Article: Venlafaxine

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).

Since venlafaxine is under patent, under current United States law, a generic will not be available to U.S. citizens until 2008. The European patent on the drug will hold until 2017.

Trade Names

Venlafaxine is marketed under the tradenames Effexor^® in the UK, Efexor^®, Efectin^®, Effexor XR^® and Efectin ER^®

Uses

Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, and social anxiety disorder in adults. It is known as one of the most activating of the newer antidepressants. While this can be helpful to some, as a number of depressed patients report feeling exhausted and unmotivated, to others it poses the risk of increased anxiety and agitation.

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. It has also been found to reduce the severity of 'hot-flashes' in menopausal women^[1]. 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, and responses to psychiatric medications vary significantly from individual to individual.)

Off-label / Investigational Uses

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.

Description of Compound

The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [α- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride and it has the empirical formula of C₁₇H₂₇NO₂ · HCl. It is a white to off-white crystalline solid, 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).

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.^[2][3] It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitter in the synapse. At low and medium dosages, venlafaxine inhibits serotonin reuptake alone, similarly to a selective serotonin reuptake inhibitor (SSRI). At higher dosages (from about 225 mg/day), venlafaxine inhibits the reuptake of norepinephrine as well as serotonin. At high dosages (starting around 300 mg/day), it inhibits dopamine reuptake in addition to serotonin and norepinephrine.

Pharmacokinetics

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 3–4 weeks.

An Effexor XR^® 75 mg Capsule

Prescribed dosages are typically in the range of 75–225 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 eliminates this problem and has largely replaced the original in use.

Side effects - Serious Adverse Reactions

As with most antidepressants, lack of sexual desire can be a very disturbing side-effect for some persons. Venlafaxine can raise blood pressure at high doses, so it is usually not the drug of choice for persons with high blood pressure. Venlafaxine should not be used in children. Caution should also be used in those with a seizure disorder.

The energizing effect of the drug may come unwanted to some, possibly leading to an increased anxiety / depressed mind state. While the specific modality of effect is not well understood, a Black Box Warning has been issued with Effexor and with other SSRI and SSRN anti-depressants advising of risk of suicide. Some studies have questioned the effectiveness of the drug in helping depression. The black box warnings advise physicians to carefully monitor patients for suicide risk at start of usage and whenever the dosage is changed. Family members should be advised of this potentially fatal side effect so they may bring the patient to a hospital emergency for surveillance and protection. This drug is particularly risky for patients whose mental condition includes poor impulse control such as Borderline Personality Disorder, and if there is comorbid substance abuse.

Venlafaxine is sometimes used for the treatment of depressive phases of bipolar disorder. However, 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.

Another risk is Serotonin syndrome. This is a serious effect that can be caused by interactions with other drugs and is potentially fatal.

Common side effects include:

• Nausea
• Dizziness
• Sleepiness
• Insomnia
• Vertigo
• Dry mouth
• Sexual dysfunction
• Sweating
• Vivid dreams
• Increased blood pressure
• Electric shock like sensations

Less Common to rare side-effects include:

• 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

Interactions

Salvia divinorum Report of a man prescribed venlafaxine who experienced two seizure-like episodes on the two occasions that they tried to smoke Salvia divinorum. seizure-like Submitted via interaction form, Nov 2005, by PR

Amphetamine Case Report Dangerous Single case report of a 32 year old man prescribed both amphetamine (5mg x 3 per day) and venlafaxine (150mg x 1 per day) who presented with "marked agitation, anxiety, shivering and tremor." anxiety, shivering, tremor, serotonin syndrome Prior FH 2002

Lithium Case Report Dangerous Single case report of 50 year old woman prescribed both lithium and venlafaxine who was reported to have experienced serotonin syndrome. serotonin syndrome Mekler G 1997

Metoclopramide Case Report Dangerous Case report of 32 year old woman prescribed venlafaxine and administered metoclopramide in a hospital after an injury. She "developed movement disorder and a period of unresponsiveness. After a second dose of metoclopramide, these symptoms recurred and were associated with confusion, agitation, fever, diaphoresis, tachypnea, tachycardia, and hypertension." tachycardia, confusion, hypertension, serotonin syndrome Fisher AA 2002

Phenelzine (MAOI) Case Report Life-Threatening Several case reports of potentially dangerous interactions. One case report of 44 year-old woman who accidentally ingested phenelzine with venlafaxine and was admitted to an emergency department with lower extremity tremors and rapid respiration where she was diagnosed with serotonin syndrome. Other case reports involve patients who experienced serotonin syndrome while transitioning from phenelzine to venlafaxine. anxiety, tremors, rapid respiration, serotonin syndrome Weiner LA Diamond S 1998

Propafenone Case Report Dangerous Single case report of patient treated for bipolar affective disorder in which venlafaxine given with propafenone caused "markedly increased serum levels of venlafaxine correlating with unexpected psychopathological changes." psychosis Pfeffer F 2001

Tranylcypromine Case Report Life-Threatening One case report of 60 year-old woman who accidentally ingested venlafaxine while on a chronic prescription of tranylcypromine and experienced "altered mental status that progressed to hyperthermia and coma. She recovered quickly and without complications." hyperthermia, coma Hodgman MJ 1997

Trimipramine Case Report Life-Threatening Single case report of 25 year-old woman on 150mg per day of venlaxine and 100mg per day of trimipramine hospitalized when seizures occurred. Both drugs were discontinued and seizures stopped and did not recur. seizures Schlienger RG 2000

Severe discontinuation syndrome

Venlafaxine may cause potentially severe withdrawal symptoms upon sudden discontinuation (the recommended discontinuation is a drop of 37.5 mg per week; sudden stops are usually advised only in emergencies). These have a tendency to be significantly stronger than the withdrawal effects of other antidepressants including the tricyclic antidepressants, but are similar in nature to those of SSRIs such as Paroxetine (Paxil® or Seroxat®).

Discontinuation effects may include irritability, hostility, headache, nausea, fatigue, dysphoria and the fairly-unique "brain shivers". Rarer withdrawal symptoms include shaking legs, tremor, vertigo, dizziness and paresthesia. Other non-specific mental symptoms may include impaired concentration, bizarre dreams, agitation and suicidal thoughts.

Antidepressant withdrawal effects do not indicate addiction, but are rather the results of the brain attempting to reach neurochemical stability after an abrupt change. These can be minimized or avoided by tapering off of the medication over a period of weeks.

The distinction between "withdrawal" effects and addiction may be nothing less than semantics to make a distinction between a prescribed anti-depressant and illicit drugs, as addicts also suffer withdrawal effects when trying to stop taking an illicit drug. This is in the vein of the use of the term "self-medicating" to feel good as a euphemism for addiction. People reading about a drug like Effexor should be aware of these choices of words to minimize the actual reality of withdrawal "effects".

Studies by Wyeth-Ayerst and others have reported occasional cases of withdrawal symptoms severe enough to require permanent use. In some of these cases, successful discontinuation was eventually achieved by the addition of fluoxetine, which was later discontinued itself without difficulty.

It is important for patients to be aware of these risks so their choice to take this drug is balanced against the severity of potential side effects. A petition to Wyeth, signed by more than 11,000 patients as of June 2006, argues that disclosure regarding the side effects and efficacy is neither full nor accurate and asks Wyeth to improve the Effexor documentation for patients and medical professionals.[4]

"Patel Carolina & Associates PLLC" filed a lawsuit in 2004 due to the discontinuation side effects of the drug.