Serum Procainamide Levels As Therapeutic Guides

Koch‐Weser, Jan

doi:10.2165/00003088-197702060-00001

Cited by 40 publications

(7 citation statements)

References 66 publications

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“…In these electrophysiological experiments, disopyramide and quinidine produced significant muscarinic receptor blockade at concentrations which are thought to occur in the clinical setting (Niarchos, 1976;Sokolow and Edgar, 1950;Winkle et al, 1975). However, procainamide did not exert anticholinergic effects except at concentrations that would be considered to be toxic in patients (Winkle et al, 1975;Koch-Weser, 1977).…”

Section: Effects Of Atropine Disopyramide Quinidine and Procainamimentioning

confidence: 85%

Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade.

Mirro¹,

Manalan²,

Bailey³

et al. 1980

Circulation Research

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We studied the interaction of disopyramide, quinidine, and procainamide with cardiac muscarinic receptors. In electrophysiological experiments, the effects of disopyramide, quinidine, procainamide, and atropine were determined on spontaneously depolarizing guinea pig right atria (GPRA) both in the presence and absence of pharmacologically induced (physostigmine) cholinergic stimulation. All four agents demonstrated a concentration-dependent antagonism of the negative chronotropic effects of physostigmine. The order of anticholinergic potency was atropine greater than disopyramide greater than quinidine greater than procainamide. The ability of disopyramide to antagonize the physostigmine induced slowing was stereoselective, (+)disopyramide greater than (-)disopyramide. In contrast, the ability of quinidine to antagonize the negative chronotropic effects of physostigmine was non-stereoselective, quinidine = quinine. In parallel experiments, we studied the ability of disopyramide, quinidine, procainamide, and atropine to compete with the radiolabeled muscarinic receptor antagonist [3H] quinuclidinyl benzilate ([3H]QNB) for binding to muscarinic receptors in crude homogenates of GPRA and membrane vesicles from canine ventricular myocardium. All four agents inhibited [3H]QNB binding to muscarinic receptors. The order of anticholinergic potency determined by the receptor binding studies was identical to that determined by the physiological studies. The interaction of disopyramide with muscarinic receptors was stereoselective, (+)disopyramide > (-)disopyramide. Quinidine was only slightly more potent than quinine in inhibiting [3H]QNB binding to muscarinic receptors. Interaction of antiarrhythmic drugs with muscarinic receptors satisfied criteria for a competitive interaction. The data from this study localize the anticholinergic effects of disopyramide and quinidine to the muscarinic receptor.

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Section: Effects Of Atropine Disopyramide Quinidine and Procainamimentioning

confidence: 85%

Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade.

Mirro¹,

Manalan²,

Bailey³

et al. 1980

Circulation Research

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“…Nevertheless, ranitidine could impair the gastrointestinal absorption of some drugs, which may lead to less than optimal therapeutic response. Further, because of the narrow therapeutic indices of procainamide (Koch-Weser, 1977) and NAPA (Roden et al, 1980) in a small, select group of patients with elevated blood ranitidine concentrationse.g., the elderly and those with liver cirrhosis (Young et al, 1982) -the combination of intravenous procainamide and ranitidine could possibly result in toxic antiarrhythmic blood concentrations, necessitating dosage reduction.…”

Section: Discussionmentioning

confidence: 99%

Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man.

Somogyi¹,

Bochner²

1984

Brit J Clinical Pharma

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The pharmacokinetics of oral procainamide (1 g) were investigated in six healthy subjects during chronic dosing with ranitidine 150 mg twice daily, and in three of the subjects when ranitidine 750 mg was administered over 12 h. The procainamide area under the plasma concentration‐time curve was significantly (PQ0.02) increased by ranitidine (27.761.5 vs 31.561.8 mg l‐1 h) with a significant reduction in renal clearance (379632 vs 309630 ml/min, PQ0.02). There was no change in half‐life. The N‐acetylprocainamide (NAPA) area under the plasma concentration‐time curve was also significantly (PQ0.02) elevated by ranitidine (8.661.2 vs 9.761.3 mg 1‐1 h) due to a reduction in renal clearance from 187630 to 168628 ml/min. The larger dose of ranitidine produced greater alterations in the procainamide and NAPA pharmacokinetics. Ranitidine reduced the absorption of procainamide by 10% and by 24% at the higher dose level. Two‐hourly renal clearance values of procainamide were significantly (PQ0.05) reduced in the 2 to 10 h period and for NAPA between 0 to 6 and 8 to 10 h. The larger ranitidine dose reduced the renal clearances of procainamide and NAPA over the control period at each 2‐hourly time period. The reductions in renal clearance are most likely mediated by competition for the renal tubular cationic secretory pathway. Clinical implications arising from this study suggest a reduction in procainamide dosage may be necessary in a small, select number of patients with high plasma ranitidine concentrations, e.g., the elderly; furthermore, failure of therapeutic response for some drugs may be due to ranitidine‐induced impaired gastrointestinal absorption.

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“…We conclude that ischemic myocardium, a potential site of antiarrhythmic drug action, represents a progression of pharmacokinetic compartments increasingly distal from the central compartment, depending on the severity of ischemia. CircRes 46: [789][790][791][792][793][794][795] 1980 THE HEART is generally considered to be in rapid distribution equilibrium with the central pharmacokinetic compartment because it is highly perfused (Gibaldi and Perrier, 1975;Koch-Weser, 1977). However, if the rate of drug equilibration between plasma and myocardium is related to perfusion, then ischemic areas of myocardium should behave as peripheral pharmacokinetic compartments.…”

mentioning

confidence: 99%

“…THE HEART is generally considered to be in rapid distribution equilibrium with the central pharmacokinetic compartment because it is highly perfused (Gibaldi and Perrier, 1975;Koch-Weser, 1977). However, if the rate of drug equilibration between plasma and myocardium is related to perfusion, then ischemic areas of myocardium should behave as peripheral pharmacokinetic compartments.…”

mentioning

confidence: 99%

Procainamide delivery to ischemic canine myocardium following rapid intravenous administration.

Wenger

Browning

Masterton

et al. 1980

Circulation Research

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SUMMARY This study delineates the time course of procainamide accumulation in myocardium after bolus administration and its relationship to regional myocardial blood flow. The left circumflex coronary artery was ligated in 28 open-chest dogs. This was followed 40 minutes later by injection into the left atrium of labeled microspheres. 14 C-labeled procainamide, 1.5 mg/kg, was then administered as a single 1-minute infusion in 24 dogs, and four dogs were killed at each of six different times (1.5-15 minutes) after onset of drug infusion. In four additional dogs, the same dose of labeled drug was administered as a 1-minute infusion repeated every 5 minutes; after the fifth dose, the animals were killed. Myocardial sections were analyzed for regional blood flow and regional procainamide concentration. In the ischemic region, procainamide accumulated more slowly, and peak concentrations were lower than in the nonischemic region, being lowest in the most severely ischemic sections. The drug was thus distributed heterogenously through the myocardium early after bolus administration. Over time, however, this distribution became more homogenous with concentrations in nonischemic sections falling off more rapidly than in ischemic sections. Predicted steady state concentrations were achieved after 15 minutes in mildly ischemic sections (0.31-0.90 ml/min per g) but had not been reached by 25 minutes in severely ischemic sections. We conclude that ischemic myocardium, a potential site of antiarrhythmic drug action, represents a progression of pharmacokinetic compartments increasingly distal from the central compartment, depending on the severity of ischemia. CircRes 46: [789][790][791][792][793][794][795] 1980 THE HEART is generally considered to be in rapid distribution equilibrium with the central pharmacokinetic compartment because it is highly perfused (Gibaldi and Perrier, 1975;Koch-Weser, 1977). However, if the rate of drug equilibration between plasma and myocardium is related to perfusion, then ischemic areas of myocardium should behave as peripheral pharmacokinetic compartments. Depending on their blood flow, such areas might therefore be classifiable as more proximal or more distal, that is, requiring less or more time to equilibrate with the central compartment.Because ventricular premature depolarizations in patients with coronary artery disease probably originate from areas of ischemic myocardium (Waldo and Kaiser, 1973;Boineau and Cox, 1973), the sites of action of antiarrhythmic drugs may be in periph- Original manuscript received April 24, 1979; accepted for publication January 23, 1980. eral pharmacokinetic compartments. Using the R-V interval of coupled premature ventricular depolarizations as a measure of drug effect, analyzed the response of patients given repeated 1-minute infusions of procainamide every 5 minutes and observed that in most patients the drug probably continued to accumulate over the 5-minute time course. Based on those findings, they postulated that procainamide's site of action ...

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Serum Procainamide Levels As Therapeutic Guides

Cited by 40 publications

References 66 publications

Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade.

Anticholinergic effects of disopyramide and quinidine on guinea pig myocardium. Mediation by direct muscarinic receptor blockade.

Dose and concentration dependent effect of ranitidine on procainamide disposition and renal clearance in man.

Procainamide delivery to ischemic canine myocardium following rapid intravenous administration.

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