Lessons learnt in the pharmacokinetic analysis of the effect of haemoperfusion for acute overdose with sustained‐release diltiazem

Abstract

SummaryThe effect of charcoal haemoperfusion on the pharmacokinetics of diltiazem is described in a patient with severe clinical toxicity following acute overdose. The patient presented within 3 h following acute ingestion of multiple medications including sustained-release diltiazem. Routine resuscitation and supportive care were administered, but hypotension did not resolve despite intravenous fluids and infusions of calcium, adrenaline, noradrenaline and vasopressin. Multipledoses of activated charcoal, haemodialysis and charcoal haemoperfusion were prescribed to expedite the elimination of diltiazem. The maximum diltiazem concentration (577 lg.l )1 ) was recorded 7 h post ingestion which was followed by an erratic and prolonged elimination phase.The maximum clearance of diltiazem due to haemoperfusion was calculated to be 19.4 and 15.1 ml.min )1 at different times, equating to removal of approximately 1.5 mg diltiazem during 4 h of haemoperfusion. Haemoperfusion did not appear to remove sufficient diltiazem to recommend its routine use in the treatment of patients with acute diltiazem overdose. Severe cardiovascular depression and death is reported from self-poisoning with diltiazem. In overdose these effects manifest as bradycardia and hypotension which relates more to decreased systemic vascular resistance than cardiac contractility [1]. Standard and sustained-release formulations of diltiazem differ in their pharmacokinetic profile. Acute poisoning with the standard formulation usually leads to a rapid onset of toxicity which largely resolves within 12 h. This differs from the more frequently used sustainedrelease formulation where toxicity is delayed in onset and prolonged [1,2]. For example, in two recent cases only mild hypotension preceded the development of a cardiac arrest more than 13 and 18 h post ingestion [3,4]. The variable time-course of toxicity relates to unpredictable changes in the concentration of diltiazem. This may reflect erratic absorption from an aggregate of sustainedrelease tablets [2], or dose-related factors such as ileus [5][6][7] or changes in clearance due to enzyme saturation or hepatic hypoperfusion with marked hypotension [1,8].The initial management of acute diltiazem poisoning includes gastrointestinal decontamination and the administration of intravenous fluids and calcium. Unfortunately, many cases are refractory to these first-line treatments, requiring other interventions, including atropine, glucagon, vasopressors, temporary pacing, balloon pump,

Transmembrane pH-Gradient Liposomes To Treat Cardiovascular Drug Intoxication

“…This implies that DTZ is highly distributed in tissues and only a small fraction circulates in the blood. The DTZ metabolite DAD possesses around 25−50% of the pharmacological activity of the parent drug. , It is produced by lung, liver, and blood esterases. − Its PK profile in rats is similar to that of DTZ, with high V d and rapid plasmatic clearance (Cl). ,, The large V d , combined with high plasma protein binding (70−80%) of DTZ and DAD, explains the inadequacy of conventional hemodialysis and hemoperfusion detoxification techniques . It also justifies the need for effective circulating colloidal detoxifying agents to limit distribution toward the peripheral compartments .…”

Molecular adsorbent recirculating system (MARS) and continuous veno-venous hemodiafiltration (CVVHDF) for diltiazem removal: An in vitro study

“…20 These observations corroborate clinical studies highlighting a good efficacy for both systems. 16,21 Diltiazem concentration with CVVHDF system decreased to 49 and 311 μg/L, proportionally to the initial concentration of 631 and 4708 µg/L, respectively, reaching a plateau after 2 h of experiment. In the same way, EC decreases quickly during the first hour, regardless to the initial concentration.…”

“…In our context, adsorption is an important mechanism responsible for the purification. Roberts et al 21 documented a case with a hemodialysis treatment of a patient following a diltiazem poisoning. Hemodialysis provided a net decrease in the blood concentration of diltiazem despite no marked improvement in the patient clinical condition.…”

Treatment of Severe Amlodipine Toxicity With Molecular Adsorbent Recirculating System

“…Four cases have been published in which plasmapheresis was performed on adults with calcium channel blocker overdose to decrease drug concentrations and improve hemodynamics 9, 10, 11. Case reports exist for hemoperfusion, 12 charcoal hemoperfusion, 13 and continuous venovenous hemodiafiltration 14, 15…”