Quinine - Drug Monograph

Introduction

Quinine is a natural alkaloid derived from the bark of the Cinchona tree, historically used for its antimalarial properties. While its use has declined with the development of newer antimalarials, it remains an important therapeutic agent for specific medical indications. Quinine is also known for its presence in tonic water and historical use for nocturnal leg cramps, though this indication is no longer recommended due to safety concerns.

Mechanism of Action

Quinine exerts its antimalarial effects through several mechanisms. It accumulates in the acidic food vacuoles of Plasmodium parasites, where it inhibits hemozoin polymerization, leading to toxic buildup of free heme. Additionally, quinine interferes with parasite carbohydrate metabolism and DNA replication. Its mechanism in muscle cramps is less understood but may involve reduced excitability of motor end plates and increased refractory period of muscle fibers.

Indications

• FDA-approved: Treatment of uncomplicated Plasmodium falciparum malaria (in combination with other antimalarials)
• Off-label uses: Babesiosis (in combination with clindamycin)
• Historical use: Nocturnal leg cramps (no longer recommended due to risk-benefit profile)

Dosage and Administration

• 542 mg base (650 mg salt) orally every 8 hours for 3-7 days
• Typically administered with doxycycline, tetracycline, or clindamycin

• CrCl 10-50 mL/min: Reduce dose by 30-50%
• CrCl <10 mL/min: Reduce dose by 50-70%

Pharmacokinetics

• Absorption: Rapid and nearly complete from GI tract; bioavailability ~80%
• Distribution: Widely distributed; Vd ~1.8 L/kg; protein binding 70-85%
• Metabolism: Extensive hepatic metabolism via CYP3A4
• Elimination: Renal excretion (20% unchanged); half-life 8-14 hours
• Special populations: Elimination prolonged in elderly and those with hepatic/renal impairment

Contraindications

• Hypersensitivity to quinine or related compounds
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency
• Myasthenia gravis
• Optic neuritis
• Tinnitus or history of quinine-induced thrombocytopenia
• Prolonged QT interval or concomitant drugs that prolong QT interval

Warnings and Precautions

• Black Box Warning: Serious hematological reactions including thrombocytopenic purpura and hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP)
• Cardiac effects: May cause QT prolongation, ventricular arrhythmias, and syncope
• Hypoglycemia: Particularly dangerous in pregnant women and children
• Cinchonism: Syndrome including tinnitus, hearing loss, nausea, and visual disturbances
• Hematologic: Monitor for signs of hemolysis and thrombocytopenia
• Pregnancy: Category C; use only if potential benefit justifies potential risk

Drug Interactions

• CYP3A4 inhibitors (ketoconazole, ritonavir): Increased quinine levels
• CYP3A4 inducers (rifampin, phenytoin): Decreased quinine levels
• QT-prolonging drugs (antiarrhythmics, macrolides): Increased arrhythmia risk
• Warfarin: Enhanced anticoagulant effect
• Digoxin: Increased digoxin levels
• Neuromuscular blocking agents: Enhanced neuromuscular blockade

Adverse Effects

• Cinchonism (tinnitus, hearing loss, blurred vision, nausea)
• Hypoglycemia
• GI disturbances (nausea, vomiting, abdominal pain)

• Thrombocytopenia (including immune-mediated)
• Hemolytic anemia
• Cardiac arrhythmias (torsades de pointes)
• Severe hypersensitivity reactions
• Acute renal failure
• Blindness (usually reversible)

Monitoring Parameters

• Clinical: Signs of cinchonism, bleeding, hemolysis, cardiac symptoms
• Laboratory: CBC with platelets, glucose, renal function, LFTs
• ECG: Baseline and periodic monitoring for QT prolongation
• Ophthalmologic: Visual acuity and field testing with prolonged use
• Therapeutic levels: 8-15 mg/L for malaria (toxic >10 mg/L)

Patient Education

• Take with food to minimize GI upset
• Report immediately: ringing in ears, hearing changes, visual disturbances, unusual bleeding/bruising, palpitations, or dizziness
• Be aware of hypoglycemia symptoms (sweating, shaking, confusion)
• Avoid tonic water consumption during therapy
• Do not use for leg cramps without medical supervision
• Inform all healthcare providers of quinine use
• Keep out of reach of children due to risk of fatal overdose

References

1. FDA Prescribing Information: Qualaquin (quinine sulfate) 2. World Health Organization. Guidelines for the treatment of malaria. 3rd edition. 2015 3. Tracy JW, Webster LT Jr. Drugs used in the chemotherapy of protozoal infections. In: Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. 2006 4. Eperon G, et al. Treatment of malaria in children. Clin Infect Dis. 2003;37(10):1340-1348 5. Centers for Disease Control and Prevention. Malaria Treatment Guidelines. 2020 6. Liles NW, Page EE. Quinine: a valuable legacy for the future. Br J Haematol. 2015;168(1):13-15 7. Tan KR, et al. Quinine: a medicine for today, a history for tomorrow. J Travel Med. 2015;22(5):289-291