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History

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. [1] In 1936 it was found by Mautz that by applying it directly on the myocardium, the ventricular threshold for electrical stimulation was elevated. [2] This mechanism is responsible for the antiarrhythmic effect. But due to the short duration of action, caused by rapid enzymatic hydrolysis, its therapeutic applications were limited. [3] In addition, procaine also caused tremors and respiratory depression. [4] [3] 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. [1] [4] 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.

Structure

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 an synthetic organic compound with the chemical formula C13-H21-N3-O.[5]

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.[6][7]

Procainamide belongs to the aminobenzamides. This are aromatic carboxylic acid derivatives consisting of an amide with a benzamide moiety and a triethylamine attached to the amide nitrogen.[8][9][5]

Synthesis

Quite a few approaches exist in respect of the procainamide synthesis. For instance, reactions of the polyamine N,N-diethylethylenediamine provide different ways when reacting with different carbonyl compounds [10]. One useful possibility is an acylation reaction of N,N diethylethylenediamine with 4-nitrobenzoic acid chloride and a subsequent hydrogenation reaction of the resulting substance. This reaction is a nucleophilic acyl substitution by which the primary amine attaches to the carbonyl carbon of the acylating agent, forming an intermediate, and ultimately replaces the chloride ion.[11][10][12] Because the amino group (-NH2) is such a strong base it can replace the chloride ion, which is a weaker base and therefore the better leaving group. The departing chloride ion will form HCl (hydrochloric acid) as a product of this reaction. For this reason, twice as much N,N-diethylethylenediamine as 4-nitrobenzoic acid chloride is needed in order to prevent that all amine get protonated by the acid. Protonated amine would no longer function as a nucleophile and the reaction would not take place.[11]

4-nitro-N-2-(diethylamino)-ethyl-benzamide

The resulting compound of the acylation is 4-nitro-N-2-(diethylamino)-ethyl-benzamide which undergoes an hydrogenation reaction by which its nitro group (-NO2) is reduced into an amino group (-NH2).[13][10][12] The reduction of the nitro group into an amino group is carried out by a catalytic hydrogenation. For the reaction to take place, a metal catalyst is necessary in order to weaken the strong H-H bond of the hydrogen and the pi bond between the nitrogen and the oxygen. The addition of hydrogen reduces the number of N-O bonds and the result is procainamide.[11]

An less profitable alternative is the acylation of N,N-diethylethylenediamine with 4-aminobenzoic acid ethyl ester in the presence of aluminum complexes. This reaction takes places without a hydrogenation.[14] N,N-diethylethylenediamine

A third possibility to synthesize procainamide is the reaction of N,N-diethylethylenediamine with 4-Aminobenzoic acid (PABA) without dehydration reaction reagents or through the addition of the Lewis acid boron trifluoride etherate. The amine can also react with 4-Aminobenzoic acid by making use of a compound/reagent, such as dicyclohexyl carbodiimide (DCC), which activate the carbonyl group by providing a good leaving group.[11][13][14] Dicyclohexyl carbodiimide

Reactivity and reactions

Benzamides are, in terms of structure, amides.[15] 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.[11]

Available forms

Oral

Procainamide is taken orally in cases of less urgent arrhythmias. Procainamide hydrochloride produces therapeutic plasma concentrations at a daily dose of 50mg/kg given in three hour dosage intervals. This keeps the fluctuations of plasma level below 50%. But it is recommended to adjust the dosage and interval for the individual patient.[16]

Intramuscular

An alternative to oral administration is intramuscular. This route is suited for patients that are nauseated or vomiting. The recommended dosage of 50mg/ kg is given by injections of 1/8 to 1/4 of the dose every three to six hours. [16]

Intravenous

For more severe cases of arrhythmias a loading dose of 10-15 mg/kg and further administration at a rate of 20mg/min up to 50mg/min, for a maximum dose of 1 to 1.5 g is advised. Blood pressure should be monitored as hypotension may occur. [17]

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. [18]

Metabolism

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. [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. [20]

Efficacy and side effects

Efficacy

To have a high efficacy, the antiarrhythmic drug procainamide has to be induced frequently to obtain and maintain an adequate serum concentration. Because of its short half-life it has to be induced 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. [21] Furthermore procainamide has to be induced orally, while other antiarrhythmic drugs like quinidine are simpler to induce via an intravenous infusion and are therefore used more frequently. Usage of intravenous procainamide showed some side effects, but the best and safest efficacy is at an infusion of 25 to 50 mg per minute by a dose of 20mg/kg. However, high toxicity occurs at a rate of 100 mg or higher per minute.[22]

Adverse effects

There are many side effects following the induction of procainamide. These adverse effects are ventricular dysrhythmia, bradycardia, hypotension and shock. The adverse effects occure 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.[23]

Toxicity

There is just a close line between the plasma concentrations of the therapeutic and toxic effect, therefore a high risk for toxicity.[23] 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.[24]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.[25]
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.[26]

Effects on animals

One of the side effects of procainamide treatment is systemic lupus erythematosus, which only occurs in human and not in animals. This has to do with the different metabolism of procainamide in the species. For example humans have a specific N-acyltransferase and therefore form more N-acylated metabolites of procainamide then mice. The two species also differ in N-oxidation of procainamide, while in humans tertiary amine oxidation was the dominant reaction, in mice the dominant reaction was the primary amine hydroxylation. But further investigations have to be done, because the real cause of systemic lupus erythematosus is not know yet. One of the candidates as cause are the N-oxide metabolites, which are heavily influenced by the human CYP2D6, but this has to be further investigated in animal models.[27] Also the connection between the anticancer drug cisplatin and procainamide in pregnant mice was investigated. Cisplatin has a high toxic and lethal effect to embryos, and many other side effects. The tests showed that procainamide works as protector against most of the cisplatin side effects, and that it increases the antitumor activity of cisplatin. Furthermore the co-administration of procainamide to a cisplatin treated pregnant mice did not change the chance of fetal survival, but led to partial improvement of the fetal condition. It seems that procainamide influences the permeability of the placenta to cisplatin, so that less cisplatin is transported to the fetus. In summary, procainamide does not increase the survival chance, nor worsens the fetal health condition, but reduces the embryotoxic effects of cisplatin.[28]

References

  1. ^ a b MJA Walker: Antiarrhythmic drug research. Br J Pharmacol 2006;147;S222-S231. doi: 10.1038/sj.bjp.0706500
  2. ^ Hollman A (February 1992). "Procaine and procainamide". Br Heart J 67 (2): 143. doi:10.1136/hrt.67.2.143.
  3. ^ 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. Pp699-715.
  4. ^ 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
  5. ^ a b DrugBank. Procainamide (2013, September 16) Retrieved March 27, 2015 from http://www.drugbank.ca/drugs/DB01035
  6. ^ Adams HR. 1995. Drugs Acting on the Cardiovascular System. Veterinary Pharmacology and Therapeutics. Seventh Edition: 451-500
  7. ^ Plumb DC. 1999. Veterinary Drug Handbook. PharmaVet Publishing, White Bear Lake (USA)
  8. ^ ChEBI. procainamide (CHEBI:8428). (n.d.). Retrieved April 8, 2015 from http://www.ebi.ac.uk/chebi/searchFreeText.do?searchString=51-06-9
  9. ^ DeRuiter J. 2005. Amides and Related Functional Groups. Principles of Drug Action 1
  10. ^ a b c Pearson, Anthony J., and Robert A. Dubbert. "Intramolecular alkyne–alkyne and alkyne–alkene couplings promoted by iron carbonyls." J. Chem. Soc., Chem. Commun. 3 (1991): 202-203.
  11. ^ a b c d e Bruice PY. 2012. Organic Chemistry. Seventh Edition. University of California Santa Barbara. Prentice Hall
  12. ^ a b Vardanyan R, Hruby V. 2006. Synthesis of Essential Drugs. Elsevier Science.
  13. ^ a b Encyclopædia Britannica. Carboxylic acid (2015) Retrieved March 28, 2015 from http://www.britannica.com/EBchecked/topic/95261/carboxylic-acid/277758/Polyesters
  14. ^ a b Hager H, Bruchhausen F, Beirat W, Dannhardt G, Ebel S, Frahm AW, Hackenthal E, Holzgrabe U. 2013. Hagers Handbuch der Pharmazeutischen Praxis. Springer Berlin Heidelberg.
  15. ^ CliniPharm Wirkstoffdaten: Procainamid. (n.d.). Retrieved March 27, 2015 from http://www.chemicalland21.com/industrialchem/organic/BENZAMIDE.htm
  16. ^ a b Jan Koch-Weser, MD; Stuart W. Klein, MD. Procainamide Dosage Schedules, Plasma Concentrations, and Clinical Effects. doi:10.1001/jama.1971.03180220036006.
  17. ^ Elliott M. Antman. Cardiovascular Therapeutics: A Companion to Braunwald's Heart Disease 4th Edition. ISBN 978-1-4557-0101-8. P410
  18. ^ 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
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ Halpern, STEPHEN W., et al. "Efficacy of intravenous procainamide infusion in converting atrial fibrillation to sinus rhythm. Relation to left atrial size." British heart journal 44.5 (1980): 589-595.
  23. ^ a b Lawson, D. H., and H. Jick. "Adverse reactions to procainamide." British journal of clinical pharmacology 4.5 (1977): 507-511.
  24. ^ 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.
  25. ^ Roberts, Stephen M., et al. "Procainamide hydroxylamine lymphocyte toxicity—I. Evidence for participation by hemoglobin." International journal of immunopharmacology 11.4 (1989): 419-427.
  26. ^ Gay, Royal J., and David F. Brown. "Pacemaker failure due to procainamide toxicity." The American journal of cardiology 34.6 (1974): 728-732.
  27. ^ Li, Fei, et al. "Metabolomics reveals the metabolic map of procainamide in humans and mice." Biochemical pharmacology 83.10 (2012): 1435-1444.
  28. ^ Ognio, Emanuela, et al. "Study of feasibility of the treatment with procainamide hydrochloride and cisplatin in pregnant mice." Chemico-biological interactions 164.3 (2006): 232-240.
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