2016, 101: Pages 179-187. DOI: 10.1016/j.neuropharm.2015.09.020
[2] S YANAURA. [Effects of peripheral airway response on the cough reflex (author’s transl)].[J]. Folia Pharmacologica Japonica, 1980, 76 8: 709-716. |
