Editing Procainamide

{{Short description|Medication to treat cardiac arrhythmias}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| verifiedrevid = 477172111
| IUPAC_name = 4-amino-''N''-(2-diethylaminoethyl) benzamide
| image = Procainamide.svg
| image_class = skin-invert-image
<!--Clinical data-->
| tradename =  Pronestyl, Procan, Procanbid, others
| synonyms =
| pronounce = {{IPAc-en|p|r|oʊ|ˈ|k|eɪ|n|əm|aɪ|d}}
| Drugs.com = {{drugs.com|monograph|procainamide-hydrochloride}}
| pregnancy_US = C
| legal_UK = POM
| routes_of_administration = [[Intravenous therapy|IV]], [[Intramuscular injection|IM]], by mouth
<!--Pharmacokinetic data-->
| bioavailability = 85% (by mouth)
| protein_bound = 15 to 20%
| metabolism = [[Liver]] ([[CYP2D6]]-mediated)
| elimination_half-life = ~2.5 to 4.5 hours
| excretion = [[Kidney]]
<!--Identifiers-->
| IUPHAR_ligand = 4811
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 51-06-9
| ATC_prefix = C01
| ATC_suffix = BA02
| ATC_supplemental = 
| PubChem = 4913
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01035
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4744
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = L39WTC366D
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08421
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8428
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 640
<!--Chemical data-->
| C=13 | H=21 | N=3 | O=1
| smiles = O=C(c1ccc(N)cc1)NCCN(CC)CC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H21N3O/c1-3-16(4-2)10-9-15-13(17)11-5-7-12(14)8-6-11/h5-8H,3-4,9-10,14H2,1-2H3,(H,15,17)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = REQCZEXYDRLIBE-UHFFFAOYSA-N
}}

'''Procainamide''' ('''PCA''') is a medication of the [[antiarrhythmic agent|antiarrhythmic class]] used for the treatment of [[cardiac arrhythmia]]s. It is a [[sodium channel blocker]] of [[Cardiac muscle cell|cardiomyocytes]]; thus it is classified by the [[Vaughan Williams classification]] system as class Ia. In addition to blocking the ''I''<sub>Na</sub> current, it inhibits the ''I''<sub>Kr</sub> rectifier K+ current.<ref name=Osadchii>{{cite journal | vauthors = Osadchii OE | title = Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea-pig | journal = Fundamental & Clinical Pharmacology | volume = 28 | issue = 4 | pages = 382–393 | date = August 2014 | pmid = 23952942 | doi = 10.1111/fcp.12046 | s2cid = 5086017 }}</ref> Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.<ref name=Zamponi>{{cite journal | vauthors = Zamponi GW, Sui X, Codding PW, French RJ | title = Dual actions of procainamide on batrachotoxin-activated sodium channels: open channel block and prevention of inactivation | journal = Biophysical Journal | volume = 65 | issue = 6 | pages = 2324–2334 | date = December 1993 | pmid = 8312472 | pmc = 1225974 | doi = 10.1016/S0006-3495(93)81291-8 | bibcode = 1993BpJ....65.2324Z }}</ref>

==Uses==
===Medical===
Procainamide is used for treating ventricular [[arrhythmias]]: ventricular [[ectopia (medicine)|ectopy]] and [[tachycardia]] and supraventricular arrhythmias: [[atrial fibrillation]], and re-entrant and automatic supraventricular tachycardia.<ref name=Gould>{{cite book | veditors = Gould LA |title=Drug Treatment of Cardiac Arrhythmias |date=1983 |publisher=Futura Publishing Company |location=Mount Kisco |isbn=0879931906 |pages=73–74}}</ref> For example, it can be used to convert new-onset [[atrial fibrillation]], and although was initially thought to be suboptimal for this purpose, a growing body of literature is amounting in support for this exact cause.<ref>{{cite journal | vauthors = Stiell IG, Sivilotti ML, Taljaard M, Birnie D, Vadeboncoeur A, Hohl CM, McRae AD, Rowe BH, Brison RJ, Thiruganasambandamoorthy V, Macle L, Borgundvaag B, Morris J, Mercier E, Clement CM, Brinkhurst J, Sheehan C, Brown E, Nemnom MJ, Wells GA, Perry JJ | title = Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial | journal = Lancet | volume = 395 | issue = 10221 | pages = 339–349 | date = February 2020 | pmid = 32007169 | doi = 10.1016/S0140-6736(19)32994-0 | s2cid = 210978499 }}</ref><ref>{{cite journal | vauthors = Fenster PE, Comess KA, Marsh R, Katzenberg C, Hager WD | title = Conversion of atrial fibrillation to sinus rhythm by acute intravenous procainamide infusion | journal = American Heart Journal | volume = 106 | issue = 3 | pages = 501–504 | date = September 1983 | pmid = 6881022 | doi = 10.1016/0002-8703(83)90692-0 }}</ref>

It is administered by mouth, by intramuscular injection, or intravenously.<ref name="ten">{{cite journal | vauthors = Koch-Weser J, Klein SW | title = Procainamide dosage schedules, plasma concentrations, and clinical effects | journal = JAMA | volume = 215 | issue = 9 | pages = 1454–1460 | date = March 1971 | pmid = 5107621 | doi = 10.1001/jama.1971.03180220036006 }}</ref><ref>{{cite book | veditors = Antman EM, Sabatine MS |title=Cardiovascular Therapeutics: A companion to Braunwald's heart disease |page=410 |date=2013 |publisher=Elsevier/Saunders |location=Philadelphia, PA |isbn=978-1-4557-0101-8 |edition=4th}}</ref>

===Others===
It has also been used as a [[chromatography]] resin because it somewhat binds protein.<ref>{{cite web| title=Procainamide Sepharose 4 Fast Flow| website=GE Healthcare Life Sciences| url=http://www.gelifesciences.com/webapp/wcs/stores/servlet/catalog/en/GELifeSciences-cz/products/AlternativeProductStructure_17319/28411101| access-date=2017-07-24| archive-date=2021-08-29| archive-url=https://web.archive.org/web/20210829162220/https://www.cytivalifesciences.com/country-selection?originalItemPath=%2fshop%2fchromatography%2fresins%2faffinity-specific-groups%2fprocainamide-sepharose-4-fast-flow-p-03714| url-status=dead}}</ref><ref>{{cite journal | vauthors = De la Hoz D, Doctor BP, Ralston JS, Rush RS, Wolfe AD | title = A simplified procedure for the purification of large quantities of fetal bovine serum acetylcholinesterase | journal = Life Sciences | volume = 39 | issue = 3 | pages = 195–199 | date = July 1986 | pmid = 3736320 | doi = 10.1016/0024-3205(86)90530-8 }}</ref><ref>{{cite journal | vauthors = Ralston JS, Main AR, Kilpatrick BF, Chasson AL | title = Use of procainamide gels in the purification of human and horse serum cholinesterases | journal = The Biochemical Journal | volume = 211 | issue = 1 | pages = 243–250 | date = April 1983 | pmid = 6870822 | pmc = 1154348 | doi = 10.1042/bj2110243 }}</ref><ref>{{cite journal | vauthors = Saxena A, Luo C, Doctor BP | title = Developing procedures for the large-scale purification of human serum butyrylcholinesterase | journal = Protein Expression and Purification | volume = 61 | issue = 2 | pages = 191–196 | date = October 2008 | pmid = 18602477 | doi = 10.1016/j.pep.2008.05.021 }}</ref>

==Side effects==
There are many side effects following the induction of procainamide. These adverse effects are [[ventricular dysrhythmia]], [[bradycardia]], [[hypotension]] and [[shock (circulatory)|shock]]. The adverse effects occur even more often if the daily doses are increased. Procainamide may also lead to [[drug fever]] and other [[allergic response]]s. There is also a chance that [[drug-induced lupus erythematosus]] occurs, which at the same time leads to [[arthralgia]], [[myalgia]] and [[pleurisy]]. Most of these side effects may occur due to the [[acetylation]] of procainamide.<ref name="adverse">{{cite journal | vauthors = Lawson DH, Jick H | title = Adverse reactions to procainamide | journal = British Journal of Clinical Pharmacology | volume = 4 | issue = 5 | pages = 507–511 | date = October 1977 | pmid = 911600 | pmc = 1429167 | doi = 10.1111/j.1365-2125.1977.tb00777.x }}</ref>

===Toxicity===
There is a close line between the plasma concentrations of the therapeutic and toxic effect, therefore a high risk for toxicity.<ref name="adverse" /> Many symptoms resemble [[systemic lupus erythematosus]] because procainamide reactivates [[hydroxylamine]] and [[nitroso]] metabolites, which bind to [[histone|histone proteins]] and are toxic to [[lymphocytes]]. The hydroxylamine and nitroso metabolites are also toxic to bone marrow cells and can cause [[agranulocytosis]]. These metabolites are formed due to the activation of [[polymorphonuclear leukocytes]]. These leukocytes release [[myeloperoxidase]] and [[hydrogen peroxide]], which oxidize the primary aromatic amine of procainamide to form procainamide hydroxylamine. The release of hydrogen peroxide is also called a [[respiratory burst]], which occurs for procainamide in [[monocytes]] but not in [[lymphocytes]]. Furthermore, the metabolites can be formed by activated [[neutrophils]]. These metabolites could then bind to their cell membranes and cause a release of [[autoantibodies]] which would react with the neutrophils.<ref>{{cite journal | vauthors = Uetrecht J, Zahid N, Rubin R | title = Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes | journal = Chemical Research in Toxicology | volume = 1 | issue = 1 | pages = 74–78 | date = January 1988 | pmid = 2979715 | doi = 10.1021/tx00001a013 }}</ref> Procainamide hydroxylamine has more [[cytotoxicity]] by hindering the response of lymphocytes to [[T-cell]] and B-cell [[mitogens]]. Hydroxylamine can also generate [[methemoglobin]], a protein that could hinder further oxygen exchange.<ref>{{cite journal | vauthors = Roberts SM, Adams LE, Donovan-Brand R, Budinsky R, Skoulis NP, Zimmer H, Hess EV | title = Procainamide hydroxylamine lymphocyte toxicity--I. Evidence for participation by hemoglobin | journal = International Journal of Immunopharmacology | volume = 11 | issue = 4 | pages = 419–427 | date = 1989 | pmid = 2476407 | doi = 10.1016/0192-0561(89)90089-1 }}</ref>

It was also detected that the antiarrhythmic drug procainamide interferes with pacemakers. A toxic level of procainamide leads to decrease in ventricular conduction velocity and increase of the ventricular refractory period. This results in a disturbance in the artificial membrane potential and leads to a [[supraventricular tachycardia]] which induces failure of the [[pacemaker]] and death.<ref>{{cite journal | vauthors = Gay RJ, Brown DF | title = Pacemaker failure due to procainamide toxicity | journal = The American Journal of Cardiology | volume = 34 | issue = 6 | pages = 728–732 | date = November 1974 | pmid = 4422040 | doi = 10.1016/0002-9149(74)90164-7 }}</ref> Thus, it prolongs QT interval of action potential and increases the risk of [[torsade de pointes]].<ref name=Osadchii/>

Procainamide could initiate [[leukopenia]] and/or [[agranulocytosis]], which are serious hematologic disorders, and is also known for causing gastrointestinal disturbances and aggravating pre-existing abnormalities in impulse initiation and propagation.<ref name=Gould/>

==Pharmacology==

===Mechanism of action===
Procainamide works as an [[anti-arrhythmic]] agent and is used to treat [[cardiac arrhythmia]]. It induces rapid block of the [[batrachotoxin|batrachotoxin (BTX)-activated]] [[sodium channels]] of the heart muscle and acts as antagonist to long-gating closures. The block is voltage-dependent and can occur from both sides; either from the intracellular or the extracellular side. Blocking from the extracellular side is weaker than from the intracellular side because it occurs via the [[hydrophobic pathway]]. Procainamide is present in charged form and probably requires a direct hydrophobic access to the binding site for blocking of the channel. Furthermore, blocking of the channel shows a decreased voltage sensitivity, which may result from the loss of voltage dependence of the blocking rate. Due to its charged and hydrophilic form, procainamide has its effect from the internal side, where it causes blockage of voltage-dependent, open channels. With increasing concentration of procainamide, the frequency of long blockage becomes less without the duration of blockage being affected. The rate of fast blocking is determined by the membrane depolarization. Membrane [[depolarization]] leads to increased blocking and decreased unblocking of the channels. Procainamide slows the conduction velocity and increases the [[Refractory period (physiology)|refractory period]], such that the maximal rate of depolarization is reduced.<ref name=Zamponi/> It is also said to be a [[binding selectivity|selective]] [[muscarinic acetylcholine receptor|muscarinic acetylcholine]] [[M3 receptor|M<sub>3</sub> receptor]] antagonist.<ref name="LavradorCabralVeríssimo2023">{{cite journal | vauthors = Lavrador M, Cabral AC, Veríssimo MT, Fernandez-Llimos F, Figueiredo IV, Castel-Branco MM | title = A Universal Pharmacological-Based List of Drugs with Anticholinergic Activity | journal = Pharmaceutics | volume = 15 | issue = 1 | date = January 2023 | page = 230 | pmid = 36678858 | pmc = 9863833 | doi = 10.3390/pharmaceutics15010230 | doi-access = free | url = }}</ref>

===Metabolism===
Procainamide is metabolized via different pathways. The most common one is the [[acetylation]] of procainamide to the less-toxic [[N-acetylprocainamide]].<ref>{{cite journal | vauthors = Roden DM, Reele SB, Higgins SB, Wilkinson GR, Smith RF, Oates JA, Woosley RL | title = Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide | journal = The American Journal of Cardiology | volume = 46 | issue = 3 | pages = 463–468 | date = September 1980 | pmid = 6158263 | doi = 10.1016/0002-9149(80)90016-8 }}</ref> The rate of acetylation is genetically determined. There are two phenotypes that result from the acetylation process, namely the slow and rapid acetylator. Procainamide can also be oxidized by the [[cytochrome P-450]] to a reactive oxide metabolite. But it seems that acetylation of the nitrogen group of procainamide decrease the amount of the chemical that would be available for the oxidative route.<ref name="Uetrecht, J. P. 1981">{{cite journal | vauthors = Uetrecht JP, Freeman RW, Woosley RL | title = The implications of procainamide metabolism to its induction of lupus | journal = Arthritis and Rheumatism | volume = 24 | issue = 8 | pages = 994–1003 | date = August 1981 | pmid = 6169352 | doi = 10.1002/art.1780240803 }}</ref> Other metabolites of procainamide include desethyl-N-acetylprocainamide, desethylprocainamide, p-aminobenzoic acid, which are excreted via the urine.  N-acetyl-4-aminobenzoic acid as well as N-acetyl-3-hydroxyprocainamide, N-acetylprocainamide-N-oxide and N-acetyl-4-aminohippuric acid are also metabolites of procainamide.<ref name="Uetrecht, J. P. 1981"/>

==Chemistry==
4-amino-N-2-(diethylamino)ethyl-benzamide (also known as [[Diethylethanolamine|para-amino-N-2-(diethylamino)ethyl-benzamide]] because the amino substituent is attached to the para-position, [[Arene substitution patterns]] of the [[benzene ring]]) is a synthetic [[organic compound]] with the chemical formula  C13-H21-N3-O.<ref name="Drug">{{cite web |date=27 June 2018 |title=Procainamide |url=http://www.drugbank.ca/drugs/DB01035 |website=www.drugbank.ca |access-date=28 June 2018}}</ref>

Procainamide is structurally similar to [[procaine]], but in place of an ester group, procainamide contains an amide group. This substitution is the reason why procainamide exhibits a longer half-life time than procaine.<ref>{{cite book | vauthors = Adams HR |year=1995 |title=Drugs Acting on the Cardiovascular System. Veterinary Pharmacology and Therapeutics |edition=7th |pages=451–500}}</ref><ref>{{cite book | vauthors = Plumb DC |year=1999 |title=Veterinary Drug Handbook |publisher=PharmaVet Publishing |location=White Bear Lake, USA}}</ref>

Procainamide belongs to the [[benzamides|aminobenzamides]]. These are [[aromatic]] [[carboxylic acid]] derivatives consisting of an amide with a [[benzamide]] moiety and a [[triethylamine]] attached to the [[amide]] [[nitrogen]].<ref name="Drug"/><ref>{{cite web |author=EBI Web Team |title=CHEBI:8428 - procainamide |url=http://www.ebi.ac.uk/chebi/searchFreeText.do?searchString=51-06-9 |website=www.ebi.ac.uk |access-date=28 June 2018}}</ref><ref>{{cite book | vauthors = DeRuiter J |year=2005 |chapter=Amides and Related Functional Groups |title=Principles of Drug Action |page=1}}</ref>

In certain lines, the ''para''-amino group might become a target site to attach further paraphernalia, e.g. ''ref.'' Ex18 in {{US patent|7115750}}.

==History==
Procainamide was approved by the US FDA on June 2, 1950, under the brand name "Pronestyl".<ref name=dafda>{{cite web |author= US Food and Drug Administration |author-link= US Food and Drug Administration |title= Drugs at FDA: FDA Approved Drug Products |url= https://www.accessdata.fda.gov/scripts/cder/daf/ |publisher= [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) |location= USA |access-date= 2012-08-13}}</ref> It was launched by [[Bristol-Myers Squibb]] in 1951.<ref name="pmid18610401">{{cite journal | vauthors = Hollman A | title = Procaine and procainamide | journal = British Heart Journal | volume = 67 | issue = 2 | pages = 143 | date = February 1992 | pmid = 18610401 | pmc = 1024743 | doi = 10.1136/hrt.67.2.143 }}</ref>
Due to the [[Japanese occupation of the Dutch East Indies|loss of Indonesia]] in [[World War II]], the source for [[cinchona alkaloids]], a precursor of [[quinidine]], was reduced. This led to research for a new [[antiarrhythmic drug]]. As a result, [[procaine]] was discovered, which has similar cardiac effects as quinidine.<ref name="one">{{cite journal | vauthors = Walker MJ | title = Antiarrhythmic drug research | journal = British Journal of Pharmacology | volume = 147 | issue = Suppl 1 | pages = S222–S231 | date = January 2006 | pmid = 16402108 | pmc = 1760742 | doi = 10.1038/sj.bjp.0706500 }}</ref> In 1936 it was found by Mautz that by applying it directly on the [[myocardium]], the ventricular threshold for electrical stimulation was elevated.<ref name="pmid18610401"/> This mechanism is responsible for the antiarrhythmic effect. However, due to the short duration of action, caused by rapid enzymatic hydrolysis, its therapeutic applications were limited.<ref name="three">{{cite book | vauthors = Moe GK, Abildskov A |chapter=Antiarrhythmic drugs | veditors = Goodman LS, Gilman A |title=Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition=3rd |location=New York |publisher=Macmillan |year=1965 |pages=699–715}}</ref> In addition, procaine also caused tremors and [[respiratory depression]].<ref name="three" /><ref name="two">{{cite book |chapter=Historical development of antiarrhythmic drug therapy | veditors = Lüderitz BB |title=History of Disorders of Cardiac Rhythm |edition=3rd |location=New York |publisher=Wiley-Blackwell |year=2002 |pages=87–114}}</ref> All these adverse features stimulated the search for an alternative to procaine. Studies were done on various congeners and metabolites and this ultimately led to the discovery of procainamide by Mark ''et al''. It was found that procainamide was effective for treating [[ventricular arrhythmias]], but it had the same toxicity profile as quinidine, and it could cause [[systemic lupus erythematosus]]-like syndrome.<ref name="one" /><ref name="two" /> These negative characteristics slowed the search for new antiarrhythmics based on the chemical structure of procainamide. In 1970 only five drugs were reported. These were the [[cardiac glycosides]], [[quinidine]], [[propranolol]], [[lidocaine]] and [[diphenylhydantoin]]. In January 1996, extended release procainamide hydrochloride (Procanbid extended-release tablets) was approved by the FDA.<ref>{{cite web |vauthors = Mishina E, Marroum P |year=2002 |url= https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/20545s007_Procanbid_biopharmr.pdf |archive-url= https://web.archive.org/web/20170218125158/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/20545s007_Procanbid_biopharmr.pdf |url-status= dead |archive-date= February 18, 2017 |title=Center for Drug Evaluation and Research Approval Package For: Application Number NDA 20-545/S007 |work=Clinical Pharmacology and Bioharmaceutics Review}}</ref>

== References ==
{{reflist}}

{{Antiarrhythmic agents}}
{{Muscarinic acetylcholine receptor modulators}}

[[Category:4-Aminophenyl compounds]]
[[Category:Antiarrhythmic agents]]
[[Category:Benzamides]]
[[Category:Diethylamino compounds]]
[[Category:M3 receptor antagonists]]
[[Category:Sodium channel blockers]]