Fluoxetine

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of fluoxetine
1: 1 mixture of ( R ) -form (top)
and ( S ) -form (bottom)
General
Non-proprietary name Fluoxetine
other names
  • ( RS ) - N -Methyl-3-phenyl-3- (4-trifluoromethylphenoxy) propylamine ( IUPAC )
  • Fluoxetinum ( Latin )
Molecular formula
  • C 17 H 18 F 3 NO (free base)
  • C 17 H 18 F 3 NO HCl ( hydrochloride )
Brief description

white to almost white, crystalline powder (hydrochloride)

External identifiers / databases
CAS number
EC number 611-209-7
ECHA InfoCard 100.125.370
PubChem 3386
ChemSpider 3269
DrugBank DB00472
Wikidata Q422244
Drug information
ATC code

N06 AB03

Drug class

Antidepressants

Mechanism of action

Selective serotonin reuptake inhibitor

properties
Molar mass 309.33 g · mol -1
Melting point
  • 179-182 ° C ( oxalate )
  • 158.4–158.9 ° C (hydrochloride)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
05 - Corrosive 07 - Warning 09 - Dangerous for the environment

danger

H and P phrases H: 302-318-400
P: 273-280-305 + 351 + 338
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Fluoxetine is a drug used against depression ( antidepressant ). It belongs to the class of selective serotonin reuptake inhibitors (SSRI). In 1975 the pharmaceutical company Eli Lilly was granted a patent for fluoxetine. After zimelidine, it was the second drug of the antidepressant generation of the SSRI and was launched in the USA in 1988 under the trade name Prozac (in Germany in 1990 as "Fluctin"). The active ingredient is only available on prescription in Germany.

Mechanism of action

The main action is to inhibit the uptake of serotonin ( SERT ) from the synaptic cleft , thereby prolonging the effect of serotonin . In addition, fluoxetine has direct effects on the serotonin receptors 5-HT 2C of the central nervous system . In high doses, fluoxetine can also inhibit the reuptake of norepinephrine .

Binding affinities of fluoxetine (K i ) in (nM)
Target Fluoxetine Norfluoxetine
SERT 1 19th
NET 660 2700
DAT 4180 420
5-HT 2A 200 300
5-HT 2B 5000 5100
5-HT 2C 72.6 91.2
α 1 3000 3900
M 1 870 1200
M 2 2700 4600
M 3 1000 760
M 4 2900 2600
M 5 2700 2200
H 1 3250 10,000

Its inhibitory effect on drug-degrading enzyme systems, such as cytochrome P450 2D6 or (also from the cytochrome P450 group) CYP2C19, is associated with numerous drug interactions.

Fluoxetine also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ) in high concentrations .

Fluoxetine inhibits SARS-CoV-2 in low concentrations in vitro , as tests with a virus isolate from a patient have shown. It does not target serotonin, but inhibits protein expression: After exposure to both fluoxetine isomers, SARS-CoV-2 viruses form the building blocks necessary for reproduction in humans to a reduced extent, so that virus replication is reduced. The researchers see this as having potential for the treatment of COVID-19 , also against the background that the patent has long expired and the agent is cheaply available from various companies. Fluoxetine, on the other hand, does not work against rabies viruses , human respiratory syncytial viruses , human herpes viruses 8 or herpes simplex viruses type 1 .

Therapeutic use

Indications

Fluoxetine is used to treat depression , obsessive-compulsive disorder and bulimia - as a supplement to psychotherapy to reduce binge eating and self-induced vomiting. The dose should be reviewed and, if necessary, adjusted within three to four weeks of starting treatment and thereafter when clinically indicated.

Prozac weekly , which contains 90 mg instead of 20 mg of fluoxetine, has been on the market in the USA for some time , so Prozac weekly only needs to be taken once a week. However, withdrawal symptoms are relatively rare compared to other SSRIs such as paroxetine .

Contraindications

Fluoxetine should not be used in conditions with abnormally high mood, so-called acute manic states.

Fluoxetine must not be taken together with certain medicines for depression or Parkinson's disease (so-called MAOIs ), as this can cause very serious (or even fatal) side effects.

Patients are allowed to use fluoxetine no earlier than 14 days after the end of treatment with an irreversible MAO inhibitor or take one day after stopping treatment with a reversible MAOI. Patients must also wait at least five weeks after stopping fluoxetine before taking any MAOIs. Switching from fluoxetine to an MAO inhibitor and vice versa must only be carried out under careful medical supervision.

Side effects

According to the manufacturer, the most common side effects associated with fluoxetine include: nausea (22% of the patients treated with fluoxetine complained of nausea, but only 9% of the placebo control group), insomnia (19% to 10%), fatigue (12 % / 5%), anorexia (10% / 3%), anxiety (12% / 6%), nervousness (13% / 8%), asthenia (11% / 6%), tremor (9% / 2%) . The side effects that were the main reasons for discontinuing fluoxetine treatment are anxiety, insomnia and nervousness, and mania in pediatric studies. Aggressive and suicidal thoughts and / or actions can also occur. In addition, sometimes severe rashes and hives can occur (7% of test subjects), which led to premature discontinuation of treatment in a third of those affected. Akathisia (restlessness and inability to remain still in one position) is also a rather common side effect. Akathisia usually starts immediately after starting therapy (or when the dose is increased) and usually disappears after treatment is stopped or the dose is decreased. Propranolol may also relieve symptoms. Similar to other SSRIs, sexual dysfunction - including anorgasmia and decreased libido  - is a very common side effect. In some cases, sexual dysfunction may persist after discontinuation ( SSRI-related sexual dysfunction ).

Interactions

In combination with drugs that also have an effect on the serotonin system or affect the metabolism of serotoninic drugs, the so-called serotonin syndrome can occur. In clinical pharmacology deaths have been documented sporadically. Therefore particular caution is required here. Medicinal substances with this effect are St. John's wort, monoamine oxidase inhibitors (e.g. moclobemide), linezolid (antibiotic), tramadol , triptans , lithium and tryptophan .
With other CNS -active substances (such as phenytoin , carbamazepine , haloperidol , clozapine , diazepam , alprazolam and tricyclic antidepressants ) a shift in blood levels and symptoms of toxicity can occur. Abnormal skin bleeding and other bleeding have been observed
with the concomitant use of anticoagulants and other medicinal products that affect platelet function (for example, atypical neuroleptics , tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs ) .

Fluoxetine is also strongly bound to plasma protein (94 percent) and is an inhibitor of numerous drug-degrading enzymes that are metabolised by the liver, such as CYP2D6 and CYP2C9 / 19. Due to the metabolism, drugs with a narrow therapeutic range (e.g. carbamazepine, tricyclic antidepressants or flecainide ) must be adjusted in their dose, otherwise the plasma concentration can be increased and lead to undesirable effects. Fluoxetine also slows down the breakdown of diazepam. In principle, alcohol should be avoided with centrally acting drugs.

Fluoxetine has a relatively long half-life of around 4 to 6 days and its active metabolite, norfluoxetine, around 4 to 16 days. As a result, active substance remains in the body for several weeks after it is discontinued, which must be taken into account in the event of interactions with other drugs.

Use in children and adolescents

Fluoxetine is not indicated in children under eight years of age. In children over eight years of age and adolescents, it is indicated for moderate to severe episodes of depression, taking into account the risk of suicide, in combination with simultaneous psychotherapeutic treatment. Fluoxetine can cause suicidal or hostile behavior in young people in these age groups. There are limited long-term data on the safety in young people of this age group for growth and mental development. The indication “ obsessive compulsive disorder ” had to be withdrawn due to the side effects and is now classified as “questionable”.

Other Information

chemistry

Stereochemistry

Fluoxetine is a chiral drug with a stereocenter . The active isomer ( eutomer ) is ( S ) -fluoxetine. The racemate , the 1: 1 mixture of the ( S ) and the ( R ) isomers, is used therapeutically .

synthesis

Several multi-stage syntheses for fluoxetine ( racemate ) and the specific production of ( R ) - or ( S ) -fluxocetine are described in the literature.

The synthesis described first starting from β-dimethylaminopropiophenone and p -trifluoromethylphenol leads to racemic fluoxetine. In this process, β-dimethylaminopropiophenone is reduced with diborane and reacted with thionyl chloride to give N , N -dimethyl-3-chloro-3-phenylpropylamine and then with p -trifluoromethylphenol to give N , N -dimethyl-3- (4-trifluoromethylphenoxy) -3-phenylpropylamine . This reaction product is reacted with N -Methylcyanamid in a Rosenmund-von Braun reaction to N -methyl- N reacted -3-phenylpropylamine-cyano-3- (4-trifluoromethylphenoxy). The cyanamide group inserted in this way is saponified in a strongly alkaline medium, the reaction product fluoxetine being formed.

history

Based on the observation that the serotinergic H1 antihistamine diphenhydramine shows antidepressant effects, the search for an active substance that acts selectively on serotonin with less sedating and fewer anticholinergic side effects began. Fluoxetine was then developed by the pharmaceutical company Lilly by the chemists Klaus Schmiegel , David T. Wong , Ray W. Fuller and Bryan B. Molloy and introduced on the market in 1987 as the world's supposedly first SSRI. This claim was later withdrawn because in fact, zimelidine was one of the first SSRIs to hit the market. The manufacturer achieved large sales with it; it is widely used in the USA and Great Britain, among others. In the USA, the number of fluoxetine users is estimated at 20 million. It was celebrated there as a miracle drug after its introduction in 1987 and was considered a yuppie drug because of its drive- boosting effect.

Trade names

Monopreparations

Felicium (A), Floccin (A), Fluctin (D) (no longer available), Fluctine (A, CH), Fluocim (CH), Fluoxifar (CH), Fluxet (D), Mutan (A), NuFluo ( A), positive (A), Prozac (GB, USA), numerous generics (D, A, CH)

Veterinary medicine

Reconcile

Web links

Commons : Fluoxetine  - Collection of Images, Videos, and Audio Files

Individual evidence

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  2. ↑ a b Fluoxetine hydrochloride data sheet from Sigma-Aldrich , accessed on April 2, 2011 ( PDF ).
  3. ↑ a b Entry on fluoxetine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  4. ↑ DE69233124T2 DE69233124T2
  5. ↑ Psychiatric Drugs Timeline .
  6. ↑ taz conversation: with John Rengen about advertising methods in connection with fluoxetine , January 11, 2007.
  7. ^ A b Carlsson A, Wong DT: A note on the discovery of selective serotonin reuptake inhibitors . In: Life Sci . 61, No. 12, 1997, p. 1203. doi : 10.1016 / S0024-3205 (97) 00662-0 . PMID 9315511 .
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  10. ↑ Torsten Kratz, Albert Diefenbacher: Psychopharmacotherapy in old age. Avoidance of drug interactions and polypharmacy. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f. (July 22) 2019, pp. 508-517, especially pp. 509-511.
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  44. ↑ AM comp. d. Switzerland (August 2009).
  45. ↑ AGES-PharmMed (August 2009).