Citalopram
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| Non-proprietary name | Citalopram | ||||||||||||
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| Molar mass | 324.39 g · mol -1 | ||||||||||||
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||
Citalopram is a drug from the group of selective serotonin reuptake inhibitors (SSRI) and is used as an antidepressant in the treatment of depression. It is also used for other mental illnesses.
Citalopram was originally developed and patented by the Danish pharmaceutical company Lundbeck in 1989. There have been numerous generics since the patent expired in 2003 . With 290 million DDD ( defined daily dose ), Citalopram was the most frequently prescribed psychotropic drug in Germany in 2016 .
Citalopram is a racemic mixture of the enantiomers resulting from the synthesis ; the eutomer is escitalopram , which is also used as an SSRI.
indication
Originally developed to treat epilepsy , it is often used to treat depressive disorders as well as disorders associated with emotional instability (e.g. borderline personality disorder or bipolar disorder ) because of its mood-balancing effects . However, it can trigger mania in bipolar disorder . It can also be used to treat generalized anxiety , but has to be dosed about twice as high as usual for depression. It can also be used to treat panic attacks and post-traumatic stress disorder (PTSD).
In the case of depression, the mood-enhancing effect occurs after about two weeks, but the full effectiveness will probably only develop after two to four weeks of treatment.
The effect of SSRIs on the depressive syndrome depends on the severity of the illness. In mild depression, there is often no statistically demonstrable superiority over the administration of dummy drugs ( placebo ). In the case of more severe depression, however, around 50–75 percent of patients respond to an SSRI, while around 25–33 percent of patients respond to placebo.
Pharmacodynamics
The main and side effects of the selective serotonin reuptake inhibitor (SSRI) citalopram can be derived from the table below. From the binding affinities ( K i values ) in the table it can be seen that citalopram, which is considered here as a racemate, functions almost exclusively as a selective serotonin reuptake inhibitor, which happens through the specific inhibition of the serotonin transporter (SERT), with both the Norepinephrine transporter (NET), as well as the dopamine transporter (DAT) for citalopram no relevant therapeutic u. represents a molecular target .
| receptor | K i (nM) |
|---|---|
| SERT | 1.6 |
| NET | 6190 |
| 5-HT 2C | 617 |
| α 1 | 1211 |
| M 1 | 1430 |
| H 1 | 283 |
Pharmacokinetics
Citalopram has a relatively long half-life of about 36 hours (1.5 days); the substance is metabolized in the liver. As it is not sedating , the daily dose can also be taken in the morning.
unwanted effects
Unwanted effects such as sleep disorders, insomnia, nausea , dry mouth , gastrointestinal complaints, nervousness , headache , dizziness , tremors , palpitations, increased sweating , accommodation disorders of the eyes or weakness can occur immediately, but usually subside after a few days. As with all serotonin reuptake inhibitors, sexual disorders (especially orgasm difficulties ) must be expected. In some cases, they can persist for months or years after stopping the SSRI ( SSRI-related sexual dysfunction ). A common (1–10%) side effect is rhinitis .
The so-called serotonin syndrome can occur as a very rare side effect , which in extreme cases can be fatal. As with all SSRIs, this risk is greatly increased in combination with both serotonin precursors ( tryptophan and 5-HTP) and with MAOIs .
High fever, excitement, confusion, tremors, and short, jerky jerks of individual muscles can be signs of this serotonin syndrome. If a patient observes such symptoms, he must inform his doctor immediately.
Thoughts of suicide and worsening of an existing depression are further possible side effects if, in the context of depressive symptoms, there are sometimes thoughts of harming or committing suicide. Such thoughts may be intensified the first time you use antidepressants.
These thoughts are more likely to occur if you have previously had thoughts of killing or harming yourself, especially in young adults. Results from clinical studies have shown an increased risk of suicidal behavior in young adults aged 25 and under with a psychiatric illness who were treated with an antidepressant.
Citalopram has a prolonging effect on the QT interval . In October 2011 the first manufacturer Lundbeck announced new instructions for use for the original preparation Cipramil in cooperation with the responsible German authority ( BfArM ) . They are based on the evaluation of a study which showed a dose-dependent QT prolongation in the ECG under citalopram. The maximum dose of citalopram has generally been reduced to 40 mg daily and to 20 mg daily in the elderly and in patients with impaired liver function. These restrictions are to be extended to all generic approvals of citalopram in the implementation of a revised risk-benefit assessment by the Committee for Human Medicinal Products , which is why a step-by-step process was initiated in Germany . For a long QT syndrome Citalopram is contraindicated, as well as the concomitant use of citalopram with other drugs known to prolong the QT interval. Citalopram can lead to rash decisions (high spirits) as well as extremely increased personality behavior or willingness to conflict.
Like other antidepressants , citalopram may induce withdrawal symptoms , which should be taken into account when discontinuing therapy.
Interactions
Citalopram must not be taken at the same time as moclobemide (Aurorix, generics) or tranylcypromine (jatrosome, generics) (other drugs used to treat depression). They are among the so-called MAO inhibitors, which must not be used together with serotonergic agents, as this also increases the risk of serotonin syndrome. While there is a serotonin deficiency in a bad mood, there is then a life-threatening excess of serotonin.
A switch between citalopram and MAO-A inhibitors may only be made under careful medical supervision, and therapy-free days must be switched on. Citalopram must not be taken at the same time as pimozide .
Citalopram should not be used in patients who are being treated concomitantly with serotonergic active substances (e.g. tramadol , sumatriptan , oxitriptan or tryptophan (serotonin precursors)), as this can lead to an intensification of serotonergic effects ( serotonin syndrome ). A dangerous serotonin syndrome can also occur when the pain reliever fentanyl is administered at the same time , as was warned in March 2013.
Simultaneous administration of citalopram and St. John's wort preparations should be avoided. There are also interactions with a number of other drugs.
In comparison with other antidepressants, citalopram shows only a slight inhibition of the isoenzyme cytochrome P450 1A2 with regard to the cytochrome P450 enzyme system .
Application form
Citalopram can be administered orally ( film-coated tablet , drops) or intravenously (infusion). The active ingredient is mainly used as citalopram hydrobromide .
Use in pregnant women
There are insufficient data from the use of citalopram in pregnant women. However, animal studies have shown developmental delays in the fetus. It is not certain whether these results can be transferred to humans. Citalopram should only be used during pregnancy if clearly necessary. However, sudden discontinuation of citalopram during pregnancy should be avoided. Newborns should be closely monitored if citalopram was used in the last trimester of pregnancy.
Weaning problems
As an SSRI, citalopram has no dependency potential in the conventional sense (tests with animals with free access to SSRIs did not result in an independent increase in the dose). If you stop taking citalopram suddenly, you may experience symptoms such as dizziness, headache, nausea, sensory disturbances, tremors, anxiety, palpitations, increased sweating, nervousness and sleep disorders. Citalopram is therefore tapered off .
chemistry
Stereochemistry
Citalopram is chiral , it has a stereocenter . Hence there are two stereoisomers , the ( S ) -form and the ( R ) -form. Both the racemate [1: 1 mixture of the ( S ) form and ( R ) form] and the eutomer escitalopram [( S ) form] are used as medicinal substances . The pharmacological effects of the two enantiomers were investigated, with an earlier response to escitalopram being observed in some cases compared to citalopram.
synthesis
Citalopram can be produced in a four-step synthesis. In the first step, 5-bromophthalide is reacted with 4-fluorophenylmagnesium bromide to form a benzophenone intermediate. After reduction with lithium aluminum hydride and subsequent ring closure, a benzofuran intermediate is obtained. The third step involves the nucleophilic substitution of the bromine for a cyano function using copper (I) cyanide . The target compound is then obtained by reacting with 3-dimethylaminopropyl chloride in the presence of sodium hydride and dimethyl sulfoxide .
Trade names
Cipramil (D), Seropram (A, CH), numerous generics (D, A, CH)
Other trade names are Cipram (worldwide) and Celexa (USA, Canada).
Web links
- Critical evaluation
- Citalopram at Drugs.com - Drug Information Online
- Celexa at RxList - The Internet Drug Index
- Citalopram ODT at RxList
Individual evidence
- ↑ a b Data sheet Citalopram hydrobromide from Sigma-Aldrich , accessed on June 16, 2011 ( PDF ).
- ↑ Martin J. Lohse, Bruno Müller-Oerlinghausen: Psychopharmaka . In: U. Schwabe, D. Paffrath, W.-D. Ludwig, J. Klauber (Ed.): Drug Ordinance Report 2017 . Springer-Verlag GmbH, Berlin 2017, ISBN 978-3-662-54629-1 , p. 681-708 .
- ^ Swiss Society for Obsessive Compulsive Disorders: Drug Treatment of Obsessive Compulsive Disorders .
- ↑ H.-J. Möller, G. Laux, H.-P. Kapfhammer: Psychiatry and Psychotherapy. 3. Edition. Springer, Heidelberg 2008. 2 volumes. Volume 2, p. 426
- ↑ , Owens JM, Knight DL, Nemeroff CB Second generation SSRIs: human monoamine transporter binding profile of escitalopram and R-fluoxetine . In: Encephale . 28, No. 4, Jul-Aug 2002, pp. 350-5. PMID 12232544 .
- ↑ a b Rote-Hand-Brief from Lundbeck on October 31, 2011. (PDF; 133 kB) Retrieved on November 2, 2011 .
- ↑ Citalopram: dose-dependent QT interval prolongation: additions to the product information, negative benefit-risk ratio of the 60 mg strength . Federal Institute for Pharmaceuticals and Medical Products. Retrieved December 14, 2013.
- ↑ Rote-Hand-Liefe on Fentanyl®-Janssen and Durogesic SMAT (12, 25, 50, 75, 100 µg / h), transdermal patch (active ingredient: fentanyl): New warning notice, notification from the higher federal authority BfArM of March 11, 2013.
- ↑ a b Technical information Cipramil; Information as of 10/2007.
- ↑ 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, p. 509.
- ↑ J. Hyttel, KP Bøgesø, J. Perregaard and C. Sánchez: The pharmacological effect of citalopram Resides in the (S) - (+) - enantiomer , Journal of Neural Transmission 88 (1992) 157-160.
- ↑ JM Gorman et al .: Efficacy comparison of escitalopram and citalopram in the treatment of major depressive disorder, pooled analysis of placebo-controlled trails . CNS Spectrums 7, Suppl. 1 (2002) 40-44.
- ^ SA Montgomery: Escitalopram (S-enantiomer of citalopram): clinical efficacy and onset of action predicted from a rat model . Pharmacol. Toxicol. 88 (2001) 282-286.
- ^ A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications , 4th edition (2001) Thieme-Verlag Stuttgart, ISBN 978-1-58890-031-9 .
- ↑ Red List online, as of June 2010.
- ↑ AM comp. d. Switzerland, as of June 2010.
- ↑ AGES-PharmMed, as of June 2010.
