Editing Procaine

{{Short description|Local anesthetic drug}}
{{Redirect-distinguish|Allocaine|List of cocaine analogues#Analogs sensu stricto{{!}}Allococaine}}
{{Redirect|Novocaine}}
{{Drugbox| Verifiedfields = changed
| verifiedrevid = 420414847
| IUPAC_name = 2-(diethylamino)ethyl 4-aminobenzoate
| image = procaine.svg
| image_class = skin-invert-image
| image2 = Procaine-3D-xray.png

<!--Clinical data-->
| Drugs.com = {{drugs.com|monograph|novocain}}
| pregnancy_AU = B2
| pregnancy_US = C
| legal_AU = S4
| routes_of_administration = [[wikt:parenteral|Parenteral]]

<!--Pharmacodynamic data-->
| bioavailability = N/A
| metabolism = [[Hydrolysis]] by plasma esterases
| elimination_half-life = 40–84 seconds
| excretion = [[Kidney|Renal]]

<!--Identifiers-->
<!--| CASNo_Ref = {{cascite|correct|CAS}}-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 59-46-1
| ATC_prefix = N01
| ATC_suffix = BA02
| ATC_supplemental = {{ATC|C05|AD05}} {{ATC|S01|HA05}}
| PubChem = 4914
| IUPHAR_ligand = 4291
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00721
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4745
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4Z8Y51M438
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08422
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 8430
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 569
| NIAID_ChemDB = 019136

<!--Chemical data-->
| C=13 | H=20 | N=2 | O=2
| smiles = O=C(OCCN(CC)CC)c1ccc(N)cc1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H20N2O2/c1-3-15(4-2)9-10-17-13(16)11-5-7-12(14)8-6-11/h5-8H,3-4,9-10,14H2,1-2H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MFDFERRIHVXMIY-UHFFFAOYSA-N
}}

'''Procaine''' is a [[local anesthetic]] drug of the [[amino esters|amino ester]] group. It is most commonly used in [[dentistry|dental procedures]] to numb the area around a tooth<ref name=denistryismain>{{cite news|url=https://www.medicalnewstoday.com/articles/321880|title=How long does numbness last after the dentist?|publisher=Medical News Today|date=May 22, 2018|access-date=July 14, 2020}}</ref> and is also used to reduce the pain of [[intramuscular injection]] of [[penicillin]]. Owing to the ubiquity of the [[trade name]] '''Novocain''' (without the "e" in the original German patent) or '''Novocaine''' (with the "e" in the US patent), in some regions, procaine is referred to [[Generic trademark|generically]] as '''novocaine'''. It acts mainly as a [[sodium channel blocker]].<ref>{{cite web | url = http://www.drugbank.ca/drugs/DB00721 | work = DrugBank | title = Procaine (DB00721) | date = 2009-06-23 }}</ref> Today, it is used therapeutically in some countries due to its [[sympatholytic]], [[anti-inflammatory]], [[perfusion]]-enhancing, and [[Mood disorder|mood-enhancing]] effects.<ref>{{cite journal | vauthors = Hahn-Godeffroy JD | title = Procain-Reset: Ein Therapiekonzept zur Behandlung chronischer Erkrankungen. | trans-title = Procaine reset: A therapy concept for the treatment of chronic diseases. | journal = Schweizerische Zeitschrift für Ganzheitsmedizin | trans-journal = [[Swiss Journal of Integrative Medicine]] | language = de | date = 2011 | volume = 23 | issue = 5 | pages = 291–6 | doi =  10.1159/000332021 | doi-access = free }}</ref>

Procaine was first synthesized in 1905,<ref>{{cite book | vauthors = Ritchie JM, Greene NM | veditors = Gilman AG, Rall TW, Nies AS, Taylor P | title = Goodman and Gilman's The Pharmacological Basis of Therapeutics |chapter=Local Anesthetics | page = [https://archive.org/details/goodmangilmansphe8good/page/311 311] |edition=8th |publisher=Pergamon Press |location=New York |year=1990 |isbn=0-08-040296-8 |chapter-url-access=registration |chapter-url=https://archive.org/details/goodmangilmansphe8good |url= https://archive.org/details/goodmangilmansphe8good | url-access = registration }}</ref> shortly after [[amylocaine]].<ref>{{cite web | vauthors = Minard R | url = http://courses.chem.psu.edu/chem36/SynFa06Web/Expt86.pdf | title = The Preparation of the Local Anesthetic, Benzocaine, by an Esterification Reaction | quote = Adapted from ''Introduction to Organic Laboratory Techniques: A Microscale Approach'', Pavia, Lampman, Kriz & Engel, 1989. | date = 18 October 2006 | access-date = 10 March 2011 | archive-url = https://web.archive.org/web/20110720030826/http://courses.chem.psu.edu/chem36/SynFa06Web/Expt86.pdf | archive-date = 20 July 2011 | url-status = dead }}</ref> It was created by the chemist [[Alfred Einhorn]] who gave the chemical the trade name Novocain, from the [[Latin]] ''nov-'' (meaning "new") and ''-caine'', a common ending for [[alkaloid]]s used as anesthetics. It was introduced into medical use by surgeon [[Heinrich Braun]].

Prior to the discovery of [[amylocaine]] and procaine, [[cocaine]] was a commonly used local anesthetic.<ref name="Ruetsch_2001">{{cite journal | vauthors = Ruetsch YA, Böni T, Borgeat A | title = From cocaine to ropivacaine: the history of local anesthetic drugs | journal = Current Topics in Medicinal Chemistry | volume = 1 | issue = 3 | pages = 175–82 | date = August 2001 | pmid = 11895133 | doi = 10.2174/1568026013395335 }}</ref> Einhorn wished his new discovery to be used for amputations, but for this surgeons preferred [[general anesthesia]]. Dentists, however, found it very useful.<ref>{{cite journal| vauthors = Drucker P |title=The discipline of innovation|journal=Harvard Business Review|date=May 1985|volume=3|issue=3|page=68 |pmid=10272260| url = https://hbr.org/2002/08/the-discipline-of-innovation }}</ref>

==Pharmacology==
[[File:US Navy 020623-M-7929S-040 Dental Officer participating in exercise Landing Force Cooperation Readiness and Training (LF CARAT).jpg|left|thumb|Procaine application before removal of a decayed tooth]]
The primary use for procaine is as an anaesthetic.

Aside from its use as a dental anesthetic, procaine is used less frequently today, since more effective (and [[hypoallergenic]]) alternatives such as [[lidocaine]] (Xylocaine) exist. Like other local anesthetics (such as [[mepivacaine]], and [[prilocaine]]), procaine is a vasodilator,  thus is often coadministered with [[epinephrine]] for the purpose of [[vasoconstriction]]. Vasoconstriction helps to reduce bleeding, increases the duration and quality of anesthesia, prevents the drug from reaching systemic circulation in large amounts, and overall reduces the amount of anesthetic required.<ref name="pmid8250339">{{cite journal | vauthors = Sisk AL | title = Vasoconstrictors in local anesthesia for dentistry | journal = Anesthesia Progress | volume = 39 | issue = 6 | pages = 187–93 | date = 1992 | pmid = 8250339 | pmc = 2148619 }}</ref> As a [[dental anesthesia|dental anesthesic]], for example, more novocaine is needed for root canal treatment than for a simple filling.<ref name=denistryismain /> Unlike [[cocaine]], a vasoconstrictor, procaine does not have the [[euphoria|euphoric]] and addictive qualities that put it at risk for abuse.

Procaine, an [[ester]] anesthetic, is metabolized in the [[blood plasma|plasma]] by the enzyme [[Butyrylcholinesterase|pseudocholinesterase]] through [[hydrolysis]] into [[para-Amino benzoic acid|para-amino benzoic acid]] (PABA), which is then excreted by the [[kidney]]s into the [[urine]].

A 1% procaine injection has been recommended for the treatment of extravasation complications associated with venipuncture, steroids, and antibiotics.  It has likewise been recommended for treatment of inadvertent intra-arterial injections (10&nbsp;ml of 1% procaine), as it helps relieve pain and vascular spasm.

Procaine is an occasional additive in illicit street drugs and is presented and sold usually as cocaine or [[heroin]]. <ref>{{cite web | title = Procaine | url = http://www.ecstasydata.org/search.php?substance1=2023 | work = ecstasydata.org }}</ref>

==Adverse effects==
Application of procaine leads to the depression of neuronal activity. The depression causes the nervous system to become hypersensitive, producing restlessness and shaking, leading to minor to severe convulsions.{{citation needed|date=July 2022}} Studies on animals have shown the use of procaine led to the increase of [[dopamine]] and [[serotonin]] levels in the brain.<ref name="pmid2622091">{{cite journal | vauthors = Sawaki K, Kawaguchi M | title = Some correlations between procaine-induced convulsions and monoamines in the spinal cord of rats | journal = Japanese Journal of Pharmacology | volume = 51 | issue = 3 | pages = 369–76 | date = November 1989 | pmid = 2622091 | doi = 10.1254/jjp.51.369 | doi-access = free }}</ref> Other issues may occur because of varying individual tolerance to procaine dosage. Nervousness and dizziness can arise from the excitation of the central nervous system, which may lead to respiratory failure if overdosed. Procaine may also induce weakening of the [[myocardium]], leading to [[cardiac arrest]].<ref>{{cite web | url = https://www.drugs.com/pro/novocain.html | work = drugs.com | title = Novocain Official FDA information | date = August 2007 }}</ref>

Procaine can also cause allergic reactions causing individuals to have problems with breathing, rashes, and swelling. Allergic reactions to procaine are usually not in response to procaine itself, but to its metabolite PABA. Allergic reactions are in fact quite rare, estimated to have an incidence of 1 per 500,000 injections. About one in 3000 white North Americans is homozygous (i.e. has two copies of the abnormal gene) for the most common atypical form of the enzyme pseudocholinesterase,<ref>{{cite book | first = Ludwig | last = Ombregt | name-list-style = vanc | chapter = Procaine: Principles of Treatment | pages = 83–115 | title = A System of Orthopaedic Medicine | edition = 3rd | date = 2013 | doi = 10.1016/B978-0-7020-3145-8.00005-3 | isbn = 978-0-7020-3145-8 | publisher = Churchill Livingstone }}</ref><ref name=OMIM_BCh>{{cite web |title=Butyrylcholinesterase |url=http://www.omim.org/entry/177400 |website=OMIM |access-date=4 September 2015}}</ref> and do not hydrolyze ester anesthetics such as procaine. This results in a prolonged period of high levels of the anesthetic in the blood and increased toxicity.

However, certain populations in the world such as the [[Arya Vysya|Vysya community]] in India commonly have a deficiency of this enzyme.<ref name="OMIM_BCh" />

==Synthesis==
Procaine can be [[organic synthesis|synthesized]] in two ways. 
[[File:Procaine synthesis.png|class=skin-invert-image|center|500px|thumb|Procaine synthesis<ref>{{Cite journal | vauthors = Einhorn A, Fiedler K, Ladisch C, Uhlfelder E | doi = 10.1002/jlac.19093710204| title = Ueber p-Aminobenzoësäurealkaminester| journal = Justus Liebig's Annalen der Chemie| volume = 371| issue = 2| pages = 142–161| year = 1909 | url = https://zenodo.org/record/1427583}}</ref><ref>Einhorn A [[Hoechst AG|Höchst Ag]] {{US patent|812554}}; {{Cite patent|country=DE|number=179627|pubdate=1906-12-11|title=Verfahren zur Darstellung von p-Aminobenzoësäureaalkaminestern [Method for the prepareation of p-aminobenzoic acid alkamine esters]|assign=[[Hoechst AG|Höchst A.M.]]}}; {{Cite patent|country=DE|number=194748|pubdate=1908-01-28|title=Verfahren zur Darstellung von p-Aminobenzoësäureaalkaminestern [Method for the prepareation of p-aminobenzoic acid alkamine esters]|assign=[[Hoechst AG|Höchst A.M.]]}}, addendendum to DE 179627.</ref>]]
#The first consists of the direct reaction of [[benzocaine]] with [[2-diethylaminoethanol]] using [[sodium ethoxide]]-[[ethanol]] solution as the solvent and base. 
#The second is by oxidizing [[4-nitrotoluene]] to [[4-nitrobenzoic acid]], which is further reacted with [[thionyl chloride]], the resulting [[acyl chloride]] is then reacted with 2-diethylaminoethanol to give Nitrocaine. Finally, the nitro group is reduced by hydrogenation over [[Raney nickel]] catalyst.

== See also ==
*[[Chloroprocaine]]
*[[Peter DeMarco]]

== References ==
{{Reflist}}

== Further reading ==
{{Refbegin}}
* {{cite journal | vauthors = Hahn-Godeffroy JD | title = Wirkungen und Nebenwirkungen von Procain: Was ist gesichert? | journal = Komplement Integr. Med. | date = 2007 | volume = 2 | pages = 32–4 }}
{{Refend}}

{{Vasoprotectives}}
{{Local anesthetics}}
{{Ion channel modulators}}
{{Authority control}}

[[Category:Dental equipment]]
[[Category:Local anesthetics]]
[[Category:1905 introductions]]
[[Category:German inventions]]
[[Category:4-Aminobenzoate esters]]
[[Category:Sodium channel blockers]]
[[Category:Diethylamino compounds]]
[[Category:Withdrawn drugs]]
[[Category:4-Aminophenyl compounds]]