Venlafaxine
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| Image:Venlafaxine-2D-skeletal.png | |
| Image:Venlafaxine-3D-vdW.png | |
| Venlafaxine
| |
| Systematic (IUPAC) name | |
| 1-[2-dimethylamino-1- (4-methoxyphenyl)- ethyl]cyclohexan-1-ol | |
| Identifiers | |
| CAS number | 93413-69-5 |
| ATC code | N06AX16 |
| PubChem | 5656 |
| DrugBank | APRD00125 |
| Chemical data | |
| Formula | C17H27NO2 |
| Mol. weight | 277.402 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 45% |
| Protein binding | 27% |
| Metabolism | Hepatic |
| Half life | 5 ± 2 hours (parent compound); 11 ± 2 hours (active metabolite) |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
C |
| Legal status |
Rx-only, not a controlled drug |
| Routes | Oral |
Venlafaxine hydrochloride is a prescription antidepressant first introduced by Wyeth in 1993. It belongs to class of antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRI). As of August 2006, generic venlafaxine is available in the United States. It was previously available only under the brand names Effexor and Effexor XR. It is also available in the UK under the name "Efexor XL".
Contents |
[edit] Trade names
Venlafaxine is marketed under the tradenames, Efexor®, Efectin®, Effexor XR® and Efectin ER®
[edit] Description of compound
The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride and it has the empirical formula of C17H27NO2. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the analgesic tramadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or reversible inhibitors of monoamine oxidase (RIMAs).<ref name="QJM2003-Whyte">Whyte I, Dawson A, Buckley N (2003). "Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants". QJM 96 (5): 369-74. PMID 12702786.</ref>
[edit] Mechanism of action
Venlafaxine is a bicyclic antidepressant, and is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor.<ref>[No Authors listed]. Acute Effectiveness of Additional Drugs to the Standard Treatment of Depression. ClinicalTrials.gov. Retrieved on 23 June, 2005.</ref><ref>Goeringer K, McIntyre I, Drummer O (2001). "Postmortem tissue concentrations of venlafaxine". Forensic Sci Int 121 (1-2): 70-5. PMID 11516890.</ref> It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitter in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline) Additionally, in high doses it weakly inhibits the reuptake of dopamine.<ref name="CNSDrugs2001-Wellington">Wellington K, Perry C (2001). "Venlafaxine extended-release: a review of its use in the management of major depression.". CNS Drugs 15 (8): 643-69. PMID 11524036.</ref>
[edit] Pharmacokinetics
Venlafaxine is well absorbed with at least 92% of an oral dose being absorbed into systemic circulation. Venlafaxine is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine, which is just as potent a serotonin-norepinephrine reuptake inhibitor as the parent compound, meaning that the differences in metabolism between extensive and poor metabolizers are not clinically important. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys.<ref name="Medicinedatasheet-Wyeth">Effexor Medicines Data Sheet. Wyeth Pharmaceuticals Inc (2006). Retrieved on 17 September, 2006.</ref> The half-life of venlafaxine is relatively short, therefore patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed doses can result in the withdrawal symptoms.<ref name="ANZ JPsych1998-parker">Parker G, Blennerhassett J (1998). "Withdrawal reactions associated with venlafaxine". Aust N Z J Psychiatry 32 (2): 291-4. PMID 9588310.</ref>
[edit] Indications
[edit] Approved
Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, and panic disorder in adults only. It is also used for other general depressive disorders.<ref name="Medicinedatasheet-Wyeth"/>
[edit] Off-label / investigational uses
Many doctors are starting to prescribe venlafaxine "off label" for the treatment of diabetic neuropathy (in a similar manner to duloxetine) and migraine prophylaxis (in some people, however, venlafaxine can exacerbate or cause migraines). Studies have shown venlafaxine's effectiveness for these conditions.<ref>Rowbotham M, Goli V, Kunz N, Lei D (2004). "Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study". Pain 110 (3): 697-706. PMID 15288411.</ref><ref>Ozyalcin S, Talu G, Kiziltan E, Yucel B, Ertas M, Disci R (2005). "The efficacy and safety of venlafaxine in the prophylaxis of migraine". Headache 45 (2): 144-52. PMID 15705120.</ref> It has also been found to reduce the severity of 'hot-flashes' in menopausal women.<ref>Mayo Clinic staff (2005). Beyond hormone therapy: Other medicines may help. Hot flashes: Ease the discomfort of menopause. Mayo Clinic. Retrieved on 19 August, 2005.</ref><ref> Schober C, Ansani N (2003). "Venlafaxine hydrochloride for the treatment of hot flashes". Ann Pharmacother 37 (11): 1703-7. PMID 14565812.</ref>
Substantial weight loss in patients with major depression, generalized anxiety disorder, and social phobia has been noted, but the manufacturer does not recommend use as an anorectic either alone or in combination with phentermine or other amphetamine-like drugs.<ref name="Medicinedatasheet-Wyeth"/>
Venlafaxine is not approved for the treatment of depressive phases of bipolar disorder; this has some potential danger as venlafaxine can induce mania, mixed states, rapid cycling and/or psychosis in some bipolar patients, particularly if they are not also being treated with a mood stabilizer.<ref name="Medicinedatasheet-Wyeth"/>
[edit] Contraindications
Venlafaxine is not recommended in patients hypersensitive to venlafaxine. It should never be used in conjunction with a monoamine oxidase inhibitor (MAOI), due to the potential to develop a potentially deadly condition known as serotonin syndrome. Caution should also be used in those with a seizure disorder. Venlafaxine is not approved for use in children or adolescents.<ref name="Medicinedatasheet-Wyeth"/> However, Wyeth do provide information on cautions if venlafaxine is prescribed to this age group as a non-approved use. Studies in these age groups have not established its efficacy or safety.<ref>Courtney D (2004). "Selective serotonin reuptake inhibitor and venlafaxine use in children and adolescents with major depressive disorder: a systematic review of published randomized controlled trials". Can J Psychiatry 49 (8): 557-63. PMID 15453105.</ref>
[edit] Pregnancy, labor and delivery
There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed.<ref name="Medicinedatasheet-Wyeth"/> Prospective studies have not shown any statistically significant congenital malformations.<ref>Gentile S (2005). "The safety of newer antidepressants in pregnancy and breastfeeding". Drug Saf 28 (2): 137-52. PMID 15691224.</ref> There have, however, been some reports of effects on new born infants.<ref>de Moor R, Mourad L, ter Haar J, Egberts A (2003). "[Withdrawal symptoms in a neonate following exposure to venlafaxine during pregnancy]". Ned Tijdschr Geneeskd 147 (28): 1370-2. PMID 12892015.</ref> In view of the possibility of severe discontinuation syndrome and the difficulties this presents, use of venlafaxine for pregnant women is not generally indicated.[citation needed]
[edit] Dose range
Prescribed dosages are typically in the range of 75 to 225 mg per day, but higher dosages are sometimes used for the treatment of severe or treatment-resistant depression. Because of its relatively short half-life of 5 hours, venlafaxine should be administered in divided dosages throughout the day. The extended release version (largely manufactured on spheronization equipment) eliminates this problem and has largely replaced the original in use.
[edit] Available forms
Effexor is distributed in pentagon-shaped peach-colored tablets of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg. There is also an extended-release version distributed in capsules of 37.5 mg (gray/peach), 75 mg (peach), and 150 mg (brownish red).
[edit] Venlafaxine Extended Release (XR)
Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release version (sometimes referred to as controlled release) controls the release of the drug into the gut over a longer period of time than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of patients suffering from nausea as a side effect resulting in a lower number of patients stopping their treatment due to nausea.<ref>DeVane CL. (2003). "Immediate-release versus controlled-release formulations: pharmacokinetics of newer antidepressants in relation to nausea". J Clin Psychiatry 64 (Suppl 18): 14-9. PMID 14700450.</ref>
[edit] Effectiveness
Venlafaxine is an effective anti-depressant for many persons; however, it seems to be especially effective for those with treatment-resistant depression. Some of these persons have taken two or more antidepressants prior to venlafaxine with no relief. Patients suffering with severe long-term depression typically respond better to venlafaxine than other drugs. However, venlafaxine has been reported to be more difficult to discontinue than other anti-depressants. In addition, a September 2004 Consumer Reports study ranked venlafaxine as the most effective among six commonly prescribed antidepressants. However, this should not be considered a definitive finding, since responses to psychiatric medications can vary significantly from individual to individual.
[edit] Adverse effects
As with most antidepressants, lack of sexual desire is a common side effect. Venlafaxine can raise blood pressure at high doses, so it is usually not the drug of choice for persons with hypertension.
It has a higher rate of treatment emergent mania than many modern antidepressants, and many people find it to be a more activating medication than other antidepressants. Paradoxically, some users find it highly sedating and find that it must be taken in the evening.
[edit] Suicide Ideation/Risk
A Black Box Warning has been issued with Effexor and with other SSRI and SNRI anti-depressants advising of risk of suicide. Thoughts of suicide (suicide ideation) as potential risk of suicide as shown in studies by Wyeth and reported on their datasheet for Effexor were twice that of placebo (4% compared to 2%, however, no suicides occurred in these trials).<ref name="Medicinedatasheet-Wyeth"/> The black box warnings advise physicians to carefully monitor patients for suicide risk at start of usage and whenever the dosage is changed. There is an additional risk if a physician misinterprets patient expression of adverse effects such as panic or akathisia as symptoms of worsening depression rather than effects of the medication and increases dose. Assessment of patient history and comorbid risk factors such as drug abuse are recommended when evaluating the safety of venlafaxine for individual patients. These cautions are emphasized in Wyeth's information sheet with special precautions if prescribed to children. The extent of this effect and the actual risk are not known as studies may exclude individuals with higher risk.
In the UK, one study evaluated whether risk factors for suicide were more prevalent among patients prescribed venlafaxine than patients prescribed other antidepressants. Results showed patients prescribed venlafaxine were more likely to have attempted suicide in the previous year, although it was concluded that venlafaxine had been selectively prescribed to a patient population with a higher burden of suicide risk factors to begin with, and that this might have led to a higher future risk of suicide independent of any drug effect. Studies with baseline data are required to determine the actual risk with venlafaxine.<ref>Mines D, Hill D, Yu H, Novelli L (2005). "Prevalence of risk factors for suicide in patients prescribed venlafaxine, fluoxetine, and citalopram". Pharmacoepidemiol Drug Saf 14 (6): 367-72. PMID 15883980.</ref>
Several patients have reported acute relapse into depression upon withdrawal, along with a strong sensation of "electric shocks in the brain".<ref>my therapy discussion</ref>
[edit] Serotonin Syndrome
Another risk is Serotonin syndrome. This is a serious effect that can be caused by interactions with other drugs and is potentially fatal.<ref>Adan-Manes J, Novalbos J, López-Rodríguez R, Ayuso-Mateos J, Abad-Santos F (2006). "Lithium and venlafaxine interaction: a case of serotonin syndrome". J Clin Pharm Ther 31 (4): 397-400. PMID 16882112.</ref> This risk necessitates clear information to patients and proper medical history. For example, the drug abuse by at risk patients of certain non-prescription drugs can cause this serious effect and emphasizes the importance of good medical history sharing between General Practitioners and Psychiatrists as both may prescribe Venlafaxine. Involvement of family in awareness of risk factors is highlighted in Wyeth information sheets on Effexor.
[edit] Common side effects
- Nausea
- Ongoing Irritable Bowel Syndrome
- Dizziness
- Fatigue
- Insomnia
- Vertigo
- Dry mouth
- Sexual dysfunction
- Sweating
- Vivid dreams
- Increased blood pressure
- Electric shock-like sensations
- Increased anxiety at the start of treatment
- Akathisia (Agitation)
[edit] Less common to rare side-effects
- Cardiac arrhythmia
- Increased serum cholesterol
- Gas or stomach pain
- Abnormal vision
- Nervousness, agitation or increased anxiety akathisia
- Panic Attacks
- Depressed feelings
- Suicidal thoughts suicidal ideation
- Confusion
- Neuroleptic malignant syndrome
- Loss of appetite
- Constipation
- Tremor
- Drowsiness
- Allergic skin reactions
- External bleeding
- Serious bone marrow damage (thrombocytopenia, agranulocytosis)
- Hepatitis
- Pancreatitis
- Seizure
- Tardive dyskinesia
- Difficulty swallowing
- Psychosis
- Hostility
- Activation of mania/hypomania.
- Weight Loss (of concern when treating anorexic patients)
- Weight gain (effect not clear, but of concern when treating young women who may have Body Dysmorphic Disorder).
- Homicidal Thoughts Homicidal Ideations
[edit] Sexual Side Effects
Venlafaxine and other SNRIs and SSRIs have been shown to cause sexual side effects in some patients, both males and females.<ref>Werneke U, Northey S, Bhugra D (2006). "Antidepressants and sexual dysfunction". Acta Psychiatr Scand 114 (6): 384-97. PMID 17087787.</ref> Although usually reversible, these sexual side effects can, in rare cases, last for months or years after the drug has been completely withdrawn. This disorder is known as Post SSRI Sexual Dysfunction.
[edit] Dose dependency of adverse events
A comparison of adverse event rates in a fixed-dose study comparing venlafaxine 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine use. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value <= 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.<ref name="Medicinedatasheet-Wyeth"/>
[edit] Physical and Psychological Dependency
In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.<ref name="Medicinedatasheet-Wyeth"/>
Notwithstanding these in-vitro and non-human research findings, some patients using venlafaxine may become dependent on this drug. This is especially noted if a patient misses a dose, but can also occur when reduction of dosage is done with a doctor's care. This may result in experiencing withdrawal symptoms described as severe discontinuation syndrome. The high risk of withdrawal symptoms may reflect venlafaxines short half-life.<ref name="DrugSaf2001-Haddad"/> Missing even a single dose can induce discontinuation effects in some patients.<ref name="ANZ JPsych1998-parker"/> Discontinuation is similar in nature to those of SSRIs such as Paroxetine (Paxil® or Seroxat®). Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms.<ref name="AmJPsych1997-fava">Fava M, Mulroy R, Alpert J, Nierenberg A, Rosenbaum J (1997). "Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine". Am J Psychiatry 154 (12): 1760-2. PMID 9396960.</ref>
As the drug has direct impact on mood (i.e. anti-depressant), many users who have suffered the effects of attempted withdrawal from this drug define their dependency on the drug also as being addicted.<ref name="DrugSaf2001-Haddad">Haddad P (2001). "Antidepressant discontinuation syndromes". Drug Saf 24 (3): 183-97. PMID 11347722.</ref> Although many other drugs can cause withdrawal symptoms which are not associated with addiction or dependence, for example, anticonvulsants, beta-blockers, nitrates, diuretics, centrally acting antihypertensives, sympathomimetics, heparin, tamoxifen, dopaminergic agents, antipsychotics, and lithium,<ref name="DrugSaf2001-Haddad"/> addiction or dependence is a more common effect described for drugs that (are thought to, or may) improve mental well-being.<ref> Double D (1997). "Prescribing antidepressants in general practice. People may become psychologically dependent on antidepressants". BMJ 314 (7083): 829. PMID 9081020.</ref> An internet petition of effexor users and family members with more than 12,000 signatories describes the impact of discontinuation of this drug. It is therefore important that prescribing doctors explain the details of this drug to patients with care.
[edit] Overdose
Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities.<ref>Blythe D, Hackett L (1999). "Cardiovascular and neurological toxicity of venlafaxine". Hum Exp Toxicol 18 (5): 309-13. PMID 10372752.</ref> Venlafaxines toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants than the SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity.<ref name="QJM2003-Whyte"/> Deaths have been reported following large doses.<ref>Mazur J, Doty J, Krygiel A (2003). "Fatality related to a 30-g venlafaxine overdose". Pharmacotherapy 23 (12): 1668-72. PMID 14695048.</ref><ref>Banham N (1998). "Fatal venlafaxine overdose". Med J Aust 169 (8): 445, 448. PMID 9830400.</ref>
[edit] Management of Overdosage
There is no specific antidote for venlafaxine and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anti-convulsants. Forced diuresis, hemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of venlafaxine, due to the drug's high volume of distribution.<ref>Hanekamp B, Zijlstra J, Tulleken J, Ligtenberg J, van der Werf T, Hofstra L (2005). "Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report.". Neth J Med 63 (8): 316-8. PMID 16186642.</ref>
[edit] Footnotes
<references />
[edit] External links
[edit] Drug information
- U.S. Federal Drug Administration information on Effexor
- Efexor patient information leaflet Efexor patient information leaflet
- Effexor XR® prescribing information for healthcare professionals (pdf) (USA only)
- Detailed Patient/Parent Information on Effexor exellent
[edit] Industry pages
- The Offical website of Effexor XR The Official website of Effexor XR
[edit] Patient experiences
- Effexor petition by users detailing severe discontinuation effects and concerns
- Effexor Side Effects Patient comments.
[edit] Chemical data
| Phenethylamines edit |
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{2C-B} {2C-C} {2C-D} {2C-E} {2C-I} {2C-N} {2C-T-2} {2C-T-21} {2C-T-4} {2C-T-7} {2C-T-8} {3C-E} {4-FMP} {Amphetamine} {Bupropion} {Cathine} {Cathinone} {DESOXY} {Diethylcathinone} {Dimethylcathinone} {DOC} {DOB} {DOI} {DOM} {bk-MBDB} {Dopamine} {Br-DFLY} {Ephedrine} {Epinephrine} {Escaline} {Fenfluramine} {Levalbuterol} {Levmetamfetamine} {MBDB} {MDA} {MDMA} {MDMC/Methylone} {MDEA} {Mescaline} {Methamphetamine} {Methcathinone} {Methylphenidate} {Norepinephrine} {Phentermine} {Salbutamol} {Tyramine} {Venlafaxine} |
