Morphine is 90% metabolized by glucuronidation by UGT2B7 and sulfation at positions 3 and 6. Morphine can also be metabolized to codeine, normorphine, and morphine ethereal sulfate.
/Heroin/ is converted metabolically by ester hydrolysis first to 6-monoacetylmorphine (heroin-specific metabolite) and then to morphine by hydrolysis for the second acetate ester. When the heroin base enters the body, it is fairly lipophilic, so a portion of the dose readily crosses the blood-brain barrier into the central nervous system where the hydrolysis of the two esters can take place. Morphine is less lipophilic than heroin and does not cross back across the blood-brain barrier as readily. Morphine readily undergoes the additional phase I metabolic transformation of oxidative N-demethylation by CYP2D6. Phase II (conjugation) reactions of morphine include formation of the glucuronide conjugates at the hydroxyl moieties at positions 3 and 6. The glucuronides are then excreted. Note that the aromatic ring stays intact throughout the metabolic transformations, illustrating the stability imparted by aromaticity.
Morphine is metabolized principally in the liver and undergoes conjugation with glucuronic acid principally at the 3-hydroxyl group. Secondary conjugation also occurs at the 6-hydroxyl group to form the 6-glucuronide, which is pharmacologically active, and to a limited extent the 3,6-diglucuronide. Plasma concentrations of the 3-glucuronide, which is inactive, and the 6-glucuronide substantially exceed those of unchanged drug, and the latter metabolite appears to contribute substantially to the drug's pharmacologic activity. Elimination of the drug may be reduced substantially in neonates compared with older children and adults. Morphine is excreted in urine mainly as morphine-3-glucuronide. In addition to the 3,6-diglucuronide, other minor metabolites that have been described includes normorphine and the 3-ethereal sulfate. ... In patients with renal impairment, accumulation of morphine-6-glucuronide occurs, which can result in enhanced and prolonged opiate activity.
The major pathway for the metabolism of morphine is conjugation with glucuronic acid. The two major metabolites formed are morphine-6-glucuronide and morphine-3-glucuronide. Small amounts of morphine-3,6-diglucuronide also may be formed.
IDENTIFICATION AND USE: Morphine is white and crystalline solid. It is an opiate agonist used, often in the form of its sulfate salt, to relieve severe, acute pain or moderate to severe, chronic pain. The drug is also used parenterally as a supplement for analgesia during labor. Morphine is the drug of choice in relieving pain of myocardial infarction. It may be used in veterinary care as an analgesic (narcotic), preanesthetic, antitussive, and antiperstaltic. HUMAN EXPOSURE AND TOXICITY: Morphine sulfate misuse is essentially observed among regular heroin injectors. The most serious adverse effect of morphine is respiratory depression. Constipation is a common side effect. In patients with myocardial infarction, morphine causes a decrease in systemic vascular resistance which may result in a transient fall in systemic arterial pressure leading to severe hypotension. Morphine should be used with caution in patients with toxic psychoses. Several manufacturers recommended that morphine sulfate should not be used in patients with known or suspected paralytic ileus. All opioid analgesics are metabolized by the liver and should be used with caution in patients with hepatic disease because increased bioavailability after oral administration of cumulative effects may occur. Morphine has the potential to precipitate or exacerbate asthmatic attacks and should be avoided in patients with a history of asthma. An increased fracture risk is seen in users of morphine and opiates. The reason for this may be related to the risk of falls due to central nervous system effects such as dizziness. Low-dose morphine analgesia received during neonatal intensive care was associated with early alterations in cerebral structure and short-term neurobehavioral problems that did not persist into childhood. ANIMAL STUDIES: The clinical signs associated with morphine intoxication in animals differ from those in man. While humans usually die in coma, animals die during or after a series of convulsion. Intoxicated dogs show signs of vomition, delirium, clonic spasms and stertorous breathing. In the cat, a hypnotic effect is rarely seen, the action being that of motor excitement. Reversible lens opacities developed in mice, rats, and guinea pigs in less than an hour after administration of morphine, which has been explained by a reduction in blinking, a resultant exposure of the cornea, increased evaporation, and dehydration of the anterior segment of the eye, causing temporary loss of transparency. A study with rats pointed out the risk of hepatic damage due to long term usage of morphine via disturbance of oxidant-antioxidant balance. Morphine might increase testicular cell apoptosis and reduce sperm concentration by upregulating the expressions of Bax and Caspase-3 in the rat model of morphine tolerance. In the newborn rat, morphine causes profound respiratory depression. In a mouse study, opioid receptors were spatiotemporally expressed in the uterus during the peri-implantation period. It was further observed, that although systemic morphine treatment exerts no apparent adverse influence on preimplantation ovarian secretion of progesterone and estrogen, the aberrant activation of opioid signaling by morphine induces impaired luminal epithelial differentiation, decreased stromal cell proliferation, and poor angiogenesis, and thus hampers uterine receptivity and embryo implantation. In a rat study, swimming exercise was found to be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence. In another rat study, results suggested that prior morphine exposure can increase abuse liability of subsequent morphine treatments even when that morphine exposure occurs in the context of a pain state. ECOTOXICITY STUDIES: Opioids are considered as emerging contaminants in aquatic ecosystems. Mussels were exposed to morphine for 14 days. Morphine reduced the lysosome membrane stability of bivalves, and induced significant changes in the activity of antioxidant enzymes as well as lipid peroxidation levels. Slight increase in primary DNA fragmentation was noticed, while no fixed genetic damage and alterations of the filtering rate were found.
The precise mechanism of the analgesic action of morphine is unknown. However, specific CNS opiate receptors have been identified and likely play a role in the expression of analgesic effects. Morphine first acts on the mu-opioid receptors. The mechanism of respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to increases in carbon dioxide tension and to electrical stimulation.
It has been shown that morphine binds to and inhibits GABA inhibitory interneurons. These interneurons normally inhibit the descending pain inhibition pathway. So, without the inhibitory signals, pain modulation can proceed downstream.
Therapy with morphine has not been linked to serum enzyme elevations. Hepatitis B and C are common among persons with opiate addiction and illicit injection drug use, but the opiates themselves appear to have little hepatotoxic potential. There have been no convincing cases of idiosyncratic acute, clinically apparent liver injury attributed to morphine. Morphine has little hepatic metabolism and is generally excreted unchanged in the urine, perhaps accounting for their relative lack of hepatotoxicity.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of morphine are given in the Overview section of the Opioids.
Drug Class: Opioids
Morphine is absorbed in the alkaline environments of the upper intestine and rectal mucosa. The bioavailability of morphine is 80-100%. There is significant first-pass metabolism, therefore oral doses are 6 times larger than parenteral doses to achieve the same effect. Morphine reaches steady-state concentrations after 24-48 hours. Parenteral morphine has a Tmax of 15 minutes and oral morphine has a Tmax of 90 minutes, with a Cmax of 283nmol/L. The AUC of morphine is 225-290nmol\*h/L.
70-80% of an administered dose is excreted within 48 hours. Morphine is predominantly eliminated in the urine with 2-10% of a dose recovered as the unchanged parent drug. 7-10% of a dose of morphine is eliminated in the feces.
Morphine crosses the placenta at term. ... Pregnant patients in labor clear the parent compound almost twice as fast. Infants younger than 1 month of age have prolonged half-life of morphine compared to older children. The clearance of morphine approaches adult values in the second month of life. The milk to plasma ratio of morphine is 2.5:1. Although significant infant plasma levels may develop, breast-feeding can usually be performed safely. A breast-feeding infant may absorb 0.8% to 12% of the maternal dose.
The invention relates to novel 3-amino pyrrolidine derivatives, as well as methods for modulating calcium channel activity and for treating conditions associated with calcium channel function. In particular, the compounds generally contain at least one benzhydril moiety, and are useful in treating conditions which benefit from blocking calcium ion channels.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[EN] HYBRID MU OPIOID RECEPTOR AND NEUROPEPTIDE FF RECEPTOR BINDING MOLECULES, THEIR METHODS OF PREPARATION AND APPLICATIONS IN THERAPEUTIC TREATMENT<br/>[FR] RÉCEPTEUR D'OPIOÏDE MU HYBRIDE ET MOLÉCULES DE LIAISON DE RÉCEPTEUR DE NEUROPEPTIDE FF, LEURS PROCÉDÉS DE PRÉPARATION ET D'APPLICATIONS DANS UN TRAITEMENT THÉRAPEUTIQUE
申请人：CENTRE NAT RECH SCIENT
公开号：WO2019170919A1
公开（公告）日：2019-09-12
The present invention relates to molecules binding the mu opioid receptor (MOR) and the neuropeptide FF receptor (NPFFR) and in particular molecules having a MOR agonist and NPFFR modulatory activity. The present invention relates to pharmaceutical compositions, and in particular useful in the treatment of pain and/or hyperalgesia.
