Procainamide

Procainamide

Systematic (IUPAC) name
4-amino-N-(2-diethylaminoethyl) benzamide
Clinical data
AHFS/Drugs.com	monograph
Pregnancy category	US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only)
Routes of administration	IV, IM, oral
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
Identifiers
CAS Number	51-06-9 Y
ATC code	C01BA02 (WHO)
PubChem	CID: 4913
IUPHAR/BPS	4811
DrugBank	DB01035 Y
ChemSpider	4744 Y
UNII	L39WTC366D Y
KEGG	D08421 Y
ChEBI	CHEBI:8428 Y
ChEMBL	CHEMBL640 Y
Chemical data
Formula	C13H21N3O
Molecular mass	235.325 g/mol
SMILES O=C(c1ccc(N)cc1)NCCN(CC)CC
InChI InChI=1S/C13H21N3O/c1-3-16(4-2)10-9-15-13(17)11-5-7-12(14)8-6-11/h5-8H,3-4,9-10,14H2,1-2H3,(H,15,17) Y Key:REQCZEXYDRLIBE-UHFFFAOYSA-N Y
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Procainamide INN (/proʊˈkeɪnəmaɪd/; trade names Pronestyl, Procan, Procanbid) is a pharmaceutical antiarrhythmic agent used for the medical treatment of cardiac arrhythmias, 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.

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.

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.

Toxicity

There is just 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. 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.
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.

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.

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.

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.

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.

Reactivity and reactions

Benzamides are, in terms of structure, amides. 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.

Available forms

Oral

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%. But it is recommended to adjust the dosage and interval for the individual patient.

Intramuscular

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

Intravenous

For more severe cases of arrhythmias iv medication is given.

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. 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.

History

Procainamide was approved by the US FDA on June 2, 1950, under the brand name Pronestyl. It was launched by Bristol-Myers Squibb in 1951.
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. 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. But due to the short duration of action, caused by rapid enzymatic hydrolysis, its therapeutic applications were limited. In addition, procaine also caused tremors and respiratory depression. 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 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.

Other 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. 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.

External links

• PubPK - Procainamide