Procainamide

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Procainamide
Clinical data
Pronunciation/proʊˈkeɪnəmaɪd/
Trade namesPronestyl, Procan, Procanbid, others
AHFS/Drugs.comMonograph
Routes of
administration		IV, IM, by mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability85% (by mouth)
Protein binding15 to 20%
MetabolismLiver (CYP2D6-mediated)
Elimination half-life~2.5 to 4.5 hours
ExcretionKidney
Identifiers
  • 4-amino-N-(2-diethylaminoethyl) benzamide
JSmol)
  • O=C(c1ccc(N)cc1)NCCN(CC)CC
  • 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) checkY
  • Key:REQCZEXYDRLIBE-UHFFFAOYSA-N checkY
  (verify)

Procainamide (PCA) is a medication of the

Vaughan Williams classification system as class Ia. 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]

Uses

Medical

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, 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]

Others

It has also been used as a chromatography resin because it somewhat binds protein.[8][9][10][11]

Side effects

There are many side effects following the induction of procainamide. These adverse effects are

drug fever and other allergic responses. There is also a chance that drug-induced lupus erythematosus occurs, which at the same time leads to arthralgia, myalgia and pleurisy. Most of these side effects may occur due to the acetylation of procainamide.[12]

Toxicity

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

mitogens. Hydroxylamine can also generate methemoglobin, 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 a

torsade de pointes.[1]

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.[3]

Pharmacology

Mechanism of action

Procainamide works as an

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.[2]

Metabolism

Procainamide is metabolized via different pathways. The most common one is 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]

Chemistry

4-amino-N-2-(diethylamino)ethyl-benzamide (also known as

benzene ring) is a synthetic organic compound with the chemical formula C13-H21-N3-O.[18]

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.[19][20]

Procainamide belongs to the

aromatic carboxylic acid derivatives consisting of an amide with a benzamide moiety and a triethylamine attached to the amide nitrogen.[18][21][22]

In certain lines, the para-amino group might become a target site to attach further paraphernalia, e.g. ref. Ex18 in U.S. patent 7,115,750.

History

Procainamide was approved by the US FDA on June 2, 1950, under the brand name "Pronestyl".

Bristol-Myers Squibb in 1951.[24]
Due to the
diphenylhydantoin. In January 1996, extended release procainamide hydrochloride (Procanbid extended-release tablets) was approved by the FDA.[28]

References

  1. ^
    S2CID 5086017
    .
  2. ^
    PMID 8312472
    .
  3. ^
    ISBN 0879931906
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  4. S2CID 210978499
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  5. PMID 6881022
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  6. PMID 5107621
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  7. ISBN 978-1-4557-0101-8
    .
  8. ^ "Procainamide Sepharose 4 Fast Flow". GE Healthcare Life Sciences. Archived from the original on 2021-08-29. Retrieved 2017-07-24.
  9. PMID 3736320
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  10. PMID 6870822
    .
  11. PMID 18602477
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  12. ^
    PMID 911600
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  13. PMID 2979715
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  14. PMID 2476407
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  15. PMID 4422040
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  16. PMID 6158263
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  17. ^
    PMID 6169352
    .
  18. ^ a b "Procainamide". www.drugbank.ca. 27 June 2018. Retrieved 28 June 2018.
  19. ^ Adams HR (1995). Drugs Acting on the Cardiovascular System. Veterinary Pharmacology and Therapeutics (7th ed.). pp. 451–500.
  20. ^ Plumb DC (1999). Veterinary Drug Handbook. White Bear Lake, USA: PharmaVet Publishing.
  21. ^ EBI Web Team. "CHEBI:8428 - procainamide". www.ebi.ac.uk. Retrieved 28 June 2018.
  22. ^ DeRuiter J (2005). "Amides and Related Functional Groups". Principles of Drug Action. p. 1.
  23. U.S. Food and Drug Administration
    (FDA). Retrieved 2012-08-13.
  24. ^
    PMID 18610401
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  25. ^
    PMID 16402108
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  26. ^ a b Moe 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.
  27. ^ a b Lüderitz BB, ed. (2002). "Historical development of antiarrhythmic drug therapy". History of Disorders of Cardiac Rhythm (3rd ed.). New York: Wiley-Blackwell. pp. 87–114.
  28. ^ Mishina E, Marroum P (2002). "Center for Drug Evaluation and Research Approval Package For: Application Number NDA 20-545/S007" (PDF). Clinical Pharmacology and Bioharmaceutics Review.
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