Ambroxol

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Structural formula
Ambroxol structural formula
General
Non-proprietary name Ambroxol
other names

trans -4 - [(2,4-Dibromanilin-6-yl) methylamino] cyclohexanol

Molecular formula
  • C 13 H 18 Br 2 N 2 O (ambroxol)
  • C 13 H 18 Br 2 N 2 O HCl (ambroxol hydrochloride )
Brief description

white to yellowish, crystalline powder (hydrochloride)

External identifiers / databases
CAS number
  • 18683-91-5 (Ambroxol)
  • 23828-92-4 (ambroxol hydrochloride)
EC number 242-500-3
ECHA InfoCard 100,038,621
PubChem 2132
ChemSpider 10276826
DrugBank DB06742
Wikidata Q221637
Drug information
ATC code

R05 CB06

Drug class

Expectorant , local anesthetic

properties
Molar mass 378.10 g · mol -1
Physical state

firmly

Melting point

233–234.5 ° C (decomposition) (Ambroxol hydrochloride)

solubility
  • slightly soluble in water (hydrochloride)
  • soluble in methanol (hydrochloride)
  • practically insoluble in dichloromethane , acetone and diethyl ether (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
no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data

2720 ​​mg kg −1 ( LD 50 ,  mouse ,  oral , hydrochloride)

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ambroxol is a drug primarily used to treat productive coughs with thick, stuck phlegm.

Pharmacologically, Ambroxol is one of the cough relievers ( expectorants ) that are used in the therapy of acute and chronic diseases of the lower respiratory tract , which are associated with a disruption of mucus formation and transport. Ambroxol can also be used to treat acute sore throats .

The active ingredient is used pharmaceutically in its salt form as ambroxol hydrochloride .

Pharmacological properties

Expectorant effect

Ambroxol has a normalizing effect on both the serous and the mucous bronchial mucus by influencing the peribronchial glands and thus reducing the viscosity . The increased availability of the body's own surfactant with its surfactant properties contributes to the secretolytic effect. Ambroxol has an effect on mucociliary clearance (the removal of mucus from the bronchi), which has been shown in various clinical studies. The stimulation of the bronchial ciliated epithelium makes a contribution to improved mucociliary transport. Thanks to its antioxidant and anti-inflammatory properties, ambroxol also reduces processes that can damage the lungs. The protective effect of ambroxol has been shown in various studies. A significant reduction in the exacerbation rate of infections has been described for long-term therapy with ambroxol in patients with COPD . A cellular mechanism of ambroxol was discovered which explains this expectorant effect: Ambroxol activates the exocytosis of lamellar bodies by releasing Ca 2+ from acidic Ca 2+ stores. It does this by diffusing ambroxol into lysosomes and neutralizing lysosomal pH. This lysosomal secretion is probably also responsible for the positive effects of ambroxol in lysosomal storage diseases (Gaucher disease) and some Parkinson's diseases.

Pain relieving effect

Modern physiological studies show that ambroxol inhibits voltage-dependent sodium channels in pain-sensitive peripheral nerve cells. The inhibition was up to 50 times stronger than with other local anesthetics such as lidocaine or benzocaine. Current work has shown that ambroxol binds to the binding site for local anesthetics in the sodium channel pore, which is not surprising due to the chemical structure of ambroxol (local anesthetic structure according to Löfgren). Its effectiveness in the treatment of sore throats has been clinically proven in a total of five studies on over 1700 patients. In all studies, ambroxol was statistically significantly superior to placebo treatment in the clinically relevant range. However, the pain-relieving effect compared to placebo is assessed to be too low to recommend general use. In addition, it was observed in the studies that ambroxol significantly reduces the redness in the throat - as a clinical sign of an inflammatory reaction. The anti-inflammatory properties of ambroxol are supported by further data.

Clinical information

Hypersensitivity reactions, nausea, abdominal pain and vomiting are occasionally observed as side effects. As the occurrence of severe skin reactions ( Stevens-Johnson syndrome , Lyell syndrome ) in temporal connection with the use of ambroxol has been reported very rarely , if changes in the skin or mucous membranes occur, the intake must be stopped and medical advice sought immediately.

Expectorants containing ambroxol should only be used in children under two years of age on medical advice. Sore throat tablets containing ambroxol should not be used in children under 12 years of age.

Ambroxol crosses the placental barrier and is excreted in breast milk. The use of Ambroxol is not recommended during pregnancy and breastfeeding or should only be used after careful risk-benefit assessment.

Pharmaceutical information

Pure ambroxol hydrochloride: a white powder

Ambroxol is used in the form of its hydrochloride . There are various dosage forms for treating coughs, such as drops, juice, tablets, sustained-release capsules, effervescent tablets or inhalation concentrate. Lozenges are available for sore throats, which allow local treatment by acting on the mucous membrane of the mouth and throat.

Major published routes to ambroxol

synthesis

Ambroxol is the potent metabolite of bromhexine . The structure was designed by Dr. Karl Thomae GmbH (today: Boehringer Ingelheim ) enlightened and secured through synthesis. Vasicine served as the lead structure for the pharmacological development of bromhexine itself . Three synthesis routes to Ambroxol were patented in 1966. 17 years later, another process was filed that involves a redox reaction of sulfonyl hydrazides, the McFadyen-Stevens reaction , in which the aldehyde is captured in situ as a Schiff base , which is then reduced (see reaction scheme). Six years later this route was registered again from another side. Ambroxol is now exclusively produced in the Far East using this process.

Trade names

Monopreparations

Ambrobeta (D), Ambrobene (A), AmbroHexal (D, A), Ambrolan (A), Ambroxol-Ratiopharm (D), Expit (D), Frenopect (D), Larylin Cough Solver (D), Lindoxyl (D ), Lysopain (CH), Mucabrox (CH), Mucoangin (D, A), Mucosan (A), Mucosolvan (D, A, CH), Paediamuc (D), numerous generics (D, A)

Combination preparations

Ambrodoxy (D), Ambroxol comp (D), Broncho-Euphyllin (D), Doxy comp (D), Doxy plus (D), Mucospas (A), Spasmo-Mucosolvan (D)

Individual evidence

  1. ↑ a b c d European Pharmacopoeia . 6.2
  2. ^ The Merck Index . An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 66.
  3. ↑ a b German Pharmacopoeia. (DAB) 1999.
  4. ↑ a b Ambroxol hydrochloride data sheet from Sigma-Aldrich , accessed on May 9, 2017 ( PDF ).
  5. ↑ Sample Search for Ambroxol in a presentation on the STN version of "Pharmaceutical Substances".
  6. ↑ J. Germouty, JL Jirou-Najou: Clinical Efficacy of Ambroxol in the Treatment of Bronchial Stasis. Clinical Trial in 120 Patients at Two Different Doses . In: Respiration . tape 51 , Suppl. 1, 1987, pp. 37-41 , doi : 10.1159 / 000195273 , PMID 3299566 ( karger.com [accessed October 27, 2019]).
  7. ↑ R. Chianese, V. Maiorano, A. Bisceglie, N. Carnimeo: Controlled clinical trial of a new preparation for the treatment of bronchial hypersecretive pneumopathies. In: Arch Med Interna. 35 (2), 1983, pp. 139-154.
  8. ↑ TA de Castro, DV Cacanindin: Clinical Trial on Ambroxol in Acute and Chronic Bronchitis. In: Philipp J Intern Med. 26 (6), 1988, pp. 363-367.
  9. ↑ Wunderer among others: The cleaning system of the respiratory tract . In: Medical monthly for pharmacists . 32, 2009, pp. 42-47.
  10. ↑ M. Post, JJ Batenburg, EAJM Schuurmans, V. Oldenborg, AJ van der Molen: The perfused rat lung as a model for studies on the formation of surfactant and the effect of Ambroxol on this process . In: Lung . tape 161 , no. 1 , December 1983, pp. 349-359 , doi : 10.1007 / BF02713884 .
  11. ↑ Y. Kapanci, G. Elemer: ambroxol and secretion surfactant. Experimental studies on the incorporation of 3H-palmitate into pulmonary surfactant. Elsevier 1983, pp. 263-272.
  12. ^ Marie-Claude Prevost, Georges Soula, Louis Douste-Blazy: Biochemical Modifications of Pulmonary Surfactant after Bromhexine Derivate Injection . In: Respiration . tape 37 , no. 4 , 1979, p. 215–219 , doi : 10.1159 / 000194030 ( karger.com [accessed October 27, 2019]).
  13. ^ MF Heath, W. Jacobson: The inhibition of lysosomal phospholipase A from rabbit lung by ambroxol and its consequences for pulmonary surfactant . In: Lung . tape 163 , no. 1 , December 1, 1985, pp. 337-344 , doi : 10.1007 / BF02713834 .
  14. ↑ R. Chianese, V. Maiorano, A. Bisceglie, N. Carnimeo: Controlled clinical trial of a new preparation for the treatment of bronchial hypersecretive pneumopathies. In: Arch Med Interna. 35 (2), 1983, pp. 139-154.
  15. ^ C. Grassi, M. Luisetti, V. de Rose, A. Fietta, F. Sacchi, M. Genghini et al: Biomedical and functional changes in bronchoalveolar parameters induced by ambroxol treatment of chronic bronchitis . Elsevier 1983: 361-370.
  16. ^ CH Ericsson, J. Juhász, E. Jönsson, B. Mossberg: Ambroxol therapy in simple chronic bronchitis: effects on subjective symptoms and ventilatory function . In: European Journal of Respiratory Diseases . tape 69 , no. 4 , October 1986, p. 248-255 , PMID 3545883 .
  17. ↑ Zenglin Liao, Jiajia Dong, Wei Wu, Ting Yang, Tao Wang: Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARγ / NF-κB pathway . In: Respiratory Research . tape 13 , no. 1 , 2012, p. 110 , doi : 10.1186 / 1465-9921-13-110 , PMID 23199346 , PMC 3545883 (free full text).
  18. ↑ Mario Malerba, Beatrice Ragnoli: Ambroxol in the 21st century: pharmacological and clinical update . In: Expert Opinion on Drug Metabolism & Toxicology . tape 4 , no. 8 , August 1, 2008, p. 1119-1129 , doi : 10.1517 / 17425255.4.8.1119 , PMID 18680446 .
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  20. ^ A. Gillissen, D. Nowak: Characterization of N-acetylcysteine ​​and ambroxol in anti-oxidant therapy . In: Respiratory Medicine . tape 92 , no. 4 , April 1, 1998, pp. 609-623 , doi : 10.1016 / S0954-6111 (98) 90506-6 .
  21. ↑ Adrian Gillissen, Birgit archipelago Ling, Małgorzata Jaworska, Almut Bartling, Kurt Rasche Oxidant scavenger function of ambroxol in vitro: a comparison withn-acetylcysteine . In: Research in Experimental Medicine . tape 196 , no. 1 , December 1, 1996, p. 389-398 , doi : 10.1007 / BF02576864 .
  22. ↑ a b K. M. Beeh, J. Beier, A. Esperester, LD Paul: Antiinflammatory properties of ambroxol . In: European Journal of Medical Research . tape 13 , no. 12 , December 3, 2008, p. 557-562 , PMID 19073395 .
  23. ^ C. Grassi, M. Luisetti, V. de Rose, A. Fietta, F. Sacchi, M. Genghini et al: Biomedical and functional changes in bronchoalveolar parameters induced by ambroxol treatment of chronic bronchitis. Elsevier 1983, pp. 361-370.
  24. ↑ K. Nobata, M. Fujimura, Y. Ishiura, S. Myou, S. Nakao: Ambroxol for the prevention of acute upper respiratory disease . In: Clinical and Experimental Medicine . tape 6 , no. 2 , June 1, 2006, p. 79-83 , doi : 10.1007 / s10238-006-0099-2 .
  25. ↑ UH Cegla: Long-term therapy for 2 years with Ambroxol (Mucosolvan®) sustained-release capsules in patients with chronic bronchitis. Results of a double-blind study on 180 patients. In: Prax Klin Pneumol. 42, 1988, pp. 715-721.
  26. ↑ UH Cegla: Mucolytics - Are they useful in chronic mucus hypersecretion? Prophylaxis / treatment of airway mucus of COPD. In: Eur Respir Rev. 2 (9), 1992, pp. 289-291.
  27. ↑ Giorgio Fois, Nina Hobi, Edward Felder, Andreas Ziegler, Pika Miklavc: A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca2 + release from acidic Ca2 + stores . In: Cell Calcium . tape 58 , no. 6 , December 2015, p. 628–637 , doi : 10.1016 / j.ceca.2015.10.002 ( elsevier.com [accessed October 27, 2019]).
  28. ↑ Alisdair McNeill, Joana Magalhaes, Chengguo Shen, Kai-Yin Chau, Derralyn Hughes, Atul Mehta, Tom Foltynie, J. Mark Cooper, Andrey Y. Abramov, Matthew Gegg, Anthony HV Schapira: Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells . In: Brain . tape 137 , no. 5 , May 2014, p. 1481-1495 , doi : 10.1093 / brain / awu020 .
  29. ↑ Jennifer Reckzeh: The effect of the secretolytic ambroxol on neuronal sodium channels through the interaction with the local anesthetic binding site. Dissertation . Friedrich-Alexander University, Erlangen-Nuremberg 2010.
  30. ↑ Thomas Weiser, Nicola Wilson: Inhibition of Tetrodotoxin (TTX) -Resistant and TTX-Sensitive Neuronal Na + Channels by the Secretolytic Ambroxol . In: Molecular Pharmacology . tape 62 , no. 3 , September 1, 2002, pp. 433-438 , doi : 10.1124 / mol.62.3.433 , PMID 12181417 ( aspetjournals.org [accessed October 27, 2019]).
  31. ^ Weiser: Comparison of the effects of four Na + channel analgesics on TTX-resistant Na + currents in rat sensory neurons and recombinant Nav1.2 channels. In: Neurosci Lett. 395 (3), Mar 13, 2006, pp. 179-184. Epub 2005 Nov 15.
  32. ↑ Gaida et al .: Ambroxol, a Nav1.8-preferring Na (+) channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. In: Neuropharmacology . 49 (8), Dec 2005, pp. 1220-1227. Epub 2005 Sep 21.
  33. ↑ Andreas Leffler, Jennifer Reckzeh, Carla Nau: Block of sensory neuronal Na + channels by the secreolytic ambroxol is associated with an interaction with local anesthetic binding sites . In: European Journal of Pharmacology . tape 630 , no. 1 , March 25, 2010, p. 19-28 , doi : 10.1016 / j.ejphar.2009.12.027 .
  34. ↑ Wunderer et al.: Local anesthetics for pain therapy in pharyngitis. 27, 10, 2004, pp. 342-347.
  35. ↑ a b Jürgen Fischer, Uwe Pschorn, Jean-Michel Vix, Hubertus Peil, Bernhard Aicher: Efficacy and Tolerability of Ambroxol Hydrochloride Lozenges in Sore Throat . In: drug research . tape 52 , no. 4 , April 2002, p. 256-263 , doi : 10.1055 / s-0031-1299889 .
  36. ↑ a b Alexander Schutz, Hans-Jürgen Gund, Uwe Pschorn, Bernhard Aicher, Hubertus Peil: Local Anesthetic Properties of Ambroxol Hydrochloride Lozenges in View of Sore Throat . In: drug research . tape 52 , no. 3 , March 2002, p. 194-199 , doi : 10.1055 / s-0031-1299879 .
  37. ↑ a b c C. de Mey et al .: Efficacy and Safety of Ambroxol Lozenges in the treatment of Acute Uncomolicated Sore Throat. In: DrugRes. 58 (11), 2008, pp. 557-568.
  38. ↑ egms.de: Ambroxol for a sore throat: A meta-analysis . In: Forum Medicine. 21st, 45th Congress of General and Family Medicine.
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  42. ↑ EP 130 224 (1983): Liebenow W., Grafe I. (Ludwig Heuman & Co GmbH): Process for the preparation of 2-amino-3,5-dibromobenzylamines.
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