Quinine is an alkaloid that occurs naturally in the bark of the quinine tree. The benefits of cinchona bark were first recognized in 1630 in South America, where cinchona is indigenous to certain regions. In 1640 it was introduced to Spain for the treatment of fever. The early use of quinine for all types of febrile illness was erroneous and resulted from the observed reduction in fever in malaria patients; it has no antipyretic qualities. Quinine was isolated from the quinine bark in 1820 and is still sourced from the natural source. Quinine is the levorotatory isomer of quinidine, a more potent, but more toxic, antimalarial. Quinine is used to treat the chloroquine resistant strains of Plasmodium falciparum
Mechanism of action: exact mechanism of the drug of antiprotozary action in the treatment of malaria is not fully understood, but quinine is concentrated in parasitized erythrocytes and has a schizonticidal action. Quinine raises the pH of parasitic acidic vesicles and can alter molecular transport and phospholipase activity. It is active against asexual erythrocytic forms of Plasmodium falciparum, P. malariae, P. ovale or P. vivax. Quinine does not provide a cure for malaria, as it is not effective against the exoerythrocytic forms of the parasite. Antimytonic activity occurs through direct action on the muscle fiber, increasing the refractory period. It also decreases the excitability of the motor plate, reducing the response to repetitive nerve stimulation. Quinine also affects the distribution of calcium within the muscle fiber. It is widely used for the effective relief of nighttime leg cramps. Quinine has a curare-type action and counteracts the effects of neostigmine and physostigmine. Quinine produces cardiovascular effects similar to those of quinidine, but normal oral dosage levels have little effect in patients without cardiac dysfunction. Intravenous administration, no longer used in the USA, can cause severe hypotension. Quinine has been shown to prolong the QT interval.
Pharmacokinetics: Quinine is almost completely absorbed from the gastrointestinal tract, and peak serum levels are reached in approximately 1-3 hours. Plasma levels are higher in malaria patients because malaria can cause decreased liver function, with a consequent reduction in clearance. It is widely distributed in the liver, lungs, kidneys, and spleen, but the volume of distribution is less in malaria patients. There is a certain distribution in the CSF, and the drug crosses the placenta and is excreted in breast milk. In healthy adults, approximately 70% binds to plasma proteins; union is greater in patients with malaria. Quinine is extensively metabolized in the liver, primarily to hydroxy metabolites. The plasma half-life is between 8 to 21 hours, and is shorter in children and longer in malaria patients. Acidic urine increases the excretion rate, which is largely the metabolites, with only a small amount as unchanged drug. Small amounts can be excreted in the stool.
Indications: Dosage The following organisms are generally considered susceptible to quinine in vitro: Babesia microti; Plasmodium falciparum; Plasmodium malariae; Plasmodium ovale; Plasmodium vivax. For the treatment of chloroquine resistant attacks of malaria: Oral administration: Adults: 650 mg PO every 8 hours for at least 3 days (7 days in Southeast Asia), with the simultaneous administration of 250 mg of tetracycline every 6 hours for 7 days; Or the concurrent administration of 1.5 g of sulfadoxine and 75 mg of pyrimethamine combinations as a single dose; Or concomitant administration of 900 mg of clindamycin 3 times a day for 3 days; Or the simultaneous administration of 100 mg of doxycycline every 12 hours for 7 days. Children: 25 mg / kg / day PO divided into three doses every 8 hours, for at least 3 days (7 days in Southeast Asia), with the simultaneous administration of 5 mg / kg tetracycline every 6 hours for 7 days ( only for children over 8 years old); Or the concurrent administration of 6.7 to 13.3 mg / kg of clindamycin three times a day for 3 days; Or the concurrent or consecutive administration of 1.25 mg / kg of pyrimethamine in combination with 25 mg / kg of sulfadoxine as a single dose. The maximum dose of quinine 2 g / day. For the treatment of babesiosis †: Oral administration: Adults: 650 mg PO 3-4 times a day with the simultaneous administration of IV clindamycin for 7-10 days. Children †: Safe dose has not been established. The suggested dose is 25 mg / kg / day, divided every 8 hours for 7 days. Maximum single dose is 650 mg. Patients with renal insufficiency: CrCl> 50 ml / min: adjustment of the necessary dose. ClCr 10-50 ml / min: reduce the recommended dose by 25% and extend the dosing interval for every 8-12 hours. Creatinine clearance <10 ml / min: Reduce the recommended dose by 30-50% and extend the dosing interval every 24 hours.
Contraindications quinine stimulates insulin release and should not be used in patients with hypoglycemia. P. falciparum malaria attacks can also induce hypoglycemia, and pregnant women and children are more susceptible. Quinine should not be used in patients with optic neuritis or tinnitus, as it can aggravate these conditions. The drug can affect the retina and optic nerve as part of a syndrome called zinc-induced zinc, which can also affect hearing. Quinine can induce hemolytic anemia in patients with G6PD deficiency. Normal doses have been used without adverse effects, but the drug should be used with extreme caution. Because quinine can induce thrombocytopenia, its use is contraindicated in any patient with a history of purpura or conditions associated with thrombotic thrombocytopenia. Intramuscular injections should be administered with caution to patients who received quinine. IM injections can cause bleeding, bruising, or bruising due to the side effects of quinine platelet therapy. Quinine should not be used in patients with sewage fever, which may follow chronic falciparum malaria infection as they may be predisposed to complications such as anemia and hemolysis with kidney failure. Quinine should not be used in patients with a known allergy to mefloquine, quinidine, quinine, or hypersensitivity. Patients with mefloquine hypersensitivity or quinidine hypersensitivity may have cross sensitivity to quinine. Quinine should not be used in patients with myasthenia gravis. Quinine produces neuromuscular blockage exacerbating muscle weakness and can cause respiratory distress and dysphagia in myasthenic patients. Patients with cardiac arrhythmias may be at risk of developing quinine-induced arrhythmias. Quinine-treated patients have demonstrated prolonged QT intervals.
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Quinine is classified as pregnancy category X by the manufacturer, however some doctors feel quinine should be used for chloroquine resistant Plasmodium falciparum malaria. Because of this, a reference text classifies quinine as category D. Quinine can cause a birth defect and has been associated with intrauterine fetal death. Large doses can be oxytocic, and quinine has been used as an abortifacient. Aside from the effects on the fetus, quinine is also more likely to induce hypoglycemia in pregnant women. Other less toxic drugs are available for the treatment of malaria during pregnancy. Quinine is excreted in breast milk and should be used with caution during lactation however, the American Academy of Pediatrics considers quinine to be compatible with lactation.
NTERACTIONS quinine appears to inhibit renal tubular secretion of amantadine resulting in a slight increase in serum amantadine concentrations. The clinical significance of this drug interaction is unclear, however patients, especially the elderly, should be monitored for increased adverse reactions to amantadine if quinine is added. Quinine, at doses above 430 mg / day, also appears to potentiate astemizole toxicity. Due to the severity of astemizole toxicity, quinine should not be administered to patients receiving astemizole. It would also be prudent to avoid quinine within 7 days after discontinuing astemizole, due to prolonged elimination of astemizole. Because similar concerns exist for terfenadine, quinine and terfenadine should not be used concomitantly. Serum digoxin or digitoxin levels may be elevated when quinine is administered concomitantly. Large doses of quinine can affect the clearance of digitalis glycosides and require a dose adjustment to avoid digoxin toxicity. Lower doses may have no effect on digital clearance. Cimetidine but not ranitidine reduced the liver clearance of quinine and prolongs its half-life. Peak serum quinine concentrations were unaffected. The clinical significance of this pharmacokinetic interaction is unclear. Flecainide clearance may be modestly inhibited by quinine, increasing serum flecainide concentrations. Although changes were also observed on the ECG, it is not clear whether this was the result of elevated serum flecainide concentrations or the combined action of the two drugs on conduction. Until further data is available, the concomitant use of these two drugs should be avoided whenever possible. Alkalinization of urine by drugs such as sodium bicarbonate and acetazolamide, can decrease the renal clearance of quinine. Increased plasma levels of quinine following reduced clearance may increase the risk of toxicity. The aluminum salts in antacids can delay or reduce the absorption of quinine. Quinine may increase the hypoprothrombinemic effects of warfarin. The mechanism of this reaction is depression of the liver enzyme system responsible for the synthesis of vitamin K-dependent clotting factors. It is also worth noting that quinine may interfere with platelet aggregation and therefore the risk of bleeding. increases if quinine is used in patients receiving warfarin or other anticoagulants. Adjustment of the anticoagulant dose may be necessary during quinine therapy. Quinine can increase the effects of neuromuscular blockers, which could cause acute respiratory failure. The possibility of zinconism increases if quinine and quinidine are administered concomitantly. Quinine can inhibit levobupivacaine metabolism. Concurrent adminiatration of quinine and levobupivacaine can cause an increase in systemic levobupivacaine levels resulting in toxicity. Rifampin is a powerful inducer of liver metabolism. Rifampin has been shown to significantly accelerate quinine clearance and reduce its half-life. Higher quinine doses may be required in patients receiving rifampicin. Quinine inhibits cytochrome P450 isoenzyme 3A4 and may decrease zonisamide metabolism. Although not studied, a prolonged terminal half-life of zonisamide can result when the two drugs are administered together. Quinine should not be used concomitantly with mefloquine because additive cardiac effects may cause arrhythmias and seizures. Sequential administration should also be done with caution because mefloquine has a long half-life. Do not administer mefloquine until at least 12 hours have elapsed after discontinuation of quinine. Quinine inhibits the hepatic CYP3A4 isoenzyme and may decrease the metabolism of benzodiazepines that are metabolized by oxidation. Increased toxicity can be seen in some patients who combine quinine with anxiolytics or hypnotic benzodiazpine. Quinine should be used with caution with dofetilide, as it is a cytochrome CYP 3A4 inhibitor and has been associated with QT prolongation in some patients and may increase the risk of dofetilide-induced proarrhythmias. Quinine inhibits cytochrome P450 isoenzyme 3A4 and may decrease alosetron metabolism. Although not studied, increased plasma alosetron concentrations may result when the two drugs are administered together. Tacrolimus is metabolized by cytochrome P450 3A4, a quinine-inhibited isoezyme. Decreased tacrolinus metabolism can lead to toxicity. Close monitoring of tacrolimus blood levels is warranted with concurrent therapy. Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are excreted by renal tubular secretion (eg, quinine) can decrease metformin clearance by competing for common renal tubular transport systems. Careful monitoring of patients and adjustment of the dose of metformin and / or the interfering cationic drug are recommended. Prilocaine-treated patients receiving concurrent quinine are at increased risk of developing methemoglobinemia. Hepatic CYP3A4 is partially responsible for the metabolism of galantamine. The bioavailability of galantamine can be increased when co-administered with an inhibitor of this enzyme, including quinine. Doctors should be aware that some food and beverage products contain quinine. Tonic water commonly contains quinine and can have additive effects when taken with quinine medications.
Adverse Reactions A number of adverse effects may result from a reaction known as zinconia, a cinchona poisoning and characterized by tinnitus, headache, deafness, and occasionally anaphylactoid shock. Severe zinconia also produces other effects on the central nervous system, GI tract, skin, and cardiovascular system. Mild symptoms do not indicate discontinuation of the drug, but severe symptoms may require it. Severe gastrointestinal symptoms can produce nausea / vomiting, abdominal pain and diarrhea with local irritating effects and also with a centrally mediated effect. Other CNS effects can cause headache, fever, confusion, and syncope. Quinine can affect the optic nerve and retina, causing visual impairment, photophobia, night blindness, diplopia, or scotoma. In general, adverse effects are reversible with discontinuation of the drug, but can lead to optic atrophy in severe cases. Extreme redness of the skin accompanied by general itching may be the result of hypersensitivity to quinine. Maculopapular rash, fever, erythema, urticaria, vasculitis, and wheezing have been observed during quinine therapy, and patients should be closely monitored for symptoms, especially those with asthma. If signs of hypersensitivity appear are present, the drug should be discontinued. Photosensitivity has also been reported during quinine therapy, but it appears to be relatively rare. Quinine treatment can cause several possible adverse hematological reactions. Agranulocytosis can be characterized by fever and sore throat; Unusual tiredness or weakness may indicate anemia secondary to hemolysis, which occurs more frequently in patients with G6PD deficiency; and unusual bleeding or bruising may indicate thrombocytopenia or hypoprothrombinemia. Quinine can affect insulin secretion, and patients at risk should be monitored for hypoglycemic effects. Hypoglycemia is more likely to occur in pregnant women, children, or patients with severe cases of malaria. Quinine produces cardiovascular effects similar to those of quinidine, but normal oral dosage levels have little effect in patients without existing cardiac dysfunction. Intravenous administration, no longer used in the USA, can cause severe hypotension. Quinine has been shown to prolong the QT interval. There may be symptoms of angina pectoris.
