| Indication |
For the acute and maintenance treatment of major depressive
disorder (MDD), as well as acute management of generalized anxiety
disorder. Also used for the management of neuropathic pain associated
with diabetic peripheral neuropathy, and fibromyalgia. Has been used in
the management of moderate to severe stress urinary incontinence (SUI)
in women. |
| Pharmacodynamics |
Duloxetine is in a class of medications called selective
serotonin and norepinephrine reuptake inhibitors (SSNRIs) and primarily
targets major depressive disorders (MDD) and stress urinary incontinence
(SUI). Duloxetine is also used to treat pain and tingling caused by
diabetic neuropathy (damage to nerves that can develop in people who
have diabetes). Known also as LY248686, it is a potent dual inhibitor of
serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake,
possessing comparable affinities in binding to NE and 5-HT transport
sites. Interestingly, its behavior contrasts to most other dual-reuptake
inhibitors. Furthermore, duloxentine lacks affinity for monoamine
receptors within the central nervous system. |
| Mechanism of action |
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. The antidepressant and pain inhibitory actions of duloxetine
are believed to be related to its potentiation of serotonergic and
noradrenergic activity in the CNS. The mechanism of action of duloxetine
in SUI has not been determined, but is thought to be associated with
the potentiation of serotonin and norepinephrine activity in the spinal
cord, which increases urethral closure forces and thereby reduces
involuntary urine loss. |
| Absorption |
Orally administered duloxetine hydrochloride is well absorbed. |
| Volume of distribution |
|
| Protein binding |
Protein binding is greater than 90%. |
| Metabolism |
The major biotransformation pathways for duloxetine involve
oxidation of the naphthyl ring followed by conjugation and further
oxidation. Both CYP2D6 and CYP1A2 catalyze the oxidation of the naphthyl
ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine
glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. The major
circulating metabolites have not been shown to contribute significantly
to the pharmacologic activity of duloxetine. |
| Route of elimination |
Many additional metabolites have been identified in urine, some
representing only minor pathways of elimination. Most (about 70%) of the
duloxetine dose appears in the urine as metabolites of duloxetine;
about 20% is excreted in the feces. |
| Half life |
12 hours (range 8-17 hours) |
| Clearance |
Not Available |
| Toxicity |
Oral, rat LD50: 491 mg/kg for males and 279 mg/kg for
females. Symptoms of overdose include tremors, convulsions, reduced
activity, slow pupillary response, intermittent tremors, and rigidity. |
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