Quinine

Not to be confused with quinone.

Quinine

Systematic (IUPAC) name
(R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)- 8-vinylquinuclidin-2-yl)methanol
Clinical data
Trade names	Qualaquin
AHFS/Drugs.com	monograph
MedlinePlus	a682322
Pregnancy cat.	C (USA), D (Au)
Legal status	quinine is now banned in Australia unless specifically for malaria due to its tendency to kill blood platelets.[citation needed]
Routes	Oral, intravenous
Pharmacokinetic data
Bioavailability	76 to 88%
Protein binding	~70%
Metabolism	Hepatic (mostly CYP3A4 and CYP2C19-mediated)
Half-life	~18 hours
Excretion	Renal (20%)
Identifiers
CAS number	130-95-0 Y
ATC code	M09AA01 P01BC01
PubChem	CID 8549
DrugBank	DB00468
ChemSpider	84989 Y
UNII	A7V27PHC7A Y
KEGG	D08460 Y
ChEBI	CHEBI:15854 N
ChEMBL	CHEMBL170 Y
Chemical data
Formula	C20H24N2O2
Mol. mass	324.417 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19-,20+/m0/s1 Y Key:LOUPRKONTZGTKE-WZBLMQSHSA-N Y
Physical data
Melt. point	177 °C (351 °F)
N(what is this?)  (verify)

Quinine (US: /ˈkwaɪnaɪn/, UK: /ˈkwɪniːn, kwɪˈniːn/) is a natural white crystalline alkaloid having antipyretic (fever-reducing), antimalarial, analgesic (painkilling), anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic. Quinine contains two major fused-ring systems: the aromatic quinoline and the bicyclic quinuclidine.

Though it has been synthesized in the lab, quinine occurs naturally in the bark of the cinchona tree. The medicinal properties of the cinchona tree were originally discovered by the Quechua Indians of Peru and Bolivia; later, the Jesuits were the first to bring the cinchona to Europe.

Quinine was the first effective treatment for malaria caused by Plasmodium falciparum, appearing in therapeutics in the 17th century. It remained the antimalarial drug of choice until the 1940s, when other drugs replaced it. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical situations, i.e., as in impoverished regions. Quinine is available with a prescription in the United States and over-the-counter, in very small quantities, in tonic water. Quinine is also used to treat lupus and arthritis. Quinine was also frequently prescribed in the U.S. as an "off-label" treatment for nocturnal leg cramps, but this has since been prohibited, in effect, by an FDA statement warning against the practice.^[1]

Quinine is very sensitive to ultraviolet light (UV) and will fluoresce in direct sunlight, due to its highly conjugated resonance structure (see Quinoline).

Mechanism of action against P. falciparum

As with other quinoline anti-malarial drugs, the mechanism of action of quinine has not been fully resolved. The most widely accepted hypothesis of quinine action is based on the well-studied and closely related quinoline drug, chloroquine. This model involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, leading to their death.

History

Quinine^[2] is an effective muscle relaxant, long used by the Quechua Indians of Peru to halt shivering due to low temperatures. The Peruvians would mix the ground bark of cinchona trees with sweetened water to offset the bark's bitter taste, thus producing tonic water.

Quinine has been used in unextracted form by Europeans since at least the early 17th century. Quinine was first used to treat malaria in Rome in 1631.^[3] During the 17th century, malaria was endemic to the swamps and marshes surrounding the city of Rome. Malaria was responsible for the death of several popes, many cardinals and countless common Roman citizens. Most of the priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the febrile phase of the disease. The Jesuit brother Agostino Salumbrino (1561–1642), an apothecary by training who lived in Lima, observed the Quechua using the bark of the cinchona tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was unrelated to its effect in controlling shivering from rigors, it was still a successful medicine for malaria. At the first opportunity, Salumbrino sent a small quantity to Rome to test as a malaria treatment. In the years that followed, cinchona bark was known as Jesuit's bark or Peruvian Bark and became one of the most valuable commodities shipped from Peru to Europe.

The form of quinine most effective in treating malaria was found by Charles Marie de La Condamine in 1737.^[4][5] Quinine was isolated and named in 1820 by French researchers Pierre Joseph Pelletier and Joseph Bienaimé Caventou.^[6] The name was derived from the original Quechua (Inca) word for the cinchona tree bark, "quina" or "quina-quina", which roughly means "bark of bark" or "holy bark". Prior to 1820, the bark was first dried, ground to a fine powder and then mixed into a liquid (commonly wine) which was then drunk. Large-scale use of quinine as a prophylaxis started around 1850.

Quinine also played a significant role in the colonization of Africa by Europeans. It has been said that quinine was the prime reason that Africa ceased to be known as the "white man's grave". A historian has stated that "it was quinine's efficacy that gave colonists fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa".^[7]

To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the export of cinchona seeds and saplings beginning in the early 19th century. The Dutch government persisted in its attempt to smuggle the seeds, and by the 1930s Dutch plantations in Java were producing 22 million pounds of cinchona bark, or 97% of the world's quinine production.^[7] During World War II, Allied powers were cut off from their supply of quinine when the Germans conquered The Netherlands and the Japanese controlled the Philippines and Indonesia. The United States, however, had managed to obtain four million cinchona seeds from the Philippines and began operation of cinchona plantations in Costa Rica. Nonetheless, such supplies came too late; tens of thousands of U.S. troops in Africa and the South Pacific died due to the lack of quinine.^[7] Despite controlling the supply, the Japanese did not make effective use of quinine, and thousands of Japanese troops in the Southwest Pacific died as a result.^[8]

Synthetic quinine

Main article: quinine total synthesis

Cinchona trees remain the only economically practical source of quinine. However, under wartime pressure, research towards its synthetic production was undertaken. A formal chemical synthesis was accomplished in 1944 by American chemists R.B. Woodward and W.E. Doering.^[9] Since then, several more efficient quinine total syntheses have been achieved,^[10] but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine, was discovered by William Henry Perkin in 1856 while he was attempting to synthesize quinine.

Dosing and indication

As of 2006, quinine is no longer recommended by the WHO as first line treatment for malaria and should be used only when artemisinins are not available.^{[11][12][13][14]}

Quinine is a basic amine and is always presented as a salt. Various preparations that exist include the hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate. This makes quinine dosing complicated since each of the salts has a different weight.

The following amounts of each salt form contain equal amounts of quinine itself:

• quinine base 100 mg
• quinine bisulfate 169 mg
• quinine dihydrochloride 122 mg
• quinine hydrochloride 111 mg
• quinine sulfate (actually (quinine)₂H₂SO₄∙2H₂O) 121 mg
• quinine gluconate 160 mg.

All quinine salts may be given orally or intravenously (IV); quinine gluconate may also be given intramuscularly (IM) or rectally (PR).^[15][16] The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; in practice this is corrected by giving a half dose again.

The IV dose of quinine is 8 mg/kg of quinine base every eight hours; the IM dose is 12.8 mg/kg of quinine base twice daily; the PR dose is 20 mg/kg of quinine base twice daily. Treatment should be given for seven days. For at least the IV formulation a loading dose of 20 mg/kg is required.

The preparations available in the UK are quinine sulfate (200 mg or 300 mg tablets) and quinine hydrochloride (300 mg/ml for injection). Quinine is not licensed for IM or PR use in the UK. The adult dose in the UK is 600 mg quinine dihydrochloride IV or 600 mg quinine sulfate orally every eight hours. For nocturnal leg cramps, the dosage is 200–300 mg at night.^[17]

In the United States, quinine sulfate is commercially available in 324-mg tablets under the brand name Qualaquin; the adult dose is two tablets every eight hours. There is no injectable preparation of quinine licensed in the U.S.: quinidine is used instead.^[18][19]

Adverse effects

Main article: Cinchonism

Quinine can, in therapeutic doses, cause cinchonism; in rare cases, it may even cause death (usually by pulmonary edema). The development of mild cinchonism is not a reason for stopping or interrupting quinine therapy and the patient should be reassured. Blood glucose levels and electrolyte concentrations must be monitored when quinine is given by injection. The patient should ideally be in cardiac monitoring when the first quinine injection is given (these precautions are often unavailable in developing countries where malaria is endemic).

Cinchonism is much less common when quinine is given by mouth, but oral quinine is not well tolerated (quinine is exceedingly bitter and many patients will vomit after ingesting quinine tablets): Other drugs such as Fansidar (sulfadoxine (sulfonamide antibiotic) with pyrimethamine) or Malarone (proguanil with atovaquone) are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless,^[20] but is available commercially only in Japan. Blood glucose, electrolyte and cardiac monitoring are not necessary when quinine is given by mouth.

Quinine can cause paralysis if accidentally injected into a nerve. It is extremely toxic in overdose, and the advice of a poisons specialist should be sought immediately. 

Quinine in some cases can lead to constipation,^[21] erectile dysfunction or diarrhea.

The New York Times Magazine described a case, presenting with fever, hypotension, and blood abnormalities mimicking septic shock.^[22]

Abortifacient

Despite popular belief, quinine is not an effective abortifacient (abortion pill) (in the US, quinine is listed as Pregnancy category D ^[23]). Pregnant women who take toxic doses of quinine will suffer from renal failure before experiencing any kind of quinine-induced abortion.^[24] Indeed, quinine is the only drug recommended by the WHO as firstline treatment for uncomplicated malaria in pregnancy.^[25]

Disease interactions

Quinine can cause hemolysis (bleeding) in G6PD deficiency (an inherited deficiency), but again this risk is small and the physician should not hesitate to use quinine in patients with G6PD deficiency when there is no alternative. Quinine can also cause drug-induced immune thrombocytopenic purpura (ITP). Symptoms can be severe enough to require hospitalization and platelet transfusion, with several cases resulting in death.^[26]

Quinine can cause abnormal heart rhythms and should be avoided if possible in patients with atrial fibrillation, conduction defects or heart block.

Hearing impairment

Some studies have related the use of quinine and hearing impairment, in particular high-frequency loss, but it has not been conclusively established whether such impairment is temporary or permanent.^[27]

Regulation by the United States Food and Drug Administration

From 1969 to 1992, the U.S. Food and Drug Administration (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death.^[28] In 1994, the FDA banned the use of over-the-counter (OTC) quinine as a treatment for nocturnal leg cramps. Pfizer Pharmaceuticals had been selling the brand name Legatrin for this purpose. Doctors may still prescribe quinine, but the FDA has ordered firms to stop marketing unapproved drug products containing quinine. The FDA is also cautioning consumers about off-label use of quinine to treat leg cramps. Quinine is approved for treatment of malaria, but is also commonly prescribed to treat leg cramps and similar conditions. Because malaria is life-threatening, the risks associated with quinine use are considered acceptable when used to treat that affliction.^[29]

Though Legatrin was banned by the FDA for the treatment of leg cramps, drug manufacturer URL Mutual has branded a quinine-containing drug named "Qualaquin". Qualaquin is marketed as a treatment for malaria and is sold in the United States only by prescription. In 2004, the CDC reported only 1,347 confirmed cases of malaria in the United States.^[30]

Non-medical uses of quinine

Tonic water, in normal light and "black light".

In some areas, non-medical use of quinine is regulated. For example, in the United States and in Germany, quinine is limited to between 83–85 parts per million.^[31]

Beverages

Quinine is a flavour component of tonic water and bitter lemon. According to tradition, the bitter taste of anti-malarial quinine tonic led British colonials in India to mix it with gin, thus creating the gin and tonic cocktail, which is still popular today in many parts of the world, especially the U.K., United States, Canada, Australia, and New Zealand. In France, quinine is an ingredient of an apéritif known as Quinquina or "Cap Corse". In Italy, the traditional flavoured wine Barolo Chinato is infused with quinine and local herbs and is served as a digestif. In Canada and Italy, quinine is an ingredient in the carbonated chinotto beverages Brio and San Pellegrino Chinotto. In Scotland, the company A.G. Barr uses quinine as an ingredient in the carbonated and caffeinated beverage Barr's Irn-Bru. In the United Kingdom, Australia, New Zealand, South Africa and Egypt, quinine is an ingredient in Schweppes and other Indian tonic waters. In Uruguay and Argentina, quinine is an ingredient of a Pepsico Inc. tonic water named Paso de los Toros. In South Africa, quinine is an ingredient of a Clifton Instant Drink named Chikree produced by Tiger Food Brands.

Scientific

Because of its relatively constant and well-known fluorescence quantum yield, quinine is also used in photochemistry as a common fluorescence standard.

Quinine (and quinidine) are used as the chiral moiety for the ligands used in Sharpless asymmetric dihydroxylation.

Bark of Remijia contains 0.5–2% of quinine. The bark is cheaper than bark of Cinchona and as it has an intense taste, it is used for making tonic water.^[32]

Other

Quinine is sometimes used as a cutting agent in street drugs such as cocaine and heroin.^[33]

Quinine is used as a treatment for Cryptocaryon irritans (commonly referred to as white spot, crypto or marine ich) infection of marine aquarium fish.^[34]

See also

• Luis Jerónimo de Cabrera, 4th Count of Chinchón and Jesuit's bark, for the story of its introduction into Europe
• Pharmacology
• Warburg's Tincture

References

1. ^ "FDA Drug Safety Communication: New risk management plan and patient Medication Guide for Qualaquin (quinine sulfate)". Food and Drug Administration. 2010-08-07. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm218202.htm. Retrieved 2011-02-21. 
2. ^ History of quinine: Friedrich A. Flückiger and Daniel Hanbury, Pharmacographia: A history of the principal drugs of vegetable origin, met with in Great Britain and British India (London, England: Macmillan and Co., 1874), pages 302-331: Cortex Cinchonæ.
3. ^ Toovey S (May 2004). "The Miraculous Fever-Tree. The Cure that Changed the World Fiametta Rocco; Harper Collins, San Francisco, 2004, 348 pages, Paperback, ISBN 0-00-6532357". Travel Med Infect Dis 2 (2): 109–10. doi:10.1016/j.tmaid.2004.05.001. PMID 17291968. 
4. ^ de la Condamine (1738) "Sur l'arbre du quinquina" (On the quinquina tree) Histoire de l'Académie royale des Sciences, pages 226-243.
5. ^ See also: Joseph de Jussieu, Description de l'arbre à quinquina: mémoire inédit de Joseph de Jussieu (1737) (Description of the quinquina tree: unpublished memoir of Joseph de Jussieu (1737)). De Jussieu accompanied de la Condamine on the latter's expedition to Peru.
6. ^ Pelletier and Caventou (1820) "Suite: Des recherches chimiques sur les quinquinas" (Continuation: Chemical research on quinquinas), Annales de Chimie et de Physique, vol. 15, pages 337-365. The authors name quinine on page 348: "..., nous avons cru devoir la nommer quinine, pour la distinguer de la cinchonine par un nom qui indique également son origine." (..., we thought that we should name it "quinine" in order to distinguish it from cinchonine by means of a name that also indicates its origin.)
7. ^ ^{a b c} Conner, Clifford D. (2005). A People's History of Science: Miners, Midwives, and 'Low Mechanicks'. New York: Nation Books. pp. 95–96. ISBN 1560257482.  Also cites Porter, Roy (1998). The Greatest Benefit to Mankind: A Medical History of Humanity. New York: W. W. Norton. pp. 465–466. ISBN 0393046346. 
8. ^ Malaria among Japanese troops during World War II:
   • Philippines, 1942: Louis Morton, The Fall of the Philippines (Washington, D.C.: United States Army, 1953), Chapter 29, page 524.
   • New Guinea: Alan Hawk, "Remembering the war in New Guinea: Japanese Medical Corps -- malaria".
   • Southwest Pacific: Lt. Gen. Leonard D. Heaton, ed., Preventive Medicine in World War II: Volume VI, Communicable Diseases: Malaria (Washington, D.C.: Department of the Army, 1963), Chapter 8, pages 401 and 434.
   • Burma, 1943: U.S. War Department, "Notes on Japanese Medical Services," Tactical and Technical Trends, no. 36 (October 21, 1943).
9. ^ Woodward R, Doering W (1944). "The Total Synthesis of Quinine". J Am Chem Soc 66 (849). 
10. ^ Kaufman, Teodoro S.; Rúveda, Edmundo A. (2005). "Die Jagd auf Chinin: Etappenerfolge und Gesamtsiege". Angewandte Chemie, Int. Ed. 117 (6): 876–907. doi:10.1002/ange.200400663. 
11. ^ World Health Organization (2006). "Guidelines for the treatment of malaria". World Health Organization. http://apps.who.int/malaria/docs/TreatmentGuidelines2006.pdf. Retrieved 10 August 2009. 
12. ^ Dorndorp A, Nosten F, Stepniewska K, et al. (2005). "Artesunate verus quinine for treatment of severe falciparum malaria: a randomised trial". Lancet 366: 717–25. doi:10.1016/S0140-6736(05)67176-0. PMID 16125588. 
13. ^ Reyburn, H; Mtove, G; Hendriksen, I; Von Seidlein, L (2009). "Oral quinine for the treatment of uncomplicated malaria". Brit J Med 339: b2066. doi:10.1136/bmj.b2066. PMID 19622550. 
14. ^ Achan J, Tibenderana JK, Kyabayinze D, et al. (2009). "Effectiveness of quinine versus artemether-lumefantrine for treating uncomplicated faciparum malaria in Ugandan children". Brit Med J 338: b2763. 
15. ^ Barennes H, et al. (1996). "Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria". Brit J Clin Pharmacol 41 (5): 389. doi:10.1046/j.1365-2125.1996.03246.x. 
16. ^ Barennes, H.; Balima-Koussoubé, T; Nagot, N; Charpentier, JC; Pussard, E (2006). "Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial". Brit Med J 332 (7549): 1055–57. doi:10.1136/bmj.332.7549.1055. PMC 1458599. PMID 16675812. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1458599. 
17. ^ BNF 56: Nocturnal leg cramps Accessed 30/11/2008
18. ^ Center for Disease Control (1991). "Treatment with Quinidine Gluconate of Persons with Severe Plasmodium falciparum Infection: Discontinuation of Parenteral Quinine". Morb Mort Weekly Rep 40 (RR-4): 21–23. http://www.cdc.gov/mmwr/preview/mmwrhtml/00043932.htm. Retrieved 2006-05-06. 
19. ^ Magill, A; Panosian, C (2005). "Making Antimalarial Agents Available in the United States". New Engl J Med 353 (4): 335–337. doi:10.1056/NEJMp058167. PMID 16000347. 
20. ^ Jamaludin A, Mohamad M, Navaratnam V, et al. (1988). "Relative bioavailability of the hydrochloride, sulphate and ethyl carbonate salts of quinine". Br J Clin Pharmacol 25 (2): 261–3. PMC 1386482. PMID 3358888. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1386482. 
21. ^ Optically active isomers of quinine and quinidine and their respective biological action Accessed 26/1/2009
22. ^ Sanders, L. "Poison Pill", The New York Times Magazine, 4/13/2008.
23. ^ http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8546
24. ^ Dannenberg AL; Behal, FJ (1983). "Use of quinine for self-induced abortion". The Southern Medical Journal 76 (7): 846–849. PMID 6867792. 
25. ^ Yeka A, Achan J, D'Alessandro U, Talisuna AO (2009). "Quinine monotherapy for treating uncomplicated malaria in the era of artemisinin-based combination therapy: an appropriate public health policy?". Lancet Infect Dis 9 (7): 448–452. doi:10.1016/S1473-3099(09)70109-4. PMID 19555904. 
26. ^ "NPS warns on quinine". Auspharm e News, 6 January 2010.
27. ^ Department of Clinical Pharmacology, Huddinge University Hospital, Sweden (1994). "The concentration-effect relationship of quinine-induced hearing impairment". Clin Pharmacol Ther 55 (3): 317–323. doi:10.1038/clpt.1994.32. PMID 8143397. 
28. ^ "FDA Orders Stop to Marketing Of Quinine for Night Leg Cramps". FDA Consumer Magazine. Food and Drug Administration. July–August 1995. Archived from the original on 2008-01-15. http://web.archive.org/web/20080115020839/http://www.fda.gov/fdac/departs/695_updates.html. Retrieved 2009-07-31. 
29. ^ "FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About Off-Label Use of Quinine to Treat Leg Cramps". United States Food and Drug Administration. 2006-12-11. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108799.htm. Retrieved 2009-07-31. 
30. ^ "Malaria Surveillance - United States, 2004". Center for Disease Control. 2006-11-22. http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5504a2.htm. Retrieved 2009-11-22. 
31. ^ Ballestero, JA; Plazas, PV; Kracun, S; Gómez-Casati, ME; Taranda, J; Rothlin, CV; Katz, E; Millar, NS et al.; et al. (2005). "Effects of Quinine, Quinidine, and Chloroquine on α9α10 Nicotinic Cholinergic Receptors". Molecular Pharmacology 68 (3): 822–829. doi:10.1124/mol.105.014431. PMID 15955868. 
32. ^ Hobhouse, Henry (2004) (in Czech). Šest rostlin, které změnily svět. Prague: Akademie věd České republiky. pp. 59. ISBN 802001179X. 
33. ^ Microgram Bulletin, Volume 42, Number 10, October 2009, Page 79. Retrieved 21 April 2010.
34. ^ Porritt, M., Cryptocaryon irritans, Reef Culture Magazine, 1. Retrieved 9th Jul 2009

Further reading

• Hobhouse, Henry. Seeds of Change Six Plants that Transformed Mankind. 2005. ISBN 1-59376-049-3.
• Stockwell, J. R. "Aeromedical considerations of malaria prophylaxis with mefloquine hydrochloride". Aviation, Space, and Environmental Medicine 1982; 3(10):1011–3.
• Wolff RS, Wirtschafter D, Adkinson C (June 1997). "Ocular quinine toxicity treated with hyperbaric oxygen". Undersea Hyperb Med 24 (2): 131–4. PMID 9171472. http://archive.rubicon-foundation.org/2278. Retrieved 2008-08-13. 

External links

• Jesuits' Powder
• From intox databank
• From inchem
• Database file on Quinine from rain-tree.com
• Catalytic Asymmetric Synthesis of Quinine and Quinidine
• Summary article on history of Quinine in Chemical and Engineering News
• Quinine news page - Alcohol and Drugs History Society