Ambroxol

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Ambroxol
Ambroxol structural formulae.png
Ambroxol ball-and-stick.png
Clinical data
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ATC code
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  • In general: ℞ (Prescription only)
Identifiers
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ChEMBL
ECHA InfoCard100.038.621 Edit this at Wikidata
Chemical and physical data
FormulaC13H18Br2N2O
Molar mass378.10
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Ambroxol is a drug that breaks up phlegm, used in the treatment of respiratory diseases associated with viscid or excessive mucus. Recently, a hypothesis suggested that it may have a potential role in treatment of Paget's disease of bone, Parkinsonism, and other common diseases of aging-associated diseases involving dysfunction of autophagy.[1] It is the active ingredient of Mucosolvan, Mucobrox, Mucol, Lasolvan, Mucoangin, Surbronc, Ambolar, and Lysopain. The substance acts on mucus membranes, restoring the physiological clearance mechanisms of the respiratory tract (which play an important role in the body’s natural defence mechanisms) through several mechanisms, including breaking up phlegm, stimulating mucus production, and stimulating synthesis and release of surfactant by type II pneumocytes.[2][3] Surfactant acts as an anti-glue factor by reducing the adhesion of mucus to the bronchial wall, in improving its transport and in providing protection against infection and irritating agents.[4][5] Ambroxol is often administered as an active ingredient in cough syrup.

Medical uses[edit]

Ambroxol is indicated as "secretolytic therapy in bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus transport. It promotes mucus clearance, facilitates expectoration and eases productive cough, allowing patients to breathe freely and deeply".[6]

Ambroxol hydrochloride tablets in Japan

There are many different formulations developed since the first marketing authorisation in 1978. Ambroxol is available as syrup, tablets, pastilles, dry powder sachets, inhalation solution, drops and ampules as well as effervescent tablets.

Ambroxol also provides pain relief in acute sore throat. Pain in sore throat is the hallmark of acute pharyngitis.[7] Sore throat is usually caused by a viral infection. The infection is self limited and the patient recovers normally after a few days. What is most bothering for the patient is the continuous pain in the throat maximized when the patient is swallowing. The main goal of treatment is thus to reduce pain. The main property of ambroxol for treating sore throat is the local anaesthetic effect, described first in the late 1970s,[8][9] but explained and confirmed in more recent work.

Side effects[edit]

Field tests to date have not uncovered specific contraindications of ambroxol. However, caution is suggested for patients with gastric ulceration, and usage during the first trimester of pregnancy is not recommended.[10]

Mechanism of action[edit]

Ambroxol is a potent inhibitor of the neuronal Na+ channels.[11] This property led to the development of a lozenge containing 20 mg of ambroxol. Many state-of-the-art clinical studies[7] have demonstrated the efficacy of ambroxol in relieving pain in acute sore throat, with a rapid onset of action, with its effect lasting at least three hours. Ambroxol is also anti-inflammatory, reducing redness in a sore throat.

Ambroxol has recently been shown to increase activity of the lysosomal enzyme glucocerebrosidase. Because of this it may be a useful therapeutic agent for both Gaucher disease and Parkinson's disease.[12]

It was also recently shown that ambroxol triggers exocytosis of lysosomes by releasing calcium from acidic cellular calcium stores. This occurs by diffusion of ambroxol into lysosomes and lysosomal pH neutralization.[3] This mechanism is most likely responsible for the mucolytic effects of the drug, but may also explain the reported activity in Gaucher and Parkinson's disease.

Both ambroxol and its parent drug bromhexine have been shown to induce autophagy in several cell types, and ambroxol was shown to potentiate rifampicin therapy in a model of tuberculosis through host directed effects.[13][14]

Synthesis[edit]

Ambroxol synthesis.[15]

References[edit]

  1. ^ Numan M (2017). "Ambroxol hydrochloride, a chaperone therapy for Paget's disease of bone and other common autophagy-mediated aging diseases?". Integrative Clinical Medicine. 1 (2). doi:10.15761/ICM.1000107.
  2. ^ Seifart C, Clostermann U, Seifart U, Müller B, Vogelmeier C, von Wichert P, Fehrenbach H (February 2005). "Cell-specific modulation of surfactant proteins by ambroxol treatment". Toxicology and Applied Pharmacology. 203 (1): 27–35. doi:10.1016/j.taap.2004.07.015. PMID 15694461.
  3. ^ a b Fois G, Hobi N, Felder E, Ziegler A, Miklavc P, Walther P, Radermacher P, Haller T, Dietl P (December 2015). "A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca²⁺ release from acidic Ca²⁺ stores". Cell Calcium. 58 (6): 628–37. doi:10.1016/j.ceca.2015.10.002. PMID 26560688.
  4. ^ Sanderson RJ, Paul GW, Vatter AE, Filley GF (September 1976). "Morphological and physical basis for lung surfactant action". Respiration Physiology. 27 (3): 379–92. doi:10.1016/0034-5687(76)90066-9. PMID 989610.
  5. ^ Kido H, Okumura Y, Yamada H, Mizuno D, Higashi Y, Yano M (November 2004). "Secretory leukoprotease inhibitor and pulmonary surfactant serve as principal defenses against influenza A virus infection in the airway and chemical agents up-regulating their levels may have therapeutic potential". Biological Chemistry. 385 (11): 1029–34. doi:10.1515/bc.2004.133. PMID 15576322.
  6. ^ Malerba M, Ragnoli B (August 2008), "Ambroxol in the 21st century: pharmacological and clinical update", Expert Opin Drug Metab Toxicol., 4 (8): 1119–29, doi:10.1517/17425255.4.8.1119, PMID 18680446
  7. ^ a b de Mey C, et al. (2008), "Efficacy and safety of ambroxol lozenges in the treatment of acute uncomplicated sore throat", Arzneimittelforschung, 58 (11): 557–68, doi:10.1055/s-0031-1296557, PMID 19137906
  8. ^ Püschmann S, Engelhorn R (1978). "[Pharmacological study on the bromhexine metabolite ambroxol (author's transl)]". Arzneimittel-Forschung. 28 (5a): 889–98. PMID 581987.
  9. ^ Klier KF, Papendick U (December 1977). "[The local anesthetic effect of NA872-containing eyedrops]". Medizinische Monatsschrift. 31 (12): 575–8. PMID 593223.
  10. ^ "Ambroxol". Drugs.com. Retrieved 21 January 2014.
  11. ^ Weiser T (March 2006). "Comparison of the effects of four Na+ channel analgesics on TTX-resistant Na+ currents in rat sensory neurons and recombinant Nav1.2 channels". Neuroscience Letters. 395 (3): 179–84. doi:10.1016/j.neulet.2005.10.058. PMID 16293367.
  12. ^ McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, Foltynie T, Cooper JM, Abramov AY, Gegg M, Schapira AH (May 2014). "Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells". Brain. 137 (Pt 5): 1481–95. doi:10.1093/brain/awu020. PMID 24574503.
  13. ^ Choi SW, Gu Y, Peters RS, Salgame P, Ellner JJ, Timmins GS, Deretic V (July 2018). "Ambroxol induces autophagy and potentiates Rifampin antimycobacterial activity". Antimicrobial Agents and Chemotherapy: AAC.01019–18. doi:10.1128/AAC.01019-18. PMID 30012752.
  14. ^ Chauhan S, Ahmed Z, Bradfute SB, Arko-Mensah J, Mandell MA, Won Choi S, et al. (October 2015). "Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential". Nature Communications. 6: 8620. doi:10.1038/ncomms9620. PMC 4624223. PMID 26503418.
  15. ^ "Laboratory Synthesis Of Ambroxol". Synthesis of Drugs. 30 November 2011.