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药品详细

Paroxetine(帕罗西汀)

化学结构式图
中文名
帕罗西汀
英文名
Paroxetine
分子式
C19H20FNO3
化学名
(3S,4R)-3-[(2H-1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine
分子量
Average: 329.3654
Monoisotopic: 329.142721716
CAS号
61869-08-7
ATC分类
N06A 未知
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Paroxetine hydrochloride and paroxetine mesylate belong to a class of antidepressant agents known as selective serotonin-reuptake inhibitors (SSRIs). Despite distinct structural differences between compounds in this class, SSRIs possess similar pharmacological activity. As with other antidepressant agents, several weeks of therapy may be required before a clinical effect is seen. SSRIs are potent inhibitors of neuronal serotonin reuptake. They have little to no effect on norepinephrine or dopamine reuptake and do not antagonize α- or β-adrenergic, dopamine D2 or histamine H1 receptors. During acute use, SSRIs block serotonin reuptake and increase serotonin stimulation of somatodendritic 5-HT1A and terminal autoreceptors. Chronic use leads to desensitization of somatodendritic 5-HT1A and terminal autoreceptors. The overall clinical effect of increased mood and decreased anxiety is thought to be due to adaptive changes in neuronal function that leads to enhanced serotonergic neurotransmission. Side effects include dry mouth, nausea, dizziness, drowsiness, sexual dysfunction and headache (see Toxicity section below for a complete listing of side effects). Side effects generally occur during the first two weeks of therapy and are usually less severe and frequent than those observed with tricyclic antidepressants. Paroxetine hydrochloride and mesylate are considered therapeutic alternatives rather than generic equivalents by the US Food and Drug Administration (FDA); both agents contain the same active moiety (i.e. paroxetine), but are formulated as different salt forms. Clinical studies establishing the efficacy of paroxetine in various conditions were performed using paroxetine hydrochloride. Since both agents contain the same active moiety, the clinical efficacy of both agents is thought to be similar. Paroxetine may be used to treat major depressive disorder (MDD), panic disorder with or without agoraphobia, obsessive-compulsive disorder (OCD), social anxiety disorder (social phobia), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD) and premenstrual dysphoric disorder (PMDD). Paroxetine has the most evidence supporting its use for anxiety-related disorders of the SSRIs. It has the greatest anticholinergic activity of the agents in this class and compared to other SSRIs, paroxetine may cause greater weight gain, sexual dysfunction, sedation and constipation.

生产厂家
  • Actavis elizabeth llc
  • Alphapharm pty ltd
  • Apotex inc
  • Aurobindo pharma ltd
  • Caraco pharmaceutical laboratories ltd
  • Glaxosmithkline
  • Mylan pharmaceuticals inc
  • Noven therapeutics llc
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa
  • Teva pharmaceuticals usa inc
  • Zydus pharmaceuticals usa inc
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Baldwin DS, Anderson IM, Nutt DJ, Bandelow B, Bond A, Davidson JR, den Boer JA, Fineberg NA, Knapp M, Scott J, Wittchen HU: Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2005 Nov;19(6):567-96. Pubmed
  2. Baldwin D, Bobes J, Stein DJ, Scharwachter I, Faure M: Paroxetine in social phobia/social anxiety disorder. Randomised, double-blind, placebo-controlled study. Paroxetine Study Group. Br J Psychiatry. 1999 Aug;175:120-6. Pubmed
  3. Yonkers KA, Gullion C, Williams A, Novak K, Rush AJ: Paroxetine as a treatment for premenstrual dysphoric disorder. J Clin Psychopharmacol. 1996 Feb;16(1):3-8. Pubmed
  4. Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier B: Effect of SSRI antidepressants on ejaculation: a double-blind, randomized, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine, and sertraline. J Clin Psychopharmacol. 1998 Aug;18(4):274-81. Pubmed
  5. Waldinger MD, Zwinderman AH, Olivier B: SSRIs and ejaculation: a double-blind, randomized, fixed-dose study with paroxetine and citalopram. J Clin Psychopharmacol. 2001 Dec;21(6):556-60. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Phenylpiperidines
Substructures
  • Acetals and Derivatives
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Ethers
  • Benzene and Derivatives
  • Phenylpiperidines
  • Dioxoles
  • Hydroquinones
  • Catechols
  • Halobenzenes
  • Heterocyclic compounds
  • Aromatic compounds
  • Benzodioxoles
  • Anisoles
  • Phenylpropylamines
  • Aryl Halides
  • Phenyl Esters
  • Piperidines
适应症
药理
Indication Labeled indications include: major depressive disorder (MDD), panic disorder with or without agoraphobia, obsessive-compulsive disorder (OCD), social anxiety disorder (social phobia), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and premenstrual dysphoric disorder (PMDD). Unlabeled indications include: eating disorders, impulse control disorders, vasomotor symptoms of menopause, obsessive-compulsive disorder (OCD) in children, and mild dementia-associated agitation in nonpsychotic individuals.
Pharmacodynamics Paroxetine, an antidepressant drug of the selective serotonin reuptake inhibitor (SSRI) type, has no active metabolites and has the highest specificity for serotonin receptors of all the SSRIs. It is used to treat depression resistant to other antidepressants, depression complicated by anxiety, panic disorder, social and general anxiety disorder, obsessive-compulsive disorder (OCD), premenstrual dysphoric disorder, premature ejaculation, and hot flashes of menopause in women with breast cancer.
Mechanism of action Paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake. Paroxetine likely inhibits the reuptake of serotonin at the neuronal membrane, enhances serotonergic neurotransmission by reducing turnover of the neurotransmitter, therefore it prolongs its activity at synaptic receptor sites and potentiates 5-HT in the CNS; paroxetine is more potent than both sertraline and fluoxetine in its ability to inhibit 5-HT reuptake. Compared to the tricyclic antidepressants, SSRIs have dramatically decreased binding to histamine, acetylcholine, and norepinephrine receptors.
Absorption Paroxetine hydrochloride is slowly, but completely absorbed following oral administration. The oral bioavailability appears to be low due to extensive first-pass metabolism. Paroxetine hydrochloride oral tablets and suspension are reportedly bioequivalent. Paroxetine mesylate is completely following oral administration. Absorption of either salt form is not substantially affected by food.
Volume of distribution

3.1-28 L/kg observed in animal studies
Protein binding ~ 95% bound to plasma proteins.
Metabolism
Paroxetine is extensively metabolized, likely in the liver. The main metabolites are polar and conjugated products of oxidation and methylation, which are readily eliminated by the body. The predominant metabolites are glucuronic acid and sulfate conjugates. Paroxetine metabolites do not possess significant pharmacologic activity (less than 2% that of parent compound). Paroxetine is metabolized by cytochrome P450 (CYP) 2D6. Enzyme saturation appears to account for the nonlinear pharmacokinetics observed with increasing dose and duration of therapy.
Route of elimination Paroxetine is extensively metabolized and the metabolites are primarily excreted in the urine and to some extent in the feces.
Half life 21-24 hours
Clearance Not Available
Toxicity LD50=500mg/kg (orally in mice). Symptoms of overdose include: coma, dizziness, drowsiness, facial flushing, nausea, sweating, tremor, vomiting. Side effects include: nervous system effects such as asthenia, somnolence, dizziness, insomnia, tremor, and nervousness; GI effects such as nausea, decreased appetite, constipation, diarrhea, and dry mouth; impotence, ejaculatory dysfunction (principally ejaculatory delay), and other male genital disorders; female genital disorders (principally anorgasmia or difficulty reaching climax/orgasm); and sweating. Discontinuation syndrome may occur with abrupt withdrawal. Symptoms of discontinuation syndrome include flu-like symptoms, insomnia, nausea, imbalance, sensory changes, and hyperactivity.
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 129-131 °C Not Available
logP 3.6 Not Available
Predicted Properties
Property Value Source
water solubility 8.53e-03 g/l ALOGPS
logP 3.1 ALOGPS
logP 3.15 ChemAxon
logS -4.6 ALOGPS
pKa (strongest basic) 9.77 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 4 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 39.72 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 88.02 ChemAxon
polarizability 34.48 ChemAxon
药物相互作用
Drug Interaction
Acenocoumarol The SSRI, paroxetine, increases the effect of the anticoagulant, acenocoumarol.
Almotriptan Increased risk of CNS adverse effects
Amphetamine Risk of serotoninergic syndrome
Anisindione The SSRI, paroxetine, increases the effect of the anticoagulant, anisindione.
Asenapine Paroxetine is a substrate of CYP2D6 and concomitant therapy with asenapine (CYP2D6 inhibitor) increases concentrations of paroxetine 2-fold. May require dosing adjustments.
Atomoxetine The CYP2D6 inhibitor, paroxetine, may increase the effect and toxicity of atomoxetine.
Benzphetamine Amphetamines may enhance the adverse/toxic effect of Serotonin Modulators. The risk of serotonin syndrome may be increased. Monitor patients closely for signs and symptoms of serotonin syndrome (e.g., agitation, tremor, tachycardia, etc.) when using amphetamines and serotonin modulators in combination.
Carvedilol The SSRI, paroxetine, may increase the bradycardic effect of the beta-blocker, carvedilol.
Desvenlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Dexfenfluramine Risk of serotoninergic syndrome
Dextroamphetamine Risk of serotoninergic syndrome
Dextromethorphan Combination associated with possible serotoninergic syndrome
Dicumarol The SSRI, paroxetine, increases the effect of anticoagulant, dicumarol.
Diethylpropion Risk of serotoninergic syndrome
Dihydrocodeine Opioid analgesics may enhance the 5HT effects of SSRIs to cause serotonin syndrome. It is recommended to monitor therapy.
Eletriptan Increased risk of CNS adverse effects
Fenfluramine Risk of serotoninergic syndrome
Frovatriptan Increased risk of CNS adverse effects
Galantamine Paroxetine increases the effect and toxicity of galantamine
Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Iloperidone Paroxetine is a strong CYP2D6 inhibitor that increases serum concentration of iloperidone and likelihood of observing adverse effects such as QT prolongation. Reduce dose of iloperidone by 50%
Isocarboxazid Possible severe adverse reaction with this combination
Ketoprofen Concomitant therapy may result in additive antiplatelet effects and increase the risk of bleeding. Monitor for increased risk of bleeding during concomitant therapy.
Linezolid Combination associated with possible serotoninergic syndrome
Mazindol Risk of serotoninergic syndrome
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Methamphetamine Risk of serotoninergic syndrome
Metoprolol The SSRI increases the effect of the beta-blocker
Moclobemide Possible severe adverse reaction with this combination
Naratriptan Increased risk of CNS adverse effects
Oxycodone Increased risk of serotonin syndrome
Phendimetrazine Risk of serotoninergic syndrome
Phenelzine Possible severe adverse reaction with this combination
Phentermine Risk of serotoninergic syndrome
Phenylpropanolamine Risk of serotoninergic syndrome
Pimozide Increased risk of cardiotoxicity and arrhythmias.
Propafenone Paroxetine may increase the effect and toxicity of propafenone.
Propranolol The SSRI, paroxetine, may increase the bradycardic effect of the beta-blocker, propranolol.
Rasagiline Possible severe adverse reaction with this combination
Risperidone The SSRI, paroxetine, increases the effect and toxicity of risperidone.
Rizatriptan Increased risk of CNS adverse effects
Selegiline Possible severe adverse reaction with this combination
Sibutramine Risk of serotoninergic syndrome
St. John's Wort St. John's Wort increases the effect and toxicity of the SSRI, paroxetine.
Sumatriptan Increased risk of CNS adverse effects
Tamoxifen Paroxetine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.
Tamsulosin Paroxetine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Paroxetine is initiated, discontinued, or dose changed.
Terbinafine Terbinafine may reduce the metabolism and clearance of Paroxetine. Consider alternate therapy or monitor for therapeutic/adverse effects of Paroxetine if Terbinafine is initiated, discontinued or dose changed.
Tetrabenazine Paroxetine is a strong CYP2D6 inhibitor thus increasing half life of dihydrotetrabenazine moieties. Dose of tetrabenazine should be reduced
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Tiaprofenic acid Additive antiplatelet effects increase the risk of bleeding. Consider alternate therapy or monitor for increased bleeding.
Tipranavir Tipranavir increases the concentration of Paroxetine. The Paroxetine dose may require an adjustment.
Tolmetin Increased antiplatelet effects may enhance the risk of bleeding. Alternate therapy may be considered or monitor for inreased bleeding during concomitant therapy.
Tolterodine Paroxetine may decrease the metabolism and clearance of Tolterodine. Monitor for adverse/toxic effects of Tolterodine.
Tramadol Tramadol may increase the risk of serotonin syndrome and seizures. Paroxetine may decrease the effect of Tramadol by decreasing active metabolite production.
Tranylcypromine Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.
Trazodone Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Treprostinil The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Paroxetine. Monitor for increased bleeding during concomitant thearpy.
Trimipramine The SSRI, Paroxetine, may decrease the metabolism and clearance of Trimipramine. Increased risk of serotonin syndrome. Monitor for changes in Trimipramine efficacy and toxicity if Paroxetine is initiated, discontinued or dose changed.
Triprolidine The CNS depressants, Triprolidine and Paroxetine, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.
Venlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Warfarin The SSRI, paroxetine, increases the effect of the anticoagulant, warfarin.
Zolmitriptan Use of two serotonin modulators, such as zolmitriptan and paroxetine, may increase the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.
Zuclopenthixol Paroxetine, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if paroxetine is initiated, discontinued or dose changed.
食物相互作用
  • Take without regard to meals. Avoid alcohol.

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