Quinine
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Quinine
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| Systematic (IUPAC) name | |
| (R)-(6-methoxyquinolin-4-yl)((2S,4S,8R)- 8-vinylquinuclidin-2-yl)methanol | |
| Identifiers | |
| CAS number | |
| ATC code | M09 P01 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | C20H24N2O2 |
| Mol. mass | 324.417 g/mol |
| Physical data | |
| Melt. point | 177 °C (351 °F) |
| Pharmacokinetic data | |
| Bioavailability | 76 to 88% |
| Protein binding | ~70% |
| Metabolism | Hepatic (mostly CYP3A4 and CYP2C19-mediated) |
| Half life | ~18 hours |
| Excretion | Renal (20%) |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral, intravenous |
Quinine (IPA: /ˈkwaɪnaɪn (US), kwɪˈniːn, ˈkwɪniːn (GB)/) is a natural white crystalline alkaloid having antipyretic (fever-reducing), 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.[citation needed] Quinine is also used to treat nocturnal leg cramps and arthritis, and there have been attempts (with limited success) to treat prion diseases. It was once a popular heroin adulterant and is now not as popular in the world, although many countries (such as Scotland) still have quinine-contaminated heroin selling on the streets.[citation needed]
Originally discovered by the Quechua Indians of Peru, the bark of the cinchona tree was first brought to Europe by the Jesuits.
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[edit] Chemical structure
Quinine contains two major fused-ring systems: The aromatic quinoline and the bicyclic quinuclidine.
[edit] 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.
[edit] History
Quinine is an effective muscle relaxant, long used by the Quechua Indians of Peru to halt shivering brought on by cold temperatures. Made from the bark of cinchona trees, the Peruvians would mix the ground up bark with sweetened water to offset the bark's bitter taste, thus producing tonic water.
Quinine has 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 swamps and marshes surrounding the city of Rome. Over time, malaria was responsible for the death of several popes, many cardinals and countless common citizens of Rome. Most of the priests trained in Rome had seen malaria victims and were familiar with the shivering brought on by the cold phase of the disease. The Jesuit brother Agostino Salumbrino (1561-1642), an apothecary by training 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.
The correct form of quinine best used to treat malaria was found by Charles Marie de La Condamine in 1737. Quinine 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.
Quinine also played a significant role in the colonization of Africa by Europeans. As the harbinger of modern pharmacology, quinine was the prime reason 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".[1]
To maintain their monopoly on cinchona bark, Peru and surrounding countries began outlawing the exportation of cinchona seeds and saplings beginning in the early 19th century. The Dutch government persisted in their attempts 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.[1] During World War II, Allied powers were cut off from their supply of quinine when the Germans conquered Holland and the Japanese controlled the Philippines and Indonesia. The United States, however, had managed to obtain four million cinchona seeds from the Philippines and begin operation of cinchona plantations in Costa Rica. It had come too late, however, and an estimated 60,000 US troops in Africa and the South Pacific died as a result of the lack of quinine.[1]
[edit] Synthetic quinine
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 R.B. Woodward and W.E. Doering.[2] Since then, several more efficient quinine total syntheses have been achieved,[3] 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.
[edit] 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 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).[4][5] The main problem with the rectal route is that the dose can be expelled before it is completely absorbed; this can be 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.
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 200-300mg at night.[6]
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.[7][8]
Quinine is not recommended for malaria prevention (prophylaxis) because of its side-effects and poor tolerability, not because it is ineffective. When used for prophylaxis, the dose of quinine sulfate is 300–324mg once daily, starting one week prior to travel and continuing for four weeks after returning.
[edit] 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 poisons specialist should be sought immediately.
Quinine in some cases can lead to constipation[9], erectile dysfunction, and a loose stool or in rare cases many loose stools.[citation needed]
[edit] Abortifacient
Despite popular belief, quinine is an ineffective abortifacient (in the US, quinine is listed as Pregnancy category C [1]). Pregnant women who take toxic doses of quinine will suffer from renal failure before experiencing any kind of quinine-induced abortion.[10]
[edit] Disease interactions
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 defects or heart block.
Quinine can worsen hemoglobinuria, myasthenia gravis and optic neuritis.[citation needed]
[edit] 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.[11]
[edit] 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.[12] 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. As of 2008, pharmacists will not sell quinine even if the patient has used a prescription for it in the past.[citation needed] 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 condition. However, because of the drug's risks the FDA believes it should not be used to prevent or treat leg cramps.[13]
[edit] Non-medical uses of quinine
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, parts of Australia and even Lhasa, Tibet.
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.[14]
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.[15] In order to achieve a therapeutic dose of quinine from tonic water, a person would have to drink between 6 and 12 litres in a 24-hour period.[16]
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 sometimes added to the recreational drugs cocaine, heroin and others 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 caffeinated beverage Irn-Bru.
In England, Australia, New Zealand and Egypt, quinine is an ingredient in Schweppes and other Indian tonic waters, at a concentration of 0.4 mg/l.[citation needed]
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.
[edit] See also
- Pharmacology
- Luis Jerónimo Fernández de Cabrera and Jesuit's bark, for the story of its introduction into Europe
- Stockwell JR. Aeromedical considerations of malaria prophylaxis with mefloquine hydrochloride. Aviation, Space, and Environmental Medicine 1982; 3(10):1011-3
[edit] References
- ^ 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.
- ^ Woodward R, Doering W (1944). "The Total Synthesis of Quinine". J Am Chem Soc 66 (849).
- ^ Kaufman, Teodoro S.; Rúveda, Edmundo A. (2005). "Die Jagd auf Chinin: Etappenerfolge und Gesamtsiege". Angewandte Chemie, Int. Ed. 117 (6): 876–907. doi:.
- ^ 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:.
- ^ Barennes, H. (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:. PMID 16675812.
- ^ BNF 56: Nocturnal leg cramps Accessed 30/11/2008
- ^ 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 on 2006-05-06.
- ^ Magill A, Panosian C (2005). "Making Antimalarial Agents Available in the United States". New Engl J Med 353 (4): 335–337. doi:.
- ^ Optically active isomers of quinine and quinidine and their respective biological action Accessed 26/1/2009
- ^ Dannenberg AL (1983). "Use of quinine for self-induced abortion". The Southern Medical Journal 76 (7): 846–849. PMID 0038-4348.
- ^ 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. PMID 8143397.
- ^ FDA Consumer Magazine (1995 July-August). "FDA Orders Stop to Marketing Of Quinine for Night Leg Cramps". http://www.fda.gov/fdac/departs/695_updates.html. Retrieved on 2008-02-15.
- ^ United States Food and Drug Administration (December 2006). "FDA Orders Unapproved Quinine Drugs from the Market and Cautions Consumers About Off-Label Use of Quinine to Treat Leg Cramps". http://www.fda.gov/bbs/topics/NEWS/2006/NEW01521.html. Retrieved on 2008-02-15.
- ^ Hobhouse, Henry (2004) (in Czech). Šest rostlin, které změnily svět. Prague: Akademie věd České republiky. pp. 59. ISBN 802001179X.
- ^ Ballestero, Jimena A.; et al. (2005). "Effects of Quinine, Quinidine, and Chloroquine on α9α10 Nicotinic Cholinergic Receptors". Molecular Pharmacology 68 (3): 822–829. doi:.
- ^ "Whole Foods Markets: Ingredients: Quinine". Whole Foods Market, IP, L.P.. http://www.wholefoodsmarket.com/wholebody/ingredients/quinine.html. Retrieved on 2008-06-21.
[edit] Additional reading
- 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 on 2008-08-13.
[edit] 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
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