Malaria Site: Quinine

Quinine is the chief alkaloid of cinchona bark (known as 'Fever Bark'), a tree found in South America. It has a colourful history of more than 350 years. Calancha, an Augustinian monk of Lima, first wrote about the curative properties of cinchona powder in "fevers and tertians" as early as in 1633. By 1640, the bark had already found its way into Europe, thanks to the Jesuit fathers (hence the name 'Jesuit's bark'). Eminent philosopher Cardinal de Lugo popularised the bark in Rome (hence it is also called Cardinal's bark). In 1820, Pelletier and Caventou isolated quinine and cinchonine from cinchona. Even today, quinine is obtained entirely from the natural sources due the difficulties in synthesising the complex molecule.

See History of Quinine

Mechanism of action: Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is said to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme.

	Food Vacuole		Heme polymerase
Hemoglobin		Toxic Heme		Non Toxic Hemazoin (Malarial Pigment)
	Degradation		? Inhibited by Quinine

As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine.

Absorption, fate and excretion: Quinine is readily absorbed when given orally or intramuscularly. Peak plasma concentrations are achieved within 1 - 3 hours after oral dose and plasma half-life is about 11 hours. In acute malaria, the volume of distribution of quinine contracts and clearance is reduced, and the elimination half-life increases in proportion to the severity of the illness. Therefore, maintenance dose of the drug may have to be reduced if the treatment is continued for more than 48 hours. The drug is extensively metabolised in the liver and only 10% is excreted unchanged in the urine. There is no cumulative toxicity on continued administration.

Adverse effects: Quinine is a potentially toxic drug. The typical syndrome of quinine side effects is called as cinchonism and it can be mild in usual therapeutic dosage or could be severe in larger doses. Mild cinchonism consists of ringing in the ears, headache, nausea and disturbed vision. Functional impairment of the eighth nerve results in tinnitus, decreased auditory acuity and vertigo. Visual symptoms consist of blurred vision, disturbed colour perception, photophobia, diplopia, night blindness, and rarely, even blindness. These changes are due to direct neurotoxicity, although vascular changes may contribute to the problem.

Gastrointestinal symptoms like nausea, vomiting, abdominal pain and diarrhoea may be seen. Rashes, sweating, angioedema can occur. Excitement, confusion, delirium are also seen in some patients. Coma, respiratory arrest, hypotension, and death can occur with over dosage. Quinine can also cause renal failure. Massive hemolysis and hemoglobinuria can occur, especially in pregnancy or on repeated use. Hypoprothrombinemia, agranulocytosis are also reported.

Quinine has little effect on the heart in therapeutic doses and hence regular cardiac monitoring is not needed. However it can cause hypotension in the event of overdose.

Quinine reduces the excitability of the motor end plate and thus antagonises the actions of physostigmine. It can cause respiratory distress and dysphagia in patients of myasthenia gravis.

Quinine stimulates insulin secretion and in therapeutic doses it can cause hypoglycemia. This can be more severe in patients with severe infection and in pregnancy. Hypoglycemia in malaria may go unnoticed and could even cause death. Therefore, it is advisable to monitor blood glucose levels at least once in 4-6 hours while quinine is administered, especially in severe infection and in pregnancy. Quinine induced hypoglycemia can recur even after administration of 25% or 50% dextrose. In such situations, maintenance with a 10% dextrose infusion is advisable. Resistant hypoglycemia due to quinine can be managed with Injection Octreotide, 50 microgram subcutaneously, every 6 to 8 hours.

Contraindications: Hypersensitivity in the form of rashes, angioedema, visual and auditory symptoms are indications for stopping the treatment. It is contraindicated in patients with tinnitus and optic neuritis. It should be used with caution in patients with atrial fibrillation. Hemolysis is indication for immediately stopping the drug. It is also contraindicated in patients suffering from myasthenia gravis.

Availability: It is available as tablets and capsules containing 300 or 600 mg of the base. It is also available as injections, containing 300mg /ml.

Intra venous: 20 mg of salt/kg in 10 ml/kg isotonic saline or 5% dextrose over 4 hours, then 10 mg of salt/kg in saline or dextrose over 4 hours, every 8 hours until patient is able to take orally or for 5-7 days.

Intra muscular: 20 mg/kg stat, followed by 10 mg/kg 8 hourly by deep intra muscular injections for 5-7 days

Quinidine: The antiarrhythmic drug related to quinine can also be used in the treatment of severe P. falciparum malaria. Dose is 10 mg of base / kg by infusion over 1-2 hours, followed by 0.02 mg/kg/min with ECG monitoring.