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document
Pharmacokinetics and pharmacodynamics of intravenous diltiazem in patients with atrial fibrillation or atrial flutter . BACKGROUND Diltiazem , a calcium channel blocker , has been shown to be safe and effective in the treatment of patients in atrial fibrillation and/or atrial flutter . However , there have been no pharmacokinetic/pharmacodynamic studies of diltiazem in these patients . METHODS AND RESULTS The pharmacokinetics and pharmacodynamics of intravenous diltiazem were determined in 32 patients with atrial fibrillation or atrial flutter ( mean +/- SD age , 66 +/- 7 years ; mean baseline heart rate , 131 +/- 10 beats per minute ) after 20 mg or 20 mg followed by 25-mg bolus doses and a 10 and 15 mg/hr infusion for 24 hours . After the 10 and 15 mg/hr infusions of diltiazem , mean +/- SD elimination half-life was 6.8 +/- 1.8 and 6.9 +/- 1.5 hours , volume of distribution was 411 +/- 151.8 and 299 +/- 70.8 I , and systemic clearance was 42 +/- 12.4 and 31 +/- 8.3 l/hr , respectively . Percentages of the plasma concentrations of the principal metabolites desacetyldiltiazem and N-desmethyldiltiazem to diltiazem were < 15 % and < 10 % , respectively . Thirty of 32 patients maintained response throughout the 24-hour infusion of diltiazem . Using a sigmoidal Emax pharmacodynamic model , a strong relation ( mean +/- SD r2 , 0.78 +/- 0.2 ) was observed between plasma diltiazem concentration and percent heart rate reduction . Mean +/- SD Emax ( maximum percent reduction in heart rate from baseline ) and EC50 ( plasma diltiazem concentration that achieves half Emax ) were 52 +/- 17 % and 110 +/- 84 ng/ml , respectively . The model predicts that mean plasma diltiazem concentration of 79 , 172 , and 294 ng/ml are required to produce a 20 % , 30 % , and 40 % reduction in heart rate , respectively . A relation between plasma diltiazem concentration and percent change in systolic blood pressure ( SBP ) or diastolic blood pressure ( DBP ) from baseline was not observed ( mean +/- SD r2 , SBP/DBP : 0.35 +/- 0.24/0.36 +/- 0.2 ) . There were no untoward side effects observed . CONCLUSIONS First , the pharmacokinetics of diltiazem in patients with atrial fibrillation or atrial flutter is nonlinear with an apparent dose-dependent decrease in systemic clearance with increasing infusion rate . Second , using a sigmoidal Emax model , there is a strong relation between plasma diltiazem concentration and percent heart rate reduction . Third , the plasma concentrations of the principal metabolites desacetyldiltiazem and N-desmethyldiltiazem are low and are not expected to contribute significantly to the pharmacodynamics of intravenous diltiazem in these patients .
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Intervention_Pharmacological
diltiazem
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Intervention_Pharmacological
Diltiazem
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Intervention_Pharmacological
intravenous diltiazem
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Intervention_Pharmacological
diltiazem
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Intervention_Pharmacological
diltiazem
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Outcome_Physical
Percentages of the plasma concentrations of the principal metabolites desacetyldiltiazem and N-desmethyldiltiazem to diltiazem
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Outcome_Physical
plasma diltiazem concentration
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Outcome_Physical
percent heart rate reduction
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Outcome_Physical
EC50
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Outcome_Physical
plasma diltiazem concentration
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Outcome_Physical
heart rate
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Outcome_Physical
systolic blood pressure ( SBP )
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Outcome_Physical
diastolic blood pressure ( DBP )
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Participant_Condition
patients with atrial fibrillation or atrial flutter .
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Participant_Condition
patients in atrial fibrillation and/or atrial flutter .