Antiarrhythmic efficacy of N‐acetylprocainamide in patients with premature ventricular contractions

Lee, Woong-Ku; Strong, John M.; Kehoe, Richard F.; Dutcher, John S.; Atkinson, Arthur J.

doi:10.1002/cpt1976195part1508

Cited by 59 publications

(12 citation statements)

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“…(J 975) concluded that the compounds are nearly equipotent. Subsequent studies (Lee et a!., 1976;Atkinson et a!., 1977) suggest, however, that higher plasma concentrations of NAP A than of procainamide may be required to suppress premature ventricular contractions and to cause certain electrocardiographic and haemodynamic changes.…”

Section: The Potency Of Napamentioning

confidence: 93%

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Serum Procainamide Levels As Therapeutic Guides

Koch‐Weser

1977

Clinical Pharmacokinetics

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Dosage schedules o( procaillamide should be individualised. because the amount of the drug required to colllrol velllricular tachyarrhythmias varies widely among patiellls. Individual differences in procainamide pharmacokinetics are responsible for most of this variation and are reflected by the serum COllcelllratioll (!f the drug. Proc(1inamide concelllratiolls ill serum and in myocardial interstitial fluid must equilibrate rapidly and be similar at equilibrium. The effects lif the drug Oil the myocardial cell membrane are proportional to the concentration at that site. develop quickly alld are readily reversible. Accordingly. there is a useful relation between the serulII concentration and the illtensity (I{ cardiac action lif procainamide.Procainamide serum levels are most helpful fiJI' adjusting dosage schedules in patiellls whose response to the drug is difficult to el'aluate or appears to be abnormal. Serum concentrations of 4 to 10mg/ litre correct alld prevel1l over 90 % ofvelllricular tachyarrhythmias responsive to procainamide without causing important adverse effects. Lower concelllrations are partially effective in some patiellts. A dditional therapeutic benefit is rarely obtained by raising the serul11 level above IOmg/ litre. alld serious toxicity becomes illcreasingly common above 12mg/ litre. Sen/m concentration i/!formation must always be illlerpreted in the light lif all other clinical il!formatirJlJ. since the type o( arrhythmia and many other factors influence the response (!f the heart to procainamide. N-Acetylprocainamide. a metabolite (!f procainamide. possess antiarrhythmic activity and is not measured by the usual methods for determining serum procainamide. The concentration ratio I!f drug and metabolite in serum varies greatly among patiellls. and their potency ratio against Farious ventricular dysrhythmias in man remains in question. By measuring Nacetylprocainamide as well as procainamide. it may ultimately be possible to de.fine a therapeutic rallge (Jf the sum (!f the appropriately weighted concentrations lif the 2 compounds.For the present. tile therapist must rely primarily on·the serum concelllration (!f procainamide for supplementillg his c1illicaljudgmelll.

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Section: The Potency Of Napamentioning

confidence: 93%

“…1975;Bagwell et al. 1976;Lee et al. 1976;Atkinson et ai., 1977), but it remains unclear how important the antiarrhythmic effects of NAP A are in procainamide-treated patients.…”

Section: The Influence Q( Active Metabolitesmentioning

confidence: 95%

Serum Procainamide Levels As Therapeutic Guides

Koch‐Weser

1977

Clinical Pharmacokinetics

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“…An additional problem is that it appears that the antiarrhYthmic efficacy ofN-acetylprocainamide may not be similar to that of the parent drug, despite early evidence to the contrary (Atkinson et aI., 1977;Kluger et al, 1978;Lee et al, 1976;Lertora et al, 1979). More recent clinical studies in patients with chronic, high frequency ventricular ectopic depolarisations have indicated relatively poor crossefficacy between the two compounds (Roden et al.…”

Section: J J J Procainamidementioning

confidence: 99%

Drug Metabolites in Renal Failure

Verbeeck

Branch

Wilkinson

1981

Clinical Pharmacokinetics

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The effects of impaired renal function on drug disposition and responsiveness have generally been examined with respect to alterations in the behaviour of unchanged drug. For drugs which are extensively excreted via the kidneys various approaches have been applied to modify dosage regimens in order to optimise drug concentration-time profiles. However. it is now recognised that even if urinary excretion is not an important route of drug elimination, renal failure may affect the body's handling of a drug and its clinical effects. This may occur by the greater than normal accumulation of drug metabolites which are predominantly excreted in the urine, leading to a situation analogous to coadministration of another drug and the possible sequelae of a drug-drug interaction.The accumulation of pharmacologically and/or toxicologically active metabolites in renal failure occurs in several instances and can significantly alter clinical effects at the pharmacodynamic level. Accumulated inactive metabolites, especially those formed by conjugation with glucuronic acid, may also lead to a change in drug action by way of regeneration of the parent drug. This in turn may alter the disposition characteristics of the precursor drug even though urinary excretion is not an important pathway of elimination in individuals with normal renal function.It is also possible that metabolites may have a direct dispositional interaction with the parent drug. This would most likely occur through competition for non-linear processes such as plasma and tissue binding, active transport and enzyme-mediated reactions. The degree of such inhibition would be dependent on the relalive affinities and concentrations of the interacting compounds, and thus renal failure could exaggerate this type of phenomenon. However, these types of interactions are not well substantiated, probably because of their complexity and subtlety.The higher than normal accumulation of metabolites in renal failure may also affect diagnostic procedures either directly or indirectly. For example, the metabolite may interfere with the analysis of an endogenous compound used for diagnostic purposes. Alternatively, the disposition of the drug may be used in a diagnostic fashion, as occurs with the determination of drug acetylation phenotype. In the laller instance, methodologies based on parent drug-metabolite ratios in the plasma and/or urine may well be misleading when applied to patients with impaired renal function.

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“…It has been reported that NAPA has anti arrhythmic effect , and also that the relative potency of the anti arrhythmic effect of NAPA varied from 30 to 100% compared with PA Bagwell, E. E. et al, 1976 ;Elson, J. et al, 1975 ;Lee, W-K. et al, 1976 ;Atkinson, A. J. Jr. et al, 1977). Further, the biological half-life of NAPA is 6 hr (Strong, J. M. et al, 1975) and the protein binding of NAPA is reported to be slightly less than that, of PA (Koch-Weser, J., 1971a ; Reidenberg, M. M. et al, 1975 ;Bagwell, E. E. et al, 1974).…”

Section: ) Determination Of Pa and Napamentioning

confidence: 99%

Pharmacokinetics of Procainamide in Japanese Subjects

Shimamura

1979

Rinsho yakuri/Japanese Journal of Clinical Pharmacology and The

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Medicine SummaryThe present study was undertaken to elucidate the pharmacokinetics of procainamide (PA) in 4 Japanese who were found to be so-called fast acetylators. PA was injected intravenously and the serum concentrations of PA and N-acteylprocainamide (NAPA) were determined, following which the pharmacokinetic parameters of PA were calculated. In this study, it was found that the elimination rate ranged from 0.22 to 0.43hr-1, the apparent volume of distribution (Vd area) ranged from 1.80 to 3.57 1/kg, body clearance (Clb) ranged from 0 .65 to 1.39 l/kg/hr, and the area under the curve (AUC) ranged from 2.99 to 5.22Even after repeated oral administration to Japanese subjects , the serum con centration of PA did not reach the therapeutic range recommended by previous workers, while on the other hand, a remarkable increase in serum concentration of NAPA accompanied by the equilibrium state of serum PA concentration was noted. From the present results, it was suggested that the serum concentrations of both PA and NAPA should be taken into consideration in order to evaluate the antiarrhythmic effect after PA administration to Japanese subjects, most of whom are fast acetylators.Key Words : Procainamide, Pharmacokinetics, N-acetylprocainamide , Fast acetylator, Japanese PA is an antiarrhythmic agent in wide use.Recently however,

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Antiarrhythmic efficacy of N‐acetylprocainamide in patients with premature ventricular contractions

Cited by 59 publications

References 5 publications

Serum Procainamide Levels As Therapeutic Guides

Serum Procainamide Levels As Therapeutic Guides

Drug Metabolites in Renal Failure

Pharmacokinetics of Procainamide in Japanese Subjects

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