Quinine

Quinine

Overview
Quinine (ˈkwaɪnaɪn, ˈkwɪniːn, kwɪˈniːn) is a natural white crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...

line alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 having antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 (fever-reducing), antimalarial
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...

, analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 (painkilling), anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 properties and a bitter taste. It is a stereoisomer of quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

 which, unlike quinine, is an anti-arrhythmic. Quinine contains two major fused-ring systems: the aromatic quinoline
Quinoline
Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown...

 and the bicyclic quinuclidine
Quinuclidine
Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...

.

Though it has been synthesized in the lab, quinine occurs naturally in the bark of the cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

 tree.
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Encyclopedia
Quinine (ˈkwaɪnaɪn, ˈkwɪniːn, kwɪˈniːn) is a natural white crystal
Crystal
A crystal or crystalline solid is a solid material whose constituent atoms, molecules, or ions are arranged in an orderly repeating pattern extending in all three spatial dimensions. The scientific study of crystals and crystal formation is known as crystallography...

line alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

 having antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 (fever-reducing), antimalarial
Antimalarial drug
Antimalarial medications, also known as antimalarials, are designed to prevent or cure malaria. Such drugs may be used for some or all of the following:* Treatment of malaria in individuals with suspected or confirmed infection...

, analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

 (painkilling), anti-inflammatory
Anti-inflammatory
Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

 properties and a bitter taste. It is a stereoisomer of quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

 which, unlike quinine, is an anti-arrhythmic. Quinine contains two major fused-ring systems: the aromatic quinoline
Quinoline
Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown...

 and the bicyclic quinuclidine
Quinuclidine
Quinuclidine is an organic compound and a bicyclic amine and used as a catalyst and a chemical building block. It is a strong base with pKa of the conjugate acid of 11.0. This is due to greater availability of the nitrogen lone pair...

.

Though it has been synthesized in the lab, quinine occurs naturally in the bark of the cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

 tree. The medicinal properties of the cinchona tree were originally discovered by the Quechua
Quechuas
Quechuas is the collective term for several indigenous ethnic groups in South America who speak a Quechua language , belonging to several ethnic groups in South America, especially in Peru, Ecuador, Bolivia, Chile, Colombia and Argentina.The Quechuas of Ecuador call themselves as well as their...

 Indians of Peru
Peru
Peru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....

 and Bolivia
Bolivia
Bolivia officially known as Plurinational State of Bolivia , is a landlocked country in central South America. It is the poorest country in South America...

; later, the Jesuits were the first to bring the cinchona to Europe.

Quinine was the first effective treatment for malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

 caused by Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...

, 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
Tonic water
Tonic water is a carbonated soft drink in which quinine is dissolved. Originally used as a prophylactic against malaria, tonic water usually now has a significantly lower quinine content and is consumed for its distinctively bitter taste...

. Quinine is also used to treat lupus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...

 and arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

. 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
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 statement warning against the practice.

Quinine is very sensitive to ultraviolet light (UV) and will fluoresce in direct sunlight, due to its highly conjugated resonance structure (see Quinoline
Quinoline
Quinoline is a heterocyclic aromatic organic compound. It has the formula C9H7N and is a colourless hygroscopic liquid with a strong odour. Aged samples, if exposed to light, become yellow and later brown...

).

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
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...

. This model involves the inhibition of hemozoin
Hemozoin
Hemozoin is a disposal product formed from the digestion of blood by some blood-feeding parasites. These hematophagous organisms such as Malaria parasites , Rhodnius and Schistosoma digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin...

 biocrystallization
Biocrystallization
Biocrystallization is the formation of crystals from organic macromolecules by living organisms. This may be a stress response, a normal part of metabolism such as processes that dispose of waste compounds, or a pathology. Template mediated crystallization is qualitatively different from in vitro...

, which facilitates the aggregation of cytotoxic heme
Heme
A heme or haem is a prosthetic group that consists of an iron atom contained in the center of a large heterocyclic organic ring called a porphyrin. Not all porphyrins contain iron, but a substantial fraction of porphyrin-containing metalloproteins have heme as their prosthetic group; these are...

. Free cytotoxic heme accumulates in the parasites, leading to their death.

History


Quinine is an effective muscle relaxant, long used by the Quechua
Quechuas
Quechuas is the collective term for several indigenous ethnic groups in South America who speak a Quechua language , belonging to several ethnic groups in South America, especially in Peru, Ecuador, Bolivia, Chile, Colombia and Argentina.The Quechuas of Ecuador call themselves as well as their...

 Indians of Peru
Peru
Peru , officially the Republic of Peru , is a country in western South America. It is bordered on the north by Ecuador and Colombia, on the east by Brazil, on the southeast by Bolivia, on the south by Chile, and on the west by the Pacific Ocean....

 to halt shivering due to low temperatures. The Peruvians would mix the ground bark of cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

 trees with sweetened water to offset the bark's bitter taste, thus producing tonic water
Tonic water
Tonic water is a carbonated soft drink in which quinine is dissolved. Originally used as a prophylactic against malaria, tonic water usually now has a significantly lower quinine content and is consumed for its distinctively bitter taste...

.

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. During the 17th century, malaria was endemic to the swamp
Swamp
A swamp is a wetland with some flooding of large areas of land by shallow bodies of water. A swamp generally has a large number of hammocks, or dry-land protrusions, covered by aquatic vegetation, or vegetation that tolerates periodical inundation. The two main types of swamp are "true" or swamp...

s and marsh
Marsh
In geography, a marsh, or morass, is a type of wetland that is subject to frequent or continuous flood. Typically the water is shallow and features grasses, rushes, reeds, typhas, sedges, other herbaceous plants, and moss....

es surrounding the city of Rome
Rome
Rome is the capital of Italy and the country's largest and most populated city and comune, with over 2.7 million residents in . The city is located in the central-western portion of the Italian Peninsula, on the Tiber River within the Lazio region of Italy.Rome's history spans two and a half...

. Malaria was responsible for the death of several pope
Pope
The Pope is the Bishop of Rome, a position that makes him the leader of the worldwide Catholic Church . In the Catholic Church, the Pope is regarded as the successor of Saint Peter, the Apostle...

s, many cardinal
Cardinal (Catholicism)
A cardinal is a senior ecclesiastical official, usually an ordained bishop, and ecclesiastical prince of the Catholic Church. They are collectively known as the College of Cardinals, which as a body elects a new pope. The duties of the cardinals include attending the meetings of the College and...

s and countless common Roman citizens. Most of the priest
Priest
A priest is a person authorized to perform the sacred rites of a religion, especially as a mediatory agent between humans and deities. They also have the authority or power to administer religious rites; in particular, rites of sacrifice to, and propitiation of, a deity or deities...

s trained in Rome had seen malaria victims and were familiar with the shivering
Shivering
Shivering is a bodily function in response to early hypothermia in warm-blooded animals. When the core body temperature drops, the shivering reflex is triggered to maintain homeostasis. Muscle groups around the vital organs begin to shake in small movements in an attempt to create warmth by...

 brought on by the febrile phase of the disease. The Jesuit brother Agostino Salumbrino (1561–1642), an apothecary
Apothecary
Apothecary is a historical name for a medical professional who formulates and dispenses materia medica to physicians, surgeons and patients — a role now served by a pharmacist and some caregivers....

 by training who lived in Lima
Lima
Lima is the capital and the largest city of Peru. It is located in the valleys of the Chillón, Rímac and Lurín rivers, in the central part of the country, on a desert coast overlooking the Pacific Ocean. Together with the seaport of Callao, it forms a contiguous urban area known as the Lima...

, observed the Quechua using the bark of the cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

 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
Jesuit's bark
Jesuit's Bark, also called Peruvian Bark, is the historical name of the most celebrated specific remedy for all forms of malaria. It is so named because it was obtained from the bark of several species of the genus Cinchona, of the order Rubiaceae, that have been discovered at different times and...

 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
Charles Marie de La Condamine
Charles Marie de La Condamine was a French explorer, geographer, and mathematician. He spent ten years in present-day Ecuador measuring the length of a degree latitude at the equator and preparing the first map of the Amazon region based on astronomical observations.-Biography:Charles Marie de La...

 in 1737. Quinine was isolated and named in 1820 by French researchers Pierre Joseph Pelletier
Pierre Joseph Pelletier
Pierre-Joseph Pelletier was a French chemist who did notable research on vegetable alkaloids, and was the co-discoverer of quinine and strychnine.- Further reading :...

 and Joseph Bienaimé Caventou
Joseph Bienaimé Caventou
Joseph Bienaimé Caventou was a French chemist.He was a professor at the École de Pharmacie in Paris. He collaborated with Pierre-Joseph Pelletier in a Parisian laboratory located behind an apothecary. He was a pioneer in the use of mild solvents to isolate a number of active ingredients from...

. The name was derived from the original Quechua
Quechua languages
Quechua is a Native South American language family and dialect cluster spoken primarily in the Andes of South America, derived from an original common ancestor language, Proto-Quechua. It is the most widely spoken language family of the indigenous peoples of the Americas, with a total of probably...

 (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
Gold Coast (region)
The Gold Coast was the region of West Africa which is now the nation of Ghana. Early uses of the term refer literally to the coast and not the interior. It was not until the 19th century that the term came to refer to areas that are far from the coast...

, Nigeria
Nigeria
Nigeria , officially the Federal Republic of Nigeria, is a federal constitutional republic comprising 36 states and its Federal Capital Territory, Abuja. The country is located in West Africa and shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in...

 and other parts of west Africa".

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
Netherlands
The Netherlands is a constituent country of the Kingdom of the Netherlands, located mainly in North-West Europe and with several islands in the Caribbean. Mainland Netherlands borders the North Sea to the north and west, Belgium to the south, and Germany to the east, and shares maritime borders...

 government persisted in its attempt to smuggle the seeds, and by the 1930s Dutch plantations in Java
Java
Java is an island of Indonesia. With a population of 135 million , it is the world's most populous island, and one of the most densely populated regions in the world. It is home to 60% of Indonesia's population. The Indonesian capital city, Jakarta, is in west Java...

 were producing 22 million pounds of cinchona bark, or 97% of the world's quinine production. During World War II
World War II
World War II, or the Second World War , was a global conflict lasting from 1939 to 1945, involving most of the world's nations—including all of the great powers—eventually forming two opposing military alliances: the Allies and the Axis...

, Allied powers were cut off from their supply of quinine when the Germans conquered The Netherlands and the Japanese controlled the Philippines
Philippines
The Philippines , officially known as the Republic of the Philippines , is a country in Southeast Asia in the western Pacific Ocean. To its north across the Luzon Strait lies Taiwan. West across the South China Sea sits Vietnam...

 and Indonesia
Indonesia
Indonesia , officially the Republic of Indonesia , is a country in Southeast Asia and Oceania. Indonesia is an archipelago comprising approximately 13,000 islands. It has 33 provinces with over 238 million people, and is the world's fourth most populous country. Indonesia is a republic, with an...

. The United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, however, had managed to obtain four million cinchona seeds from the Philippines and began operation of cinchona plantations in Costa Rica
Costa Rica
Costa Rica , officially the Republic of Costa Rica is a multilingual, multiethnic and multicultural country in Central America, bordered by Nicaragua to the north, Panama to the southeast, the Pacific Ocean to the west and the Caribbean Sea to the east....

. 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. 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.

Synthetic quinine



Cinchona trees
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

 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
Robert Burns Woodward
Robert Burns Woodward was an American organic chemist, considered by many to be the preeminent organic chemist of the twentieth century...

 and W.E. Doering. Since then, several more efficient quinine total syntheses
Quinine total synthesis
In total synthesis, the Quinine total synthesis describes the efforts in synthesis of quinine over a 150 year period. The development of synthetic quinine is considered a milestone in organic chemistry although it has never been produced industrially as a substitute for natural occurring quinine...

 have been achieved, but none of them can compete in economic terms with isolation of the alkaloid from natural sources. The first synthetic organic
Organic chemistry
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, composition, reactions, and preparation of carbon-based compounds, hydrocarbons, and their derivatives...

 dye
Dye
A dye is a colored substance that has an affinity to the substrate to which it is being applied. The dye is generally applied in an aqueous solution, and requires a mordant to improve the fastness of the dye on the fiber....

, mauveine
Mauveine
Mauveine, also known as aniline purple and Perkin's mauve, was the first synthetic organic chemical dye.Its chemical name is3-amino-2,±9-dimethyl-5-phenyl-7-phenazinium acetate...

, 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 artemisinin
Artemisinin
Artemisinin , also known as Qinghaosu , and its derivatives are a group of drugs that possess the most rapid action of all current drugs against falciparum malaria. Treatments containing an artemisinin derivative are now standard treatment worldwide for falciparum malaria...

s are not available.

Quinine is a basic amine
Amine
Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

 and is always presented as a salt. Various preparations that exist include the hydrochloride
Hydrochloride
In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....

, dihydrochloride, sulfate
Sulfate
In inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...

, 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 intravenous
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...

ly (IV); quinine gluconate may also be given intramuscular
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...

ly (IM) or rectally (PR). 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
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

. 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.

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
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

 is used instead.

Adverse effects



Quinine can, in therapeutic doses, cause cinchonism
Cinchonism
Cinchonism or quinism is a pathological condition in humans caused by an overdose of quinine or its natural source, cinchona bark. Quinine is medically used to treat malaria. In much smaller amounts, quinine is an ingredient of tonic drinks, acting as a bittering agent...

; in rare cases, it may even cause death (usually by pulmonary edema
Pulmonary edema
Pulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...

). 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
Sulfadoxine
Sulfadoxine is an ultra-long-lasting sulfonamide often used in combination with pyrimethamine to treat or prevent malaria....

 (sulfonamide antibiotic) with pyrimethamine
Pyrimethamine
Pyrimethamine is a medication used for protozoal infections. It is commonly used as an antimalarial drug , and is also used in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.-Mechanism of action:Pyrimethamine interferes with...

) or Malarone (proguanil
Proguanil
Proguanil is a prophylactic antimalarial drug.Proguanil is effective against sporozoites.Proguanil hydrochloride is marketed as Paludrine by AstraZeneca.-Mechanism:...

 with atovaquone
Atovaquone
Atovaquone is a chemical compound that belongs to the class of naphthalenes. Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity. Its average wholesale price is about US$2.13 per standard 250 mg. tablet...

) are often used when oral therapy is required. Quinine ethyl carbonate is tasteless and odourless, 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
Toxicology
Toxicology is a branch of biology, chemistry, and medicine concerned with the study of the adverse effects of chemicals on living organisms...

 should be sought immediately.

Quinine in some cases can lead to constipation, erectile dysfunction or diarrhea.

The New York Times Magazine
The New York Times Magazine
The New York Times Magazine is a Sunday magazine supplement included with the Sunday edition of The New York Times. It is host to feature articles longer than those typically in the newspaper and has attracted many notable contributors...

described a case, presenting with fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, and blood abnormalities mimicking septic shock
Septic shock
Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome and death...

.

Abortifacient


Despite popular belief, quinine is not an effective abortifacient
Abortifacient
An abortifacient is a substance that induces abortion. Abortifacients for animals that have mated undesirably are known as mismating shots....

 (abortion pill) (in the US, quinine is listed as Pregnancy category
Pregnancy category
The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. It does not include any risks conferred by pharmaceutical agents or their metabolites that are present in breast...

 D ). Pregnant women who take toxic doses of quinine will suffer from renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

 before experiencing any kind of quinine-induced abortion. Indeed, quinine is the only drug recommended by the WHO as firstline treatment for uncomplicated malaria in pregnancy.

Disease interactions


Quinine can cause hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...

 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.

Quinine can cause abnormal heart rhythms and should be avoided if possible in patients with atrial fibrillation
Atrial fibrillation
Atrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...

, conduction defects or heart block
Heart block
A heart block can be a blockage at any level of the electrical conduction system of the heart .* Blocks that occur within the sinoatrial node are described as SA nodal blocks....

.

Hearing impairment


Some studies have related the use of quinine and hearing impairment
Hearing impairment
-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...

, in particular high-frequency loss, but it has not been conclusively established whether such impairment is temporary or permanent.

Regulation by the United States Food and Drug Administration


From 1969 to 1992, the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) received 157 reports of health problems related to quinine use, including 23 which had resulted in death. In 1994, the FDA banned the use of over-the-counter
Over-the-counter drug
Over-the-counter drugs are medicines that may be sold directly to a consumer without a prescription from a healthcare professional, as compared to prescription drugs, which may be sold only to consumers possessing a valid prescription...

 (OTC) quinine as a treatment for nocturnal leg cramps. Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...

 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.

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.

Non-medical uses of quinine



In some areas, non-medical use of quinine is regulated. For example, in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 and in Germany
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...

, quinine is limited to between 83–85 parts per million.

Beverages


Quinine is a flavour component of tonic water
Tonic water
Tonic water is a carbonated soft drink in which quinine is dissolved. Originally used as a prophylactic against malaria, tonic water usually now has a significantly lower quinine content and is consumed for its distinctively bitter taste...

 and bitter lemon
Bitter lemon
Bitter lemon is a carbonated soft drink flavoured with quinine and lemon.-The drink:The signature bitter taste is produced by a combination of the quinine and the lemon pith used in manufacturing the drink. The principal difference between tonic water and bitter lemon is the addition of lemon juice...

. According to tradition, the bitter taste of anti-malarial quinine tonic led British colonials in India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

 to mix it with gin
Gin
Gin is a spirit which derives its predominant flavour from juniper berries . Although several different styles of gin have existed since its origins, it is broadly differentiated into two basic legal categories...

, thus creating the gin and tonic
Gin and tonic
A gin and tonic is a highball cocktail made with gin and tonic water poured over ice. It is usually garnished with a slice or wedge of lime, or lemon. The amount of gin varies according to taste...

 cocktail, which is still popular today in many parts of the world, especially the U.K., United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

, Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

, and New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...

. In France
France
The French Republic , The French Republic , The French Republic , (commonly known as France , is a unitary semi-presidential republic in Western Europe with several overseas territories and islands located on other continents and in the Indian, Pacific, and Atlantic oceans. Metropolitan France...

, quinine is an ingredient of an apéritif
Aperitif
Apéritifs and digestifs are alcoholic drinks that are normally served with meals.-Apéritifs:An apéritif is usually served before a meal to stimulate the appetite. This contrasts with digestifs, which are served after a meal for the purpose of aiding digestion...

 known as Quinquina
Quinquina
In France, quinquina is a collective name for bitters having quinine as one of their main ingredients. Quinquina is also known as Peruvian Bark.It originates from South America...

 or "Cap Corse". In Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...

, the traditional flavoured wine Barolo Chinato is infused with quinine and local herbs and is served as a digestif. In Canada
Canada
Canada is a North American country consisting of ten provinces and three territories. Located in the northern part of the continent, it extends from the Atlantic Ocean in the east to the Pacific Ocean in the west, and northward into the Arctic Ocean...

 and Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...

, quinine is an ingredient in the carbonated chinotto beverages Brio and San Pellegrino Chinotto. In Scotland
Scotland
Scotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...

, the company A.G. Barr
A.G. Barr
A.G. Barr plc or commonly known as Barr's is a British soft drinks manufacturer, based in Cumbernauld, North Lanarkshire, Scotland. It is particularly notable for the manufacture of the popular Scottish drink, Irn-Bru. A.G. Barr is the largest manufacturer of soft drinks in the United Kingdom...

 uses quinine as an ingredient
Ingredient
An ingredient is a substance that forms part of a mixture . For example, in cooking, recipes specify which ingredients are used to prepare a specific dish. Many commercial products contain a secret ingredient that is purported to make them better than competing products...

 in the carbonated and caffeinated beverage Barr's Irn-Bru
Irn-Bru
Irn-Bru is a carbonated soft drink produced in Westfield, Cumbernauld, Scotland. It is made by A.G. Barr of Glasgow since moving out of their original Parkhead factory in the mid-1990s and at a second manufacturing site in Mansfield, England...

. In the United Kingdom
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...

, Australia
Australia
Australia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...

, New Zealand
New Zealand
New Zealand is an island country in the south-western Pacific Ocean comprising two main landmasses and numerous smaller islands. The country is situated some east of Australia across the Tasman Sea, and roughly south of the Pacific island nations of New Caledonia, Fiji, and Tonga...

, South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...

 and Egypt
Egypt
Egypt , officially the Arab Republic of Egypt, Arabic: , is a country mainly in North Africa, with the Sinai Peninsula forming a land bridge in Southwest Asia. Egypt is thus a transcontinental country, and a major power in Africa, the Mediterranean Basin, the Middle East and the Muslim world...

, quinine is an ingredient in Schweppes and other Indian tonic waters. In Uruguay
Uruguay
Uruguay ,officially the Oriental Republic of Uruguay,sometimes the Eastern Republic of Uruguay; ) is a country in the southeastern part of South America. It is home to some 3.5 million people, of whom 1.8 million live in the capital Montevideo and its metropolitan area...

 and Argentina
Argentina
Argentina , officially the Argentine Republic , is the second largest country in South America by land area, after Brazil. It is constituted as a federation of 23 provinces and an autonomous city, Buenos Aires...

, quinine is an ingredient of a Pepsico
PepsiCo
PepsiCo Inc. is an American multinational corporation headquartered in Purchase, New York, United States, with interests in the manufacturing, marketing and distribution of grain-based snack foods, beverages, and other products. PepsiCo was formed in 1965 with the merger of the Pepsi-Cola Company...

 Inc. tonic water
Tonic water
Tonic water is a carbonated soft drink in which quinine is dissolved. Originally used as a prophylactic against malaria, tonic water usually now has a significantly lower quinine content and is consumed for its distinctively bitter taste...

 named Paso de los Toros. In South Africa
South Africa
The Republic of South Africa is a country in southern Africa. Located at the southern tip of Africa, it is divided into nine provinces, with of coastline on the Atlantic and Indian oceans...

, 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
Fluorescence
Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation of a different wavelength. It is a form of luminescence. In most cases, emitted light has a longer wavelength, and therefore lower energy, than the absorbed radiation...

 quantum yield
Quantum yield
The quantum yield of a radiation-induced process is the number of times that a defined event occurs per photon absorbed by the system. The "event" may represent a chemical reaction, for example the decomposition of a reactant molecule:...

, quinine is also used in photochemistry
Photochemistry
Photochemistry, a sub-discipline of chemistry, is the study of chemical reactions that proceed with the absorption of light by atoms or molecules.. Everyday examples include photosynthesis, the degradation of plastics and the formation of vitamin D with sunlight.-Principles:Light is a type of...

 as a common fluorescence standard
Standard (metrology)
In the science of measurement, a standard is an object, system, or experiment that bears a defined relationship to a unit of measurement of a physical quantity. Standards are the fundamental reference for a system of weights and measures, against which all other measuring devices are compared...

.

Quinine (and quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...

) are used as the chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....

 moiety for the ligands used in Sharpless asymmetric dihydroxylation
Sharpless asymmetric dihydroxylation
Sharpless asymmetric dihydroxylation is the chemical reaction of an alkene with osmium tetroxide in the presence of a chiral quinine ligand to form a vicinal diol....

.

Bark of Remijia
Remijia
Remijia is a genus of flowering plants in the family Rubiaceae. Within the family, it is a member of the subfamily Cinchonoideae and the tribe Cinchoneae....

contains 0.5–2% of quinine. The bark is cheaper than bark of Cinchona
Cinchona
Cinchona or Quina is a genus of about 38 species in the family Rubiaceae, native to tropical South America. They are large shrubs or small trees growing 5–15 metres in height with evergreen foliage. The leaves are opposite, rounded to lanceolate and 10–40 cm long. The flowers are white, pink...

and as it has an intense taste, it is used for making tonic water
Tonic water
Tonic water is a carbonated soft drink in which quinine is dissolved. Originally used as a prophylactic against malaria, tonic water usually now has a significantly lower quinine content and is consumed for its distinctively bitter taste...

.

Other


Quinine is sometimes used as a cutting agent
Cutting agent
A cutting agent is a chemical used to "cut" illicit drugs with something less expensive than the drug itself.-Overview:The classical model of drug cutting A cutting agent is a chemical used to "cut" (dilute) illicit drugs with something less expensive than the drug itself.-Overview:The classical...

 in street drugs
Illegal drug trade
The illegal drug trade is a global black market, dedicated to cultivation, manufacture, distribution and sale of those substances which are subject to drug prohibition laws. Most jurisdictions prohibit trade, except under license, of many types of drugs by drug prohibition laws.A UN report said the...

 such as cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

 and heroin.

Quinine is used as a treatment for Cryptocaryon irritans (commonly referred to as white spot, crypto or marine ich) infection of marine aquarium
Marine aquarium
A marine aquarium is an aquarium that keeps marine plants and animals in a contained environment. Marine aquaria are further subdivided by hobbyists into fish only , fish only with live rock , and reef aquaria. Fish only tanks often showcase large or aggressive marine fish species and generally...

 fish.

See also

  • Luis Jerónimo de Cabrera, 4th Count of Chinchón and Jesuit's bark
    Jesuit's bark
    Jesuit's Bark, also called Peruvian Bark, is the historical name of the most celebrated specific remedy for all forms of malaria. It is so named because it was obtained from the bark of several species of the genus Cinchona, of the order Rubiaceae, that have been discovered at different times and...

    , for the story of its introduction into Europe
  • Pharmacology
    Pharmacology
    Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...

  • Warburg's Tincture
    Warburg's Tincture
    Warburg's tincture was a pharmaceutical drug, now obsolete. It was invented in 1834 by Dr Carl Warburg.Warburg's tincture was well known in the Victorian era as a medicine for fevers, especially tropical fevers, including malaria. It was considered, by some, to be superior to quinine.Warburg's...


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
    Malaria prophylaxis
    Malaria prophylaxis is a preventative treatment of malaria.Most adults from endemic areas have a degree of long-term infection, which tends to recur, and also possess partial immunity ; the resistance reduces with time, and such adults may become susceptible to severe malaria if they have spent a...

     with mefloquine hydrochloride". Aviation, Space, and Environmental Medicine
    Aviation, Space, and Environmental Medicine
    Aviation, Space, and Environmental Medicine is a peer-reviewed scientific journal in the field of aviation / aerospace medicine.Aviation, Space, and Environmental Medicine was founded as the Journal of Aviation Medicine in 1930 by Louis H...

    1982; 3(10):1011–3.

External links