quinine

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of quinine
General
Surname quinine
other names
  • (-) - (8 α , 9 R ) -6'-methoxycinchonan-9-ol
  • (-)-Quinine
  • 1- (6-Methoxyquinolin-4-yl) -1- (5-vinyl-1-azabicyclo [2.2.2] oct-2-yl) methanol (syst.)
  • 1- (6-Methoxyquinolin-4-yl) -1- (5-vinyl-1,4-ethanopiperidin-2-yl) methanol
  • QUININE ( INCI )
Molecular formula C 20 H 24 N 2 O 2
Brief description

white, odorless crystalline solid

External identifiers / databases
CAS number 130-95-0
EC number 205-003-2
ECHA InfoCard 100.004.550
PubChem 3034034
ChemSpider 84989
DrugBank DB00468
Wikidata Q189522
Drug information
ATC code
Drug class

Muscle relaxants , antimalarials

properties
Molar mass 324.42 g mol −1
Physical state

firmly

Melting point
  • 177 ° C
  • 57 ° C (trihydrate)
pK s value
  • 8.15-8.58 (quinine-H + / quinine)
  • 3.85-4.32 (quinine-2 · H + / quinine-H + )
solubility

very sparingly soluble in water (0.5 g l −1 at 20 ° 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
08 - Dangerous to health 07 - Warning

danger

H and P phrases H: 315-319-317-334
P: 261-280-284-304 + 340-305 + 351 + 338-342 + 311
Toxicological data
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Quinine ( listen ? / I ) is a natural chemical compound found in cinchona bark from the group of quinoline alkaloids . It is a white, very poorly water-soluble, crystalline powder with a bitter taste that is used as a bitter and medicinal substance . One diastereomer of quinine is quinidine . Audio file / audio sample

Occurrence

Quinine is obtained from the bark of the cinchona tree (often Cinchona pubescens , red cinchona tree, or Cinchona officinalis ) (family Rubiaceae , subfamily Cinchonoideae ).

Quinoline alkaloids are found in the bark of the cinchona tree.

The place of origin is the high forest (1500–2700 m above sea level) of the Andes ( Venezuela to Bolivia ). The name of the plant comes from the indigenous people ( Quechua quina-quina 'bark of the bark'), who already knew about the fever-reducing properties.

The Latin name Cinchona , after which the quinine was later named, probably got the plant after the Countess of Chinchón, wife of the viceroy Luis Jerónimo de Cabrera of the Spanish colonies, who allegedly got her from the malaria in 1638 by the doctor de Vega with a brew of bark powder could be cured. Jesuits ensured the spread of the remedy in Europe, hence the names Jesuit bark and cardinal powder.

Quinine is obtained in quantities of approx. 300 to 500 tons per year by bark extraction from cultivated plants, mainly in Indonesia , Malaysia and the Democratic Republic of the Congo ; some species contain 11 to 15 percent quinine in the bark.

history

Around 1630, South American Indians used plants of the Cinchona genus from the Andes area within Colombia and Bolivia for the first time against shivering from the cold. They also used it successfully for tremors caused by malarial fever .

Legend has it that in the 17th century the personal physician of the then Spanish viceroy of Peru managed to cure his wife, Condesa de Chinchon (1599–1640), who had malaria . This is said to have given the cinchona tree its name. A few years later, the Jesuit Barnabas Cobo (1582–1657) brought the cinchona to Madrid. There she reached the Jesuit Cardinal Juan de Lugo (1583-1660), who introduced the cinchona powder in Rome. He is considered the real propagandist of cinchona bark. For this reason, the Jesuits were solely responsible for sales. This led to a religious dispute, because many doctors protested against the monopoly of the Jesuits in the cinchona bark trade.

The effect of cinchona bark was controversial. There were doubters such as the French doctor Jean-Jacques Chifflet or the Parisian dean Guy Patin . The medical histories of two famous early patients confirm the controversies surrounding the effects of quinine:

  • On the one hand, the viceroy of the Netherlands Ferdinand von Habsburg died in 1641 of tertian fever (malaria). This led to quarrels after the cinchona bark was introduced in the Netherlands in 1645.
  • On the other hand, Archduke Leopold Wilhelm of Austria , who also fell ill with the fever in 1652, received extracts from the cinchona bark despite the concerns of his personal physician Chifflet and then recovered. In the event of a relapse, his brother, Emperor Ferdinand III. , from taking the drug again, whereupon Wilhelm died of malaria fever.

Although the Protestant countries were not convinced of the effects of cinchona bark , the English doctor Robert Talbor brewed a cinchona bark and sold it at a high price to Louis XIV in 1679. In 1663 the medicine had prevailed in Germany, although Georg Ernst Stahl rejected the use of cinchona bark . It was not until 1709 that Francesco Torti investigated the effectiveness of cinchona bark against malaria and was able to prove it. In the late 18th century, cinchona bark manifested itself as a therapeutic against malaria. One factor in this was the colonization of India, America and Southeast Asia in particular. The problem at that time, however, was that the bark still had to be imported from South America, which was very expensive on the one hand and very cumbersome on the other. In addition, the Andean republics gradually broke away from Spanish rule. As a result, new growing areas had to be developed.

At the beginning of the 19th century, shortly after the discovery of morphine, quinine was found as the active ingredient of cinchona bark and made a cornerstone of the emerging plant chemistry. It was already in 1792 by Antoine François de Fourcroy produced in impure state and in 1820 by Pierre Joseph Pelletier and Joseph Bienaimé Caventou by extraction with alcohol from the cinchona bark isolated. The extract was diluted with potassium hydroxide , whereupon a yellowish amorphous, very bitter-tasting precipitate formed. Pelletier and Caventou named the dried substance quinine. In 1823 it was obtained for the first time on an industrial scale from the bark of Cinchona species by the pharmacist Friedrich Koch in Oppenheim . The quinine then stimulated research in plant chemistry. From the middle of the 19th century, attempts were made to replace the expensive quinine with cheaper and / or more effective derivatives. This resulted in the poisonous breakdown product quinoline being obtained in 1856 , which in turn was used to research other febrile drugs. Via Kairin 1882, Antipyrin 1883 and other substances one came to pyramidon in 1896 , one of the first globally successful preparations of the pharmaceutical industry long before the constitution of quinine was known, which was explained by Pictet in 1911 .

In 1944, quinine was formally total synthesized by Robert B. Woodward , the actual total synthesis was only achieved by Milan R. Uskokovic in 1970.

The French François Magendie first analyzed the physiological effects of quinine around 1840.

With quinine, experimentally induced neuromuscular spasms were inhibited for the first time in 1916. Based on further research results from around 1930, two main effects of quinine crystallized out: a neurotropic (nerve-related) and a myotropic (muscle-related) effect.

properties

Quinine-containing drink under daylight (left) and UV light (right)

Quinine tastes bitter . It fluoresces in an acidic solution when exposed to ultraviolet radiation (315-380 nm) intensely light blue. The fluorescence disappears when hydrochloric acid is added , as the chloride ions it contains quench the fluorescence .

With chromium (VI) oxide (CrO 3 ) quinine can in acidic aqueous solution quinic acid and meroquinene oxidized are:

Oxidation of quinine

Effect and use

Medical use

Quinine is used to treat malaria (especially the complicated tropic malaria ); it prevents the formation of non-toxic β-hematin in the vacuoles of the blood schizonts from toxic ferriprotophyrin IX by complexing it. Contrary to earlier assumptions, the crystallization of β-hematin does not proceed enzymatically.

Malaria treatment takes place over one and a half to two weeks with oral administration of quinine salts in doses that correspond to at least 0.8 to 1.0 grams of free quinine base per day (e.g. daily dose of 1.95 grams of quinine sulfate dihydrate).

Quinine has an analgesic, narcotic and fever lowering effect in the immediate vicinity. In China , due to its antipyretic and analgesic effect, it is added in low doses to the treatment of flu-like infections .

In the pharmaceutical preparation as quinine sulphate, quinine has an antispasmodic effect and is therefore used for the prevention and treatment of muscle cramps (e.g. nocturnal calf cramps ). However, a much lower dose is used here than for malaria treatment. A daily dose of 200 to 400 milligrams is assumed. The quinine sulfate acts on the motor endplate at the connection points between nerves and muscle fibers. The function of the muscle is not impaired. The elimination half-life of quinine sulfate is 4–18 hours.

In the USA, quinine sulfate is only approved for the treatment of tropical malaria because of serious side effects, such as changes in the blood count ( thrombocytopenia ) or death. In Germany, however, the use of quinine for the prevention and treatment of nocturnal leg cramps is permitted. Studies have documented the reduction in the frequency, intensity and duration of cramps caused by quinine.

Due to the severe side effects, among other things, the Federal Institute for Drugs and Medical Devices ( BfArM ) has long required a prescription for Limptar (active ingredient quinine sulfate). The legislator has now complied with this: Since April 1, 2015, quinine has been subject to prescription, so it is no longer available for sale.

Quinine has a stimulating effect on the uterine muscles and was previously used as a means of promoting labor . In this context, quinine was aborted as an abortion drug, which often led to the death of the mother due to the intake of very high doses. The Federal Institute for Risk Assessment (BfR) warns pregnant women against consumption because of the effect on the uterine muscles.

Contraindications

Quinine can cause allergic reactions in sensitive people . In addition, the drug should be used cautiously in people who are hypersensitive to china alkaloids or xanthines. People with glucose-6-phosphate dehydrogenase deficiency , tinnitus , optic neuritis , myasthenia gravis , peptic ulcer or gastritis should avoid the product. Children, the elderly, or those with serious heart disease, liver disease, and kidney disease should not take quinine sulfate. Since quinine is teratogenic , it should not be taken by pregnant women. It is not a suitable drug during breastfeeding, as quinine is passed into the infant through breast milk .

Side effects

Possible oxidation of the hemoglobin by ingested quinine can cause methaemoglobinemia .

In the case of quinine sulphate, tinnitus , nausea and visual disturbances can occur , especially with long-term use and high doses . Other side effects affect the gastrointestinal tract , nervous system , cardiovascular system, and skin. Hypersensitivity is usually manifested by reddening of the skin, itching , fever , rash , stomach problems, ringing in the ears or visual disturbances. Rare side effects are hemoglobinuria , asthma, and thrombopenic purpura .

Quinine, like any preparation, is toxic depending on the dosage. An overdose leads to dizziness , headache , tinnitus , deafness , temporary blindness and cardiac paralysis , among other things . The side effects are based on an inhibition of enzymes of tissue respiration and a blockage of the synthesis of DNA . The lethal dose for an adult human is around five to ten grams of quinine. Death occurs from central respiratory paralysis .

Interactions

Since quinine prolongs the QT interval on the ECG , care must be taken not to take it with other drugs that also have a prolonging effect on the QT time . This could lead to torsades de pointes and cardiac arrest .

In the liver, quinine inhibits the breakdown of other active ingredients and thus increases the level of active ingredients. Interactions must be taken into account, especially with preparations such as digitalis , muscle relaxants and anticoagulants .

Non-medical use

The bitter-tasting quinine is added in small amounts to drinks such as bitter lemon or tonic water . The maximum amount permitted in Germany is 85 mg / kg in non-alcoholic beverages and 300 mg / kg in spirits . In general, it is a popular bitter maker in the food industry and can be found in bitters, for example .

However, since it is a pharmacologically active substance, its use in non-alcoholic beverages in Germany must always be indicated.

Quinine is occasionally used as an extender for heroin .

In the chemical reaction procedure, quinine or its derivatives can be used in asymmetric syntheses. Due to the fact that quinine can be obtained enantiomerically pure from nature, it is particularly used to form diastereomeric pairs with enantiomers , which differ in chemical and physical properties. This enables the previously chemically and physically identical enantiomers to be separated. Quinine also often serves as a catalyst component for the induction of specific stereochemical information so that a higher proportion of an enantiomer is obtained during a synthesis (high ee value ). Examples are epoxidations , dihydroxylations and amino hydroxylations on double bonds.

Trade names

Monopreparations
Limptar N (D, quinine sulfate)

literature

Web links

Remarks

  1. ↑ a b In the literature there are a number of values, some of which differ greatly, as pKa values ​​are strongly dependent on temperature and ionic strength. The source given as a reference lists a large number of values ​​for quinine with source and measurement conditions.

Individual evidence

  1. ↑ Entry on QUININE in the CosIng database of the EU Commission, accessed on February 26, 2020.
  2. ↑ a b c d Entry on quinine in the GESTIS substance database of the IFA , accessed on January 10, 2017(JavaScript required) .
  3. ↑ a b c Entry on China alkaloids. In: Römpp Online . Georg Thieme Verlag, accessed on June 8, 2011.
  4. ^ A b Harry G. Brittain: Profiles of Drug Substances, Excipients and Related Methodology: Critical… Academic Press, 2007, ISBN 0-12-260833-X , p. 354–356 ( limited preview in Google Book search).
  5. ↑ a b c d Entry on quinine in the ChemIDplus database of the United States National Library of Medicine (NLM)
  6. ↑ American Journal of Ophthalmology. Vol. 90, p. 403, 1980.
  7. ^ JM Arena, IL Springfield, CC Thomas: Poisoning; Toxicology, Symptoms, Treatments, 2nd Edition, 1970, p. 73.
  8. ^ Journal of Pharmacology and Experimental Therapeutics . Vol. 100, p. 408, 1950.
  9. ↑ Japanese Journal of Toxicology. Vol. 4, p. 105, 1991.
  10. ↑ Albert Gossauer: Structure and reactivity of biomolecules . Verlag Helvetica Chimica Acta, Zurich 2006, ISBN 978-3-906390-29-1 , p. 495.
  11. ↑ milestones . Edited by Bayer AG, Leverkusen, 1988, ISBN 3-921349-48-6 .
  12. ^ A b c Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Edition. Knowledge Verl.-Ges., Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 62 ff .
  13. ↑ a b c d Erika Hickel: The Medicines in History: Consolation and Deception - Salvation and Merchandise (=  Edition Lewicki-Büttner . No. 4 ). Bautz, Nordhausen 2008, ISBN 978-3-88309-419-9 , p. 180 ff .
  14. ^ Alfons Metzner: World problem health . Imhausen International Company , Lahr (Black Forest) 1961, p. 112.
  15. ↑ C. Gerhardt: Textbook of Organic Chemistry . Volume 4. Otto Eiland Verlag, Leipzig 1853, p. 113.
  16. ^ JJ Berzelius : Textbook of Organic Chemistry . Volume 5, Friedrich Vieweg and Son, Braunschweig 1856, p. 86.
  17. ↑ V. Gulliermond: About yellow cinchona bark . In: Pharmaceutisches Centralblatt , 1957, pp. 508-510.
  18. ↑ a b entry on quinine. In: Römpp Online . Georg Thieme Verlag, accessed on May 25, 2014.
  19. ^ Robert B. Woodward, Wilhelm E. von Doering: Total Synthesis of Quinine . In: Journal of the American Chemical Society , 1944, 66, pp. 849-849; doi: 10.1021 / ja01233a516 .
  20. ^ Robert B. Woodward, Wilhelm E. von Doering: Total Synthesis of Quinine . In: Journal of the American Chemical Society , 1945, 67, p. 860.
  21. ↑ Milan R. Uskokovic, Juerg Gutzwiller, Thomas Henderson: Total Synthesis of Quinine and quinidine I . In: Journal of the American Chemical Society , 1970, 92, pp. 203-204; doi: 10.1021 / ja00704a036 .
  22. ↑ Juerg Gutzwiller, Milan R. Uskokovic: Cinchona alkaloids. 2. Stereoselective total syntheses of quinine and quinidine . In: Journal of the American Chemical Society , 1978, 100, pp. 576-581; doi: 10.1021 / ja00470a036 .
  23. ↑ a b A. M. Harvey: The actions of quinine on skeletal muscle. In: The Journal of Physiology. Volume 95, Number 1, February 1939, pp. 45-67, PMID 16995079 , PMC 1393954 (free full text).
  24. ↑ Berg A. et al. In: Med.Welt 1985, 16, pp. 414-418.
  25. ^ K. spoon wood, I. Wessler. In: H. Mörl (Ed.): Muscle cramps . Springer Verlag, 1987, pp. 35-44.
  26. ↑ F. von Bruchhausen: Hager's Handbook of Pharmaceutical Practice: A drug-K . 5th edition. Springer Verlag, Berlin 1998, ISBN 3-540-61618-7 , p. 101.
  27. ↑ C. Vernon, H. Resch: The Oxidation of Optochin , in: J. Am. Chem. Soc. , 1932, 54, pp. 3455-3456, doi: 10.1021 / ja01347a072 .
  28. ^ Steinhilber, Schubert-Zsilavecz, Roth: Medicinal Chemistry . 2nd Edition. Deutscher Apotheker Verlag, Stuttgart 2010, Chapter 13.4 Antiprotozoal agents, p. 588.
  29. ↑ Beverages containing quinine can pose health problems . Federal Institute for Risk Assessment (BfR), Updated Health Assessment No. 020/2008, May 9, 2008.
  30. ↑ quinine. ( Memento from October 11, 2011 in the Internet Archive ) dge.de
  31. ↑ Limptar® N products . ( Memento of the original from February 7, 2011 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. klosterfrau.de @1@ 2Template: Webachiv / IABot / www.klosterfrau.de
  32. ↑ Limptar tablets (PDF; 17 kB) Pharmazie.com
  33. ↑ Entry on Quinine in the DrugBank of the University of Alberta , accessed November 18, 2019.
  34. ^ New risk management plan and patient Medication Guide for Qualaquin (quinine sulfate) . FDA Drug Safety Communication, July 8, 2010.
  35. ^ S. El-Tawil et al .: Quinine for muscle cramps (Review) . The Cochrane Collaboration, 2010: 12.
  36. ↑ Quinine (Limptar N): Hearing in the step-by-step plan procedure Stage II BfArM of December 20, 2013.
  37. ↑ Ordinance amending the Medicines Prescription Ordinance, the Pharmacy Operation Ordinance, the Ordinance on Pharmacy-Only and Over-the-Counter Medicines and the Medical Devices Dispensing Ordinance of December 19, 2014 ( Federal Law Gazette I p. 2371 ).
  38. ^ Publications on quinine. Federal Institute for Risk Assessment (BfR)
  39. ↑ alles-zur-allergologie.de .
  40. ↑ Specialist information Limptar tablets (PDF)
  41. ^ Methaemoglobinemia ( Memento of September 3, 2007 in the Internet Archive ) in the Roche Lexicon Medicine, 4th edition, Urban & Fischer Verlag, Munich 1984/1987/1993/1999.
  42. ↑ Virchow: About the effect of quinine on the respiratory metabolism of humans In: Naunyn-Schmiedeberg's Archives of Pharmacology , Heidelberg 1927 doi: 10.1007 / BF01863946
  43. ↑ Drug-induced QT prolongation and torsades de pointes . (PDF)
  44. ↑ Appendix 4 (to Section 2, Paragraph 3) Maximum quantities of certain substances in ready-to-eat flavored foods AromV
  45. ↑ § 5 AromV traffic ban
  46. ↑ Microgram Bulletin, Volume 42, Number 10, October 2009 ( Memento of the original from October 17, 2012 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. (PDF; 2.4 MB), Page 79. As of September 22, 2012. @1@ 2Template: Webachiv / IABot / www.justice.gov