Paroxetine
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[[Image:{{{image|Paroxetine.png}}}|{{{width|220}}}px|Paroxetine chemical structure]] | |
| (3S-trans)-3-((1,3-Benzodioxol-5-yloxy)methyl)- 4-(4-fluorophenyl)-piperidine hydrochloride IUPAC name | |
| CAS number 61869-08-7 | }}} |
| PubChem 43815 | DrugBank APRD00364 |
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19H{{#if:{{{1|}}}|{{{1}}}}}20F{{#if:{{{1|}}}|{{{1}}}|}}1N{{#if:{{{1|}}}|{{{1}}}|}}O{{#if:{{{1|}}}|{{{1}}}|}}3, Cl{{#if:{{{1|}}}|{{{1}}}|}}, 0.5 H{{#if:{{{1|}}}|{{{1}}}}}2O{{#if:{{{1|}}}|{{{1}}}|}} | molecular_weight = 374.8 | bioavailability = complete absorption from GI, but extensive first-pass-metabolization in the liver; max concentration 4.9 (with meals) to 6.4 hours (fasting) | metabolism = extensive, probable hepatic | elimination_half-life = Average 24 hours (Range 3-65 hours) | excretion = 66% urine, 37% bile | pregnancy_category = paroxetine is a possible teratogen, use in pregnancy only if strictly indicated | legal_status = Only available on prescription in most countries | routes_of_administration = Oral }}
Paroxetine or paroxetine hydrochloride (sold as Paxil® in the United States and Canada; Seroxat® in Austria, Poland, the UK and China; Aropax® in Australia, New Zealand and Brazil; Pondera® in Brazil; Deroxat® in Switzerland and France; Paroxat® in Germany, and Cebrilin in Latin America) is a selective serotonin reuptake inhibitor (SSRI) antidepressant. It was released in 1992 by the pharmaceutical company GlaxoSmithKline and has since become one of the most prescribed antidepressants on the market due to its efficacy in treating depression as well as a spectrum of anxiety disorders ranging from panic attacks to phobias.
Like some other antidepressants, it is also prescribed in the treatment of obsessive-compulsive disorder (OCD). It was the first (and as of 2002, the only) antidepressant formally approved in the United States for the treatment of social anxiety disorder, causing it to be sometimes referred to (although inaccurately) as an anti-shyness drug. Paxil is also approved in the United States for the treatment of post-traumatic stress disorder (PTSD).
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Pharmacology
Paroxetine is a potent and selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI). This activity of the drug on brain neurons is thought to be responsible for its antidepressant effects.
Paroxetine is a phenylpiperidine derivative which is chemically unrelated to the tricyclic or tetracyclic antidepressants. In receptor binding studies, paroxetine did not exhibit significant affinity for the adrenergic (α1, α2, β), dopaminergic, serotonergic (5HT1, 5HT2), or histamine receptors of rat brain membrane. A weak affinity for the muscarinic acetylcholine and noradrenaline receptors was evident. The predominant metabolites of paroxetine are essentially inactive as 5-HT reuptake inhibitors.
Chemistry
Paroxetine is chemically identified as (-)-trans-4R-(4-fluorophenyl)-3S-[(3,4-methylenedioxyphenoxy) methyl]piperidine hydrochloride hemihydrate (Immediate-Release Tablets / Oral Suspension), or (-)-(3S,4R)-4-[(p-fluorophenyl)-3-[(3,4-methylenedioxy)phenoxy]methyl] piperidine hydrochloride hemihydrate (Controlled-Release Tablets). Its empirical formula is C19H20FNO3, with a molecular weight of 374.8 (329.3703 as free base). Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water.
Side effects
Concerns are growing about the side effects of Paxil.
Recent studies have suggested that a small percentage of adolescents taking the drug are prone to becoming suicidal in the early stages of treatment. Some psychologists believe that this is due to the way the drug begins to work in many patients. The first effect most patients notice is a decrease in the lethargy and motivation they experienced during their depression. This effect happens before the depression itself improves, so children may end up with enough "energy" and motivation to act on suicidal tendencies they may have already had.
It is also important to note many adolescents who are prescribed Paxil are suicidal to begin with. However most studies have compared suicide rates in patients using Paroxetine against a control group of depressed individuals not being treated with paroxetine and the paroxetine group was reported to be twice as likely to commit suicide.
In June 2004, New York attorney general Eliot Spitzer began civil proceedings against GlaxoSmithKline over allegations that the company had suppressed five internal studies between 1998 and 2002 on the effects of the drug on both children and adults. The studies suggested that, in children, the drug had effects ranging from that of a placebo to inducing suicidal tendencies in its users. The company responded shortly later by making the results of the studies publicly available.
In March 2005, the United States Food and Drug Administration ordered the seizure of millions of tablets of Paxil after 3 years of GlaxoSmithKline's unresolved manufacturing problems. These problems involved Paxil CR, a time-release version of the drug. Some capsules were found to break in two, potentially resulting in the user taking only the active element of the drug without the time-release portion, or vice versa.
In September 2005 the Therapeutic Goods Administration (TGA) of Australia issued a warning about the potential for increased birth defects in the babies of pregnant women taking the anti-depressant Paroxetine. Early results from pharmaceutical giant GlaxoSmithKline suggest an association between taking the drug in the first three months of pregnancy and birth defects. The risk of cardiovascular defects may double from 1 to 2 percent in babies of women taking Paroxetine. A recent Dutch study suggests a 60 per cent increase in defects. The TGA is urging women not to suddenly stop taking the SSRI as withdrawal may cause harmful side effects. In December 2005, the United States Food and Drug Administration issued a similar public health advisory [1]. In this report, the FDA has decided to change paroxetine from pregnancy category C to D, indicating a higher degree of caution is warranted when using paroxetine in pregnant women.
Common side effects include:
- Drowsiness
- Nausea
- Anxiety
- Dry mouth
- Constipation
- Diarrhea
- Decreased or eliminated sexual desire
- Delayed or eliminated orgasm
- Rash
- Restlessness or akathisia
- Itch
- Sodium depletion
- Changes in urination
- Changes in appetite
Individuals experiencing any of the following symptoms should contact their doctor immediately:
- Jaw, neck, and back muscle spasms
- Fever, chills, sore throat, or flu-like symptoms
- Yellowing of the skin or eyes
- Black, tarry stools (this can indicate upper GI bleeding)
Despite these side effects, Paroxetine is effective and generally well-tolerated in adults. Paroxetine is a useful tool in treating major depression, particularly in adults who have not responded to other therapies.
Addictive potential
The manufacturers claim it is impossible to become addicted to paroxetine. Others disagree, and report dependence. The medical community generally considers that withdrawal symptoms are not enough to regard a drug as addictive; it has to leave the user needing more and more in order to gain the same desired effect. There seems to be some confusion on whether paroxetine and other SSRIs are addictive. They are not addictive in the classic sense as the user does not crave more of the drug. However, there is little or no doubt that withdrawal symptoms are present when stopping the drug and tolerance may develop over time. Withdrawal symptoms can include sensations of electric shocks in the brain, unusual dizzy feeling, gastro-intestinal upset and a host of other symptoms. Withdrawal symptoms usually disappear when another dose of the medication is taken. It is not, however, considered addictive in the strict sense because there is no actual craving for the drug (see Side Effects and Withdrawal Symptoms).
Withdrawal symptoms
There are personal and anecdotal accounts of withdrawal symptoms from paroxetine. See, for example, [2], [3] and [4]. This is referred to as 'discontinuation syndrome' and refers to problems which result upon immediate discontinuation of the drug.
Initially, the response of drug regulators (based eg on a report by Price et al, 1995) were that withdrawal symptoms (or 'discontinuation reactions' as SKB/GSK insisted) were generally mild and short-lived, an opinion that has been replaced by mounting concern. Now, it seems about a third of users have problems stopping paroxetine, and the symptoms are strikingly similar ('electric shock' paraesthesia, dizziness, flu-like symptoms, auditory hallucinations, etc). It is clear that what is under discussion is not psychological dependence.
Withdrawal symptom severity varies from individual to individual and can last from months to years. The most common and successful technique for protection against a difficult withdrawal experience is to lower dosage levels gradually over time. Symptoms arising from a dose change often don't fully appear for several weeks. Since paroxetine has a much shorter half life than other SSRIs like Prozac, people have occasionally sought to buffer their withdrawal plan with a liquid form of Prozac. In liquid form, dose diminishments of 1m.g. are easy to achieve.
Suicidal ideation is a frequently reported experience in those withdrawing from SSRIs like paroxetine. Never seek to withdraw from paroxetine or any other SSRI without supervision.
External links
- Paxil Information from Drugs.com
- Detailed Paroxetine Consumer Information: Uses, Precautions, Side Effects from medlibrary.org
- Press Release - Seroxat must not be used for treatment of children, Royal College of Psychiatrists
- The Secrets of Seroxat, BBC Panorama investigation
- Antidepressant Use in Children Soars Despite Efficacy Doubts, Washington Post, April 18, 2004
- Seroxat and Prozac 'can make people homicidal', The Guardian
- Paroxetine.com - The official paroxetine site
- Quitpaxil.org - Information for persons suffering from Paxil withdrawal syndrome
- Dependence on Antidepressants & Halting SSRIs - protocol for withdrawal
- NIH Expert Panel Report on the reproductive and developmental toxicology of Prozac (Fluoxetine)
- NIH Monograph on the potential human reproductive and developmental effects of Prozac (Fluoxetine)
fr:Paroxétine nl:Paroxetine ja:パキシル no:Paroxetin pl:Paroksetyna pt:Paroxetina ru:Пароксетин fi:Paroksetiini sv:Paroxetin