Venlafaxine

572

Molecular weight: 313.86. White to off-white crystalline solid from methanol/ethyl acetate, mp 215-217 °C. SOlubility (mg/mL): 572 water. Partition coefficient (octanol/water): 0.43 /Venlafaxine hydrochloride/

Crystals from ethyl acetate; melting point 102-104 °C; specific optical rotation: +27.6 deg (c = 1.07 in 95% ethanol) /Venlafaxine (+)form/

Crystals from ethyl acetate; melting point 102-104 °C; specific optical rotation: -27.1 deg (c = 1.04 in 95% ethanol) /Venlafaxine (-)form/

Crystals from methanol/ether; melting point 240-240.5 °C; specific optical rotation: -4.7 deg (c = 0.945 in ethanol) /Venlafaxine (+)form hydrochloride/

Crystals from methanol/ether; melting point 240-240.5 °C; specific optical rotation: +4.6 deg (c = 1.0 in ethanol) /Venlafaxine (-)form hydrochloride/

74 - 76 °C

170.7 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID8047397]；170.8 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID8047397]；170.7 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: Antidepressants]；177.7 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID8047397]

171.6 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

169.9 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

175.6 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；166.8 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；168.8 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

170.2 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

171.86 Ų [M+H]+；179.64 Ų [M+Na]+

Danger

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]；H319 (33.3%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]；H360 (33.3%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H362 (33.3%): May cause harm to breast-fed children [Reproductive toxicity, effects on or via lactation]；H411 (33.3%): Toxic to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P203, P260, P263, P264, P264+P265, P270, P273, P280, P301+P317, P305+P351+P338, P318, P330, P337+P317, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including venlafaxine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Venlafaxine hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Blood concentrations of venlafaxine in the two overdose cases were 53 mg/L and 78 mg/L. Comparison of venlafaxine concentrations in blood samples taken at different times after death revealed increases in concentrations over time, suggesting the possible postmortem redistribution of venlafaxine. /Salt not specified/

Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for venlafaxine are known. (L1712)

Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.

A 25-year-old white woman with chronic depression was treated with venlafaxine 150 mg/day and trimipramine 50 mg/day. Eleven days after increase of the trimipramine dosage to 100 mg/d, she was hospitalized because of seizures suggesting a secondary generalized grand-mal episode. The electroencephalogram showed a pathologic pattern with several generalized epileptiform discharges. Because of suspected drug-induced seizures, both antidepressants were stopped. After antidepressant drug cessation, the patient was symptom free and had no further seizure episodes within the following 12 months of follow-up. No other potential cause for the seizure episode could be identified. Both venlafaxine and trimipramine have been associated with seizures, mainly after overdose. Venlafaxine-associated seizures at therapeutic doses have not been reported in the literature. /It was/ hypothesize that a pharmacodynamic or pharmacokinetic drug interaction between venlafaxine and trimipramine involving the CYP2D6 isoenzyme may have played a role in inducing the seizures.

A patient developed neuroleptic malignant syndrome after a single dose of venlafaxine with trifluoperazine treatment. A dopamine-inhibition effect induced by one dose of venlafaxine may have augmented dopamine-receptor inhibition by trifluoperazine.

Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (Cmax) of the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect on the pharmacokinetics of O-desmethylvenlafaxine, which is present in much greater quantity in the circulation than venlafaxine. The overall pharmacological activity of venlafaxine plus O-desmethylvenlafaxine is expected to increase only slightly, and no dosage adjustment should be necessary for most normal adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine is not known and potentially could be more pronounced. Therefore, caution is advised with such patients.

For more Interactions (Complete) data for Venlafaxine (24 total), please visit the HSDB record page.

Liver test abnormalities have been reported to occur in less than 1% of patients on venlafaxine or desvenlafaxine, and elevations are usually modest and usually do not require dose modification or discontinuation. Rare instances of acute, clinically apparent episodes of liver injury with marked liver enzyme elevations with or without jaundice have been reported in patients on both venlafaxine but not desvenlafaxine, perhaps because of less overall use of the more recently approved agent. The onset of injury is usually within 1 to 3 months. The patterns of serum enzyme elevation have varied from cholestatic to hepatocellular. All cases have been self-limiting and resolved within a few months. Autoimmune (autoantibodies) and immunoallergic features (rash, fever, eosinophilia) are uncommon or mild. The estimated frequency is 1 per 5000 patients years of exposure.；Likelihood score (venlafaxine): B (highly likely rare causes of clinically apparent liver injury).；Likelihood score (desvenlafaxine): E* (suspected but unproven cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 190(SRC), determined from a log Kow of 3.20(2) and a regression-derived equation(3), indicates that Venlafaxine is expected to have moderate mobility in soil(SRC). The estimated pKa of Venlafaxine is 10.09(4), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Venlafaxine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.5X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). Biodegradation data in soil were not available(SRC, 2011).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 190(SRC), determined from a log Kow of 3.20(2) and a regression-derived equation(3), indicates that venlafaxine is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of 10.09(4) indicates venlafaxine will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 60(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data in water were not available(SRC, 2010); however its detection in wastewater treatment plant effluent(6) would indicate that biodegradation may not be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), venlafaxine, which has an estimated vapor pressure of 2.5X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase venlafaxine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1 hour(SRC), calculated from its rate constant of 1.28X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase venlafaxine may be removed from the air by wet or dry deposition(SRC).

Venlafaxine causes a lower frequency of anticholinergic, sedating, and cardiovascular adverse effects but a higher incidence of gastrointestinal complaints, sleep impairment, and sexual dysfunction than TCAs. Additionally, venlafaxine may impair sexual function, resulting in diminished libido, impotence, or difficulty achieving orgasm. Sexual dysfunction frequently results in noncompliance. Sexual dysfunction can sometimes be alleviated by lowering the dose or instituting drug-free weekends and holidays in appropriate patients.；Venlafaxine is prescribed for the long term, and it carries severe risks if not taken as directed or stopped abruptly. Abrupt cessation of venlafaxine can lead to severe adverse effects such as irritability, tiredness, restlessness, anxiety, insomnia, trouble sleeping, nightmares, headache, sweating, dizziness, tingling, or "pins and needles" feeling, shaking, confusion, nausea, vomiting, or diarrhea. Some patients find withdrawal symptoms uncomfortable. Common adverse effects of venlafaxine include headache, nausea, insomnia, dizziness, somnolence, xerostomia, asthenia, hypertension, impotence, decreased libido, anorgasmia, constipation, weight loss, abnormal dreams, diarrhea, abdominal pain, blurred vision, anxiety, tremor, hypercholesterolemia, and hyponatremia. Severe adverse effects include serotonin syndrome and seizures.；Venlafaxine can cause depression exacerbation and hypomania/mania. Venlafaxine can also cause abnormal bleeding, altered platelet function, and anaphylaxis/anaphylactoid reaction. Venlafaxine can cause fatal skin conditions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme. Venlafaxine can also cause deterioration of glaucoma angle closure and seizures. Venlafaxine has implications linking it to the syndrome of inappropriate antidiuretic hormone secretion (SIADH), hypertension, arrhythmia, interstitial lung disease, eosinophilic pneumonia, pancreatitis, and hepatotoxicity.；Drug-Drug Interactions；* Venlafaxine can interact with many other medications or herbs.；* Concomitant administration of desvenlafaxine with other serotonergic drugs should be avoided due to the risk of serotonin syndrome resulting from hyperstimulation of brainstem 5HT-1A receptors. Concurrent use of venlafaxine with SNRIs, SSRIs, triptans, TCAs, opioids, lithium, buspirone, amphetamines, tramadol, tryptophan, and St John's wort is not recommended. Vigilant monitoring for symptoms indicative of serotonin syndrome is imperative when venlafaxine is administered alongside these medications. If serotonin syndrome is suspected, prompt evaluation and consideration for discontinuation of venlafaxine and the other serotonergic agents involved are warranted to mitigate potential adverse effects and ensure patient safety.；* Venlafaxine should be used cautiously with sedating medications, such as central nervous system depressants and alcohol.；* The coadministration of venlafaxine with antiplatelet or anticoagulant medications may increase the risk of bleeding. This risk is attributed to venlafaxine's potential impact on serotonin release by platelets. Close monitoring for signs of bleeding is essential when initiating or discontinuing venlafaxine in patients receiving antiplatelet or anticoagulant therapy. Clinicians should be vigilant for bleeding complications and consider appropriate interventions as necessary.；* Patients should not take venlafaxine with MAOIs, linezolid, and methylene blue.；* Venlafaxine should not be ingested with drugs for weight loss, such as phentermine. Concurrent use of venlafaxine phentermine may cause excessive weight loss, serotonin syndrome, tachycardia, and psychosis.；* The risk of bleeding may increase when taking venlafaxine with warfarin and NSAIDs such as aspirin, ibuprofen, and naproxen.；* Clarithromycin, ritonavir, and ketoconazole can inhibit the breakdown of venlafaxine, leading to its accumulation in the body.；* Concurrent use of venlafaxine with lorazepam zolpidem or diphenhydramine can result in increased sedation.；* The efficacy of metoprolol is reduced when administered with venlafaxine.；* The risk of QT prolongation increases when venlafaxine and haloperidol are administered concurrently.

Women participating in a prospective investigation of perinatal pharmacokinetics from January 2001 through July 2006 who were treated with venlafaxine and who chose to continue venlafaxine during lactation were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient, and serial samples were collected over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Venlafaxine and desvenlafaxine concentrations were determined using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. Thirteen women and their nursing infants participated, providing 106 breast milk samples. The mean milk/plasma ratio was 275.3% (95% CI = 144.8% to 405.7%). There were statistically significant time courses of excretion for venlafaxine (R = 0.36, F = 6.82, P < .02), desvenlafaxine (R = 0.48, F = 4.41, P < .009), and combined venlafaxine/desvenlafaxine (R = 0.51, F = 5.16, P < .004), with the highest venlafaxine and desvenlafaxine concentrations in the breast milk occurring 8 hours after maternal ingestion. Infant plasma concentrations for combined venlafaxine/desvenlafaxine were 37.1% of maternal plasma concentrations. The theoretical infant venlafaxine/desvenlafaxine dose was 0.208 mg/kg/d, and the relative infant venlafaxine/desvenlafaxine dose was 8.1%. The theoretical and relative infant doses for desvenlafaxine were 197% and 224% higher, respectively, than those for venlafaxine.

Signs and Symptoms of Overdose；Symptoms of an overdose of venlafaxine can include tachycardia, unusual sleepiness, dilated pupils, seizures, vomiting, cardiac arrhythmias, hypotension, muscle aches or pains, or dizziness. Severe toxicity of venlafaxine, especially when combined with other antidepressants such as SSRI, SNRI, or MAOI, can lead to serotonin syndrome. Serotonin syndrome is a possibly life-threatening condition associated with increased serotonergic activity in the central nervous system.；Serotonin syndrome may present with a spectrum of clinical findings, including autonomic hyperactivity, mental status changes, and neuromuscular abnormalities. Serotonin syndrome characteristically presents with myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, and potentially death. No laboratory tests exist to confirm the diagnosis, as serotonin concentrations do not correlate clinically with symptoms. Hunter Toxicity Criteria Decision Rules can be used to form the diagnosis.；To meet the criteria, the patient must be taking a serotonergic agent and fulfill 1 of the following conditions:；* Spontaneous clonus；* Inducible clonus with agitation or diaphoresis；* The presence of ocular clonus plus agitation or diaphoresis；* Tremor with hyperreflexia；* Hypertonia with a temperature above 38 °C plus ocular clonus or inducible clonus；Management of Overdose；Management of serotonin syndrome involves promptly discontinuing all serotonergic agents with supportive care to normalize hemodynamics. Patient sedation with benzodiazepines and serotonin antagonists may also be an option. Cyproheptadine can be an option in the event of a failure with benzodiazepines and supportive care. Cyproheptadine is a histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties. Treatment with propranolol, bromocriptine, or dantrolene is not recommended. Serotonin syndrome symptoms usually resolve within 24 hours of discontinuation of the offending agent.

The exact mechanism of action of venlafaxine is unknown, but appears to be associated with the its potentiation of neurotrasmitter activity in the CNS. Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV), inhibit the reuptake of both serotonin and norepinephrine with a potency greater for the 5-HT than for the NE reuptake process. Both venlafaxine and the ODV metabolite have weak inhibitory effects on the reuptake of dopamine but, unlike the tricyclics and similar to SSRIs, they are not active at histaminergic, muscarinic, or alpha(1)-adrenergic receptors.

/AQUATIC SPECIES/ The effects of embryonic and larval exposure to environmentally relevant (ng/L) concentrations of common antidepressants, fluoxetine, sertraline, venlafaxine, and bupropion (singularly and in mixture) on C-start escape behavior were evaluated in fathead minnows (Pimephales promelas). Embryos (postfertilization until hatching) were exposed for 5 days and, after hatching, were allowed to grow in control well water until 12 days old. Similarly, posthatch fathead minnows were exposed for 12 days to these compounds. High-speed (1,000 frames/s) video recordings of escape behavior were collected and transferred to National Institutes of Health Image for frame-by-frame analysis of latency periods, escape velocities, and total escape response (combination of latency period and escape velocity). When tested 12 days posthatch, fluoxetine and venlafaxine adversely affected C-start performance of larvae exposed as embryos. Conversely, larvae exposed for 12 days posthatch did not exhibit altered escape responses when exposed to fluoxetine but were affected by venlafaxine and bupropion exposure. Mixtures of these four antidepressant pharmaceuticals slowed predator avoidance behaviors in larval fathead minnows regardless of the exposure window. The direct impact of reduced C-start performance on survival and, ultimately, reproductive fitness provides an avenue to assess the ecological relevance of exposure in an assay of relatively short duration.

Venlafaxine was detected downstream from a single source wastewater treatment plant on Boulder Creek (Colorado) and Fourmile Creek (Iowa) at ranges of 140 to 220 ng/L and 102 to 210 ng/L, respectively; detection limit = 0.5 ng/L. Sampling was conducted in April and March of 2005, respectively. Concentration ranges in July and April of 2006 ranged from 99.5 to 672 ng/L and 146 to 690 ng/L(1).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including venlafaxine hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Venlafaxine hydrochloride/

N06AX16

N06AX16

N - Nervous system；N06 - Psychoanaleptics；N06A - Antidepressants；N06AX - Other antidepressants；N06AX16 - Venlafaxine

QN - Nervous system；QN06 - Psychoanaleptics；QN06A - Antidepressants；QN06AX - Other antidepressants；QN06AX16 - Venlafaxine

Venlafaxine is an antidepressant agent that works to ameliorate the symptoms of various psychiatric disorders by increasing the level of neurotransmitters in the synapse. Venlafaxine does not mediate muscarinic, histaminergic, or adrenergic effects.

The exact mechanism of action of venlafaxine in the treatment of various psychiatric conditions has not been fully elucidated; however, it is understood that venlafaxine and its active metabolite O-desmethylvenlafaxine (ODV) potently and selectively inhibits the reuptake of both serotonin and norepinephrine at the presynaptic terminal. This results in increased levels of neurotransmitters available at the synapse that can stimulate postsynaptic receptors. It is suggested that venlafaxine has a 30-fold selectivity for serotonin compared to norepinephrine: venlafaxine initially inhibits serotonin reuptake at low doses, and with higher doses, it inhibits norepinephrine reuptake in addition to serotonin. Venlafaxine and ODV are also weak inhibitors of dopamine reuptake.

The mechanism of the antidepressant action of venlafaxine in humans is believed to be associated with its potentiation of neurotransmitter activity in the CNS. Preclinical studies have shown that venlafaxine and its active metabolite, O-desmethylvenlafaxine, are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. Venlafaxine and O-desmethylvenlafaxine have no significant affinity for muscarinic cholinergic, H1-histaminergic, or a1-adrenergic receptors in vitro. Pharmacologic activity at these receptors is hypothesized to be associated with the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Venlafaxine and O-desmethylvenlafaxine do not possess monoamine oxidase (MAO) inhibitory activity.

/The antinociceptive effects of the novel phentylethylamine antidepressant drug venlafaxine and its interaction with various opioid, noradrenaline and serotonin receptor subtypes were evaluated. When mice were tested with a hotplate analgesia meter, venlafaxine induced a dose-dependent antinociceptive effect following i.p. administration with an ED50 of 46.7 mg/kg (20.5; 146.5; 95% CL). Opioid, adrenergic and serotoninergic receptor antagonists were tested for their ability to block venlafaxine antinociception. Venlafaxine-induced antinociception was significantly inhibited by naloxone, nor-BNI and naltrindole but not by beta-FNA or naloxonazine, implying involvement of kappa1- and delta-opioid mechanisms. When adrenergic and serotoninergic antagonists were used, yohimbine (P < 0.005) but not phentolamine or metergoline, decreased antinociception elicited by venlafaxine, implying a clear alpha2- and a minor alpha1-adrenergic mechanism of antinociception. When venlafaxine was administered together with various agonists of the opioid and alpha2- receptor subtypes, it significantly potentiated antinociception mediated by kappa1- kappa3- and delta-opioid receptor subtypes. The alpha2-adrenergic agonist clonidine significantly potentiated venlafaxine-mediated antinociception. Summing up these results, we conclude that the antinociceptive effect of venlafaxine is mainly influenced by the kappa- and delta-opioid receptor subtypes combined with the alpha2-adrenergic receptor. These results suggest a potential use of venlafaxine in the management of some pain syndromes. However, further research is needed in order to establish both the exact clinical indications and the effective doses of venlafaxine when prescribed for pain. /Salt not specified/

Venlafaxine ... causes selective inhibition of neuronal reuptake of serotonine and norepinephrine with little effect on other neurotransmitter systems. Cases of seizures, tachycardia, and QRS prolongation have been observed following drug overdose in humans. The clinical manifestations of cardiac toxicity suggest that venlafaxine may exhibit cardiac electrophysiological effects on fast conducting cells. Consequently, studies were undertaken to characterize effects of venlafaxine on the fast inward sodium current (I(Na)) of isolated guinea pig ventricular myocytes. Currents were recorded with the whole-cell configuration of the patch-clamp technique in the presence of Ca(2+) and K(+) channel blockers. Results obtained demonstrated that venlafaxine inhibits peak I(Na) in a concentration-dependent manner with an estimated IC(50) of 8. 10(-6) M. Inhibition was exclusively of a tonic nature and rate-independent. Neither kinetics of inactivation (tau(inac)= 0.652 +/- 0.020 ms, under control conditions; tau(inac)= 0.636 +/- 0.050, in the presence of 10(-5) M venlafaxine; n = 5 cells isolated from five animals) nor kinetics of recovery from inactivation of the sodium channels (tau(re)= 58.7 +/- 1.6 ms, under control conditions; tau(re)= 54.4 +/- 1.8, in the presence of 10(-5) M venlafaxine; n = 10 cells isolated from six animals) were significantly altered by 10(-5) M venlafaxine. These observations led us to conclude that venlafaxine blocks I(Na) following its binding to the resting state of the channel. Thus, the characteristics of block of I(Na) by venlafaxine are different from those usually observed with most tricyclic antidepressants or conventional class I antiarrhythmic drugs.

The 5-HT(4) receptor may be a target for antidepressant drugs. ... The effects of the dual antidepressant, venlafaxine, on 5-HT(4) receptor-mediated signalling events /is examined/. The effects of 21 days treatment (p.o.) with high (40 mg kg(-1)) and low (10 mg kg(-1)) doses of venlafaxine, were evaluated at different levels of 5-HT(4) receptor-mediated neurotransmission by using in situ hybridization, receptor autoradiography, adenylate cyclase assays and electrophysiological recordings in rat brain. The selective noradrenaline reuptake inhibitor, reboxetine (10 mg kg(-1), 21 days) was also evaluated on 5-HT(4) receptor density. Treatment with a high dose (40 mg kg(-1)) of venlafaxine did not alter 5-HT(4) mRNA expression, but decreased the density of 5-HT(4) receptors in caudate-putamen (% reduction = 26 + or - 6), hippocampus (% reduction = 39 + or -7 and 39 + or - 8 for CA1 and CA3 respectively) and substantia nigra (% reduction = 49 + or - 5). Zacopride-stimulated adenylate cyclase activation was unaltered following low-dose treatment (10 mg kg(-1)) while it was attenuated in rats treated with 40 mg kg(-1) of venlafaxine (% reduction = 51 + or - 2). Furthermore, the amplitude of population spike in pyramidal cells of CA1 of hippocampus induced by zacopride was significantly attenuated in rats receiving either dose of venlafaxine. Chronic reboxetine did not modify 5-HT(4) receptor density. Data indicate a functional desensitization of 5-HT(4) receptors after chronic venlafaxine, similar to that observed after treatment with the classical selective inhibitors of 5-HT reuptake.

The present study was undertaken to evaluate the potential role of 5-HT1A receptors in the antidepressant-like effect and antinociceptive effect of venlafaxine. With this aim, the effect of either a selective 5-HT1A receptor antagonist (WAY-100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT1A receptor agonist (8-OH-DPAT; 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) was investigated in mice in combination with venlafaxine by means of the forced swimming test, a paradigm aimed at screening potential antidepressants, and the hot-plate test, a phasic pain model. Surprisingly, the results showed that WAY-100635 produced a large decrease in the antidepressant-like effect of venlafaxine, while 8-OH-DPAT rendered effective a non-effective dose of this antidepressant. However, in the hot-plate test WAY-100635 significantly enhanced the antinociceptive effect of venlafaxine, whereas 8-OH-DPAT counteracted its antinociceptive effect. These findings show that 5-HT1A receptors play differing roles in modulating the antidepressant-like and antinociceptive effects of venlafaxine in the models investigated. The results imply that blockade of the 5-HT1A receptors in the forebrain will counteract the favourable (antidepressant-like) effect at raphe nuclei level, and consequently, the overall effect evidenced is an antagonism. This suggests a predominant role of 5-HT1A receptors located in the forebrain area for the antidepressant-like effect. In contrast, the antinociceptive effect of venlafaxine is probably potentiated due to the blockade of somatodendritic 5-HT1A receptors in the same raphe nuclei, facilitating the descending monoaminergic pain control system.

The apparent elimination half-life is 5 ± 2 hours for venlafaxine and 11 ± 2 hours for ODV.

Apparent elimination half-life /of venlafaxine and O-desmethylvenlafaxine/ is 5 +/- 2 and 11 +/- 2 hours, respectively.

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. It primarily undergoes CYP2D6-mediated demethylation to form its active metabolite O-desmethylvenlafaxine (ODV). Venlafaxine can also undergo N-demethylation mediated by CYP2C9, and CYP2C19, and CYP3A4 to form N-desmethylvenlafaxine (NDV) but this is a minor metabolic pathway. ODV and NDV further metabolized by CYP2C19, CYP2D6 and/or CYP3A4 to form N,O-didesmethylvenlafaxine (NODV) and NODV can be further metabolized to form N, N, O-tridesmethylvenlafaxine, followed by a possible glucuronidation.

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily to O-desmethylvenlafaxine, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of O-desmethylvenlafaxine is catalyzed by CYP2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels ("poor metabolizers") had increased levels of venlafaxine and reduced levels of O-desmethylvenlafaxine compared to people with normal CYP2D6 ("extensive metabolizers"). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and O-desmethylvenlafaxine is similar in the two groups and venlafaxine and O-desmethylvenlafaxine are pharmacologically approximately equiactive and equipotent.

The biotransformation of venlafaxine (VF) into its two major metabolites, O-desmethylvenlafaxine (ODV) and N-desmethylvenlafaxine (NDV) was studied in vitro with human liver microsomes and with microsomes containing individual human cytochromes from cDNA-transfected human lymphoblastoid cells. VF was coincubated with selective cytochrome P450 (CYP) inhibitors and several selective serotonin reuptake inhibitors (SSRIs) to assess their inhibitory effect on VF metabolism. Formation rates for ODV incubated with human microsomes were consistent with Michaelis-Menten kinetics for a single-enzyme mediated reaction with substrate inhibition. Mean parameters determined by non-linear regression were: Vmax = 0.36 nmol/min/mg protein, K(m) = 41 microM, and Ks 22901 microM (Ks represents a constant which reflects the degree of substrate inhibition). Quinidine (QUI) was a potent inhibitor of ODV formation with a Ki of 0.04 microM, and paroxetine (PX) was the most potent SSRI at inhibiting ODV formation with a mean Ki value of 0.17 microM. Studies using expressed cytochromes showed that ODV was formed by CYP2C9, -2C19, and -2D6. CYP2D6 was dominant with the lowest K(m), 23.2 microM, and highest intrinsic clearance (Vmax/K(m) ratio). No unique model was applicable to the formation of NDV for all four livers tested. Parameters determined by applying a single-enzyme model were Vmax = 2.14 nmol/min/mg protein, and K(m) = 2504 microM. Ketoconazole was a potent inhibitor of NDV production, although its inhibitory activity was not as great as observed with pure 3A substrates. NDV formation was also reduced by 42% by a polyclonal rabbit antibody against rat liver CYP3A1. Studies using expressed cytochromes showed that NDV was formed by CYP2C9, -2C19, and -3A4. The highest intrinsic clearance was attributable to CYP2C19 and the lowest to CYP3A4. However the high in vivo abundance of 3A isoforms will magnify the importance of this cytochrome. Fluvoxamine (FX), at a concentration of 20 micro

On three occasions, unusually high trough plasma concentrations of venlafaxine were measured in a patient phenotyped and genotyped as being an extensive CYP2D6 metabolizer and receiving 450 mg/day of venlafaxine and multiple comedications. Values of 1.54 and of 0.60 mg/l of venlafaxine and O-desmethylvenlafaxine, respectively, were determined in the first blood sample, giving an unusually high venlafaxine to O-desmethylvenlafaxine ratio. This suggests an impaired metabolism of venlafaxine to O-desmethylvenlafaxine, and is most likely due to metabolic interactions with mianserin (240 mg/day) and propranolol (40 mg/day). Concentration of (S)-venlafaxine measured in this blood sample was almost twice as high as (R)-venlafaxine ((S)/(R) ratio: 1.94). At the second blood sampling, after addition of thioridazine (260 mg/day), which is a strong CYP2D6 inhibitor, concentrations of venlafaxine were further increased (2.76 mg/l), and concentrations of O-desmethylvenlafaxine decreased (0.22 mg/l). A decrease of the (S)/(R)-venlafaxine ratio (-20%) suggests a possible stereoselectivity towards the (R)-enantiomer of the enzyme(s) involved in venlafaxine O-demethylation at these high venlafaxine concentrations. At the third blood sampling, after interruption of thioridazine, concentrations of venlafaxine and O-desmethylvenlafaxine were similar to those measured in the first blood sample. This case report shows the importance of performing studies on the effects of either genetically determined or acquired deficiency of metabolism on the kinetics of venlafaxine.

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated O-desmethylvenlafaxine (29%), conjugated O-desmethylvenlafaxine (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion

Undergoes extensive first pass metabolism in the liver to its major, active metabolite, ODV, and two minor, less active metabolites, N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. Formation of ODV is catalyzed by cytochrome P450 (CYP) 2D6, whereas N-demethylation is catalyzed by CYP3A4, 2C19 and 2C9. ODV possesses antidepressant activity that is comparable to that of venlfaxine. Route of Elimination: Renal elimination of venlafaxine and its metabolites is the primary route of excretion. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Half Life: 5 hours

GRZ5RCB1QG

VENLAFAXINE

Mechanisms of Action [MoA] - Norepinephrine Uptake Inhibitors

Established Pharmacologic Class [EPC] - Serotonin and Norepinephrine Reuptake Inhibitor

Mechanisms of Action [MoA] - Serotonin Uptake Inhibitors

Venlafaxine is a Serotonin and Norepinephrine Reuptake Inhibitor. The mechanism of action of venlafaxine is as a Norepinephrine Uptake Inhibitor and Serotonin Uptake Inhibitor.

Drugs that selectively block or suppress the plasma membrane transport of SEROTONIN and NORADRENALINE into axon terminals and are used as ANTIDEPRESSIVE AGENTS.

A structurally and mechanistically diverse group of drugs that are not tricyclics or monoamine oxidase inhibitors. The most clinically important appear to act selectively on serotonergic systems, especially by inhibiting serotonin reuptake.

Venlafaxine is well absorbed after oral administration with an absolute bioavailability of approximately 45%. In mass balance studies, at least 92% of a single oral dose of venlafaxine was absorbed. After twice-daily oral administration of immediate-release formulation of 150 mg venlafaxine, Cmax was 150 ng/mL and Tmax was 5.5 hours. Cmax and Tmax of ODV were 260 ng/mL and nine hours, respectively. The extended-release formulation of venlafaxine has a slower rate of absorption, but the same extent of absorption as the immediate-release formulation. After once-daily administration of extended-release formulation of 75 mg venlafaxine, Cmax was 225 ng/mL and Tmax was two hours. Cmax and Tmax of ODV were 290 ng/mL and three hours, respectively. Food does not affect the bioavailability of venlafaxine or its active metabolite, O-desmethylvenlafaxine (ODV).

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%).

The apparent volume of distribution at steady-state is 7.5 ± 3.7 L/kg for venlafaxine and 5.7 ± 1.8 L/kg for ODV.

Mean ± SD plasma apparent clearance at steady-state is 1.3 ± 0.6 L/h/kg for venlafaxine and 0.4 ± 0.2 L/h/kg for ODV.

Venlafaxine is well absorbed ... .On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%

Steady-state concentrations of venlafaxine and O-desmethylvenlafaxine in plasma are attained within 3 days of oral multiple dose therapy. Venlafaxine and O-desmethylvenlafaxine exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean +/-SD steady-state plasma clearance of venlafaxine and O-desmethylvenlafaxine is 1.3 +/- 0.6 and 0.4 0.2 L/hr/kg, respectively; apparent elimination half-life is 5 +/- 2 and 11 +/- 2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5 +/- 3.7 and 5.7 +/- 1.8 L/kg, respectively. Venlafaxine and O-desmethylvenlafaxine are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).

MEDICATION

Use (kg) in Switzerland (2009): >1000；Use (kg; approx.) in Germany (2009): >10000；Use (kg; exact) in Germany (2009): 11924；Use (kg) in USA (2002): 43700；Consumption (g per capita) in Switzerland (2009): 0.13；Consumption (g per capita; approx.) in Germany (2009): 0.12；Consumption (g per capita; exact) in Germany (2009): 0.15；Consumption (g per capita) in the USA (2002): 0.15；Excretion rate: 0.46；Calculated removal (%): 19.3

For the management of major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (social phobia), panic disorder with or without agoraphobia, vasomotor symptoms in women with breast cancer and in postmenopausal women, and neuropathic pain.

Under basic conditions an aldol-type condensation of the anion nucleophile of 4-methoxyphenylacetonitrile and cyclohexanone yield 2-(2-hydroxycyclohexyl)-2-(4-methyoxyphenyl)acetonitrile. Reduction of the nitrile to the primary amine followed by N-methylation gives the product (base).

Prepn: G.E.M. Husbands et al., EP 112669; US 4535186 (1984, 1985 both to Am. Home Prods.)

Pharmaceuticals

Pharmaceuticals -> Nervous System -> Psychoanaleptics -> Antidepressants