does pushing morphine hasten death in terminal patients

The major morphine metabolite, morphine-3-glucuronide (M3G), although analgesically inactive, has been reported to antagonize morphine and to produce stimulatory effects, such as myoclonus, seizure and allodynia (Smith 2000). ( 2008) have recently supported the hypothesis that a common UGT2B7 haplotype (comprised of 10 SNPs) increases enzyme activity by regulating mRNA expression this might explain part of the phenotypic variability in the pharmacokinetics and pharmacodynamics of UGT2B7 substrates (Innocenti et al. For example, a promoter variant of UGT2B7 gene is associated with significantly reduced glucuronidation of morphine in sickle cell disease and contributes to the variability observed in the hepatic clearance of morphine in patients. UGT2B7 variants have been shown to be related to altered drug metabolism and disease risk (Di et al. UGT2B subfamily includes 7 genes as well as 5 pseudogenes. UGT2A1 and UGT2A2 proteins arise by the differential splicing of a variable first exon to the same set of 5 downstream exons. UGT2A3, which is coded by a single gene of 6 exons, and UGT2A1 and UGT2A2, which share the same C-terminal sequence but have differing N-terminal sequences. The UGT2A subfamily includes 3 members, i.e. The UGT2 family members (subdivided into UGT2A and 2B) derive from transcription of separate genes located on chromosome 4q13. Morphine-3- and morphine-6-glucuronidation by UGT2B7 hydrophilicity, lipophilicity, hydrogen bonding potential) largely determine their passive transport across the BBB, through hydrophilic paracellular and lipophilic transcellular transport. The physical-chemical characteristics of drugs (e.g. Before drugs enter the central nervous system (CNS), enzymes can transform them into metabolites that can be more or less effective or even toxic. Systemic metabolism of drugs takes place mainly in the liver but it can also occur during BBB transport, because many enzymes are present in the brain capillaries (Minn et al. However, it has been observed that many plasma binding proteins (albumin, alpha-acid-glycoprotein, globulins, high-density lipoprotein, low-density lipoprotein) can “donate” ligands to the BBB (De Boer et al.

Plasma-protein binding controls both the free (unbound) fraction of drugs/compounds and their distribution in the blood these two factors influence the amount of drugs/compounds able to pass the BBB. 1997).ĭrug transport to the brain depends on various parameters: for drugs that can easily pass the BBB, local blood flow and capillary flow area are limiting factors, whereas for other drugs BBB permeability is restrictive. Even with minimal disruption of the BBB, circulating neurotoxins, hormones and ions could enter the brain and interfere with the internal milieu, thus resulting in potential damage to neurons (Johansson et al. It can be considered as an organ protecting the brain: its integrity is essential for brain homeostasis, and many carrier-/receptor-mediated transport systems play an important role in maintaining this integrity. It eliminates (toxic) substances from the endothelial compartment and supplies the brain with nutrients and other (endogenous) compounds. The blood-brain barrier (BBB) is a dynamic interface between the blood and the brain.

Does pushing morphine hasten death in terminal patients