Clinical data
Pronunciation /prˈknəmd/
Trade names Pronestyl, Procan, Procanbid
AHFS/ Monograph
  • US: C (Risk not ruled out)
Routes of
IV, IM, oral
ATC code C01BA02 (WHO)
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 85% (oral)
Protein binding 15 to 20%
Metabolism Hepatic (CYP2D6-mediated)
Biological half-life ~2.5 to 4.5 hours
Excretion Renal
CAS Number 51-06-9 YesY
PubChem (CID) 4913
DrugBank DB01035 YesY
ChemSpider 4744 YesY
KEGG D08421 YesY
ECHA InfoCard 100.000.072
Chemical and physical data
Formula C13H21N3O
Molar mass 235.325 g/mol
3D model (Jmol) Interactive image

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.

Medical uses

This drug is used for both supraventricular and ventricular arrhythmias. For example, it can be used to convert new-onset atrial fibrillation, though it is suboptimal for this purpose.[1]

To have a high efficacy, the antiarrhythmic drug procainamide has to be dosed frequently to maintain an adequate serum concentration. Because of its short half-life it must be dosed every 3 or 4 hours. Also procainamide-induced antinuclear antibodies are formed after a 6 months treatment. But further research showed, that after a long-term therapy of procainamide, some subjects did not produce any antinuclear antibodies. Also procainamide can be acetylated to acecainide and to other reactive and toxic metabolites, which would contradict the efficacy.[2]

Side effects

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 is 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.[3]


There is just a close line between the plasma concentrations of the therapeutic and toxic effect, therefore a high risk for toxicity.[3] 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.[4] Procainamide hydroxylamine has more cytotoxicity by hindering the response of lymphocytes to T- and B-cell mitogens. Hydroxylamine can also generate methemoglobin, a protein that could hinder further oxygen exchange.[5]
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.[6]

Mechanism of action

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.[7]


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.[8]

Procainamide is structurally similar to procaine but in place of an ester group contains procainamide an amide group. This substitution is the reason why procainamide exhibit a longer half-life time than procaine.[9][10]

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.[8][11][12]

Reactivity and reactions

Benzamides are, in terms of structure, amides.[13] Carboxylic acid derivatives, to which amides belong, are electrophiles that react with nucleophiles. The electron deficiency of the carbonyl carbon is the result of the greater electronegativity of the oxygen due to which the bonding electrons to a greater extent are pulled in the direction of the oxygen. This compounds can undergo nucleophilic acyl substitution reaction as long as the attacking nucleophile is not a much weaker base than the leaving group. Therefore, substituents which are weak bases are better leaving groups. In the case of procainamide, the leaving group is the NHR group of the amide, which is such a strong base that amides are the least reactive carboxylic acid derivatives. The nucleophiles of water, alcohols, and halide ions are too weak bases, thus they cannot replace the poor leaving group of the amide. In order for a reaction to take place, it must be carried out under harsh conditions. Reactions of amides with alcohols to form esters or with water to produce carboxylic acids take place under acid conditions and in the presence of heat. Furthermore, amides can undergo hydrolysis reactions but again heat and strong acid or basic conditions are required.[14]

Available forms


Procainamide is taken orally in cases of less urgent arrhythmias. Procainamide hydrochloride produces therapeutic plasma concentrations at a daily dose of 50 mg/kg given in three hour dosage intervals. This keeps the fluctuations of plasma level below 50%. However, it is recommended to adjust the dosage and interval for the individual patient.[15]


An alternative to oral administration is intramuscular. This route is suited for patients that are nauseated or vomiting.[15]


For more severe cases of arrhythmias IV medication is given.[16]


Procainamide is metabolized via different pathways. The most common one is the acetylation of procainamide to the less toxic N-acetylprocainamide. 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.[17] 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.[17]


Procainamide was approved by the US FDA on June 2, 1950, under the brand name Pronestyl.[18] It was launched by Bristol-Myers Squibb in 1951.[19]
Due to the loss of Indonesia in World War II, the source for cinchona alkaloids, a precursor of quinidine, was strongly diminished. This led to research for a new antiarrhythmic drug. As a result, procaine was discovered, which has similar cardiac effects as quinidine.[20] In 1936 it was found by Mautz that by applying it directly on the myocardium, the ventricular threshold for electrical stimulation was elevated.[21] 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.[22] In addition, procaine also caused tremors and respiratory depression.[22][23] 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.[20][23] 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, lidocainem propranolol and diphenylhydantoin.


  1. 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.
  2. Roden, Dan M., et al. "Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide." The American journal of cardiology 46.3 (1980): 463-468.
  3. 1 2 Lawson, D. H., and H. Jick. "Adverse reactions to procainamide." British journal of clinical pharmacology 4.5 (1977): 507-511.
  4. Uetrecht, Jack, Nasir Zahid, and Robert Rubin. "Metabolism of procainamide to a hydroxylamine by human neutrophils and mononuclear leukocytes." Chemical research in toxicology 1.1 (1988): 74-78.
  5. Roberts, Stephen M., et al. "Procainamide hydroxylamine lymphocyte toxicity—I. Evidence for participation by hemoglobin." International journal of immunopharmacology 11.4 (1989): 419-427.
  6. Gay, Royal J., and David F. Brown. "Pacemaker failure due to procainamide toxicity." The American journal of cardiology 34.6 (1974): 728-732.
  7. 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. doi: 10.1016/s0006-3495(93)81291-8
  8. 1 2 DrugBank. Procainamide (2013, September 16) Retrieved March 27, 2015 from
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  16. Elliott M. Antman. Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease 4th Edition. ISBN 978-1-4557-0101-8. P410
  17. 1 2 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.
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  20. 1 2 MJA Walker: Antiarrhythmic drug research. Br J Pharmacol 2006;147;S222-S231. doi: 10.1038/sj.bjp.0706500
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  23. 1 2 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
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