Procainamide (PCA) is a medication of theantiarrhythmic class used for the treatment ofcardiac arrhythmias. It is asodium channel blocker ofcardiomyocytes; thus it is classified by theVaughan Williams classification system as class Ia. In addition to blocking theINa current, it inhibits theIKr 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 ventriculararrhythmias: ventricularectopy andtachycardia and supraventricular arrhythmias:atrial fibrillation, and re-entrant and automatic supraventricular tachycardia.[3] For example, it can be used to convert new-onsetatrial 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.[4][5]
It is administered by mouth, by intramuscular injection, or intravenously.[6][7]
There is a close line between the plasma concentrations of the therapeutic and toxic effect, therefore a high risk for toxicity.[12] Many symptoms resemblesystemic lupus erythematosus because procainamide reactivateshydroxylamine andnitroso metabolites, which bind tohistone proteins and are toxic tolymphocytes. The hydroxylamine and nitroso metabolites are also toxic to bone marrow cells and can causeagranulocytosis. These metabolites are formed due to the activation ofpolymorphonuclear leukocytes. These leukocytes releasemyeloperoxidase andhydrogen peroxide, which oxidize the primary aromatic amine of procainamide to form procainamide hydroxylamine. The release of hydrogen peroxide is also called arespiratory burst, which occurs for procainamide inmonocytes but not inlymphocytes. Furthermore, the metabolites can be formed by activatedneutrophils. These metabolites could then bind to their cell membranes and cause a release ofautoantibodies which would react with the neutrophils.[13] Procainamide hydroxylamine has morecytotoxicity by hindering the response of lymphocytes toT-cell and B-cellmitogens. Hydroxylamine can also generatemethemoglobin, a protein that could hinder further oxygen exchange.[14]
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 asupraventricular tachycardia which induces failure of thepacemaker and death.[15] Thus, it prolongs QT interval of action potential and increases the risk oftorsade de pointes.[1]
Procainamide could initiateleukopenia and/oragranulocytosis, which are serious hematologic disorders, and is also known for causing gastrointestinal disturbances and aggravating pre-existing abnormalities in impulse initiation and propagation.[3]
Procainamide works as ananti-arrhythmic agent and is used to treatcardiac arrhythmia. It induces rapid block of thebatrachotoxin (BTX)-activatedsodium 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 thehydrophobic 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. Membranedepolarization leads to increased blocking and decreased unblocking of the channels. Procainamide slows the conduction velocity and increases therefractory period, such that the maximal rate of depolarization is reduced.[2] It is also said to be aselectivemuscarinic acetylcholineM3 receptor antagonist.[16]
Procainamide is metabolized via different pathways. The most common one is theacetylation of procainamide to the less-toxicN-acetylprocainamide.[17] 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 thecytochrome 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.[18] 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.[18]
Procainamide is structurally similar toprocaine, 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.[20][21]
Procainamide was approved by the US FDA on June 2, 1950, under the brand name "Pronestyl".[24] It was launched byBristol-Myers Squibb in 1951.[25]Due to theloss of Indonesia inWorld War II, the source forcinchona alkaloids, a precursor ofquinidine, was reduced. This led to research for a newantiarrhythmic drug. As a result,procaine was discovered, which has similar cardiac effects as quinidine.[26] In 1936 it was found by Mautz that by applying it directly on themyocardium, the ventricular threshold for electrical stimulation was elevated.[25] 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.[27] In addition, procaine also caused tremors andrespiratory depression.[27][28] 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 Market al. It was found that procainamide was effective for treatingventricular arrhythmias, but it had the same toxicity profile as quinidine, and it could causesystemic lupus erythematosus-like syndrome.[26][28] 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 thecardiac glycosides,quinidine,propranolol,lidocaine anddiphenylhydantoin. In January 1996, extended release procainamide hydrochloride (Procanbid extended-release tablets) was approved by the FDA.[29]
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^abGould LA, ed. (1983).Drug Treatment of Cardiac Arrhythmias. Mount Kisco: Futura Publishing Company. pp. 73–74.ISBN0879931906.
^Stiell IG, Sivilotti ML, Taljaard M, Birnie D, Vadeboncoeur A, Hohl CM, et al. (February 2020). "Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial".Lancet.395 (10221):339–349.doi:10.1016/S0140-6736(19)32994-0.PMID32007169.S2CID210978499.
^Fenster PE, Comess KA, Marsh R, Katzenberg C, Hager WD (September 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.PMID6881022.
^De la Hoz D, Doctor BP, Ralston JS, Rush RS, Wolfe AD (July 1986). "A simplified procedure for the purification of large quantities of fetal bovine serum acetylcholinesterase".Life Sciences.39 (3):195–199.doi:10.1016/0024-3205(86)90530-8.PMID3736320.
^Saxena A, Luo C, Doctor BP (October 2008). "Developing procedures for the large-scale purification of human serum butyrylcholinesterase".Protein Expression and Purification.61 (2):191–196.doi:10.1016/j.pep.2008.05.021.PMID18602477.
^Uetrecht J, Zahid N, Rubin R (January 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.PMID2979715.
^Roberts SM, Adams LE, Donovan-Brand R, Budinsky R, Skoulis NP, Zimmer H, et al. (1989). "Procainamide hydroxylamine lymphocyte toxicity--I. Evidence for participation by hemoglobin".International Journal of Immunopharmacology.11 (4):419–427.doi:10.1016/0192-0561(89)90089-1.PMID2476407.
^Gay RJ, Brown DF (November 1974). "Pacemaker failure due to procainamide toxicity".The American Journal of Cardiology.34 (6):728–732.doi:10.1016/0002-9149(74)90164-7.PMID4422040.
^Roden DM, Reele SB, Higgins SB, Wilkinson GR, Smith RF, Oates JA, et al. (September 1980). "Antiarrhythmic efficacy, pharmacokinetics and safety of N-acetylprocainamide in human subjects: comparison with procainamide".The American Journal of Cardiology.46 (3):463–468.doi:10.1016/0002-9149(80)90016-8.PMID6158263.
^abUetrecht JP, Freeman RW, Woosley RL (August 1981). "The implications of procainamide metabolism to its induction of lupus".Arthritis and Rheumatism.24 (8):994–1003.doi:10.1002/art.1780240803.PMID6169352.
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^abMoe GK, Abildskov A (1965). "Antiarrhythmic drugs". In Goodman LS, Gilman A (eds.).Goodman and Gilman's The Pharmacological Basis of Therapeutics (3rd ed.). New York: Macmillan. pp. 699–715.
^abLüderitz BB, ed. (2002). "Historical development of antiarrhythmic drug therapy".History of Disorders of Cardiac Rhythm (3rd ed.). New York: Wiley-Blackwell. pp. 87–114.
