Procainamide pharmacokinetics

Pharmacokinetics Procainamide [pro kane A mide] is absorbed following oral administration. [Note The intravenous route is rarely used because hypotension occurs if the drug is too rapidly infused.] Procainamide has a relatively short half-life of 2-3 hours. A portion of the drug is acetylated in the liver to N-acetylprocainamide (NAPA), which has little effect on the maximum polarization of Purkinje fibers but prolongs the duration of the action potential. Thus, NAPA has properties of a Class III drug. NAPA is eliminated via the kidney, and dosages of procainamide may need to be adjusted in patients with renal failure. 

Roden DM, Reele SB, Higgins SB, Wilkinson GR, Smith RF, Oates JA, Woosley RL. Antiarrhythmic efficacy, pharmacokinetics and safety of A-acetylprocai-namide in human subjects comparison with procainamide. Am J Cardiol 1980 46 463 168. 

Note. For a review of the clinical pharmacokinetics of procainamide see E. Karlsson, Clin. Pharmacokinet., 1978, 3, 97-107. 

The following pharmacokinetic data for N-acetylprocainamide (NAPA) were obtained in a Phase I study in which procainamide and NAPA kinetics were... 

Atkinson AJ Jr, Ruo TI, Piergies AA. Comparison of the pharmacokinetic and pharmacodynamic properties of procainamide and N-acetylprocainamide. Angiology 1988 39 655-67. 

The pharmacokinetics of procainamide are altered by amiodarone, with a reduction in clearance of about 25% due to changes in both renal and non-renal clearances (62). 

Atkinson AJ Jr, Krumlovsky FA, Huang CM, del Greco F. Hemodialysis for severe procainamide toxicity clinical and pharmacokinetic observations. Clin Pharmacol Ther 1976 20(5) 585-92. 

Windle J, Prystowsky EN, Miles WM, Heger JJ. Pharmacokinetic and electrophysiologic interactions of amiodarone and procainamide. Clin Pharmacol Ther 1987 41(6) 603-10. 

Martin DE, Shen J, Griener J, Raasch R, Patterson JH, Cascio W. Effects of ofloxacin on the pharmacokinetics and pharmacodynamics of procainamide. J Clin Pharmacol 1996 36(1) 85-91. 

Koch-Weser J. Serum procainamide levels as therapeutic guides. Clin Pharmacokinet 1977 2(6) 389 02. 

Somogyi A, McLean A, Fleinzow B. Cimetidine-procainamide pharmacokinetic interaction in man evidence of competition for tubular secretion of basic drugs. Eur J Clin Pharmacol 1983 25 339-345. 

Hypotension not responsive to intravenous fluids should be managed with vasopressors, such as dopamine, norepinephrine, epinephrine, and/or phenylephrine. If seizures occur, benzodiazepines should be administered. Due to their pharmacokinetic characteristics, moderate volume of distribution, and low protein binding, procainamide and NAPA may be removed via hemodialysis and hemoperfu-sion. Both procainamide and NAPA serum concentrations should be obtained. Normal therapeutic ranges are procainamide, 3-14pgml NAPA, 12-35 pg ml Measurement of electrolytes, renal function tests, and arterial blood gases should be considered. 

Pharmacokinetic parameters of digoxin and other cardioactive drugs are summarized in Table 33-2. Digoxin, disopyra-mide, lidocaine, procainamide, and quinidine are usually quantified by immunoassay. HPLC methods to quantify the other cardioactive drugs are reviewed in a previous edition of this chapter. ... 

R. L. Galeazzi, L. Z. Benet, and L. B. Sheiner, Relationship between the pharmacokinetics and pharmacodynamics of procainamide. Clin Pharmacol Ther 20 278-289 (1976). 

Please note that it is the free acid or free base of a therapeutic agent that provides the pharmacological effect. For instance, when procainamide hydrochloride is administered to a patient, it is procainamide (free base) that is responsible for its pharmacological effect and not the hydrochloride part of the molecule. The pharmacokinetic parameters reported in the literature are obtained by measuring the free acid or base of a particular drug. 

The combination of captopril or other ACE inhibitors and procainamide possibly increases the risk of lencopenia. No pharmacokinetic interaction occurs between captopril and procainamide. 

The pharmacokinetics of procainamide are little changed by either propranoioi or metoprolol. Both sotalol and procamamide have QT-intervai proionging effects, which may be additive if they are used together. 

Preliminary results of a study in 6 healthy subjects found that long-term treatment with propranolol [period and dosage not stated] increased the procainamide half-life from 1.71 to 2.66 hours and reduced the plasma clearance by 16%. However, a later study in 8 healthy subjects found that the pharmacokinetics of a single 500-mg dose of procainamide were only slightly altered by propranolol 80 mg three times daily or metoprolol 100 mg twice daily. The procainamide half-life of 1.9 hours increased to 2.2 hours with propranolol, and to 2.3 hours with metoprolol, but no sig-ni ficant changes in total clearance occurred. No changes in the AUC of the metabolite A-acetylprocainamide were seen. It seems unlikely that a clinically important adverse interaction normally occurs between these drugs. 

Weidler DJ, Garg DC, Jallad NS, McFarland MA. The effect of long-term propranolol administration on the pharmacokinetics of procainamide in humans. Clin Pharmacol Ther (19SI ) 29, 289. 

Famotidine 40 mg daily for 5 days did not affect the pharmacokinetics or pharmacodynamics of a single 5-mg/kg intravenous dose of procainamide in 8 healthy subjects." ... 

One study found that ranitidine 150 mg twice daily for one day reduced the absorption of procainamide from the gut by 10% and reduced its renal excretion by 19%, increasing the procainamide and A-acetylprocainamide AUC by about 14%. However, no change in the steady-state pharmacokinetics of procainamide was found with ranitidine 150 mg twice daily in another study, except that ranitidine delayed the time to maximum plasma concentration (from 1.4 to 2.7 hours). In a further study, ranitidine 150 mg twice daily for 4 days caused no significant changes in the mean pharmacokinetics of oral procainamide 1 g in 13 healthy subjects. However, it appeared that subjects had either a modest 20% increase or decrease in procainamide clearance, with the direction of change related to their baseline procainamide clearance the higher the baseline clearance the greater the decrease caused by ranitidine. ... 

A single case report found that para-aminobenzoic acid (PABA) increased the serum levels of procainamide and reduced the serum levels of the procainamide metabolite N-acetylprocainamide. In contrast, a later pharmacokinetic study in healthy subjects found that PABA had no effect on serum procainamide levels, and increased serum IV-acetylprocainamide levels. 

A 61-year-old man who had sustained ventrieular tachycardia, which did not respond adequately to oral procainamide, was found to be a fast acetylator of procainamide, which resulted in particularly high serum levels of the procainamide metabolite (7V-acetylprocainamide) when compared with the procainamide levels. When he was also given para-aminobenzoic acid (PABA) 1.5 g every 6 hours for 30 hours, to suppress the production of this metabolite, the serum level of procainamide increased, that of Al-acetylproeainamide decreased, and control of his arrhythmia improved. However, a later study in 10 healthy subjects, who were also fast acety lators, found that PABA did not significantly affect the pharmacokinetics of procainamide. In addition, although PABA inhibited the production of A-acetylprocainamide, it also inhibited renal excretion, so that the AUC and elimination half-life were increased. This suggests that PABA may in fact not be useful for increasing the efficacy and safety of procainamide. ... 

The pharmacokinetics of a singie 750-mg intravenous dose of procainamide and its effects on the QT intervai were not aitered by the prior administration of probenecid 2 g in 6 heaithy subjects. No speciai precautions appear to be necessary. 

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