Tìm theo
Clomipramine
Các tên gọi khác (9 ) :
  • 3-(3-chloro-10,11-dihydro-5H-Dibenzo[b,F]azepin-5-yl)-N,N-dimethyl-1-propanamine
  • 3-(3-CHLORO-5H-dibenzo[b,F]azepin-5-yl)-N,N-dimethylpropan-1-amine
  • 3-Chloroimipramine
  • Chlorimipramine
  • Clomipramina
  • Clomipramine
  • Clomipraminum
  • g 34586
  • Monochlorimipramine
serotonin uptake inhibitors, antidepressive agents tricyclic
Thuốc Gốc
Small Molecule
CAS: 303-49-1
ATC: N06AA04
ĐG : Abic Ltd. , http://www.abic-vet.com
CTHH: C19H23ClN2
PTK: 314.852
Clomipramine, the 3-chloro analog of imipramine, is a dibenzazepine-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, clomipramine does not affect mood or arousal, but may cause sedation. In depressed individuals, clomipramine exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as clomipramine, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine-H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Clomipramine may be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy, autistic disorder, trichotillomania, onchophagia, stuttering, premature ejaculation, and premenstrual syndrome. Clomipramine is rapidly absorbed from the gastrointestinal tract and demethylated in the liver to its primary active metabolite, desmethylclomipramine.
Nhận Dạng Quốc Tế & Đặc Tính Hóa Học
Công thức hóa học
C19H23ClN2
Phân tử khối
314.852
Monoisotopic mass
314.154976453
InChI
InChI=1S/C19H23ClN2/c1-21(2)12-5-13-22-18-7-4-3-6-15(18)8-9-16-10-11-17(20)14-19(16)22/h3-4,6-7,10-11,14H,5,8-9,12-13H2,1-2H3
InChI Key
InChIKey=GDLIGKIOYRNHDA-UHFFFAOYSA-N
IUPAC Name
(3-{5-chloro-2-azatricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl}propyl)dimethylamine
Traditional IUPAC Name
clomipramine
SMILES
CN(C)CCCN1C2=CC=CC=C2CCC2=C1C=C(Cl)C=C2
Độ tan chảy
191.5-192
Độ sôi
160-170 °C at 3.00E-01 mm Hg
Độ hòa tan
0.294 mg/L
logP
5.19
logS
-4.3
pKa (Strongest Basic)
9.2
PSA
6.48 Å2
Refractivity
95.41 m3·mol-1
Polarizability
35.73 Å3
Rotatable Bond Count
4
H Bond Acceptor Count
2
H Bond Donor Count
0
Physiological Charge
1
Number of Rings
3
Bioavailability
1
Rule of Five
true
Ghose Filter
true
Dược Lực Học : Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α1 and β1 receptors are sensitized, α2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain.
Cơ Chế Tác Dụng : Clomipramine, the 3-chloro analog of imipramine, is a dibenzazepine-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, clomipramine does not affect mood or arousal, but may cause sedation. In depressed individuals, clomipramine exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake. Tertiary amine TCAs, such as clomipramine, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline and desipramine. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine-H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Clomipramine may be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy, autistic disorder, trichotillomania, onchophagia, stuttering, premature ejaculation, and premenstrual syndrome. Clomipramine is rapidly absorbed from the gastrointestinal tract and demethylated in the liver to its primary active metabolite, desmethylclomipramine. Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α1-receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type.
Dược Động Học :
▧ Absorption :
Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine.
▧ Volume of Distribution :
~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk.
▧ Protein binding :
Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α1-acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins.
▧ Metabolism :
Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N-demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N-oxide formed by N-oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N-demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical contribution remains unknown.
▧ Route of Elimination :
Urine (51-60%) and feces via biliary elimination (24-32%)
▧ Half Life :
Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism).
Độc Tính : Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.
Chỉ Định : May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome.
Tương Tác Thuốc :
  • Altretamine Risk of severe hypotension
  • Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
  • Atazanavir Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if atazanavir is initiated, discontinued or dose changed.
  • Butabarbital Barbiturates like butabarbital may increase the metabolism of tricyclic antidepressants like clomipramine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.
  • Butalbital Barbiturates such as butalbital may increase the metabolism of tricyclic antidepressants such as clomipramine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.
  • Cimetidine Cimetidine may increase the effect of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if cimetidine is initiated, discontinued or dose changed.
  • Cisapride Increased risk of cardiotoxicity and arrhythmias
  • Clonidine The tricyclic antidepressant, clomipramine, may decrease the effect of clonidine.
  • Desvenlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
  • Dihydroquinidine barbiturate Dihydroquinidine barbiturate increases the effect of the tricyclic antidepressant, clomipramine.
  • Dobutamine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of dobutamine.
  • Donepezil Possible antagonism of action
  • Dopamine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of dopamine.
  • Ephedra The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of ephedra.
  • Ephedrine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of ephedrine.
  • Epinephrine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of epinephrine.
  • Fenoterol The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of fenoterol.
  • Fluoxetine The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of clomipramine if fluoxetine is initiated, discontinued or dose changed.
  • Fluvoxamine The SSRI, fluvoxamine, may increase the serum concentration of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of clomipramine if fluvoxamine is initiated, discontinued or dose changed.
  • Galantamine Possible antagonism of action
  • Grepafloxacin Increased risk of cardiotoxicity and arrhythmias
  • Guanethidine The tricyclic antidepressant, clomipramine, decreases the effect of guanethidine.
  • Isocarboxazid Possibility of severe adverse effects
  • Isoprenaline The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of isoproterenol.
  • Mephentermine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of mephentermine.
  • Metaraminol The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of metaraminol.
  • Methoxamine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of methoxamine.
  • Moclobemide Possible severe adverse reaction with this combination
  • Norepinephrine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of norepinephrine.
  • Orciprenaline The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of orciprenaline.
  • Phenelzine Possibility of severe adverse effects
  • Phenylephrine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of phenylephrine.
  • Phenylpropanolamine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of phenylpropanolamine.
  • Pirbuterol The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of pirbuterol.
  • Procaterol The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of procaterol.
  • Pseudoephedrine The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of pseudoephedrine.
  • Quinidine Additive QTc-prolonging effects may occur. Quinidine may also increase the serum concentration of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if quinidine is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.
  • Quinidine barbiturate Quinidine barbiturate increases the effect of tricyclic antidepressant, clomipramine.
  • Rasagiline Possibility of severe adverse effects
  • Rifabutin The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, clomipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if rifabutin is initiated, discontinued or dose changed.
  • Rifampicin The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, clomipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if rifampin is initiated, discontinued or dose changed.
  • Ritonavir Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, clomipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of clomipramine if ritonavir if initiated, discontinued or dose changed.
  • Rivastigmine Possible antagonism of action
  • Salbutamol The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of salbutamol.
  • Sibutramine Increased risk of CNS adverse effects
  • Sparfloxacin Increased risk of cardiotoxicity and arrhythmias
  • Tacrine The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Clomipramine, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.
  • Tacrolimus Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
  • Tamoxifen Clomipramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.
  • Tamsulosin Clomipramine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Clomipramine is initiated, discontinued, or dose changed.
  • Terbinafine Terbinafine may reduce the metabolism and clearance of Clomipramine. Consider alternate therapy or monitor for therapeutic/adverse effects of Clomipramine if Terbinafine is initiated, discontinued or dose changed.
  • Terbutaline The tricyclic antidepressant, clomipramine, increases the sympathomimetic effect of terbutaline.
  • Terfenadine Increased risk of cardiotoxicity and arrhythmias
  • Thiabendazole The strong CYP1A2 inhibitor, Thiabendazole, may increase the effects and toxicity of Clomipramine by decreasing Clomipramine metabolism and clearance. Monitor for changes in the therapeutic and adverse effects of Clomipramine if Thiabendazole is initiated, discontinued or dose changed.
  • Thiothixene May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.
  • Ticlopidine Ticlopidine may decrease the metabolism and clearance of Clomipramine. Consider alternate therapy or monitor for adverse/toxic effects of Clomipramine if Ticlopidine is initiated, discontinued or dose changed.
  • Toremifene Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
  • Tramadol Tramadol increases the risk of serotonin syndrome and seizures. Clomipramine 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.
  • Trimethobenzamide Trimethobenzamide and Clomipramine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.
  • Trimipramine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
  • Triprolidine Triprolidine and Clomipramine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.
  • Trospium Trospium and Clomipramine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.
  • Venlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
  • Voriconazole Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
  • Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
  • Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.
  • Zolmitriptan Use of two serotonin modulators, such as zolmitriptan and clomipramine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.
  • Zuclopenthixol Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Liều Lượng & Cách Dùng : Capsule - Oral - 25 mg, 50 mg, 75 mg
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Tài Liệu Tham Khảo Thêm
drugbank
http://www.drugbank.ca/drugs/DB01242
KEGG Compound
http://www.genome.jp/dbget-bin/www_bget?cpd:C06918
KEGG Drug
http://www.genome.jp/dbget-bin/www_bget?drug:D00811
BindingDB
http://www.bindingdb.org/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50021927
National Drug Code Directory
http://www.hipaaspace.com/Medical_Billing/Coding/National.Drug.Codes/PDF/0781-2027-31
PharmGKB
http://www.pharmgkb.org/drug/PA449048
Wikipedia
http://en.wikipedia.org/wiki/Clomipramine
RxList
http://www.rxlist.com/cgi/generic/clomipr.htm
PDRhealth
http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ana1020.shtml
Drugs.com
http://www.drugs.com/cdi/clomipramine.html
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