Quinine 25297 225930449 2008-07-16T01:57:58Z 68.19.50.196 /* History */ {{drugbox | IUPAC_name = (''R'')-(6-methoxyquinolin-4-yl)((2''S'',4''S'',8''R'')- 8-vinylquinuclidin-2-yl)methanol | Othername = (''R'')-(5-ethenyl-1-azabicyclo[2.2.2]oct-2-yl)- (6-methoxyquinolin-4-yl)-methanol | image = Quinine-2D-skeletal.png | image2 = Quinine-3D-balls.png | size = 250px | CAS_number = 130-95-0 | ATC_prefix = M09 | ATC_suffix = AA01 | ATC_supplemental = {{ATC|P01|BC01}} | PubChem = 8549 | DrugBank = APRD00563 | C = 20 |H = 24 |N = 2 |O = 2 | molecular_weight = 324.417 [[Gram|g]]/[[Mole (unit)|mol]] | bioavailability = 76 to 88% | protein_bound = ~70% | metabolism = [[Liver|Hepatic]] (mostly [[CYP3A4]] and [[CYP2C19]]-mediated) | elimination_half-life = ~18 hours | excretion = [[Kidney|Renal]] (20%) | pregnancy_category = X <small>([[United States of America|USA]])</small>, D <small>([[Australia|Au]])</small> | legal_status = | routes_of_administration = Oral, [[intravenous therapy|intravenous]] | melting_point = 177 }} '''Quinine''' ({{IPAEng|ˈkwaɪnaɪn, kwɪˈniːn, ˈkwiːniːn}}) is a natural white [[crystal]]line [[alkaloid]] having [[antipyretic]] (fever-reducing), [[antimalarial drug|antimalarial]], [[analgesic]] (painkilling), and [[anti-inflammatory]] properties and a bitter taste. It is a [[stereoisomer]] of [[quinidine]]. 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 took over. Since then, many effective antimalarials have been introduced, although quinine is still used to treat the disease in certain critical situations. Quinine is available with a prescription in the [[United States of America|United States]]. Quinine is also used to treat [[Cramps#Nocturnal leg cramps|nocturnal leg cramps]] and [[arthritis]], and there have been attempts (with limited success) to treat [[prion]] diseases. It was once a popular [[heroin]] [[adulterant]]. It was first brought to Europe by Jesuits and it was also used to cure [[Louis XIV of France|King Louis XIV]]. ==Chemical structure== Quinine contains two major fused-ring systems: The [[aromatic]] [[quinoline]] and the [[bicyclic]] [[quinuclidine]]. ==Mechanism of action against P. falciparum== The drug acts by inhibiting the [[hemozoin]] [[biocrystallization]], thus facilitating an aggregation of [[cytotoxic]] [[heme]]. Toxic free heme accumulates in the parasites, leading to their death. ==History== The correct form of quinine best used to treat malaria was found by [[Charles Marie de La Condamine]] in [[1737]]. Quinine was extracted from the bark of the [[South America]]n [[cinchona]] tree and was isolated and named in [[1817]] by French researchers [[Pierre Joseph Pelletier]] and [[Joseph Bienaimé Caventou]]. 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]], although it had been used in un-extracted form by Europeans since at least the early [[1600s]]. Quinine was first used to treat malaria in Rome in 1631. During the 1600s, malaria was endemic to the [[swamp]]s and [[marsh]]es surrounding the city of [[Rome]]. Over time, malaria was responsible for the death of several [[Pope]]s, many [[Cardinal (Catholicism)|Cardinal]]s and countless common citizens of Rome. Most of the [[priest]]s trained in Rome had seen malaria victims and were familiar with the [[shivering]] brought on by the cold phase of the disease. In addition to its anti-malarial properties, quinine is an effective muscle relaxant, long used by the [[Quechua]] Indians of [[Peru]] to halt shivering brought on by cold temperatures. The [[Jesuit]] Brother Agostino Salumbrino (1561-1642), an [[apothecary]] by training and who lived in [[Lima]], observed the Quechua using the quinine-containing bark of the [[cinchona]] tree for that purpose. While its effect in treating malaria (and hence malaria-induced shivering) was entirely unrelated to its effect in controlling shivering from cold, it was still the correct medicine for malaria. At the first opportunity, he sent a small quantity to Rome to test in treating malaria. In the years that followed, cinchona bark became one of the most valuable commodities shipped from Peru to Europe. Quinine also played a significant role in the colonization of Africa by Europeans. As the harbinger of modern pharmacology, Quinine was the prime reason why Africa ceased to be known as the white man's grave. According to [[socialism|socialist]] historian [[Clifford Conner]] in "A People's History of Science", "It was quinine's efficacy that gave colonists fresh opportunities to swarm into the [[Gold Coast]], [[Nigeria]] and other parts of west Africa..." (Conner pp 95-96 also cites Porter, "The Greatest Benefit to Mankind," pp. 465-466). ===Synthetic quinine=== {{main|quinine total synthesis}} [[Cinchona|Cinchona trees]] remain the only practical source of quinine. However, under wartime pressure, research towards its artificial production was undertaken. A formal chemical synthesis was accomplished in [[1944]] by American chemists [[Robert Burns Woodward|R.B. Woodward]] and [[W.E. Doering]].<ref name="Woodward1944"> {{cite journal | author = Woodward R, Doering W | title = The Total Synthesis of Quinine | journal = [[Journal of the American Chemical Society|J Am Chem Soc]] | volume = 66 | issue = 849 | year = 1944}}</ref> Since then, several more efficient [[quinine total synthesis|quinine total syntheses]] have been achieved<ref>see review article in Angewandte Chemie, Int. Ed., 2005, 44, p. 854 ff</ref>, but none of them can compete in economic terms with isolation of the alkaloid from natural sources. ==Dosing== Quinine is a basic [[amine]] and is therefore always presented as a salt. Various preparations that exist include the [[hydrochloride]], dihydrochloride, [[sulfate]], bisulfate and [[gluconate]]. This makes quinine dosing very complicated, because each of the salts has a different weight. The following amounts of each form are equal: * quinine base 100 mg * quinine bisulfate 169 mg * quinine dihydrochloride 122 mg * quinine hydrochloride 122 mg * quinine sulfate (actually (quinine)<sub>2</sub>H<sub>2</sub>SO<sub>4</sub>∙2H<sub>2</sub>O) 121 mg * quinine gluconate 160 mg. All quinine salts may be given orally or [[Intravenous therapy|intravenous]]ly (IV); quinine gluconate may also be given [[intramuscular injection|intramuscular]]ly (IM) or rectally (PR).<ref name="Barennes1996">{{cite journal | author=Barennes H, ''et al.'' | title=Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria | journal=Brit J Clin Pharmacol | volume=41 | pages=389 | year=1996 | doi=10.1046/j.1365-2125.1996.03246.x | issue=5 }}</ref><ref name="Barennes2006">{{cite journal | title=Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately severe malaria in children: randomised clinical trial | journal=Brit Med J | volume=332 | issue=7549 | pages=1055&ndash;57 | doi=10.1136/bmj.332.7549.1055 | year=2006 | author=Barennes, H. | pmid=16675812 | unused_data=Barennes H, Balima-Koussoubé T, Nagot N, Charpentier J-C, Pussard E }}</ref> The main problem with the rectal route is that the dose can be expelled before it is completely absorbed, but this can be rectified 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. 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 [[United Kingdom|UK]]. The adult dose in the UK is 600 mg quinine dihydrochloride IV or 600 mg quinine sulfate orally every eight hours. In the United States quinine sulfate is available as 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.<ref>{{cite journal | author=Center for Disease Control | title=Treatment with Quinidine Gluconate of Persons with Severe ''Plasmodium falciparum'' Infection: Discontinuation of Parenteral Quinine | journal=Morb Mort Weekly Rep | year=1991 | volume=40 | issue=RR-4 | pages=21&ndash;23 | url=http://www.cdc.gov/mmwr/preview/mmwrhtml/00043932.htm | accessdate=2006-05-06 }}</ref><ref>{{cite journal | journal=New Engl J Med | volume=353 | pages=335&ndash;337 | year=2005 | issue=4 | title=Making Antimalarial Agents Available in the United States | author=Magill A, Panosian C | doi = 10.1056/NEJMp058167 <!--Retrieved from CrossRef by DOI bot-->}}</ref> Quinine is not recommended for malaria prevention ([[Wiktionary:prophylaxis|prophylaxis]]) because of its side effects and poor tolerability, not because it is ineffective. When used for prophylaxis, the dose of quinine sulfate is 300&ndash;324mg once daily, starting one week prior to travel and continuing for four weeks after returning. ==Side effects== :''See: [[cinchonism]]'' It is usual for quinine in therapeutic doses to 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 also ideally be in cardiac monitoring when the first quinine injection is given (these precautions are often unavailable in developing countries where malaria is most a problem). 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. 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 [[toxicology|poisons specialist]] should be sought immediately. ===Quinine and pregnancy=== In the UK, the recommendation is that pregnancy is ''not'' a contra-indication to quinine therapy for [[Plasmodium falciparum|falciparum]] malaria (which directly contradicts the US recommendation), although it should be used with caution; the reason for this is that the risks to the pregnancy are small and theoretical, as opposed to the very real risk of death from falciparum malaria. ===Quinine and interactions with other diseases=== Quinine can cause [[hemolysis]] in [[G6PD 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). Quinine can cause abnormal heart rhythms and should be avoided if possible in patients with [[atrial fibrillation]], [[conduction defect]]s or [[heart block]]. Quinine must not be used in patients with [[hemoglobinuria]], [[myasthenia gravis]] or [[optic neuritis]], because it worsens these conditions.<!-- Reference for this needed! --> ===Quinine and hearing impairment=== Some studies have related the use of quinine and [[hearing impairment]], which can cause some high-frequency loss, but it has not been conclusively established whether such impairment is temporary or permanent.<ref>{{cite journal | author=Department of Clinical Pharmacology, Huddinge University Hospital, Sweden | title=The concentration-effect relationship of quinine-induced hearing impairment | journal=Clin Pharmacol Ther | year=1994 | volume=55 | issue=3 | pages=317&ndash;323 | pmid = 8143397 }}</ref> ==Regulation by the United States Food and Drug Administration== From [[1969]] to [[1992]], the [[USA|U.S.]] [[Food and Drug Administration]] (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death.<ref>{{cite web | author=FDA Consumer Magazine | date=1995 July-August | title=FDA Orders Stop to Marketing Of Quinine for Night Leg Cramps | url=http://www.fda.gov/fdac/departs/695_updates.html | accessdate=2008-02-15}}</ref> In [[1994]], the FDA banned the use of [[Over-the-counter drug|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 justified for that condition. But because of the drug's risks, FDA believes it should not be used to prevent or treat leg cramps.<ref>{{cite web | author=United States Food and Drug Administration | date=2006 December 11 | title=FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About Off-Label Use of Quinine to Treat Leg Cramps | url=http://www.fda.gov/bbs/topics/NEWS/2006/NEW01521.html | accessdate=2008-02-15}}</ref> ==Non-medical uses of quinine== [[Image:Tonic water uv.jpg|thumb|Tonic water, in normal light and UV.]] Quinine is a flavor 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, southern Canada and parts of Australia. 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]].<ref name="Hobhouse">Henry Hobhouse (2004) ''Šest rostlin, které změnily svět''. [[Academia]], [[Akademie věd České republiky]], Praha, ISBN 80-200-1179-X, page 59. in Czech language</ref> 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]] (83-85 mg/L).<ref>Ballestero et al. (2005). Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors. Molecular Pharmacology, 68(3):822-829. </ref> In order to achieve a therapeutic dose of quinine from tonic water, a person would have to drink between 6 and 12 quarts in a 24-hour period.<ref>{{cite web |url=http://www.wholefoodsmarket.com/wholebody/ingredients/quinine.html |accessdate=2008-06-21 |title=Whole Foods Markets: Ingredients: Quinine |publisher=Whole Foods Market, IP, L.P.}}</ref> In [[France]], quinine is an ingredient of an [[apéritif]] known as [[Quinquina]]. 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]]. Quinine is often added to street drugs cocaine or ketamine in order to "cut" the product and make more profit. In [[Canada]], quinine is an ingredient in the [[carbonated]] [[chinotto]] [[beverage]] called [[Brio]]. In the [[United Kingdom]], Scottish company [[A.G. Barr]]'s uses quinine as an [[ingredient]] in the carbonated and [[caffein]]ated beverage [[Irn-Bru]]. In [[England]], [[Australia]] and [[New Zealand]], quinine is an ingredient in [[Schweppes]] and other Indian [[Tonic water]]s, at a concentration of 0.5%. In [[Uruguay]] and [[Argentina]], quinine is an ingredient of a [[Pepsico]] Inc. [[Tonic water]] named [[Paso de los Toros (drink)|Paso de los Toros]]. In [[South Africa]], quinine is an ingredient of a Clifton Instant Drink named Chikree produced by Tiger Food Brands. ==References== {{reflist|2}} ==See also== *[[Pharmacology]] *[[Luis Jerónimo Fernández de Cabrera]] and [[Jesuit's bark]], for the story of its introduction into Europe ==External links== * [http://www.companymagazine.org/v144/powder.html Jesuits' Powder] * [http://www.intox.org/databank/documents/pharm/quinine/ukpid13.htm From intox databank] * [http://www.inchem.org/documents/pims/pharm/pim464.htm From inchem] * [http://www.rain-tree.com/quinine.htm Database file on Quinine from rain-tree.com] * [http://www.organic-chemistry.org/Highlights/2004/01November.shtm Catalytic Asymmetric Synthesis of Quinine and Quinidine] * [http://pubs.acs.org/cen/coverstory/83/8325/8325quinine.html Summary article on history of Quinine in Chemical and Engineering News] * [http://historyofalcoholanddrugs.typepad.com/alcohol_and_drugs_history/quinine/index.html Quinine news page] - [[Alcohol and Drugs History Society]] {{Antimalarials}} [[Category:Ethers]] [[Category:Quinine]] [[Category:Teratogens]] [[Category:Antimalarial agents]] [[Category:Quinolines]] [[Category:Bitter compounds]] [[Category:Abortifacients]] [[Category:Quinuclidines]] [[Category:World Health Organization essential medicines]] [[ca:Quinina]] [[cs:Chinin]] [[da:Kinin]] [[de:Chinin]] [[es:Quinina]] [[eo:Kinino]] [[fr:Quinine]] [[ko:퀴닌]] [[hr:Kinin]] [[it:Chinino]] [[he:כינין]] [[hu:Kinin]] [[mk:Кинин]] [[nl:Kinine]] [[ja:キニーネ]] [[no:Kinin]] [[pl:Chinina]] [[pt:Quinina]] [[ro:Chinină]] [[ru:Хинин]] [[sk:Chinín]] [[fi:Kiniini]] [[sv:Kinin]] [[tr:Kinin]] [[zh:奎寧]]