Benzocaine

Benzocaine

Systematic (IUPAC) name
Ethyl 4-aminobenzoate
Clinical data
Trade names	Anbesol, Cepacol, Lanacane, Orajel
AHFS/Drugs.com	monograph
Pregnancy category	US: C (Risk not ruled out)
Routes of administration	Topical
Legal status
Legal status	UK: General sales list (GSL, OTC) US: OTC
Identifiers
CAS Number	94-09-7
ATC code	C05AD03 (WHO) D04AB04 (WHO), QN01AX92 (WHO), N01BA05 (WHO), R02AD01 (WHO)
PubChem	CID 2337
DrugBank	DB01086
ChemSpider	13854242
UNII	U3RSY48JW5
KEGG	D00552
ChEBI	CHEBI:116735
ChEMBL	CHEMBL278172
Chemical data
Formula	C9H11NO2
Molar mass	165.189 g/mol
SMILES O=C(OCC)c1ccc(N)cc1
InChI InChI=1S/C9H11NO2/c1-2-12-9(11)7-3-5-8(10)6-4-7/h3-6H,2,10H2,1H3 Key:BLFLLBZGZJTVJG-UHFFFAOYSA-N
(verify)

Benzocaine is a local anesthetic commonly used as a topical pain reliever or in cough drops. It is the active ingredient in many over-the-counter anesthetic ointments such as products for oral ulcers. It is also combined with antipyrine to form A/B otic drops to relieve ear pain and remove earwax.

Chemical properties

Benzocaine is the ethyl ester of p-aminobenzoic acid (PABA). It can be prepared from PABA and ethanol^[1] by Fischer esterification or via the reduction of ethyl p-nitrobenzoate. Benzocaine is sparingly soluble in water; it is more soluble in dilute acids and very soluble in ethanol, chloroform and ethyl ether. The melting point of benzocaine is 88–90 °C,^[2] and the boiling point is about 310 °C.^[3] The density of benzocaine is 1.17 g/cm³.

History

Benzocaine was first synthesized in 1890 by the German chemist Eduard Ritsert (1859–1946),^[4] in the town of Eberbach^[5] and introduced to the market in 1902 under the name "Anästhesin".^[6][7]

Mechanism of action

Pain is caused by the stimulation of free nerve endings. When the nerve endings are stimulated, sodium enters the neuron, causing depolarization of the nerve and subsequent initiation of an action potential. The action potential is propagated down the nerve toward the central nervous system, which interprets this as pain. Benzocaine acts to inhibit the voltage-dependent sodium channels (VDSCs) on the neuron membrane, stopping the propagation of the action potential.

Uses

Benzocaine is indicated to treat a variety of pain-related conditions. It may be used for:

• Local anesthesia of oral and pharyngeal mucous membranes (sore throat, cold sores, mouth ulcers, toothache, sore gums, denture irritation)^[8]
• Otic Pain (earache)^[8]
• Surgical or procedural local anesthesia^[9]

Formulations

Benzocaine can come in a variety of preparations including:
Oral preparations:

• Lozenges (ex. Cepacol, Mycinettes)^[10]

Topical preparations:

• Aerosol (ex. Topex)^[11]
• Gel (ex. Orajel)^[12]
• Paste (ex. Orabase)^[13]

Otic preparations:

• Solution (ex. Allergen)^[14]

Side effects

Benzocaine is generally well-tolerated and non-toxic when applied topically as recommended.^[15]

However, there have been reports of serious, life-threatening adverse effects (e.g., seizures, coma, irregular heart beat, respiratory depression) with over-application of topical products or when applying topical products that contain high concentrations of benzocaine to the skin.^[16]

Over-application of oral anesthetics such as benzocaine can increase the risk of pulmonary aspiration by relaxing the gag-reflex and allowing regurgitated stomach contents or oral secretions to enter the airway. Applying an oral anesthetic and consuming beverages before going to bed can be particularly hazardous.

The topical use of higher concentration (14-20%) benzocaine spray products applied to the mouth or mucous membranes has been found to be a cause of methemoglobinemia, a disorder in which the amount of oxygen carried by the blood is greatly reduced.^[17] This side effect is most common in children under 2 years of age.^[18] As a result, the FDA has stated that benzocaine products should not be used in children under 2 years of age, unless directed by and supervised by a healthcare professional.^[19] Symptoms of methemoglobinemia usually occur minutes to hours of applying benzocaine, and can occur upon the first-time use or after additional use.^[19]

Benzocaine may cause allergic reactions.^{[20][21][22][23]} These include:

• Contact dermatitis (redness and itchiness)^[24]
• Anaphylaxis (rare)^[24]

Other uses

Jiffy Toothache Drops bottle (7.75% Benzocaine)

Benzocaine is used as a key ingredient in numerous pharmaceuticals:

• Some glycerol-based ear medications for use in removing excess wax as well as relieving ear conditions such as otitis media and swimmers ear.
• Some previous diet products such as Ayds.
• Some condoms designed to prevent premature ejaculation. Benzocaine largely inhibits sensitivity on the penis, and can allow for an erection to be maintained longer (in a continuous act) by delaying ejaculation. Conversely, an erection will also fade faster if stimulus is interrupted.^[25][26]
• Benzocaine mucoadhesive patches have been used in reducing orthodontic pain.^[27]
• In Poland it is included, together with menthol and zinc oxide, in the liquid powder (not to be confused with the liquid face powder) used mainly after mosquito stings. Today's ready made Pudroderm^[28] was once used there as pharmaceutical compound.

Benzocaine is commonly found, particularly in Britain, as an impurity in street cocaine. Whilst giving a numbing effect similar to cocaine on users' gums it does not actually produce the effects of cocaine. Also benzocaine can and has been mistaken for a false positive for cocaine.^[29]

Synthesis

Prepd by the esterification of p-aminobenzoic acid:^[30][31] by the reduction of ethyl p-nitrobenzoate:^[32][33]

Benzocaine can be prepared by esterification using 4-aminobenzoic acid and ethanol. It can also be prepared by reduction of ethyl 4-nitrobenzoate to the amine.

In industrial practice, the reducing agent is usually iron and water in the presence of a little acid.^[34]

References

1. Demare, Patricia; Regla, Ignacio (2012). "Synthesis of Two Local Anesthetics from Toluene: An Organic Multistep Synthesis in a Project-Oriented Laboratory Course". Journal of Chemical Education 89: 147. doi:10.1021/ed100838a.
2. "Monographs: Pharmaceutical substances: Benzocainum – Benzocaine". The International Pharmacopoeia. Retrieved September 29, 2009.
3. D'Ans-Lax, Taschenbuch für Chemiker und Physiker, 4. Auflage, Band 2, Springer Verlag 1982, ISBN 3-540-12263-X
4. Biography of Eduard Ritsert (in German): Deutsche Biographie: Ritsert, Eduard .
5. "100 years of Dr. Ritsert". Dr. Ritsert Pharma. Retrieved March 14, 2010.
6. Harry Auterhoff, Lehrbuch der pharmazeutischen Chemie (Stuttgart, Germany: Wissenschaftliche Verlagsgesellschaft, 1968).
7. Ritsert, E. (1925) "Über den Werdegang des Anästhesins" (On the development of Anästhesin), Pharmazeutische Zeitung, vol. 60, pages 1006–1008. See also: Christoph Friedrich and Magdalena Klimonow, "150. Geburtstag: Eduard Ritsert und das Anaesthesin" (150th birthday: Eduard Ritsert and Anästhetsin [Benzocaine]"), Pharmazeutische Zeitung online. First published clinical study demonstrating the efficacy of benzocaine: Noorden, C. v. (1902) "Ueber para-Aminobenzoesäure-Ester als locales Anästhetikum" (On [an] ester of para-aminobenzoic acid as a local anaesthetic), Klinische Wochenschrift, vol. 39, pages 373–375.
8. AHFS Drug Information 2007. McEvoy GK, ed. Benzocaine. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2844-5.
9. Sultan Healthcare. Topex®metered spray (benzocaine 20%) prescribing information. Englewood, NJ; 2006.
10. "Cepacol®". Cepacol.com. Retrieved 2015-06-02.
11. "Topex® Metered Spray-Sultan Healthcare". Sultanhc.com. Retrieved 2015-06-02.
12. "Orajel™ - Oral Care for the Whole Family". Orajel.com. 2015-05-11. Retrieved 2015-06-02.
13. "Colgate Orabase Paste with Benzocaine | Indications | Dental Products". Colgateprofessional.com. Retrieved 2015-06-02.
14. "Antipyrine Benzocaine Otic – Side Effects, Dosage, Interactions". Everyday Health. 2015-03-18. Retrieved 2015-06-02.
15. Lexicomp Online, Adult and Pediatric Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; 2013; April 15, 2013.
16. Food and Drug Administration. FDA Public Health Advisory: Life-threatening side effects with use of skin products containing numbing ingredients for cosmetic procedures. 2007 Feb 6, updated 2007 Feb 9. From FDA website
17. Shua-Haim, J. R.; Gross, J. S. (1995). "Methemoglobinemia toxicity from topical benzocaine spray". Journal of the American Geriatrics Society 43 (5): 590. doi:10.1111/j.1532-5415.1995.tb06117.x. PMID 7730550.
18. "Benzocaine Topical Products: Sprays, Gels and Liquids – Risk of Methemoglobinemia". Drugs.com. Retrieved March 20, 2014.
19. Report a Serious Problem. "FDA Drug Safety Communication: Reports of a rare, but serious and potentially fatal adverse effect with the use of over-the-counter (OTC) benzocaine gels and liquids applied to the gums or mouth". Fda.gov. Retrieved 2015-06-02.
20. "Allergy to Benzocaine" (PDF). Retrieved March 20, 2014.
21. Sidhu, S. K.; Shaw, S; Wilkinson, J. D. (1999). "A 10-year retrospective study on benzocaine allergy in the United Kingdom". American Journal of Contact Dermatitis 10 (2): 57–61. doi:10.1016/s1046-199x(99)90000-3. PMID 10357712.
22. González-Rodríguez, A. J.; Gutiérrez-Paredes, E. M.; Revert Fernández, Á.; Jordá-Cuevas, E (2013). "Allergic contact dermatitis to benzocaine: The importance of concomitant positive patch test results" (PDF). Actas Dermo-Sifiliográficas 104 (2): 156–8. doi:10.1016/j.ad.2011.07.023. PMID 22551703. Retrieved March 20, 2014.
23. Leslie Goldman (February 5, 2008). "Go easy on medicated lotions, creams, gels". CNN. Retrieved March 20, 2014.
24. Cetylite Industries. Cetacaine® (benzocaine 14% , tetracaine 2% and butamben 2%) spray, gel and liquid prescribing information. Pennsauken, NJ; 2006 Sept.
25. "'Longer-lasting' condom launched". BBC News. June 17, 2002.
26. Garner, Dwight (December 15, 2002). "Endurance Condoms". The New York Times.
27. Eslamian L, Borzabadi-Farahani A, Edini HZ, Badiee MR, Lynch E, Mortazavi A. (2013). "The analgesic effect of benzocaine mucoadhesive patches on orthodontic pain caused by elastomeric separators, a preliminary study.". Acta Odontol Scand. 71 (5): 1168–73. doi:10.3109/00016357.2012.757358. PMID 23301559.
28. "Produkty | PUDRODERM" (in Polish). Retrieved 9 May 2014.
29. "Drug prices: All cut up : Cocaine is cheaper, but weaker". The Economist. August 11, 2012.
30. Salkowski, H. (1895). "Ueber Esterbildung bei aromatischen Amidosäuren". Berichte der deutschen chemischen Gesellschaft 28 (2): 1917. doi:10.1002/cber.189502802150.
31. Erlenmeyer, E.; Wanklyn, J. A. (1865). "Ueber das durch Einwirkung von Jodwasserstoff auf Mannit beziehungsweise auf Melampyrin (Dulcit) entstehende β Hexyljodür und einige seiner Derivate". Annalen der Chemie und Pharmacie 135 (2): 129. doi:10.1002/jlac.18651350202.
32. Limpricht, H. (1898). "Ueber die Verbindungen aus Benzoylchlorid oder Phtalylchlorid und den Estern der drei Oxybenzoësäuren". Justus Liebig's Annalen der Chemie 303 (3): 274. doi:10.1002/jlac.18983030303.
33. Adams, Roger and Cohen, F.L. (1928). "Ethyl p-aminobenzoate". Org. Synth. 8: 66.; Coll. Vol. 1, p. 240
34. Ali, S. L. (1983). "Benzocaine". Analytical Profiles of Drug Substances 12: 73. doi:10.1016/S0099-5428(08)60164-1. ISBN 978-0-12-260812-4.

External links

• Public Health Advisory: Benzocaine Sprays by the Food and Drug Administration.