Clozapine

Structural formula
General
Non-proprietary name	Clozapine
other names	8-chloro-11- (4-methylpiperazin-1-yl) -5 H -dibenzo [ b, e ] [1,4] diazepine ( IUPAC ) Clozapinum ( Latin )
Molecular formula	C 18 H 19 ClN 4
External identifiers / databases
CAS number 5786-21-0 EC number 227-313-7 ECHA InfoCard 100.024.831 PubChem 2818 DrugBank DB00363 Wikidata Q221361
Drug information
ATC code	N05 AH02
Drug class	Atypical neuroleptics
Mechanism of action	D 4 receptor - antagonist
properties
Molar mass	326.82 g · mol -1
Physical state	firmly
Melting point	183-184 ° C
pK s value	7.5
solubility	Water 11.8 mg l −1 (25 ° C)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances danger H and P phrases H: 301-341-361 P: 281-301 + 310
Toxicological data	36.50 mg kg −1 ( LD 50 ,  mouse ,  iv ) 150 mg kg −1 ( LD 50 ,  mouse ,  oral ) 41.6 mg kg −1 ( LD 50 ,  rat ,  iv ) 251 mg kg −1 ( LD 50 ,  rat ,  oral ) 145 mg kg −1 ( LD 50 ,  dog ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Clozapine is a drug from the group of neuroleptics that is used in the treatment of therapy-resistant psychoses . The drug, which was introduced in the German-speaking area in 1972, is considered the first representative of the atypical neuroleptics . In contrast to classic neuroleptics, atypical neuroleptics only rarely resolve extrapyramidal motor disorders such as B. tardive dyskinesia .

Clozapine is considered to be a moderately potent neuroleptic . Due to its different type of mechanism of action, it is often in such schizophrenia used that do not or classical neuroleptics inadequate medication appeal. However, it is not possible to use it as the first choice because of the sometimes life-threatening side effects, including the very rare but often life-threatening agranulocytosis .

chemistry

Clozapine is a tricyclic dibenzodiazepine derivative {8-chloro-11- (4-methyl-1-piperazinyl) -5 H -dibenzo [ b, e ] - [1,4] -diazepine}. The substance is highly lipophilic and therefore easily accessible to the CNS .

pharmacology

Action profile

Clozapine interacts with various transmitter systems . The dopaminergic , adrenergic , cholinergic , serotonergic and histaminergic systems are influenced by the clozapine effect. Clozapine is a potent antagonist of α ₁ adrenoceptors , muscarinic acetylcholine M ₁ receptors, serotonin receptors (especially 5-HT _2A and 5-HT _2C receptors) and histamine H ₁ receptors. The interaction of clozapine with dopamine receptors is of particular interest . Clozapine primarily blocks the D ₄ dopamine receptor and also D ₁ , D ₃ and D ₅ receptors with a significantly lower affinity . The D ₂ blockade, which is presumably responsible for the majority of the antipsychotic effect in the "classic" neuroleptics, is also only slightly pronounced.

Although the pharmacology of clozapine has been very well studied at the receptor level, its antipsychotic effect cannot yet be fully explained. The antiserotonergic effect, mediated by 5-HT _2A receptors, should ensure that the disruptive effect does not occur by means of a “compensatory” dopamine release in certain areas of the brain ( substantia nigra ).

Pharmacokinetics

Clozapine is more than 90% absorbed , has a bioavailability of approx. 50–60% and a plasma half-life of 8 to 14 hours, on average 12 hours. The only effective metabolite is desmethyl-clozapine . The elimination takes place through metabolism and the excretion (excretion) of the metabolites mainly renally .

Clinical indications

Clozapine is only indicated under very strict indications for therapy-resistant psychoses . In addition, it can be used as the drug of first choice (according to approval) before quetiapine because of the lack of extrapyramidal motor disruptive effects in Parkinson's patients when psychotic symptoms that require treatment occur under dopaminergic medication , as well as in Huntington's disease sufferers.

unwanted effects

Clozapine very often leads to multiple side effects. These can have long-term consequences in the case of disposition ( obesity , diabetes). Often there is hypersalivation (increased saliva secretion), especially during sleep, and, as with other neuroleptics, other anticholinergic effects.

During therapy with clozapine there is often to very frequent weight gain (4–31%), in some cases to a considerable extent. This makes patient compliance much more difficult . Fatigue or sleepiness is very common. Other clozapine-specific risks are the development of diabetes mellitus , impairment of the body's own temperature regulation (generation of hyper- and hypothermia ), increased risk of epileptic seizures and the cardiotoxicity of the substance. There is also a suspicion that it can cause a selenium deficiency .

Clozapine has also been causally linked to pleural effusion .

Agranulocytosis

The most dangerous side effect is the possible development of agranulocytosis during the entire period of use . A decrease in white blood cells (see leukopenia , neutropenia ) is common when taking clozapine; therefore the blood count is usually closely monitored in order to detect a seriously dangerous decrease in the number of granulocytes in good time. If the drug is not discontinued immediately, there is danger to life - by around 1976, agranulocytosis had occurred in several hundred clozapine patients worldwide.

Most agranulocytoses (approx. 80%) occur in the first 18 weeks of ingestion, which is why the blood count is usually checked weekly during this time and then monthly later. According to more recent data from England, the agranulocytosis probability is 0.83%.

Withdrawal psychoses

When stopping clozapine, so-called withdrawal psychoses can occur, which , in terms of clinical picture, can be more serious than the psychosis originally treated. These reactions occur particularly after long-term, high-dose ingestion and are generally interpreted as "hypersensitization reactions" and are mostly due to the anticholinergic effect of the drug. In extreme cases, discontinuation of the preparation may fail completely. Careful, slow tapering is necessary in these cases. In rare cases, this can take weeks.

Interactions

Clozapine is metabolized via the cytochrome P450 -1A2 isoenzyme . Accordingly, substances that act as inhibitors of this enzyme (e.g. caffeine , fluvoxamine , ritonavir ) lead to an increase and those that induce its activity (e.g. carbamazepine , phenytoin , rifampicin , omeprazole , smoke ingredients ) lead to an increase Decrease in the plasma concentration of clozapine. Furthermore, the bone marrow depressant effect of some drugs can be intensified, as can the effect of anticholinergic and central depressant drugs. In patients who smoke, under certain genetic constellations, the clozapine level may rise as soon as they quit smoking. There are also known cases in which the clozapine level was reduced by taking omeprazole.

history

Clozapine was synthesized by the chemists Hunziker, Smutz and Eichenberger at Wander AG in Bern in 1958 as part of a screening of around 2000 substances for new antidepressants and patented in 1960. The antipsychotic effectiveness was initially not recognized; the potential drug remained a candidate for further testing because of its sedative effects in animal experiments .

The first series of tests with human volunteers produced rather unsatisfactory results around 1962. Therefore, further studies on humans followed only from 1966 - now on patients with chronically productive schizophrenia - and the antipsychotic effect was noticeable. In 1972 Clozapine was launched under the trademark Leponex . In 1975 the so-called "Finnish Epidemic" occurred. Within a short time, 16 patients developed granulocytopenia and 8 died.

It was not until 1990 that clozapine was introduced in the USA under the trade name Clozaril with great advertising effort. It has been described in multi-page advertisements in trade journals as the most significant breakthrough in antipsychotic therapy in two decades.

Anti-paradigmatic effect, naming

Until the mid-1960s, the theory of the “ neuroleptic threshold ” formulated by the psychiatrist Hans-Joachim Haase was widely recognized, according to which an antipsychotic effect (based on the dopamine blockade) should only set in with the appearance of the undesirable Parkinson's symptoms.

The clozapine refuted this theory very impressively. According to a legend, which was never confirmed by the manufacturer, the manufacturer is said to have called the preparation Leponex ^® , which was approved in German-speaking countries in 1972 : the name is then derived from the terms lepus ( Latin for rabbit ) and nex ( Latin for death ) and therefore means something like "Ha (a) se tot".

Cumulative deaths, consequences

In the years that followed, clozapine was prescribed increasingly frequently in Europe , as many patients tolerated it much better than haloperidol, for example . With the rapidly increasing number of prescriptions, reports of fatal agranulocytosis cases increased around 1975 - first in Finland , where the drug was only newly approved that year.

Once the clozapine was determined to be the trigger, the individual governments and the respective national approval authorities responded very differently - from the consistent withdrawal from the market (Finland and USA) to the continued approval with a few warnings (Germany).

In Germany, special regulations were only made in 1979 for the prescription of Leponex ^® , which, however, were unique in the entire pharmaceutical market: the doctor concerned had to report an intended clozapine prescription to the manufacturer, he received an information package , which he had to ensure compliance with in writing, and only then is the right to prescribe. In Germany, Novartis is now offering controls for specialist staff via a special service website. This website enables pharmacists to monitor compliance with the guidelines for the controlled use of Leponex. This avoided a state ban on the supply of clozapine.

In Switzerland the procedure is a little easier: the prescriptions for Leponex ^® and Clopin ^® eco must be marked by the doctor with the comment “BBK sic” (BBK = blood count control). The pharmacist sticks the adhesive on the original package with the above note on the prescription form. In this way, the health insurance company has control over the regular laboratory analyzes.

Current situation

Despite years of efforts by various manufacturers to find an equivalent antipsychotic based on clozapine without the dangerous harmful effects, this active ingredient has remained the only one that does not trigger Parkinson's symptoms even in high doses . A related and meanwhile very frequently used substance is olanzapine , which cannot yet be reliably assessed with regard to its long-term safety.

However, olanzapine and other newer neuroleptics such as quetiapine and risperidone do not appear to have an increased risk of agranulocytosis and are therefore preferred over clozapine.

Several generic clozapine drugs have been on the market since the late 1990s .

Commercial preparations

Dosage forms

Clozapine is commercially available as a tablet and solution for oral intake.

Trade names

Clopin (CH), Elcrit (D), Lanolept (A), Leponex (D, A, CH), various generics (D)

See also

• List of antipsychotics

Web links

Commons : Clozapine  - collection of images, videos and audio files

Individual evidence

1. ↑ ^{a b c} Entry on clozapine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
2. ↑ Entry on clozapine. In: Römpp Online . Georg Thieme Verlag, accessed on August 9, 2017.
3. ↑ ^{a b} Clozapine data sheet from Sigma-Aldrich , accessed on March 23, 2011 ( PDF ).
4. ↑ ^{a b c d e} 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 .
5. ↑ 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. 511.
6. ↑ Berthold Jany, Tobias Welte: Pleural effusion in adults - causes, diagnosis and therapy. In: Deutsches Ärzteblatt. Volume 116, No. 21, (May) 2019, pp. 377-385, here: p. 380.
7. ↑ Red List 2007 Online.
8. ↑ G. Bondolfi, F. Morel, S. Crettol, F. Rachid, P. Baumann, CB Eap: Increased clozapine plasma concentrations and side effects induced by smoking cessation in 2 CYP1A2 genotyped patients. In: Ther Drug Monit . 27 (4), Aug 2005, pp. 539-543. PMID 16044115 .
9. ^ A. Frick, J. Kopitz, N. Bergemann: Omeprazole reduces clozapine plasma concentrations. A case report. In: Pharmacopsychiatry . 36 (3), May 2003, pp. 121-123. PMID 12806570 .
10. ↑ Hans Bangen: History of the drug therapy of schizophrenia. Berlin 1992, pp. 92-93.
11. ^ Andrew Solomon , Far from the Tree: Parents, Children, and the Search for Identity . Scribner , New York 2012, ISBN 978-1-4767-0695-5 , chapter Schizophrenia .
12. ^ Doctor Revers Check ( Memento from September 29, 2007 in the Internet Archive ).
13. ↑ Red List, 2014.
14. ↑ Red List, 08/2009.
15. ↑ AM comp. d. Switzerland, 08/2009.
16. ↑ AGES-PharmMed, 08/2009.

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