Identification

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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Approved, Withdrawn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
  • Butamben
  • 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)SolutionTopicalCetylite Industries, Inc.1960-01-01Not applicableUs
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 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
Humans
AATP-sensitive potassium channel
antagonist
Humans
UTransient receptor potential cation channel subfamily A member 1
inhibitor
Humans
UTransient receptor potential cation channel subfamily V member 4
inhibitor
Humans
Additional Data Available
Adverse Effects

Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.

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Additional Data Available
Contraindications

Structured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.

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Additional Data Available
Blackbox Warnings

Structured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.

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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
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.
DrugInteraction
Hyaluronidase (ovine)Hyaluronidase (ovine) can cause an increase in the absorption of Butamben resulting in an increased serum concentration and potentially a worsening of adverse effects.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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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 group
Organism
Humans
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...

Components:
NameUniProt ID
Voltage-dependent calcium channel gamma-1 subunitQ06432
Voltage-dependent calcium channel gamma-2 subunitQ9Y698
Voltage-dependent calcium channel gamma-3 subunitO60359
Voltage-dependent calcium channel gamma-4 subunitQ9UBN1
Voltage-dependent calcium channel gamma-5 subunitQ9UF02
Voltage-dependent calcium channel gamma-6 subunitQ9BXT2
Voltage-dependent calcium channel gamma-7 subunitP62955
Voltage-dependent calcium channel gamma-8 subunitQ8WXS5
Voltage-dependent calcium channel subunit alpha-2/delta-1P54289
Voltage-dependent calcium channel subunit alpha-2/delta-2Q9NY47
Voltage-dependent calcium channel subunit alpha-2/delta-3Q8IZS8
Voltage-dependent calcium channel subunit alpha-2/delta-4Q7Z3S7
Voltage-dependent L-type calcium channel subunit alpha-1CQ13936
Voltage-dependent L-type calcium channel subunit alpha-1DQ01668
Voltage-dependent L-type calcium channel subunit alpha-1FO60840
Voltage-dependent L-type calcium channel subunit alpha-1SQ13698
Voltage-dependent L-type calcium channel subunit beta-1Q02641
Voltage-dependent L-type calcium channel subunit beta-2Q08289
Voltage-dependent L-type calcium channel subunit beta-3P54284
Voltage-dependent L-type calcium channel subunit beta-4O00305
Voltage-dependent N-type calcium channel subunit alpha-1BQ00975
Voltage-dependent P/Q-type calcium channel subunit alpha-1AO00555
Voltage-dependent R-type calcium channel subunit alpha-1EQ15878
Voltage-dependent T-type calcium channel subunit alpha-1GO43497
Voltage-dependent T-type calcium channel subunit alpha-1HO95180
Voltage-dependent T-type calcium channel subunit alpha-1IQ9P0X4
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]
Kind
Protein group
Organism
Humans
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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Temperature-gated cation channel activity
Specific Function
Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in t...
Gene Name
TRPA1
Uniprot ID
O75762
Uniprot Name
Transient receptor potential cation channel subfamily A member 1
Molecular Weight
127499.88 Da
References
  1. Bang S, Yang TJ, Yoo S, Heo TH, Hwang SW: Inhibition of sensory neuronal TRPs contributes to anti-nociception by butamben. Neurosci Lett. 2012 Jan 11;506(2):297-302. doi: 10.1016/j.neulet.2011.11.026. Epub 2011 Nov 23. [PubMed:22133806]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Activation by exposure to hypotonicity within the physiological range exhibits an outward rectification (PubMed:18826956, PubMed:18695040). Also activated by heat, low pH, citrate and phorbol esters (PubMed:18826956, PubMed:18695040). Increase of intracellular Ca(2+) potentiates currents. Channel activity seems to be regulated by a calmodulin-dependent mechanism with a negative feedback mechanism (PubMed:12724311, PubMed:18826956). Promotes cell-cell junction formation in skin keratinocytes and plays an important role in the formation and/or maintenance of functional intercellular barriers (By similarity). Acts as a regulator of intracellular Ca(2+) in synoviocytes (PubMed:19759329). Plays an obligatory role as a molecular component in the nonselective cation channel activation induced by 4-alpha-phorbol 12,13-didecanoate and hypotonic stimulation in synoviocytes and also regulates production of IL-8 (PubMed:19759329). Together with PKD2, forms mechano- and thermosensitive channels in cilium (PubMed:18695040). Negatively regulates expression of PPARGC1A, UCP1, oxidative metabolism and respiration in adipocytes (By similarity). Regulates expression of chemokines and cytokines related to proinflammatory pathway in adipocytes (By similarity). Together with AQP5, controls regulatory volume decrease in salivary epithelial cells (By similarity). Required for normal development and maintenance of bone and cartilage (PubMed:26249260).
Specific Function
Actin binding
Gene Name
TRPV4
Uniprot ID
Q9HBA0
Uniprot Name
Transient receptor potential cation channel subfamily V member 4
Molecular Weight
98280.2 Da
References
  1. Bang S, Yang TJ, Yoo S, Heo TH, Hwang SW: Inhibition of sensory neuronal TRPs contributes to anti-nociception by butamben. Neurosci Lett. 2012 Jan 11;506(2):297-302. doi: 10.1016/j.neulet.2011.11.026. Epub 2011 Nov 23. [PubMed:22133806]
  2. 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
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. Daskalos D. (2012). Local anesthesia for the dental hygienist. Elsevier. [ISBN:978-0323-07371-4]

Carriers

Kind
Protein
Organism
Humans
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
Humans
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 December 02, 2019 08:57