Management of Opioid Analgesic Overdose
To the Editor: Boyer (July 12 issue)(1) reports that use of naloxone to treat opioid overdose is logical because it is a direct antagonist of mu opioid receptors. Other strategies for treating opioid-induced respiratory depression and oversedation are now plausible and should be developed as alternatives to single-drug therapy with naloxone. Ampakines, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor agonists, have been shown in clinical studies to effectively antagonize opioid-induced respiratory depression.(2) Dopaminergic agonists act directly in the respiratory centers to enhance respiration(3) and presumably in the mesocortical pathways to induce arousal. Administration of amantadine is a common practice for enhancing arousal in . . .
Available from: Mladen V. Tzvetkov
- "Severe respiratory depression is observed after morphine overdose or in the case of extremely high metabolizing rates of codeine to morphine  . Amplification of the CYP2D6 gene was assumed to be the cause of some cases of death from respiratory depression after codeine administration      . "
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ABSTRACT: We investigated whether morphine and its pro-drug codeine are substrates of the highly genetically polymorphic organic cation transporter OCT1 and whether OCT1 polymorphisms may affect morphine and codeine pharmacokinetics in humans. Morphine showed low transporter-independent membrane permeability (0.5×10(-6)cm/s). Morphine uptake was increased up to 4-fold in HEK293 cells overexpressing human OCT1. The increase was concentration-dependent and followed Michaelis-Menten kinetics (KM=3.4μM, VMAX=27pmol/min/mg protein). OCT1-mediated morphine uptake was abolished by common loss-of-function polymorphisms in the OCT1 gene and was strongly inhibited by drug-drug interactions with irinotecan, verapamil and ondansetron. Morphine uptake in primary human hepatocytes was strongly reduced by MPP(+), an inhibitor of organic cation transporters, and morphine was not a substrate of OCT3, the other organic cation transporter expressed in human hepatocytes. In concordance with the in vitro data, morphine plasma concentrations in healthy volunteers were significantly dependent on OCT1 polymorphisms. After codeine administration, the mean AUC of morphine was 56% higher in carriers of loss-of-function OCT1 polymorphisms compared to non-carriers (P=0.005). The difference remained significant after adjustment for CYP2D6 genotype (P=0.03). Codeine itself had high transporter-independent membrane permeability (8.2×10(-6)cm/s). Codeine uptake in HEK293 cells was not affected by OCT1 overexpression and OCT1 polymorphisms did not affect codeine AUCs. In conclusion, OCT1 plays an important role in the hepatocellular uptake of morphine. Carriers of loss-of-function OCT1 polymorphisms may be at higher risk of adverse effects after codeine administration, especially if they are also ultra-rapid CYP2D6 metabolizers.
Biochemical pharmacology 07/2013; 86(5). DOI:10.1016/j.bcp.2013.06.019 · 5.01 Impact Factor
Journal of medical toxicology: official journal of the American College of Medical Toxicology 03/2014; 10(3). DOI:10.1007/s13181-014-0394-3
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