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Clinical data
Pronunciation /prˈknəmd/
Trade names Pronestyl, Procan, Procanbid, others
AHFS/ Monograph
  • US: C (Risk not ruled out)
Routes of
IV, IM, by mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 85% (by mouth)
Protein binding 15 to 20%
Metabolism Liver (CYP2D6-mediated)
Biological half-life ~2.5 to 4.5 hours
Excretion Kidney
CAS Number
PubChem CID
ECHA InfoCard 100.000.072
Chemical and physical data
Formula C13H21N3O
Molar mass 235.325 g/mol
3D model (JSmol)

Procainamide is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is classified by the Vaughan Williams classification system as class Ia; thus it is a Na+ channel blocker of cardiomyocytes. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current.[1] Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.[2]



Procainamide is used for treating ventricular arrhythmias: ventricular ectopy and tachycardia and supraventricular arrhythmias: atrial fibrillation, and re-entrant and automatic supraventricular tachycardia.[3] For example, it can be used to convert new-onset atrial fibrillation, though it is suboptimal for this purpose.[4]

It is administered by mouth, by intramuscular injection, or intravenously.[5][6]


It has been also been used as a chromatography resin because it somewhat binds protein.[7][8][9][10]

Side effects[edit]

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 systemic lupus erythematosus occurs, which at the same time leads to polyarthralgia, myalgia and pleurisy. Most of these side effects may occur due to the acetylation of procainamide.[11]


There is a close line between the plasma concentrations of the therapeutic and toxic effect, therefore a high risk for toxicity.[11] 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.[12] 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.[13]

It was also detected that the antiarrhythmic drug procainamide interferes with pacemakers. Because 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.[14] Thus, it prolongs QT interval of action potential and increases the risk of torsade de pointes.[15]

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.[16]


Mechanism of action[edit]

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.[17]


Procainamide is metabolized via different pathways. The most common one is the acetylation of procainamide to the less-toxic N-acetylprocainamide.[18] 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.[19] 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.[19]


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.[20]

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.[21][22]

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.[20][23][24]


Procainamide was approved by the US FDA on June 2, 1950, under the brand name "Pronestyl".[25] It was launched by Bristol-Myers Squibb in 1951.[26]
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.[27] In 1936 it was found by Mautz that by applying it directly on the myocardium, the ventricular threshold for electrical stimulation was elevated.[28] 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.[29] In addition, procaine also caused tremors and respiratory depression.[29][30] 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.[27][30] These negative characteristics slowed down 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.[31]


  1. ^ Osadchii, Oleg E. (July 23, 2013). "Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea-pig". Fundamental & Clinical Pharmacology: 382. 
  2. ^ Zamponi, Gerald W. (1993). "Dual Actions of Procainamide on Batrachotoxin-activated Sodium Channels: Open Channel Block and Prevention of Inactivation". Biophysical Journal. 65: 2333. 
  3. ^ Gould, ed. by Lawrence A. (1983). Drug treatment of cardiac arrhythmias. Mount Kisco: Futura Publishing Company. pp. 73–74. ISBN 0879931906. 
  4. ^ Fenster, P.E.; Comess, K.A.; Marsh, R.; Katzenberg, C.; Hager, W.D. (1983). "Conversion of atrial fibrillation to sinus rhythm by acute intravenous procainamide infusion". American Heart Journal. 106 (3): 501–504. doi:10.1016/0002-8703(83)90692-0. PMID 6881022. 
  5. ^ Jan Koch-Weser, MD; Stuart W. Klein, MD. Procainamide Dosage Schedules, Plasma Concentrations, and Clinical Effects. doi:10.1001/jama.1971.03180220036006.
  6. ^ Elliott M. Antman. Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease. 4th Edition. ISBN 978-1-4557-0101-8. P410
  7. ^ "Procainamide Sepharose 4 Fast Flow". GE Healthcare Life Sciences. 
  8. ^ De la Horz D, Doctor BP, Ralston JS, Rush RS, Wolfe AD (21 Jul 1986). "A simplified procedure for the purification of large quntities of fetal bovine serum acetylcholinesterase". Life Sci. 39 (3): 195–9. PMID 3736320. 
  9. ^ Ralston JS, Main AR, Kilpatrick BF, Chasson AL (1 Apr 1983). "Use of procainamide gels in the purification of human and horse serum cholinesterases". Biochem J. 211 (1): 243–250. doi:10.1042/bj2110243. PMC 1154348Freely accessible. PMID 6870822. 
  10. ^ Saxena A, Luo C, Doctor BP (Oct 2008). "Developing procedures for the large-scale purification of human serum butyrylcholinesterase". Protein Expr Purif. 61 (2): 191–6. doi:10.1016/j.pep.2008.05.021. PMID 18602477. 
  11. ^ a b Lawson, DH; Jick, H (October 1977). "Adverse reactions to procainamide". British Journal of Clinical Pharmacology. 4 (5): 507–11. doi:10.1111/j.1365-2125.1977.tb00777.x. PMC 1429167Freely accessible. PMID 911600. 
  12. '^ Uetrecht, Jack; Zahid, Nasir; Rubin, Robert (1988). "Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes". Chemical research in toxicology 1'. 1: 74–78. doi:10.1021/tx00001a013. 
  13. '^ Roberts, Stephen M.; et al. (1989). "Procainamide hydroxylamine lymphocyte toxicity—I. Evidence for participation by hemoglobin". International journal of immunopharmacology 11'. 4: 419–427. 
  14. '^ Gay, Royal J.; Brown, David F. (1974). "Pacemaker failure due to procainamide toxicity". The American journal of cardiology 34'. 6: 728–732. 
  15. ^ Osadchii, Oleg E. (July 23, 2013). "Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea-pig". Fundamental & Clinical Pharmacology: 382. 
  16. ^ Gould, Lawrence A. (ed.) (1983). Drug treatment of cardiac arrhythmias. Mount Kisco: Futura Publishing Company. p. 74. ISBN 0879931906. 
  17. ^ Zamponi, G.W.; Sui, X.; Codding, P.W.; French, R.J. (1993). "Dual actions of procainamide on batrachotoxin-activated sodium channels: open channel block and prevention of inactivation". Biophys J. 65 (6): 2324–2334. Bibcode:1993BpJ....65.2324Z. doi:10.1016/s0006-3495(93)81291-8. 
  18. '^ Roden, Dan M.; et al. (1980). "Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide". The American journal of cardiology 46'. 3: 463–468. 
  19. ^ a b Uetrecht, J. P.; Freeman, R. W.; Woosley, R. L. (1981). "The implications of procainamide metabolism to its induction of lupus". Arthritis Rheum. 24 (8): 994–1003. doi:10.1002/art.1780240803. 
  20. ^ a b DrugBank. Procainamide (2013, September 16) Retrieved March 27, 2015 from
  21. ^ Adams HR. 1995. Drugs Acting on the Cardiovascular System. Veterinary Pharmacology and Therapeutics. Seventh Edition: 451-500
  22. ^ Plumb DC. 1999. Veterinary Drug Handbook. PharmaVet Publishing. White Bear Lake (USA).
  23. ^ ChEBI. procainamide (CHEBI:8428). (n.d.). Retrieved April 8, 2015 from
  24. ^ DeRuiter J. 2005. "Amides and Related Functional Groups". Principles of Drug Action. 1
  25. ^ US Food and Drug Administration. "Drugs at FDA: FDA Approved Drug Products". USA: U.S. Food and Drug Administration (FDA). Retrieved 2012-08-13. 
  26. ^ Hollman A (February 1992). "Procaine and procainamide". Br Heart J. 67 (2): 143. doi:10.1136/hrt.67.2.143. PMC 1024743Freely accessible. PMID 18610401. 
  27. ^ a b MJA Walker: "Antiarrhythmic drug research". Br J Pharmacol 2006;147;S222-S231. doi: 10.1038/sj.bjp.0706500
  28. ^ Hollman, A (1992). "Procaine and procainamide". Br Heart J. 67 (2): 143. doi:10.1136/hrt.67.2.143. PMC 1024743Freely accessible. PMID 18610401. 
  29. ^ a b Moe GK, Abildskov 1A. "Antiarrhythmic drugs". In: Goodlan LS, Gilman A (eds). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 3rd edition. New York: Macmillan; 1965. pp. 699-715.
  30. ^ a b "Historical development of antiarrhythmic drug therapy". In: Lüderitz B (ed). History of Disorders of Cardiac Rhythm. 3rd edition. New York; Wiley-Blackwell; 2002, pp. 87-114.
  31. ^ "Center for Drug Evaluation and Research: Drug Approval Package" (PDF). FDA. 

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