Kinetics of Disopyramide after Intravenous Infusion to Patients with Myocardial Infarction and Heart Failure

Abstract

Total body clearance, half‐life and volume of distribution of disopyramide (Norpace, Searle G.D.) was measured during a six to eight hour infusion to steady state in twenty four patients with either congestive heart failure or acute myocardial infarction and compared to eleven patients without these diseases. All patients were given a bolus injection of 150 mg disopyramide followed by a continuous infusion of 18–24 mg per hour. Serum concentration of disopyramide and its main dealkylated metabolite were determined by HPLC. The clearance in patients without myocardial infarction or congestive heart failure was 1.71 ± 0.60 ml/min./kg (X̂ ± S.D.), not significantly different from those who had either myocardial infarction, congestive heart failure or both. Half‐life was 798 min. in patients without heart failure, not significantly different from the values in the other groups. The ratio between disopyramide and its metabolite varied between 3 to 10. Twentysix % of the steady state serum concentrations of disopyramide were outside the recommended therapeutic range (2–5 μg/ml), but no adverse haemodynamic effects were observed in any of the patients. The suggested dosage regimen of disopyramide seems to result in a satisfactory response.

The influence of heart failure on the pharmacokinetics of cardiovascular and non‐cardiovascular drugs: a critical appraisal of the evidence

“…A total of 59 studies (49 on cardiovascular drugs) investigating 36 drugs (31 cardiovascular) were identified (Tables ). Twelve studies were published in the period 1970–1979 , 20 in the period 1980–1989 , 12 in the period 1990–1999 , 10 in the period 2000–2009 , and five in the period 2010–2018 .…”

“…A total of 59 studies (49 on cardiovascular drugs) investigating 36 drugs (31 cardiovascular) were identified (Tables 1-6). Twelve studies were published in the period 1970-1979 [37][38][39][40][41][42][43][44][45][46][47][48], 20 in the period 1980-1989 [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68], 12 in the period 1990-1999 [69][70][71][72][73][74][75][76][77][78][79][80], 10 in the period 2000-2009 [81][82][83][84][85]…”

“…The contrasting results reported in studies investigating digoxin [37,49,69,81,91,92], bumetanide [51,53], furosemide [38,52,53], lidocaine [42,43,60], mexiletine [61,86] and procainamide [44,[62][63][64]75] might be, at least partly, due to differences in study design and/or participant clinical and demographic characteristics. The available knowledge regarding the pharmacokinetics in HF of other drugs, such as enoximone [50], levosimendan [73], hydroflumethiazide [39], metolazone [40], carvedilol [82], metoprolol [83], nifedipine [54], bosentan [93], hydralazine [55], nicorandil [84], cibenzoline [58], disopyramide [59], ibutilide [85], enalapril [66], fosinopril [77], irbesartan [88], lisinopril [67], perindopril [87], conivaptan [89], tolvaptan [94], dabigatran [95] and darbopoetin [90] is based on results from single studies. However, the data on enoximone, reduced clearance and increased half-life in HF, ...…”

“…In the studies investigating hydroflumethiazide, carvedilol, lisinopril and perindopril, there was a marked age difference, not accounted for in statistical analysis, between HF patients and controls [39,67,82,87]. Furthermore, a significant number of these studies did not provide information regarding the NYHA functional class [40,54,59,67,82,89], age [40,50,54,83,84,89,90,93,95], sex [50,54,59,67,83,89,[93][94][95] or presence of significant renal or hepatic impairment [39,40,50,54,84,87,90,95]. Therefore, it is not possible to clearly establish whether the findings from these studies are directly relevant to the management of HF patients with specific clinical and demographic characteristics.…”

“…Seven antiarrhythmics (cibenzoline, disopyramide, ibutilide, lidocaine, mexiletine, procainamide and quinidine) were investigated in 17 studies (Table 4). No significant differences in the pharmacokinetics of cibenzoline, disopyramide and ibutilide were observed between HF patients and controls with preserved renal and liver function [58,59,85]. Studies on lidocaine reported a significant reduction in volume of distribution (À33%) and clearance (between À36% and À37%) and a significantly longer elimination half-life (between +62% and +628%) in HF patients [42,43,60].…”