Duloxetine
生产企业：Eli lilly and co
Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence.
Duloxetine is a serotonin norepinephrine reuptake inhibitor used to treat generalized anxiety disorder, neuropathic pain, osteoarthritis, and stress incontinence.
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT, 5-HT, and α adrenergic receptors. 5-HT and α are both G coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT, 5-HT, 5-HT, 5-HT, 5-HT, α-adrenergic, and α-adrenergic receptors. 5-HT, 5-HT, and α-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT and α receptors are G/G coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α receptors predominates, vasoconstriction results as the G coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction.
Indicated for: 1) Management of Major Depressive Disorder. 2) Management of Generalized Anxiety Disorder. 3) Management of diabetic peripheral neuropathy. 4) Management of fibromyalgia. 5) Management of chronic musculoskeletal pain. 6) Management of osteoarthritis of the knee in adults. 7) Management of chronic lower back pain in adults. 8) Management of stress urinary incontinence in adult women. Off-label uses include: 1) Management of chemotherapy-induced peripheral neuropathy. 2) Management of stress urinary incontinence in adult men after prostatectomy until recovery is complete.
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