Identification

Name
Butamben
Accession Number
DB11148
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Butamben is a local anesthetic in the form of n-butyl-p-aminobenzoate.[1] Its structure corresponds to the standard molecule of a hydrophilic and hydrophobic domain separated by an intermediate ester found in most of the local anesthetics. Due to its very low water solubility, butamben was considered of low usability as it is only suitable to be used as a topical anesthesia. This belief changed with the introduction of epidural suspensions of butamben.[11] All butamben-containing products were removed from the market under the belief that it is unsafe or ineffective.[10]

Structure
Thumb
Synonyms
  • Butyl aminobenzoate
External IDs
NSC-128464
Product Ingredients
IngredientUNIICASInChI Key
Butamben picrateD4ZFB7ZH5Y577-48-0ATAGSVCDFKGYPE-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Cetacaine LiquidButamben (2 %) + Benzocaine (14 %) + Tetracaine hydrochloride (2 %)LiquidTopicalCetylite Industries, Inc.1996-09-19Not applicableCanada
Cetacaine SprayButamben (2 %) + Benzocaine (14 %) + Tetracaine hydrochloride (2 %)AerosolTopicalCetylite Industries, Inc.1994-12-31Not applicableCanada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Cetacaine AnestheticButamben (0.004 g/0.2g) + Benzocaine (0.028 g/0.2g) + Tetracaine hydrochloride (0.004 g/0.2g)Aerosol, sprayTopicalCetylite Industries, Inc.1958-01-01Not applicableUs
Cetacaine AnestheticButamben (0.004 g/0.2g) + Benzocaine (0.028 g/0.2g) + Tetracaine hydrochloride (0.004 g/0.2g)SolutionTopicalCetylite Industries, Inc.1960-01-01Not applicableUs
Cetacaine Topical AnestheticButamben (0.004 g/0.2g) + Benzocaine (0.028 g/0.2g) + Tetracaine hydrochloride (0.004 g/0.2g)GelTopicalCetylite Industries, Inc.1960-01-01Not applicableUs
Cetacaine Topical AnestheticButamben (0.004 g/0.2g) + Benzocaine (0.028 g/0.2g) + Tetracaine hydrochloride (0.004 g/0.2g)GelTopicalCetylite Industries, Inc.1960-01-01Not applicableUs
Exactacain Topical AnestheticButamben (2 g/100g) + Benzocaine (14 g/100g) + Tetracaine hydrochloride (2 g/100g)Aerosol, sprayTopicalOnset Dermatologics, LLC2005-06-232012-10-31Us
One Touch Advanced Topical Anesthetic Bubble GumButamben (4 mg/.2g) + Benzocaine (28 mg/.2g) + Tetracaine hydrochloride (4 mg/.2g)GelDental; TopicalHager Worldwide, Inc.2009-02-01Not applicableUs
One Touch Advanced Topical Anesthetic CherryButamben (4 mg/.2g) + Benzocaine (28 mg/.2g) + Tetracaine hydrochloride (4 mg/.2g)GelDental; TopicalHager Worldwide, Inc.2009-02-01Not applicableUs
One Touch Advanced Topical Anesthetic Gel Cool MintButamben (4 mg/.2g) + Benzocaine (28 mg/.2g) + Tetracaine hydrochloride (4 mg/.2g)GelDental; TopicalHager Worldwide, Inc.2009-02-01Not applicableUs
One Touch Advanced Topical Anesthetic Strawberry IceButamben (4 mg/.2g) + Benzocaine (28 mg/.2g) + Tetracaine hydrochloride (4 mg/.2g)GelDental; TopicalHager Worldwide, Inc.2009-02-01Not applicableUs
Categories
UNII
EFW857872Q
CAS number
94-25-7
Weight
Average: 193.246
Monoisotopic: 193.110278727
Chemical Formula
C11H15NO2
InChI Key
IUWVALYLNVXWKX-UHFFFAOYSA-N
InChI
InChI=1S/C11H15NO2/c1-2-3-8-14-11(13)9-4-6-10(12)7-5-9/h4-7H,2-3,8,12H2,1H3
IUPAC Name
butyl 4-aminobenzoate
SMILES
CCCCOC(=O)C1=CC=C(N)C=C1

Pharmacology

Indication

Butamben was indicated for the treatment of chronic pain due to its long-duration effect.[3] It is also indicated as a surface anesthetic for skin a mucous membrane and for the relief of pain and pruritus associated with anorectal disorders.[11]

Pharmacodynamics

Butamben has been shown to selectively inhibit dorsal root pain signal transmission for periods of months when administered as epidural suspensions.[1] The effect of butamben is not related to any significant loss of motor function which indicates that it targets specifically the pain-sensing C fibers of the dorsal root.[3] When administered topically, butamben produced anesthesia by accumulating in the nerve cell membrane causing it to expand and lose its ability to depolarize and blocking the impulse transmission.[5]

Mechanism of action

Butamben acts by inhibiting the voltage-gated calcium channels in dorsal root ganglion neurons.[2] The modification in this channels is thought to cause a disturbance of the channel kinetics acceleration.[1] It is reported as well that butamben is an inhibitor of the sodium channels and a delayed rectifier of potassium currents. All the effects of butamben are performed in the root ganglion neurons which suggests that the related anesthetic effect may be caused by the reduced electrical excitability.[3]

TargetActionsOrganism
AVoltage-dependent calcium channel
inhibitor
Human
AVoltage gated sodium channel
inhibitor
human
AATP-sensitive potassium channel
antagonist
Human
Absorption

When butamben is administered epidurally in a suspension form, the physical characteristics of butamben allow a very slow release.[11] When administered topically, butamben is also reported to have a very low systemic absorption which allows for a longer duration of action.[6]

Volume of distribution

This pharmacokinetic property has not been determined.

Protein binding

As all other local anesthetics, it is thought that butamben will be highly bound to plasma proteins, mainly to alpha-1-acid glycoprotein.[4]

Metabolism

The metabolic pathway of butamben follows the same pattern of other local anesthetics and it is driven mainly by the hydrolysis via cholinesterase for the formation of inert metabolites.[7]

Route of elimination

The metabolites found in plasma after cholinesterase processing are disposed of in the urine.[7]

Half life

The effective half-life of unencapsulated butamben is registered to be of 90 minutes. Some efforts were made to prepare D, L-lactic acid capsules which increased the half-life of butamben to even 400 hours.[9]

Clearance

Clearance is flow-limited and it highly depends on the state of protein-bound form.[4]

Toxicity

In studies, the most common effect was related to the generation of a prolonged effect. It was also shown in preclinical trials to produce tissue necrosis and neuritis. The LD50 of butamben is registered to be of 67 mg/kg.[8]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Butamben.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Butamben.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Butamben.
AcetaminophenAcetaminophen may decrease the excretion rate of Butamben which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Butamben which could result in a higher serum level.
AdipiplonThe risk or severity of adverse effects can be increased when Adipiplon is combined with Butamben.
AgomelatineThe risk or severity of adverse effects can be increased when Agomelatine is combined with Butamben.
AlaproclateThe risk or severity of adverse effects can be increased when Butamben is combined with Alaproclate.
AlfaxaloneThe risk or severity of adverse effects can be increased when Butamben is combined with Alfaxalone.
AlfentanilThe risk or severity of adverse effects can be increased when Alfentanil is combined with Butamben.
Food Interactions
Not Available

References

General References
  1. Beekwilder JP, van Kempen GT, van den Berg RJ, Ypey DL: The local anesthetic butamben inhibits and accelerates low-voltage activated T-type currents in small sensory neurons. Anesth Analg. 2006 Jan;102(1):141-5. [PubMed:16368819]
  2. Beekwilder JP, Winkelman DL, van Kempen GT, van den Berg RJ, Ypey DL: The block of total and N-type calcium conductance in mouse sensory neurons by the local anesthetic n-butyl-p-aminobenzoate. Anesth Analg. 2005 Jun;100(6):1674-9. doi: 10.1213/01.ANE.0000151162.07211.DD. [PubMed:15920194]
  3. Winkelman DL, Beck CL, Ypey DL, O'Leary ME: Inhibition of the A-type K+ channels of dorsal root ganglion neurons by the long-duration anesthetic butamben. J Pharmacol Exp Ther. 2005 Sep;314(3):1177-86. doi: 10.1124/jpet.105.087759. Epub 2005 May 27. [PubMed:15923341]
  4. Shipton EA: New formulations of local anaesthetics-part I. Anesthesiol Res Pract. 2012;2012:546409. doi: 10.1155/2012/546409. Epub 2011 Dec 5. [PubMed:22190922]
  5. Schilling J. (2004). Pharmacology. A2-in-1 reference for nurses. Lippincott Williams & Wilkins. [ISBN:1-58255-320-3]
  6. Buch J. (2010). Clinically oriented pharmacology (2nd ed.). PDU Medical College.
  7. Daskalos D. (2012). Local anesthesia for the dental hygienist. Elsevier. [ISBN:978-0323-07371-4]
  8. Rossoff I. (1974). Handbook of veterinary drugs. Springer.
  9. Whateley T. (1992). Microencapsulation of drugs. Hardwood Academic Publishers.. [ISBN:3-7186-5247-1]
  10. FDA code of federal regulations [Link]
  11. Tesis [Link]
External Links
KEGG Compound
C07875
PubChem Compound
2482
PubChem Substance
347827919
ChemSpider
2388
ChEBI
3231
ChEMBL
CHEMBL127516
Wikipedia
Butamben
MSDS
Download (48.1 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SolutionTopical
LiquidTopical
AerosolTopical
GelTopical
Aerosol, sprayTopical
GelDental; Topical
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)58 ºC'MSDS'
boiling point (°C)173.5 ºC'MSDS'
water solubility140 mg/LPetrus J. Thesis. 1973.
logP2.87'MSDS'
pKa2.472Toxnet
Predicted Properties
PropertyValueSource
Water Solubility0.336 mg/mLALOGPS
logP2.88ALOGPS
logP2.47ChemAxon
logS-2.8ALOGPS
pKa (Strongest Basic)2.76ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area52.32 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity56.66 m3·mol-1ChemAxon
Polarizability21.96 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - EI-BGC-MSsplash10-00dr-2900000000-906b8d78dc5d3ad39b7d
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

Taxonomy

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 / Benzoyl derivatives / Aniline and substituted anilines / Carboxylic acid esters / Amino acids and derivatives / Monocarboxylic acids and derivatives / Primary amines / Organopnictogen compounds / Organooxygen compounds / Organic oxides
show 1 more
Substituents
Aminobenzoic acid or derivatives / Benzoate ester / Benzoyl / Aniline or substituted anilines / Amino acid or derivatives / Carboxylic acid ester / Carboxylic acid derivative / Monocarboxylic acid or derivatives / Amine / Organonitrogen compound
show 8 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
substituted aniline, primary amino compound, benzoate ester, amino acid ester (CHEBI:3231)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Voltage-gated calcium channel activity
Specific Function
This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only...
Gene Name
CACNG1
Uniprot ID
Q06432
Uniprot Name
Voltage-dependent calcium channel gamma-1 subunit
Molecular Weight
25028.105 Da
References
  1. Beekwilder JP, Winkelman DL, van Kempen GT, van den Berg RJ, Ypey DL: The block of total and N-type calcium conductance in mouse sensory neurons by the local anesthetic n-butyl-p-aminobenzoate. Anesth Analg. 2005 Jun;100(6):1674-9. doi: 10.1213/01.ANE.0000151162.07211.DD. [PubMed:15920194]
  2. Beekwilder JP, van Kempen GT, van den Berg RJ, Ypey DL: The local anesthetic butamben inhibits and accelerates low-voltage activated T-type currents in small sensory neurons. Anesth Analg. 2006 Jan;102(1):141-5. [PubMed:16368819]
2. Voltage gated sodium channel
Kind
Protein group
Organism
human
Pharmacological action
Yes
Actions
Inhibitor
References
  1. Winkelman DL, Beck CL, Ypey DL, O'Leary ME: Inhibition of the A-type K+ channels of dorsal root ganglion neurons by the long-duration anesthetic butamben. J Pharmacol Exp Ther. 2005 Sep;314(3):1177-86. doi: 10.1124/jpet.105.087759. Epub 2005 May 27. [PubMed:15923341]
Kind
Protein group
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
General Function
Phosphatidylinositol-4,5-bisphosphate binding
Specific Function
In the kidney, probably plays a major role in potassium homeostasis. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than...

Components:
References
  1. Winkelman DL, Beck CL, Ypey DL, O'Leary ME: Inhibition of the A-type K+ channels of dorsal root ganglion neurons by the long-duration anesthetic butamben. J Pharmacol Exp Ther. 2005 Sep;314(3):1177-86. doi: 10.1124/jpet.105.087759. Epub 2005 May 27. [PubMed:15923341]

Enzymes

Kind
Protein
Organism
Human
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. Daskalos D. (2012). Local anesthesia for the dental hygienist. Elsevier. [ISBN:978-0323-07371-4]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Shipton EA: New formulations of local anaesthetics-part I. Anesthesiol Res Pract. 2012;2012:546409. doi: 10.1155/2012/546409. Epub 2011 Dec 5. [PubMed:22190922]
Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Shipton EA: New formulations of local anaesthetics-part I. Anesthesiol Res Pract. 2012;2012:546409. doi: 10.1155/2012/546409. Epub 2011 Dec 5. [PubMed:22190922]

Drug created on December 03, 2015 09:51 / Updated on August 02, 2018 06:21