Loxapine
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| Non-proprietary name | Loxapine | |||||||||||||||||||||
| other names |
2-chloro-11- (4-methylpiperazin-1-yl) dibenzo [ b , f ] [1,4] oxazepine ( IUPAC ) |
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| Molecular formula | C 18 H 18 ClN 3 O | |||||||||||||||||||||
| Brief description |
colorless solid |
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| Drug information | ||||||||||||||||||||||
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| Mechanism of action |
Antagonist at D 2 receptor - 5HT 2A receptor (main mechanism of action) |
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| properties | ||||||||||||||||||||||
| Molar mass | 327.81 g · mol -1 | |||||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
151-153 ° C (succinate) |
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| solubility |
soluble in dimethyl sulfoxide (DMSO) |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | ||||||||||||||||||||||
Loxapine (trade name Adasuve ) is a synthetically prepared chemical compound from the group of dibenzoxazepine - derivatives , as drug ( neuroleptic ) for rapid control of mild-to- morbid anxiety in adult patients with schizophrenia or bipolar disorder is employed.
Clinical information
Application areas (indications)
Loxapine is indicated for the rapid control of mild to moderate agitation in adult patients with schizophrenia or bipolar disorder.
Type and duration of application
Loxapine is the first neuroleptic to be used by inhalation . It may currently only be used under inpatient conditions. It is effective in doses of 4.5 mg up to a maximum of two times 9.1 mg each. Regular treatment should be initiated immediately after treatment of the acute symptoms of agitation.
Contraindications (contraindications)
Contraindications are hypersensitivity to loxapine or the metabolite amoxapine and patients with acute respiratory symptoms or active respiratory diseases ( asthma or chronic obstructive pulmonary disease COPD ).
Drug interactions
The simultaneous use of loxapine with alcohol, sedatives and sleeping pills such as benzodiazepines or substances that impair the respiratory function (e.g. opioid pain relievers) can be associated with excessive sleepiness and respiratory dysfunction up to respiratory failure. Loxapine is broken down by the CYP1A2 enzyme system . The faster breakdown means that the blood concentration of loxapine and its metabolic products is lower in smokers than in non-smokers. Simultaneous use of active substances such as the psychotropic drug fluvoxamine , the antibiotics ciprofloxacin and enoxacin , the antihypertensive drug propranolol or the anti-inflammatory drug rofecoxib can increase the side effects of loxapine.
pregnancy and breast feeding period
Newborns who have been repeatedly exposed to antipsychotics during the third trimester of pregnancy are at risk from side effects, including extrapyramidal symptoms and / or withdrawal symptoms, the severity and duration of which may vary after delivery. Animal experiments have shown that loxapine and its metabolites are excreted in the milk of lactating bitches. The amount in which loxapine or its metabolites are excreted in breast milk is not known.
Special patient groups
The safety and efficacy of loxapine in patients under 18 years of age or over 65 years of age and in patients with impaired liver or kidney function has not been established.
Adverse effects (side effects)
Very common side effects: sedation / somnolence, taste disturbance. Common side effects: dizziness, throat irritation, dry mouth, tiredness. Uncommon side effects: upset, dyskinesis, dystonia, oculogyration (circular movement of the eyes), tremor, akathisia / restlessness, hypotension, bronchial spasms (including wheezing, shortness of breath or coughing). Loxapine affects the ability to drive and use machines.
Pharmacological properties
Mechanism of action (pharmacodynamics)
Loxapine is an antagonist of dopaminergic D2 receptors and serotonergic 5-HT2A receptors. In addition, the substance binds to noradrenergic, histaminergic and cholinergic receptors, which presumably also plays a role in the pharmacological effect. Its pharmacological classification as a more typical neuroleptic, in contrast to the chemical structure (dibenzoxazepine), which suggests classification as an atypical neuroleptic, is probably due to the extremely strong D2 antagonism (compared to 5-HT2A antagonism) and its side effect profile . This allows the effects of dopamine and serotonin to be suppressed in a targeted manner. The salt of succinic acid, loxapine succinate, is used medicinally.
Absorption and distribution in the body (pharmacokinetics)
The pharmacokinetics of inhaled loxapine are similar to intravenous administration and, due to the rapid absorption, it acts correspondingly quickly. The time to reach the maximum plasma concentration (Tmax) is two minutes, the effect occurs after about ten minutes. This shows that Locaxapine is an extremely fast and innovative alternative to previous therapy options. Loxapine is rapidly removed from the plasma and distributed into the tissues. Animal studies that were carried out following oral administration indicate an initially preferential distribution in the lungs, brain, spleen, heart and kidneys. Loxapine is 96.6% bound to human plasma proteins. It is extensively metabolized in the liver to form several metabolites. The three main metabolic pathways include hydroxylation to form 8-OH-loxapine and 7-OH-loxapine, N-oxidation to form loxapine N-oxide, and demethylation to form amoxapine. 8-OH-loxapine has no pharmacological effect on the D2 receptor, while the minor metabolite, 7-OH-loxapine, has a high binding affinity for D2 receptors; loxapine is a substrate for several CYP450 isoenzymes. In vitro studies showed that 7-OH-loxapine is primarily produced by CYP 3A4 and 2D6, 8-OH-loxapine is produced primarily by CYP 1A2, amoxapine is produced primarily by CYP 3A4,2C19 and 2C8, and loxapine- N -oxide is produced by FMO. Loxapine is largely eliminated within the first 24 hours. The metabolites are excreted with the urine in the form of conjugates and with the faeces unconjugated. The terminal elimination half-life (T½) is between 6 and 8 hours.
Chemical and pharmaceutical information
synthesis
The first step of the synthesis is the formation of a diaryl ether by means of the Williamson ether synthesis , in which a phenolate as nucleophile attacks the haloaromatic activated by the ortho nitro group in the sense of a nucleophilic aromatic substitution (S N Ar). Alternatively, catalysis by copper salts is also possible, which is also referred to as Ullmann ether synthesis. The nitro group has the function of an activator for the first reaction step. A primary aromatic amine is formed in the second step by reducing the nitro group in an acidic environment with the aid of metals such as zinc as a reducing agent .
The primary aromatic amino group is then reacted with phosgene to form the isocyanate . As phosgene is very toxic, ethyl chloroformate can also be used as an alternative . This is followed by the formation of an N , N -disubstituted urea derivative by addition of the secondary amine of methylpiperazine to the isocyanate group.
The last step of the synthesis is the somewhat modified Bischler-Napieralski reaction , which is usually used to prepare isoquinoline . Cyclodehydration occurs under the action of phosphorus oxychloride (POCl 3 ). Mechanistically, it is an electrophilic aromatic substitution (S E Ar) on the aromatic, for which several possible mechanisms are postulated.
- Alternative synthetic routes
Since the drug has been known for many years and has also been used in other countries for a long time, there are other possibilities for synthesis in the literature, including with other starting components or alternative reaction pathways. For example, the use of commercially available 2- (4-chlorophenoxy) aniline can replace the first steps or the ring closure can take place via the formation of a lactam .
Analytics
Identity verification
- Testing for chloride ions : The elimination of halogen from the organic compounds prior to the detection is carried out by hydrogenolysis with nascent hydrogen (from Zn / HCl or Raney nickel / ethanol ). The subsequent precipitation with silver nitrate (AgNO 3 ) results in a white precipitate.
- Testing for amidines : The acid-catalyzed hydrolysis yields an amide and a primary aromatic amine. After the amide has been saponified , the reaction products can be detected accordingly. Alternatively, direct detection of the amide after activation, for example by means of a hydroxamic acid reaction, is also possible.
- Testing for primary aromatic amines: The detection takes place via diazotization and coupling with electron-rich aromatics to give colored azo compounds .
- Testing for tertiary amines: Anhydrous citric acid dissolved in acetic anhydride leads to aconitic anhydride, which, with tertiary amines, gives a purple color.
- IR spectroscopy :v (CH) 3050 cm −1 = aromatic; v (CH) 3000-2850 cm −1 alkane; 2200–1700 cm −1 Aromat framework vibration ; v (C = C) 1600 cm −1 aromatic; v (CN) 1300-1200 cm −1 piperazine; 710 cm −1 ortho aromatic
- Mass spectrometry :Molecular peak 327 m / z; Isotope ratio of chlorine M + = 327 m / z, M +2 = 329 m / z. The molecular peak suggests an odd number of nitrogen atoms , which is also true for loxapine. (N = 3)
Purity testing
- Testing for heavy metals: As heavy metals such as B. zinc or copper are used, it makes sense to carry out the limit determination for heavy metals with thioacetamide reagent as a sulfite ion donor as part of the purity test.
Determination of salary
- Anhydrous titration: Since loxapine is a weakly basic drug, anhydrous titration with perchloric acid in glacial acetic acid (one equivalence point due to the tertiary amine) is possible.
- Precipitation titration: After hydrogenolysis, chloride can be determined by means of precipitation titration (silver chloride). Indexing options: Gay-Lussac , Mohr , Fajans .
See also
literature
- MS Jain, SJ Surana: Synthesis and evaluation of antipsychotic activity of 11- (40- (N-aryl carboxamido / N-aryl-a-phenylacetamido) -piperazinyl) -dibenz [b, f] [1,4] -oxazepine derivatives . In: Arabian Journal of Chemistry . 2013, doi : 10.1016 / j.arabjc.2013.07.033 .
- Wieland Gattermann: The practice of the organic chemist. 43rd edition. Walter de Gruyter, Berlin 1982, ISBN 3-11-006654-8 .
- Helmut Krauch, Werner Kunz: reactions of organic chemistry. 6th edition. Hüthig, Heidelberg 1997, ISBN 3-7785-2112-8 .
- Eberhard Ehlers: Analytics II - short textbook quantitative and instrumental pharmaceutical analysis. 11th edition. Deutscher Apotheker Verlag, Stuttgart 2008, ISBN 978-3-7692-4160-0 .
Individual evidence
- ↑ a b c d data sheet Loxapine succinate salt, solid from Sigma-Aldrich , accessed on August 28, 2014 ( PDF ).
- ↑ ChemScene: Loxapine , accessed on April 6, 2015.
- ↑ flexyx.com: Loxapine ( memento of April 13, 2013 in the Internet Archive ), accessed on April 6, 2015.
- ↑ a b c Christian Asche, Gesa Tietjens: New Drugs 2013 - Loxapine. ( Memento of July 28, 2014 in the Internet Archive ) at: apotheke-unterluess.de , accessed on July 26, 2014.
- ↑ a b c d e f ema.europa.eu: EPAR for Adasuve , accessed on April 6, 2015.
- ↑ Loxapine - approved as an inhaled antipsychotic. Springer-Medizin, July 31, 2013, accessed September 8, 2014 .
- ↑ Clarissa Muhlack: Certified training: Mental disorders. ( Memento from August 10, 2014 in the Internet Archive ) In: APOTHEKE + MARKETING 05/2014, p. 48.
- ↑ a b Eberhard Ehlers: Chemistry II - short textbook organic chemistry. 8th edition. Deutscher Apotheker Verlag, Stuttgart 2009, ISBN 978-3-7692-4884-5 .
- ^ T. Laue, A. Plagens: Name and keyword reactions of organic chemistry. 5th edition. Vieweg + Teubner, GWV Fachverlage, Wiesbaden 2006, ISBN 3-8351-0091-2 .
- ↑ a b c R.S. Vardanyan, VJ Hruby: Synthesis of Essential Drugs. Elsevier, 2006, ISBN 0-444-52166-6 .
- ^ A b c Hans Peter Latscha, Uli Kazmaier, Helmut Alfons Klein: Organic chemistry - chemistry basic knowledge. 6th edition. Springer-Verlag, Berlin / Heidelberg 2008, ISBN 978-3-540-77106-7 .
- ↑ a b J. Schmutz, F. Künzle, F. Hunziker, R. Gauch: About dibenzo [b, f] -1,4-thiazepines and oxazepines amino-substituted in the 11-position. In: Helvetica Chimica Acta . 1967, Vol. 50, pp. 245-254. doi : 10.1002 / hlca.19670500131 .
- ↑ a b c d e Eberhard Ehlers: Analytics I - short textbook qualitative pharmaceutical analytics. 9th edition. Deutscher Apotheker Verlag, Stuttgart 2007, ISBN 978-3-7692-4094-8 .
- ^ Hermann J. Roth, Kurt Eger, Reinhard Troschütz: Pharmaceutical Chemistry II - drug analysis . 3. Edition. Georg Thieme Verlag, Stuttgart 1990, ISBN 3-13-608403-9 .