Sertraline

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of sertraline
General
Non-proprietary name Sertraline
other names

(1 S , 4 S ) -4- (3,4-dichlorophenyl) -1,2,3,4-tetrahydro- N -methyl-1-naphthylamine

Molecular formula
  • C 17 H 17 Cl 2 N (sertraline)
  • C 17 H 17 Cl 2 N HCl (sertraline hydrochloride )
Brief description

white - colorless

External identifiers / databases
CAS number
  • 79617-96-2 (sertraline)
  • 79559-97-0 (sertraline hydrochloride)
PubChem 68617
DrugBank DB01104
Wikidata Q407617
Drug information
ATC code

N06 AB06

Drug class

antidepressant

Mechanism of action

Selective serotonin reuptake inhibitor

properties
Molar mass
  • 306.23 g mol −1 (sertraline)
  • 342.69 g mol −1 (sertraline hydrochloride)
density
  • 1.353 g cm −3
Melting point
  • 290–291  ° C (sertraline)
  • 243–245 ° C (sertraline hydrochloride)
boiling point
  • 416.3 ° C at 760 mmHg (sertraline hydrochloride)
Vapor pressure
  • 3.85 10 −7  mmHg at 25 ° C (sertraline hydrochloride)
pK s value
  • pKa (water): 9.48 ± 0.04 (sertraline hydrochloride)
  • pKa (methanol: water, 40:60 v / v): 8.6 (sertraline hydrochloride)
  • pKa (ethanol: water, 1: 1 v / v): 8.5 (sertraline hydrochloride) .
solubility
  • 0.107182 g l −1 (25 ° C) in phosphate buffer
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances

Hydrochloride

no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Sertraline is a tricyclic chemical compound that belongs to the halogen aromatic compounds and amines . As an antidepressant from the group of selective serotonin reuptake inhibitors ( SSRI ), the substance is used against depression , anxiety disorders , panic disorders , post-traumatic stress disorders and obsessive-compulsive disorder .

In 2009 the Federal Institute for Drugs and Medical Devices (BfArM) significantly expanded the range of indications for sertraline.

General

Sertraline can already have a drive-boosting effect when taken for the first time (but it can also increase restlessness and sweating). The mood-enhancing effect sets in after seven days at the earliest. This effect then builds up over the next 7–21 days.

The administration of sertraline is carried out solely as a tablet administered orally , wherein sertraline hydrochloride is used. The plasma half-life is approximately 23 to 26 hours. Sertraline is excreted through the kidneys. If possible, sertraline should be taken in the morning, as the drug increases drive; however, it does not depend on meals.

The dosages used in the tablets depend on the disease and are 25 mg, 50 mg, 100 mg per tablet. The maximum permissible dose is 200 mg sertraline per day, with the intake taking place independently of the meal as a single dose in the morning or evening.

In patients who do not respond to a 50 mg dose, dose increases may be useful. Dose changes should be made in 50 mg increments at intervals of at least one week up to a maximum daily dose of 200 mg . Because of the 24-hour elimination half-life of sertraline, dose changes should not be made more than once a week. The therapeutic effect can occur within seven days . However, a therapeutic response can usually only be demonstrated after a long period of time. This is especially true for obsessive-compulsive disorder.

application areas

depression

Patients with severe depression could be successfully treated with sertraline. In the short-term treatment (up to twelve weeks) of dysthymia , sertraline is superior to placebo. Long-term use of sertraline proved to be more effective than interpersonal psychotherapy in one study . Sertraline is more effective than desipramine in treating compulsive depression . In patients with comorbid panic disorder, sertraline was as effective as imipramine but had fewer side effects. However, unpublished negative studies make it difficult to assess the effectiveness. Sertraline treatment is usually started with a starting dose of 50 mg / day.

Obsessive-compulsive disorder

Sertraline is more effective than placebo in treating obsessive-compulsive disorder in both adults and children. Sertraline was more effective than fluoxetine in treating obsession , but less effective than clomipramine . Sertraline is suitable for long-term treatment of obsessive-compulsive disorders.

Panic disorder

Sertraline is more effective than placebo at treating panic disorder . It is effective in both patients with and without agoraphobia . Therapy should be initiated at 25 mg / day and the dose increased to 50 mg once daily after one week. This dose regimen reduced the incidence of the side effects typically associated with panic disorder early in treatment.

Social phobia

Sertraline can be used successfully to treat social phobia . When treating social phobia with sertraline, it can take six to twelve weeks before the treatment is successful. In patients who only became ill in adulthood, the effectiveness is higher than in other patients. Therapy should be initiated at 25 mg / day and the dose increased to 50 mg once daily after one week. This dose regimen reduced the incidence of the side effects typically associated with panic disorder early in treatment.

Post-traumatic stress disorder

Sertraline is more effective than placebo in treating post-traumatic stress disorder (PTSD for short) in civilians. In some cases, the treatment is not successful until after the twelfth week. Patients whose condition had not improved by the twelfth week experienced an improvement in symptoms in 54% of the cases by the 24th week of treatment. The more severe the symptoms, the longer it took for patients to respond to treatment. A study of war veterans suggests that sertraline is effective on them too. In another study that also looked at war veterans, sertraline was not superior to placebo. While the effectiveness of sertraline has been well documented in women with PTSD, it is less well documented in men with PTSD.

pharmacology

Mechanism of action

Sertraline is a selective serotonin reuptake inhibitor designed to increase the concentration of serotonin in the synaptic cleft in the central nervous system . Other mechanisms of action are so weak that they can be neglected ( dopamine reuptake inhibitor with one percent of its SSRI potency; antagonist on the Sigma-1 receptor with five percent of its SSRI potency; α1-adrenoceptor antagonist with one to ten percent of its SSRI potency ). Sertraline also acts as a FIASMA (functional inhibitor of acid sphingomyelinase ).

Sertraline binding profile
receptor K i (nM)
SERT 2.8
NET 925
DAT 315
5-HT 2C 2,298
α 1 188
M 1 427
H 1 6.578

The main and side effects of sertraline can be derived from the binding profile of sertraline shown in the table. Sertraline selectively blocks predominantly the serotonin transporter (SERT), while it only weakly inhibits the dopamine transporter (DAT).

Metabolism

Absorption

In humans, after taking 50 to 200 mg sertraline once a day for 14 days, maximum plasma levels are reached 4.5 to 8.4 hours after the daily dose. The bioavailability of sertraline tablets is not significantly affected by food intake.

distribution

Plasma protein binding is approximately 98%.

Biotransformation

Sertraline is subject to extensive first-pass metabolism by the liver. Based on clinical and in vitro data, it can be assumed that sertraline is metabolized by several routes including the cytochrome P450 enzymes CYP3A4, CYP2C19 and CYP2B6. In vitro, sertraline and its main metabolite, desmethyl-sertraline, are also substrates for P-glycoprotein.

elimination

The mean half-life of sertraline is around 26 hours (22 to 36 hours). Corresponding to its terminal elimination half-life, there is an approximately twofold accumulation up to the steady-state concentration, which is reached after approximately one week when taken once daily. The half-life of N-desmethyl-sertraline is 62 to 104 hours.

Both sertraline and N-desmethyl-sertraline are extensively metabolized in the human body, with the resulting metabolites being excreted in equal parts in the faeces and urine. Only a small proportion (less than 0.2%) of unchanged sertraline is found in the urine.

Linearity / non-linearity

Sertraline exhibits dose proportional pharmacokinetics over a range of 50 to 200 mg.

Side effects

Central nervous disorders such as insomnia, drowsiness, headache and dizziness, gastrointestinal disorders such as nausea, diarrhea and dry mouth, and failure to ejaculate in men have been observed very frequently (in more than ten percent of those treated) when taking sertraline .

Common side effects (in one to ten percent of those treated) include agitation , nervousness , appetite disorders , tremor , increased sweating , blurred vision , rash , vomiting, dyspepsia , sexual dysfunction , hot flashes , urination disorders , palpitations and chest pain. Other side effects on the cardiovascular system were rarely observed in comparison with tricyclic antidepressants.

In addition, numerous other negative events have been reported since the market launch, the frequency of which cannot be estimated from the available data (possibly without a causal relationship with sertraline), including hallucinations , psychoses , coma , convulsions , spasms , hepatitis , jaundice , liver failure , Stevens-Johnson Syndrome , erythema multiforme , epidermal necrolysis .

Caution should be exercised in patients who suffer or have suffered from mania (abnormal high spirits) or hypomania (less severe symptoms). Mania / hypomania was reported in 0.4% of the test patients. Furthermore, euphoria, hallucinations or depressive moods can occasionally occur.

Studies of suicidal behavior (thoughts and attempts at suicide) and hostility (predominantly aggression, oppositional behavior and anger) have been observed with the use of sertraline and other SSRIs in children and adolescents . Aggression, suicidal and hostile behavior can also occur as side effects in adults.

Interactions

Possible serotonin syndrome

The serotonergic effect of sertraline can be enhanced by an MAO inhibitor up to the life-threatening serotonin syndrome . Therefore, concomitant use with irreversible MAOIs is an absolute contraindication. Concomitant use with reversible MAOIs, including the antibiotic linezolid , is a relative contraindication and should be avoided. A sufficiently long therapy-free phase (washout phase) is recommended when changing therapy. When taking other serotoninergic drugs at the same time, such as B. Triptans , symptoms of a serotonin syndrome could be observed in individual cases. For this reason, simultaneous use with other medicinal products with a direct or indirect effect on the serotonin system such as tryptophan or St. John's wort should be avoided.

Risk of bleeding due to inhibition of platelet aggregation

The risk of bleeding may be increased if antiplatelet drugs (such as NSAIDs , acetylsalicylic acid and ticlopidine ) or other medicines that may increase the risk of bleeding are given at the same time as sertraline. Simultaneous administration of warfarin ( 4-hydroxycoumarin ) resulted in a small but statistically significant increase in prothrombin time (by 7.9%).

Increase in the plasma level through enzyme inhibition

Sertraline is a weak to moderate inhibitor of the drug-metabolizing cytochrome P450 isoenzymes CPY2C19 and CYP2D6 . Simultaneous use with drugs that are broken down via this enzyme system can lead to a moderate increase in their plasma level. These interactions can be of clinical relevance in particular when high-dose sertraline is used at the same time with drugs with a narrow therapeutic range, for example antiarrhythmics such as propafenone and flecainide and tricyclic antidepressants. Other isozymes, including CYP3A4, CYP2C9, and CYP1A2, are not inhibited in a clinically significant manner by sertraline. The cytochrome P450 inhibitor cimetidine, on the other hand, leads to a considerable decrease in the rate of elimination of sertraline.

The naturally occurring flavonoid naringenin in grapefruit , like sertraline, is metabolized via CYP3A4 . In a crossover study conducted on eight Japanese people, drinking grapefruit juice (three glasses per day) increased plasma levels of sertraline by approximately 100 percent, which is why taking sertraline with grapefruit juice is not recommended.

Other

Simultaneous use with phenytoin can in individual cases increase the phenytoin plasma level, while the sertraline level is lower compared to the respective monotherapy. For its part, sertraline can potentiate the effects of the antipsychotic drug pimozide . Simultaneous use of sertraline and pimozide is contraindicated due to its narrow therapeutic range . The consumption of alcohol should be avoided during therapy, although studies on healthy volunteers did not show any impairment of mental and psychomotor abilities after simultaneous administration of sertraline and alcohol. Concomitant use of sertraline and lithium can lead to an increase in its drug side effects , especially tremors .

Withdrawal syndrome

→ Main article: SSRI withdrawal syndrome

Abrupt discontinuation of sertraline can cause symptoms such as agitation , dizziness, headache, sleep disorders, paresthesia , agitation, anxiety, confusion, tremor , nausea and sweating, sensations that are reminiscent of light electric shocks and usually radiate from the center of the body to the extremities , or occur all over the body (“brain zaps”). To avoid this, tapering the therapy is recommended. The symptoms described are not signs of psychological addiction development, but result from the physical dependence as a result of the downregulation of the serotonin receptors.

pregnancy and breast feeding period

According to the Pharmacovigilance and Advisory Center for Embryonic Toxicology at the Charité University Clinic, sertraline is "one of the antidepressants of choice for depression during pregnancy that require pharmacological therapy. A patient who is stable should continue her medication unchanged".

If a woman takes sertraline during pregnancy, sertraline and its main metabolite, N- desmethylsertraline, can be detected in the umbilical cord blood . No controlled clinical studies have been performed in pregnant women; However, the existing data does not provide any indications that sertraline leads to congenital malformations. Sertraline and N- desmethylsertraline pass into breast milk in small amounts in breastfeeding women . Even if no harmful effects have been observed in breast-fed infants to date, they cannot be ruled out.

Manufacturing

Sertraline is produced in a multi-stage synthesis. In the first step, starting from 3,4-dichlorobenzoyl chloride and benzene in the presence of aluminum chloride, the 3,4-dichlorobenzophenone is formed in a Friedel-Crafts acylation . Followed by an aldol condensation with diethyl succinate , decarboxylation of the aldol product with hydrobromic acid and hydrogenation , 4- (3,4-dichlorophenyl) -4-phenylbutyric acid is obtained as a racemate . After this has been converted into the acid chloride, it can be cyclized to the tetrahydronaphthalene structure in a Friedel-Crafts reaction. In the following steps, the target structure is obtained after reaction with methylamine and subsequent hydrogenation of the azomethine obtained. The desired stereoisomer is then obtained after separation of the diastereomers by means of crystallization and subsequent racemate resolution with D - (-) - mandelic acid .

Sertraline synthesis01.svg

Chinese authors have described a synthesis with a stereoselective hydrogenation of an imine intermediate.

toxicology

The determination of the lowest known toxic dose (TD Lo ) resulted in an oral value of 2.857 mg / kg for men and 7 mg / kg for women when administered over two weeks. Lethal doses of 336 mg / kg (mouse, oral, LD Lo ) and 840 mg / kg (rat, oral, LD Lo ) were determined in mice and rats . Toxic effects were hallucinations and other impaired perception, nausea and vomiting, sweating in men, headaches, changes in teeth and jaws, agitation in women.

Preclinical

It could be shown that sertraline has no mutagenic effect. Ingestion of low doses of sertraline in pregnant rats decreased the probability of newborn animals surviving . A similar effect could also be observed with other antidepressants. This increased mortality, observed only within the first days after birth, was demonstrably attributable to exposure to sertraline after the 15th day of gestation. Developmental delays observed in the pups after administration of sertraline to pregnant rats were probably caused by the effects of sertraline on the dams and therefore considered to be irrelevant for the risk assessment in humans.

Trade names

Monopreparations :

  • Zoloft (D, CH, USA)
  • Adjuvin (A)
  • Gladem (A)
  • Tresleen (A)
  • Sertraline generics (A, D, CH)
  • Asentra (PL)

Web links

Commons : Sertraline  - Collection of images, videos and audio files

Individual evidence

  1. ↑ Fei Chen, Tianli Wang, Yanmei He, Ziyuan Ding, Zhiwei Li, Lijin Xu, Qing-Hua Fan: Asymmetric Hydrogenation of N-Alkyl Ketimines with Phosphine-Free, Chiral, Cationic Ru-MsDPEN Catalysts in Chemistry - A European Journal 2011 , Vol. 17, No. 4, pp. 1109-1113, doi : 10.1002 / chem.201002846 .
  2. ↑ Fei Chen, Ziyuan Ding, Yanmei He, Jie Qin, Tianli Wang, Qing-Hua Fan: Asymmetric hydrogenation of N-alkyl and N-aryl ketimines using chiral cationic Ru (diamine) complexes as catalysts: the counteranion and solvent effects, and substrate scope in Tetrahedron 2012, vol. 68, no. 26, pp. 5248-5257, doi : 10.1016 / j.tet.2012.03.019 .
  3. ↑ Rupali Kalshetti, Venkataramasubramanian, Sanjay Kamble, Arumugam Sudalai: Concise enantioselective synthesis of (+) - sertraline and (-) - CP-52002 using proline catalysis in Tetrahedron Letters 2016, Vol. 57, No. 9, pp. 1053-1055 , doi : 10.1016 / j.tetlet.2016.01.085 .
  4. ↑ Caruso, Francesco; Besmer, Angela; Rossi, Miriam: The absolute configuration of sertraline (Zoloft) hydrochloride in Acta Crystallographica Section C: Crystal Structure Communications, 1999, Vol. 55, No. 10, pp. 1712-1714, doi : 10.1107 / S0108270199008343 .
  5. ^ Hermann Hager, Franz von Bruchhausen: Hager's handbook of pharmaceutical practice. Volume 5: Substances L – Z. Springer, 1999, ISBN 3-540-62646-8 , pp. 563-565.
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