Identification

Name
Benzonatate
Accession Number
DB00868
Description

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
Thumb
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

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

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

TargetActionsOrganism
USodium channel protein type 5 subunit alpha
antagonist
Humans
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

Hover over products below to view reaction partners

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
Learn about our commercial Adverse Effects data.
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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.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

Affected organisms
  • Humans and other mammals
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.
No interactions found.
Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

Product Images
International/Other Brands
Exangit / Tesaperl (Novartis ) / Tessalon Perles / Ventussin
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BenzonatateCapsule200 mg/1OralEthex Corporation2008-12-30Not applicableUS flag
BenzonatateCapsule100 mg/1OralEthex Corporation2008-12-30Not applicableUS flag
BenzonatateCapsule100 mg/1OralGreenstone LLC2020-01-06Not applicableUS flag
TessalonCapsule100 mg/1OralPhysicians Total Care, Inc.1958-02-102011-07-31US flag
TessalonCapsule100 mg/1OralPfizer Laboratories Div Pfizer Inc1958-02-10Not applicableUS flag
TessalonCapsule200 mg/1OralPfizer Laboratories1999-06-252011-02-04US flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
BenzonatateCapsule100 mg/1OralPreferred Pharmaceuticals Inc2020-02-07Not applicableUS flag
BenzonatateCapsule100 mg/1OralNucare Pharmaceuticals,inc.2018-12-21Not applicableUS flag
BenzonatateCapsule, liquid filled100 mg/1OralREMEDYREPACK INC.2016-11-182018-10-04US flag
BenzonatateCapsule200 mg/1OralPD-Rx Pharmaceuticals, Inc.2018-05-01Not applicableUS flag
BenzonatateCapsule100 mg/1OralREMEDYREPACK INC.2020-09-09Not applicableUS flag
BenzonatateCapsule100 mg/1OralNcs Health Care Of Ky, Inc Dba Vangard Labs2017-03-22Not applicableUS flag
BenzonatateCapsule150 mg/1OralCamber Pharmaceuticals, Inc.2019-02-22Not applicableUS flag
BenzonatateCapsule100 mg/1OralCardinal Health2010-11-142011-02-28US flag50111 0851 01 nlmimage10 873243c2
BenzonatateCapsule200 mg/1OralBionpharma Inc.2016-08-15Not applicableUS flag
BenzonatateCapsule100 mg/1OralAidarex Pharmaceuticals LLC2007-07-25Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

    Learn more

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)

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
  1. 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. [PubMed:19121573]
  2. 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. [PubMed:28334901]
  3. 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. [PubMed:23258970]
  4. Burns JM, Boyer EW: Antitussives and substance abuse. Subst Abuse Rehabil. 2013 Nov 6;4:75-82. doi: 10.2147/SAR.S36761. eCollection 2013. [PubMed:24648790]
  5. 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. [PubMed:31129533]
  6. 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. [PubMed:22958367]
  7. FDA Approved Drug Products: TESSALON (benzonatate) Perle and Capsule [Link]
  8. Cayman Chemical: Benzonatate MSDS [Link]
Human Metabolome Database
HMDB0015006
KEGG Drug
D00242
PubChem Compound
7699
PubChem Substance
46506376
ChemSpider
7413
BindingDB
50240086
RxNav
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
PhaseStatusPurposeConditionsCount
3Unknown StatusTreatmentCoughing1
1CompletedBasic ScienceCoughing1
1CompletedBasic ScienceHealthy Volunteers1
1RecruitingTreatmentCoughing1

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
FormRouteStrength
CapsuleOral100 mg/1
CapsuleOral200 mg/1
Capsule, gelatin coatedOral200 mg/1
Capsule, liquid filledOral100 mg/1
Capsule, liquid filledOral200 mg/1
TabletOral100 mg/1
CapsuleOral150 mg/1
Prices
Unit descriptionCostUnit
Tessalon 200 mg capsule2.76USD capsule
Benzonatate 200 mg capsule2.03USD capsule
Tessalon Perles 100 mg capsule1.62USD capsule
Zonatuss 150 mg capsule1.59USD capsule
Tessalon perle 100 mg capsule1.4USD capsule
Benzonatate 100 mg capsule0.85USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
logP2.45HANSCH,C ET AL. (1995)
Predicted Properties
PropertyValueSource
Water Solubility0.00159 mg/mLALOGPS
logP2.09ALOGPS
logP2.35ChemAxon
logS-5.6ALOGPS
pKa (Strongest Basic)3.47ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area121.4 Å2ChemAxon
Rotatable Bond Count33ChemAxon
Refractivity161.54 m3·mol-1ChemAxon
Polarizability67.87 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9932
Blood Brain Barrier+0.9355
Caco-2 permeable+0.6067
P-glycoprotein substrateSubstrate0.6531
P-glycoprotein inhibitor INon-inhibitor0.5978
P-glycoprotein inhibitor IINon-inhibitor0.9434
Renal organic cation transporterNon-inhibitor0.7646
CYP450 2C9 substrateNon-substrate0.875
CYP450 2D6 substrateNon-substrate0.7017
CYP450 3A4 substrateNon-substrate0.6026
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9232
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.9275
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.932
Ames testNon AMES toxic0.7269
CarcinogenicityNon-carcinogens0.9182
BiodegradationReady biodegradable0.6331
Rat acute toxicity2.2423 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9013
hERG inhibition (predictor II)Non-inhibitor0.6129
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-004i-2900000000-3718c62c83080a92ccdd

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Voltage-gated sodium channel activity involved in sa node cell action potential
Specific 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 pr...
Gene Name
SCN5A
Uniprot ID
Q14524
Uniprot Name
Sodium channel protein type 5 subunit alpha
Molecular Weight
226937.475 Da
References
  1. 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. [PubMed:23258970]
  2. 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. [PubMed:28334901]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da
References
  1. 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. [PubMed:28334901]

Drug created on June 13, 2005 07:24 / Updated on June 12, 2020 10:51

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