procainamide

Procainamide is used for treating ventricular arrhythmias: ventricular ectopy and tachycardia and supraventricular arrhythmias: atrial fibrillation, and re-entrant and automatic supraventricular tachycardia.{{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}} 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.{{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 }}{{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 }}

It is administered by mouth, by intramuscular injection, or intravenously.{{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 }}{{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}}

It has also been used as a chromatography resin because it somewhat binds protein.{{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}}{{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 }}{{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 }}{{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 }}

There are many side effects following the induction of procainamide. These adverse effects are ventricular dysrhythmia, bradycardia, hypotension and shock. The adverse effects occur even more often if the daily doses are increased. Procainamide may also lead to drug fever and other allergic responses. 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.{{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 }}

There is a close line between the plasma concentrations of the therapeutic and toxic effect, therefore a high risk for toxicity. Many symptoms resemble systemic lupus erythematosus because procainamide reactivates hydroxylamine and nitroso metabolites, which bind to 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.{{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 }} 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.{{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 }}

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.{{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 }} Thus, it prolongs QT interval of action potential and increases the risk of torsade de pointes.

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.

Procainamide works as an anti-arrhythmic agent and is used to treat cardiac arrhythmia. It induces rapid block of the 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, such that the maximal rate of depolarization is reduced. It is also said to be a selective muscarinic acetylcholine M₃ receptor antagonist.{{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 = }}

Procainamide is metabolized via different pathways. The most common one is the acetylation of procainamide to the less-toxic N-acetylprocainamide.{{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 }} 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.{{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 }} 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.

4-amino-N-2-(diethylamino)ethyl-benzamide (also known as 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.{{cite web |date=27 June 2018 |title=Procainamide |url=http://www.drugbank.ca/drugs/DB01035 |website=www.drugbank.ca |access-date=28 June 2018}}

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.{{cite book | vauthors = Adams HR |year=1995 |title=Drugs Acting on the Cardiovascular System. Veterinary Pharmacology and Therapeutics |edition=7th |pages=451–500}}{{cite book | vauthors = Plumb DC |year=1999 |title=Veterinary Drug Handbook |publisher=PharmaVet Publishing |location=White Bear Lake, USA}}

Procainamide belongs to the aminobenzamides. These are aromatic carboxylic acid derivatives consisting of an amide with a benzamide moiety and a triethylamine attached to the amide nitrogen.{{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}}{{cite book | vauthors = DeRuiter J |year=2005 |chapter=Amides and Related Functional Groups |title=Principles of Drug Action |page=1}}

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

Procainamide was approved by the US FDA on June 2, 1950, under the brand name "Pronestyl".{{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= U.S. Food and Drug Administration (FDA) |location= USA |access-date= 2012-08-13}} It was launched by Bristol-Myers Squibb in 1951.{{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 }}

Due to the 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.{{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 }} In 1936 it was found by Mautz that by applying it directly on the myocardium, the ventricular threshold for electrical stimulation was elevated. 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.{{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}} In addition, procaine also caused tremors and respiratory depression.{{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}} 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. 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.{{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}}

{{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