Brands, Medical Use, Clinical Data
Drug Category
- Analgesics, Non-Narcotic
- Muscle Relaxants, Central
- Antimalarials
- P01BC01
Dosage Forms
- Capsule
- Drops
- Injection
- Tablet
Brands / Synonyms
6'-Methoxycinchonidine; 6'-Methoxycinchonine; Aflukin; Chinin; Chinine; Coco-Quinine; None; Qualaquin; Quinine Dab; Quinine, Anhydrous; Quinineanhydrous; Quinoline Alkaloid
Indications
For the treatment of malaria and leg cramps
Pharmacology
Quinine is used parenterally to treat life-threatening infections caused by chloroquine-resistant Plasmodium falciparum malaria. 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 thought to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme. 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.
Mechanism of Action
The mechanism of action of Quinine is not completely clear. This is thought to inhibit nucleic acid synthesis, protein synthesis, and glycolysis in Plasmodium falciparum and bind with hemazoin in parasitized erythrocytes.
Absorption
76 - 88%
Toxicity
Not Available
Biotrnasformation / Drug Metabolism
> 80% metabolized by the liver
Contraindications
Quinine is contraindicated in patients with known hypersensitivity, in pregnancy, in women of child bearing potential, in patients with glucose-6-phosphate dehydrogenase deficiency, in patients with tinnitus, or optic neuritis, and in patients with a history of blackwater fever.
Drug Interactions
Effects of Drugs and Other Agents on Quinine Pharmacokinetics
Antacids: Antacids containing aluminum and/or magnesium may delay or decrease absorption of quinine.
Concomitant administration of these antacids with quinine should be avoided.
Cholestyramine: In 8 healthy volunteers who received quinine sulfate 600 mg with or without 8 grams of
cholestyramine resin, no significant difference in quinine pharmacokinetic parameters was seen.
Erythromycin (CYP3A4 inhibitor): Erythromycin was shown to inhibit the metabolism of quinine in
vitro using human liver microsomes. Therefore, concomitant administration of erythromycin with quinine sulfate is
likely to increase plasma quinine concentrations, and should be avoided.
Grapefruit juice (CYP3A4 inhibitor): In a pharmacokinetic study involving 10 healthy volunteers, the
administration of a single 600 mg dose of quinine sulfate with grapefruit juice (full-strength or half-strength) did
not significantly alter the pharmacokinetic parameters of quinine. Quinine sulfate may be taken with grapefruit
juice.
Histamine H2-receptor blockers (cimetidine, ranitidine): In healthy volunteers who were given a single oral
600 mg dose of quinine sulfate after pretreatment with cimetidine (200 mg three times daily and 400 mg at bedtime for
7 days) or ranitidine (150 mg twice daily for 7 days), the apparent oral clearance of quinine decreased and the mean
elimination half- life increased significantly when given with cimetidine but not with ranitidine. Compared to
untreated controls, the mean AUC of quinine increased by only 20% with ranitidine and by 42% with cimetidine
(p<0.05) without a significant change in mean quinine Cmax. When quinine is to be given concomitantly
with a histamine H2 receptor blocker, the use of ranitidine is preferred over cimetidine. Although
cimetidine may be used concomitantly with quinine sulfate, patients should be monitored closely for adverse events
associated with quinine.
Isoniazid: Isoniazid 300 mg/day pretreatment for 1 week did not significantly alter the pharmacokinetic
parameters of quinine. Adjustment of quinine dosage is not necessary when isoniazid is given concomitantly.
Ketoconazole (CYP3A4 inhibitor): In a crossover study, healthy subjects (N=9) who received a single oral
dose of quinine hydrochloride (500 mg) concomitantly with ketoconazole (100 mg twice daily for 3 days) had a mean
quinine AUC that was higher by 45% and a mean oral clearance of quinine that was 31% lower than after receiving
quinine alone. Although no change in the quinine dosage regimen is necessary with concomitant ketoconazole, patients
should be monitored closely for adverse reactio ns associated with quinine sulfate.
Oral contraceptives (estrogen, progestin): In 7 healthy females who were using single ingredient progestin
or combination estrogen-containing oral contraceptives, the pharmacokinetic parameters of a single 600 mg dose of
quinine sulfate were not altered in comparison to those observed in 7 age- matched female control subjects not using
oral contraceptives.
Rifampin (CYP3A4 inducer): In patients with uncomplicated P. falciparum malaria who received quinine
sulfate 10 mg/kg concomitantly with rifampin 15 mg/kg/day for 7 days (N=29), the median AUC of quinine between days 3
and 7 of therapy was 75% lower as compared to those who received quinine monotherapy. In healthy volunteers (N=9) who
received a single oral 600 mg dose of quinine sulfate after 2 weeks of pretreatment with rifampin 600 mg/day, the
mean quinine AUC and C max decreased by 85% and 55%, respectively. Therefore the concomitant administration of
rifampin with quinine sulfate should be avoided .
Tetracycline: In 8 patients with acute uncomplicated P. falciparum malaria who were treated with
oral quinine sulfate (600 mg every 8 hours for 7 days) in combination with oral tetracycline (250 mg every 6 hours
for 7 days), the mean plasma quinine concentrations were about two- fold higher than in 8 patients who received
quinine monotherapy. Although tetracycline may be concomitantly administered with quinine sulfate, patients should be
monitored closely for adverse reactions associated with quinine sulfate.
Troleandomycin (CYP3A4 inhibitor): In a crossover study (N=10), healthy subjects who received a single oral
600 mg dose of quinine sulfate with the macrolide antibiotic, troleandomycin (500 mg every 8 hours) exhibited a 87%
higher mean quinine AUC, a 45% lower mean oral clearance of quinine, and a 81% lower formation clearance of the main
metabolite, 3-hydroxyquinine, than when quinine was given alone. Therefore, concomitant administration of
troleandomycin with quinine sulfate should be avoided.
Urinary alkalizers (acetazolamide, sodium bicarbonate): Urinary alkalinizing agents may increase plasma
quinine concentrations.
Effect of Quinine on the Pharmacokinetics of Other Drugs
Results of in vivo and in vitro drug interaction studies suggest that quinine has the potential to
inhibit the metabolism of drugs that are substrates of CYP3A4 and CYP2D6, as well as inhibit the biliary excretion of
drugs like digoxin.
Anticonvulsants (carbamazepine, phenobarbital, and phenytoin): A single 600 mg oral dose of quinine sulfate
increased the mean plasma C max, and AUC0-24 of single oral doses of carbamazepine (200 mg) and
phenobarbital (120 mg) but not phenytoin (200 mg) in 8 healthy subjects. The mean AUC increases of carbamazepine,
phenobarbital and phenytoin were 104%, 81% and 4%, respectively; the mean increases in C max were 56%, 53%, and 4%,
respectively. Mean urinary recoveries of the three antiepileptics over 24 hours were also profoundly increased by
quinine. If concomitant administration with carbamazepine or phenobarbital cannot be avoided, frequent monitoring of
anticonvulsant drug concentrations is recommended. Additionally, patients should be monitored closely for adverse
reactions associated with these anticonvulsants. Carbamazepine, phe nobarbital, and phenytoin are CYP3A4 inducers and
may decrease quinine plasma concentrations if used concurrently with quinine sulfate.
Astemizole (CYP3A4 substrate): Elevated plasma astemizole concentrations were reported in a subject who
experienced torsades de pointes after receiving three doses of quinine sulfate for nocturnal leg cramps concomitantly
with chronic astemizole 10 mg/day. The concurrent use of quinine with astemizole and other CYP3A4 substrates with QT
prolongation potential (e.g., cisapride, terfenadine, halofantrine, pimozide, and quinidine ) should also be
avoided
Desipramine (CYP2D6 substrate): Quinine (750 mg/day for 2 days) decreased the metabolism of desipramine in
patients who were extensive CYP2D6 metabolizers, but had no effect in patients who were poor CYP2D6 metabolizers.
Lower doses (80 mg to 400 mg) of quinine did not significantly affect the pharmacokinetics of other CYP2D6
substrates, namely, debrisoquine, dextromethorphan, and methoxyphenamine. Although clinical drug interaction studies
have not been performed, antimalarial doses (greater than or equal to 600 mg) of quinine may inhibit the metabolism
of other drugs that are CYP2D6 substrates (e.g., flecainide, debrisoquine, dextromethorphan, metoprolol,
paroxetine ). Patients taking medications that are CYP2D6 substrates with quinine sulfate should be monitored
closely for adverse reactions a sociated with these medications.
Digoxin: In 4 healthy subjects who received digoxin (0.5 to 0.75 mg/day) during treatment with quinine (750
mg/day), a 33% increase in mean steady state AUC of digoxin and a 35% reduction in the steady-state biliary clearance
of digoxin were observed compared to digoxin alone. Thus, if quinine is administered to patients receiving digo xin,
plasma digoxin concentrations should be closely monitored, and the digoxin dose adjusted, as necessary.
Halofantrine: Although not studied clinically, quinine was shown to inhibit the metabolism of halofantrine
in vitro using human liver microsomes. Therefore, concomitant administration of quinine sulfate is likely to
increase plasma halofantrine concentrations.
Mefloquine: In 7 healthy subjects who received mefloquine (750 mg) at 24 hours before an oral 600 mg dose
of quinine sulfate, the AUC of mefloquine was increased by 22% compared to mefloquine alone. In this study, the QTc
interval was significantly prolonged in the subjects who received mefloquine and quinine sulfate 24 hours apart. The
concomitant administration of mefloquine and quinine may produce electrocardiographic abnormalities (including QTc
prolongation) and may increase the risk of seizures.
Neuromuscular blocking agents (pancuronium, succinylcholine, tubocurarine): In one report, quinine
potentiated neuromuscular blockade in a patient who received pancuronium during an operative procedure, and
subsequently (3 hours after receiving pancuronium) received quinine 1800 mg daily. Quinine may also enhance the
neuromuscular blocking effects of succinylcholine and tubocurarine .
Warfarin and oral anticoagulants: Cinchona alkaloids, including quinine, may have the potential to depress
hepatic enzyme synthesis of vitamin K-dependent coagulation pathway proteins and may enhance the action of warfarin
and other oral anticoagulants. Quinine may also interfere with the anticoagulant effect of heparin. Thus, in patients
receiving these anticoagulants, the prothrombin time (PT), partial thromboplastin time (PTT), or international
normalization ratio (INR) should be closely monitored as appropriate, during concurrent therapy with quinine.
Drug/Laboratory Interactions: Quinine may produce an elevated value for urinary 17-ketogenic steroids when
the Zimmerman method is used.
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