Controlled Release Drugs in Overdose Clinical Considerations

Abstract

The main characteristic of overdose with controlled release formulations is the delay in presentation and onset of clinical effects. There is a prolonged absorption phase which leads to a delayed time to maximum plasma concentration and usually a prolonged time with levels close to the peak concentration. Absorption may continue for more than 24 hours. Overdose with controlled release formulations of toxic drugs therefore requires a longer period of observation as the onset of symptoms may be as late as 16 to 20 hours after ingestion. Treatment nomograms calculated for standard formulations are not appropriate for controlled release formulations. The optimal gastrointestinal decontamination method is controversial, but in serious overdoses it should include gastric lavage and activated charcoal followed by whole bowel irrigation as a means of clearing whole tablets from the gastrointestinal tract. Pharmacobezoar formation should be suspected if, despite apparently effective gastrointestinal decontamination, there is evidence of continuing absorption. These are best diagnosed with endoscopy and the treatment options include endoscopic removal, whole bowel irrigation and surgery.

Endoscopic removal of slow release clomipramine bezoars in two cases of acute poisoning

“…If the case history or clinical findings give reason to suspect the presence of a bezoar, or if an aggregate of radio-opaque tablets is evident on x-ray, acute gastroscopy may be considered. In this situation, endoscopy is of diagnostic value (2)(3)(4)(5)(6)(7)(8) and might also provide a treatment option (2,3,6). However, the presence of a pharmacobezoar does not always necessitate its removal and endoscopy may in some cases carry an unacceptable risk/benefit ratio (4).…”

Découverte fortuite d’une intoxication aiguë par vérapamil forme à libération prolongée : intérêt du criblage toxicologique

“…Pour les formes LP, le pic de concentration est atteint en 6 h et la demi-vie d'élimination du vérapamil est d'environ 11 h. L'allongement s'explique principalement par la formation de pharmaco-bezoards ou bezoards médicamenteux. Les pharmaco-bezoards sont composés du médicament et/ou de son véhicule et sont retrouvés dans le tractus digestif et entraî-nent un allongement de la phase d'absorption du médicament [21]. Le vérapamil sous sa forme LP est connu pour induire la formation de pharmaco-bezoards [21,22].…”

“…Les pharmaco-bezoards sont composés du médicament et/ou de son véhicule et sont retrouvés dans le tractus digestif et entraî-nent un allongement de la phase d'absorption du médicament [21]. Le vérapamil sous sa forme LP est connu pour induire la formation de pharmaco-bezoards [21,22]. Ainsi, des concré-tions de vérapamil ont été retrouvées dans le contenu gastrique lors d'une autopsie réalisée 60 h après admission chez une patiente ayant ingéré des quantités non connues de vérapamil et d'opipramol [23].…”

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

“…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].…”