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Quinine



Quinine
Systematic (IUPAC) name
(R)(5-ethenyl-1-azabicyclo[2.2.2]oct-2-yl)-

(6-methoxyquinolin-4-yl)-methanol

Identifiers
CAS number 130-95-0
ATC code M09AA01 P01BC01
PubChem 8549
DrugBank APRD00563
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.

X (USA), D (Au)

Legal status
Routes Oral, intravenous

Quinine (IPA: /ˈkwaɪnaɪn, kwɪˈniːn, ˈkwiːniːn/), (R)-(5-ethenyl-1-azabicyclo[2.2.2]oct-2-yl)-(6-methoxyquinolin-4-yl) -methanol, is a natural white crystalline alkaloid having antipyretic (fever-reducing), anti-smallpox, 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 P. 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. 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.

Additional recommended knowledge

Contents

Chemical structure

Quinine contains two major fused-ring systems: The aromatic quinoline and the bicyclic quinuclidine.

Mechanism of action

The drug works to inhibit the parasites' heme polymerase, the enzyme that polymerizes toxic heme to hemozoin. Toxic free heme accumulates in the parasites, leading to their death.

Sources of quinine

Quinine was extracted from the bark of the South American 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 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. 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 dawn of modern pharmacology, Quinine was the prime reason why Africa ceased to be known as the white man's grave. According to Clifford D. Conner in "A People's History of Science", "It was quinine's efficacy that gave colonist fresh opportunities to swarm into the Gold Coast, Nigeria and other parts of west Africa and seize fertile agricultural lands, introduce new livestock and crops, build roads and railways, drive natives into mines, and introduce all the disruptions to traditional lifestyles that cash economies brought."(Conner pp 95-96) also cites Porter, "The Greatest Benefit to Mankind, pp. 465-466)

Synthetic quinine

Main article: quinine total synthesis

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.[1] Since then, several more efficient quinine total syntheses have been achieved [2] , 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 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).[3][4] 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 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.

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.[5][6]

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 sulphate is 300–324mg 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 up 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.

In 1994, the U.S. Food and Drug Administration (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. This was soon followed by disallowing even prescription quinine for leg cramps, and all OTC sales of the drug for malaria. From 1969 to 1992, the FDA received 157 reports of health problems related to quinine use, including 23 which had resulted in death.[1]

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 and pregnancy

In very large doses, quinine also acts as an abortifacient; in the United States quinine is classed as a Category X teratogen by the Food and Drug Administration, meaning that it can cause birth defects if taken by a woman during pregnancy. In the UK, the recommendation is that pregnancy is not a contra-indication to quinine therapy for 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 defects or heart block.

Quinine must not be used in patients with hemoglobinuria, myasthenia gravis or optic neuritis, because it worsens these conditions.

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.[7]

Non-medical uses of quinine

  Quinine is a flavour component of tonic water, bitter lemon, and vermouth. 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.

In the United States, the Food and Drug Administration limits tonic water quinine to 83 parts per million, which is one-half to one-quarter the concentration used in therapeutic tonic.[citation needed]

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.

In Canada, quinine is an ingredient in the carbonated chinotto beverage called Brio.

In the United Kingdom, quinine is an ingredient in the carbonated and caffeinated beverage Irn-Bru.

References

  1. ^ Woodward R, Doering W (1944). "The Total Synthesis of Quinine". J Am Chem Soc 66 (849).
  2. ^ see review article in Angewandte Chemie, Int. Ed., 2005, 44, p. 854 ff
  3. ^ 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.
  4. ^ "Safety and efficacy of rectal compared with intramuscular quinine for the early treatment of moderately sever malaria in children: randomised clinical trial". Brit Med J 332 (7549): 1055–57.
  5. ^ 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. Retrieved on 2006-05-06.
  6. ^ Magill A, Panosian C (2005). "Making Antimalarial Agents Available in the United States". New Engl J Med 353 (4): 335–337.
  7. ^ 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. Retrieved on 2006-05-06.

See also

 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Quinine". A list of authors is available in Wikipedia.
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