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Identification
- Summary
Benzonatate is a non-narcotic oral antitussive drug used to suppress coughing.
- Generic Name
- Benzonatate
- DrugBank Accession Number
- DB00868
- Background
Benzonatate is an oral antitussive drug used in the relief and suppression of cough in patients older than ten years of age.3 Currently, benzonatate is the only non-narcotic antitussive available as a prescription drug.2 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.3 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.7 Although it not prone to drug misuse or abuse, benzonatate is associated with a risk for severe toxicity and overdose, especially in children.4
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Benzonatate (DB00868)
- Weight
- Average: 603.7419
Monoisotopic: 603.361861543 - Chemical Formula
- C30H53NO11
- Synonyms
- 2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl 4-butylaminobenzoate
- 2,5,8,11,14,17,20,23,26-nonaoxaoctacosan-28-yl p-(butylamino)benzoate
- 3,6,9,12,15,18,21,24,27-nonaoxaoctacosyl 4-butylaminobenzoate
- 4-(butylamino)benzoic acid 3,6,9,12,15,18,21,24,27-nonaoxaoctacos-1-yl ester
- Benzonatat
- Benzonatate
- Benzonatato
- Benzonatatum
- Benzononatine
- nonaethyleneglycol monomethyl ether p-n-butylaminobenzoate
- p-butylaminobenzoic acid ω-O-methylnonaethyleneglycol ester
- External IDs
- KM 65
- KM65
Pharmacology
- Indication
Benzonatate is indicated for the symptomatic relief of cough.7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Symptomatic treatment of Cough •••••••••••• ••••••• - Contraindications & Blackbox Warnings
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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.1
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.7
- Mechanism of action
Benzonatate is a local anesthetic drug that acts peripherally by anesthetizing and reducing the activity of vagal stretch receptors or nerve fibres located in the respiratory passages, lungs, and pleura.2,7 Once the stretch receptors are stimulated, they send impulses to the cough centre located in the medulla via an afferent pathway consisting of sensory nerve fibres or the vagus nerve. The efferent signal is then generated that sends impulses to the expiratory muscles to produce a cough.6 Anesthetizing these receptors by benzonatate results in the inhibition of the cough reflex activity and cough production.2,7 Benzonatate also inhibits the transmission of impulses of the cough reflex in the vagal nuclei of the medulla.5 There are several proposed mechanisms of benzonatate; it is also a potent voltage-gated sodium channel inhibitor.2
Target Actions Organism USodium channel protein type 5 subunit alpha antagonistHumans - Absorption
Following oral administration, benzonatate enters the systemic circulation via gastrointestinal absorption.3 The Cmax of benzonatate following oral administration of 100 mg in healthy Chinese volunteers was 1063 ± 460 ng/mL.5
- Volume of distribution
There is limited information on the volume of distribution of benzonatate.
- Protein binding
There is limited information on the protein binding profile of benzonatate.
- Metabolism
Benzonatate is hydrolyzed to the major metabolite 4-(butylamino)benzoic acid (BABA) by plasma butyrylcholinesterase (BChE).2
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- Route of elimination
There is limited information on the route of elimination of benzonatate.
- Half-life
The half life of benzonatate following oral administration of 100 mg in healthy Chinese volunteers was 1.01 ± 0.41 h.5
- Clearance
There is limited information on the clearance of benzonatate.
- Adverse Effects
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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.8
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.3 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.7
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.7 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.3
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAclidinium The serum concentration of Aclidinium can be increased when it is combined with Benzonatate. Ambenonium Ambenonium may increase the neuromuscular blocking activities of Benzonatate. Aprotinin Aprotinin may increase the neuromuscular blocking activities of Benzonatate. Betaine Betaine may increase the neuromuscular blocking activities of Benzonatate. Capsaicin Capsaicin may increase the neuromuscular blocking activities of Benzonatate. - Food Interactions
- Take with or without food. The absorption is unaffected by food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Images
- International/Other Brands
- Exangit / Tesaperl (Novartis ) / Tessalon Perles / Ventussin
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Benzonatate Capsule 200 mg/1 Oral Ethex Corporation 2008-12-30 Not applicable US 
Benzonatate Capsule 100 mg/1 Oral Ethex Corporation 2008-12-30 Not applicable US Tessalon Capsule 100 mg/1 Oral Pfizer Laboratories Div Pfizer Inc 1958-02-10 2022-05-31 US Tessalon Capsule 200 mg/1 Oral Pfizer Laboratories 1999-06-25 2011-02-04 US Tessalon Capsule 100 mg/1 Oral Physicians Total Care, Inc. 1958-02-10 2011-07-31 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Benzonatate Capsule 100 mg/1 Oral Greenstone LLC 2020-01-06 Not applicable US Benzonatate Capsule 200 mg/1 Oral RedPharm Drug, Inc 2019-02-22 Not applicable US Benzonatate Capsule 200 mg/1 Oral Marlex Pharmaceuticals Inc 2017-10-20 Not applicable US Benzonatate Capsule, liquid filled 200 mg/1 Oral AvKARE 2016-03-15 2020-05-31 US Benzonatate Capsule 100 mg/1 Oral Avera McKennan Hospital 2015-03-05 2017-05-24 US
Categories
- ATC Codes
- R05DB01 — Benzonatate
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as benzoic acid esters. These are ester derivatives of benzoic acid.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Benzoic acids and derivatives
- Direct Parent
- Benzoic acid esters
- Alternative Parents
- Aminobenzoic acids and derivatives / Phenylalkylamines / Benzoyl derivatives / Aniline and substituted anilines / Secondary alkylarylamines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Dialkyl ethers / Organopnictogen compounds show 2 more
- Substituents
- Amine / Amino acid or derivatives / Aminobenzoic acid or derivatives / Aniline or substituted anilines / Aromatic homomonocyclic compound / Benzoate ester / Benzoyl / Carboxylic acid derivative / Carboxylic acid ester / Dialkyl ether show 12 more
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- substituted aniline, secondary amino compound, benzoate ester (CHEBI:3032)
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 5P4DHS6ENR
- CAS number
- 104-31-4
- InChI Key
- MAFMQEKGGFWBAB-UHFFFAOYSA-N
- InChI
- InChI=1S/C30H53NO11/c1-3-4-9-31-29-7-5-28(6-8-29)30(32)42-27-26-41-25-24-40-23-22-39-21-20-38-19-18-37-17-16-36-15-14-35-13-12-34-11-10-33-2/h5-8,31H,3-4,9-27H2,1-2H3
- IUPAC Name
- 2,5,8,11,14,17,20,23,26-nonaoxaoctacosan-28-yl 4-(butylamino)benzoate
- SMILES
- CCCCNC1=CC=C(C=C1)C(=O)OCCOCCOCCOCCOCCOCCOCCOCCOCCOC
References
- Synthesis Reference
Matter, M.; U.S. Patent 2,714,608; August 2, 1955; assigned to Ciba Pharmaceutical Products, Inc.
- General References
- Dicpinigaitis PV, Gayle YE, Solomon G, Gilbert RD: Inhibition of cough-reflex sensitivity by benzonatate and guaifenesin in acute viral cough. Respir Med. 2009 Jun;103(6):902-6. doi: 10.1016/j.rmed.2008.12.008. Epub 2009 Jan 1. [Article]
- Bishop-Freeman SC, Shonsey EM, Friederich LW, Beuhler MC, Winecker RE: Benzonatate Toxicity: Nothing to Cough At. J Anal Toxicol. 2017 Jun 1;41(5):461-463. doi: 10.1093/jat/bkx021. [Article]
- Thimann DA, Huang CJ, Goto CS, Feng SY: Benzonatate toxicity in a teenager resulting in coma, seizures, and severe metabolic acidosis. J Pediatr Pharmacol Ther. 2012 Jul;17(3):270-3. doi: 10.5863/1551-6776-17.3.270. [Article]
- Burns JM, Boyer EW: Antitussives and substance abuse. Subst Abuse Rehabil. 2013 Nov 6;4:75-82. doi: 10.2147/SAR.S36761. eCollection 2013. [Article]
- Man J, Jiao F, Wang Y, Gu Y, Ding L, Shu C: Determination of benzonatate and its metabolite in human plasma by HPLC-MS/MS: A preliminary pharmacokinetic study in healthy Chinese volunteers after oral administration of benzonatate soft capsule. J Pharm Biomed Anal. 2019 Sep 5;173:134-143. doi: 10.1016/j.jpba.2019.05.030. Epub 2019 May 16. [Article]
- Polverino M, Polverino F, Fasolino M, Ando F, Alfieri A, De Blasio F: Anatomy and neuro-pathophysiology of the cough reflex arc. Multidiscip Respir Med. 2012 Jun 18;7(1):5. doi: 10.1186/2049-6958-7-5. [Article]
- DailyMed Label: Benzonatate Oral Capsules [Link]
- Cayman Chemical: Benzonatate MSDS [Link]
- External Links
- Human Metabolome Database
- HMDB0015006
- KEGG Drug
- D00242
- PubChem Compound
- 7699
- PubChem Substance
- 46506376
- ChemSpider
- 7413
- BindingDB
- 50240086
- 18993
- ChEBI
- 3032
- ChEMBL
- CHEMBL1374379
- ZINC
- ZINC000003830276
- Therapeutic Targets Database
- DAP000514
- PharmGKB
- PA164745459
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Benzonatate
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data3 Unknown Status Treatment Cough 1 somestatus stop reason just information to hide 1 Completed Basic Science Cough 1 somestatus stop reason just information to hide 1 Completed Basic Science Healthy Volunteers (HV) 1 somestatus stop reason just information to hide 1 Unknown Status Treatment Cough 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Banner pharmacaps inc
- Kv pharmaceutical co
- Mikart inc
- Orit laboratories llc
- Sun pharmaceutical industries inc
- The pharma network llc
- Zydus pharmaceuticals usa inc
- Forest laboratories inc
- Packagers
- Accucaps Industries Ltd.
- Advanced Pharmaceutical Services Inc.
- Amerisource Health Services Corp.
- Amneal Pharmaceuticals
- Apotheca Inc.
- A-S Medication Solutions LLC
- Ascend Laboratories LLC
- Atlantic Biologicals Corporation
- Atley Pharmaceuticals
- Banner Pharmacaps Inc.
- Barr Pharmaceuticals
- Bryant Ranch Prepack
- Cadila Healthcare Ltd.
- Caraco Pharmaceutical Labs
- Cardinal Health
- Catalent Pharma Solutions
- Dispensing Solutions
- Diversified Healthcare Services Inc.
- Ethex Corp.
- Forest Pharmaceuticals
- H.J. Harkins Co. Inc.
- Heartland Repack Services LLC
- Inwood Labs
- IVC Industries Inc.
- Kaiser Foundation Hospital
- KV Pharmaceutical Co.
- Lake Erie Medical and Surgical Supply
- Liberty Pharmaceuticals
- Major Pharmaceuticals
- Mallinckrodt Inc.
- Murfreesboro Pharmaceutical Nursing Supply
- Nucare Pharmaceuticals Inc.
- Palmetto Pharmaceuticals Inc.
- Patient First Corp.
- PD-Rx Pharmaceuticals Inc.
- Pharmaceutical Utilization Management Program VA Inc.
- Pharmaceutics International Inc.
- Pharmedix
- Physicians Total Care Inc.
- Pliva Inc.
- Preferred Pharmaceuticals Inc.
- Prepackage Specialists
- Prescript Pharmaceuticals
- Provident Pharmaceuticals LLC
- Qualitest
- Rebel Distributors Corp.
- Redpharm Drug
- Remedy Repack
- Resource Optimization and Innovation LLC
- Stat Rx Usa
- Stat Scripts LLC
- Swiss Caps Ag
- United Research Laboratories Inc.
- Vangard Labs Inc.
- Zydus Pharmaceuticals
- Dosage Forms
Form Route Strength Capsule Oral 100 mg/1 Capsule Oral 200 mg/1 Capsule, gelatin coated Oral 200 mg/1 Capsule, liquid filled Oral 100 mg/1 Capsule, liquid filled Oral 200 mg/1 Tablet Oral 100 mg/1 Capsule Oral Capsule Oral 100.0000 mg Capsule Oral 100.00 mg Capsule Oral 100.000 mg Suppository Rectal 50 mg Capsule Oral 150 mg/1 - Prices
Unit description Cost Unit Tessalon 200 mg capsule 2.76USD capsule Benzonatate 200 mg capsule 2.03USD capsule Tessalon Perles 100 mg capsule 1.62USD capsule Zonatuss 150 mg capsule 1.59USD capsule Tessalon perle 100 mg capsule 1.4USD capsule Benzonatate 100 mg capsule 0.85USD capsule DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
Property Value Source logP 2.45 HANSCH,C ET AL. (1995) - Predicted Properties
Property Value Source Water Solubility 0.00159 mg/mL ALOGPS logP 2.09 ALOGPS logP 2.35 Chemaxon logS -5.6 ALOGPS pKa (Strongest Basic) 3.47 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 11 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 121.4 Å2 Chemaxon Rotatable Bond Count 33 Chemaxon Refractivity 161.54 m3·mol-1 Chemaxon Polarizability 67.87 Å3 Chemaxon Number of Rings 1 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9932 Blood Brain Barrier + 0.9355 Caco-2 permeable + 0.6067 P-glycoprotein substrate Substrate 0.6531 P-glycoprotein inhibitor I Non-inhibitor 0.5978 P-glycoprotein inhibitor II Non-inhibitor 0.9434 Renal organic cation transporter Non-inhibitor 0.7646 CYP450 2C9 substrate Non-substrate 0.875 CYP450 2D6 substrate Non-substrate 0.7017 CYP450 3A4 substrate Non-substrate 0.6026 CYP450 1A2 substrate Non-inhibitor 0.9045 CYP450 2C9 inhibitor Non-inhibitor 0.907 CYP450 2D6 inhibitor Non-inhibitor 0.9232 CYP450 2C19 inhibitor Non-inhibitor 0.9025 CYP450 3A4 inhibitor Non-inhibitor 0.9275 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.932 Ames test Non AMES toxic 0.7269 Carcinogenicity Non-carcinogens 0.9182 Biodegradation Ready biodegradable 0.6331 Rat acute toxicity 2.2423 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9013 hERG inhibition (predictor II) Non-inhibitor 0.6129
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 294.3659735 predictedDarkChem Lite v0.1.0 [M-H]- 292.6595735 predictedDarkChem Lite v0.1.0 [M-H]- 227.21645 predictedDeepCCS 1.0 (2019) [M+H]+ 294.4719735 predictedDarkChem Lite v0.1.0 [M+H]+ 292.8246735 predictedDarkChem Lite v0.1.0 [M+H]+ 229.97148 predictedDeepCCS 1.0 (2019) [M+Na]+ 294.0648735 predictedDarkChem Lite v0.1.0 [M+Na]+ 237.13264 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- General Function
- This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:1309946, PubMed:21447824, PubMed:23085483, PubMed:23420830, PubMed:25370050, PubMed:26279430, PubMed:26392562, PubMed:26776555). It is a tetrodotoxin-resistant Na(+) channel isoform (PubMed:1309946). This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels (PubMed:19074138). Required for normal electrical conduction including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with XIRP2 (By similarity)
- Specific Function
- ankyrin binding
- Gene Name
- SCN5A
- Uniprot ID
- Q14524
- Uniprot Name
- Sodium channel protein type 5 subunit alpha
- Molecular Weight
- 226937.475 Da
References
- Thimann DA, Huang CJ, Goto CS, Feng SY: Benzonatate toxicity in a teenager resulting in coma, seizures, and severe metabolic acidosis. J Pediatr Pharmacol Ther. 2012 Jul;17(3):270-3. doi: 10.5863/1551-6776-17.3.270. [Article]
- Bishop-Freeman SC, Shonsey EM, Friederich LW, Beuhler MC, Winecker RE: Benzonatate Toxicity: Nothing to Cough At. J Anal Toxicol. 2017 Jun 1;41(5):461-463. doi: 10.1093/jat/bkx021. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters
- Specific Function
- acetylcholinesterase activity
- Gene Name
- BCHE
- Uniprot ID
- P06276
- Uniprot Name
- Cholinesterase
- Molecular Weight
- 68417.575 Da
References
- Bishop-Freeman SC, Shonsey EM, Friederich LW, Beuhler MC, Winecker RE: Benzonatate Toxicity: Nothing to Cough At. J Anal Toxicol. 2017 Jun 1;41(5):461-463. doi: 10.1093/jat/bkx021. [Article]
Drug created at June 13, 2005 13:24 / Updated at June 02, 2024 21:45