Quinine

Usage

• Quinine is prescribed for the treatment of uncomplicated malaria caused by Plasmodium falciparum strains resistant to chloroquine. It is also used for the prevention and treatment of nocturnal leg cramps in adults when other treatments have failed and the cramps cause regular disruption of sleep. It is specifically indicated for uncomplicated malaria when artemisinin-based combinations are not an option, and as a follow-up treatment after intravenous quinine for severe falciparum malaria when artemisinin-based combinations are unavailable.
• Pharmacological classification: Antimalarial, Skeletal Muscle Relaxant.
• Mechanism of Action: Quinine acts by inhibiting heme polymerase, an enzyme crucial for the detoxification of heme, a byproduct of hemoglobin digestion in the malaria parasite. The accumulation of toxic heme within the parasite leads to its death. Quinine also affects the parasite’s DNA replication and protein synthesis. Its precise mechanism of action in relieving leg cramps is unknown, but it is thought to decrease the excitability of the motor end-plate and increase the refractory period of skeletal muscle.

Alternate Names

• Quinine sulfate, quinine bisulfate, quinine dihydrochloride
• Brand Names: Qualaquin (USA), Numerous generic formulations available internationally

How It Works

• Pharmacodynamics: Quinine exhibits schizontocidal activity against Plasmodium species in red blood cells. It suppresses parasite growth by inhibiting heme detoxification, affecting DNA replication, and disrupting protein synthesis. For nocturnal leg cramps, it reduces muscle excitability and prolongs the refractory period, possibly by interfering with calcium-dependent muscle contraction.
• Pharmacokinetics:
  • Absorption: Quinine is readily absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations are reached in 1-3 hours.
  • Distribution: It is highly protein-bound (70-90%) and distributes widely throughout the body, crossing the placental barrier.
  • Metabolism: Quinine is primarily metabolized in the liver via CYP3A4.
  • Elimination: It is eliminated mostly via renal excretion (70%), with some biliary excretion. The elimination half-life is 11-18 hours in adults and may be prolonged in patients with renal or hepatic impairment.
• Mode of Action: Quinine inhibits heme polymerase in the malaria parasite. This leads to a toxic buildup of free heme within the parasite, ultimately causing its death.
• Elimination pathways: Renal (primarily) and hepatic. CYP3A4 plays a significant role in quinine metabolism.

Dosage

Standard Dosage

Adults:

• Malaria: 600 mg of quinine sulfate or bisulfate orally every 8 hours for 7 days. Alternatively, 648 mg of quinine sulfate (capsule form) every 8 hours for 7 days. If resistance is suspected, additional treatment with doxycycline or clindamycin may be required.
• Nocturnal Leg Cramps: 200-300 mg orally at bedtime.

Children:

• Malaria: 10 mg/kg of quinine sulfate orally every 8 hours for 7 days. The intravenous dose in children is administered at a rate not to exceed 5mg/kg/hour.

Special Cases:

• Elderly Patients: Monitor closely for adverse events, dose adjustment may be necessary based on organ function.
• Patients with Renal Impairment: Dose reduction may be required. For severe renal impairment using the intravenous formulation, the maintenance dose is reduced to 5-7 mg/kg every 8 hours. In patients with renal impairment and using oral capsules, administer 648 mg initially, followed by 324 mg every 12 hours.
• Patients with Hepatic Dysfunction: Dose adjustment may be required. For severe hepatic impairment receiving intravenous quinine, reduce maintenance dose to 5-7 mg/kg every 8 hours. Oral administration is not recommended in severe hepatic dysfunction.
• Patients with Comorbid Conditions: Close monitoring is essential, especially in patients with cardiac conditions or glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Clinical Use Cases

The following dosages are based on the information available in the sources and are generally for intravenous quinine dihydrochloride in severe malaria:

• Severe Malaria (parenteral): Initial loading dose of 20 mg/kg (maximum 1400 mg) infused over 4 hours, followed by a maintenance dose of 10 mg/kg (maximum 700 mg) every 8 hours, infused over 4 hours. In intensive care settings, an initial loading dose of 7 mg/kg can be administered over 30 minutes, immediately followed by the first maintenance infusion. If parenteral treatment is needed for over 48 hours, reduce maintenance dose to 5-7 mg/kg. No loading dose should be administered if the patient has received quinine or mefloquine in the past 12-24 hours.

Dosage Adjustments

• Adjust dose based on renal and hepatic function.

Side Effects

Common Side Effects:

• Headache, nausea, vomiting, diarrhea, abdominal pain, dizziness, blurred vision, changes in color vision, tinnitus (ringing in the ears), flushing, sweating.

Rare but Serious Side Effects:

• Cinchonism (tinnitus, headache, nausea, disturbed vision, delirium), hypoglycemia, hemolytic anemia (particularly in G6PD deficiency), thrombocytopenia, cardiac arrhythmias (including QT prolongation), severe allergic reactions.

Long-Term Effects:

• Hearing loss, vision changes.

Adverse Drug Reactions (ADR):

• Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS), severe hypoglycemia, cardiac arrhythmias.

Contraindications

• Hypersensitivity to quinine, quinidine, or mefloquine.
• History of blackwater fever, thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS).
• G6PD deficiency.
• Myasthenia gravis.
• Optic neuritis.
• Prolonged QT interval.
• Tinnitus

Drug Interactions

• CYP450 interactions: Quinine is metabolized by CYP3A4. Inhibitors (e.g., ketoconazole, erythromycin, ritonavir) can increase quinine levels. Inducers (e.g., rifampin, phenytoin) can decrease levels.
• Other Interactions:
  • Digoxin: Quinine can increase digoxin levels.
  • Warfarin: Quinine can potentiate the anticoagulant effects of warfarin.
  • Mefloquine, halofantrine, amiodarone, pimozide, thioridazine: Increased risk of cardiac arrhythmias.
  • Antacids: May reduce quinine absorption.
  • Cimetidine: inhibits quinine metabolism.
  • Medications that prolong the QT interval (e.g., amiodarone, moxifloxacin, pimozide, thioridazine, halofantrine).

Pregnancy and Breastfeeding

• Pregnancy: Quinine can cross the placenta and may cause fetal harm, including congenital malformations, deafness and phototoxicity in neonates, and hypoglycemia. It should only be used during pregnancy if the benefits outweigh the risks, specifically for the treatment of malaria. It is not recommended for leg cramps during pregnancy.
• Breastfeeding: Quinine is excreted in breast milk. It is generally considered acceptable during breastfeeding according to WHO and other expert resources if the infant does not have G6PD deficiency. However, close monitoring of the infant is recommended.

Drug Profile Summary

• Mechanism of Action: Inhibits heme polymerase in malaria parasites and decreases muscle excitability for leg cramps.
• Side Effects: Headache, nausea, tinnitus, blurred vision, hypoglycemia, hemolytic anemia, cardiac arrhythmias.
• Contraindications: Hypersensitivity, G6PD deficiency, history of TTP/HUS, myasthenia gravis, optic neuritis, prolonged QT interval.
• Drug Interactions: CYP3A4 inhibitors/inducers, digoxin, warfarin, QT prolonging drugs.
• Pregnancy & Breastfeeding: Use with caution during pregnancy only if benefits outweigh risks (malaria treatment only). Generally acceptable during breastfeeding if the infant does not have G6PD deficiency. Close monitoring is advised.
• Dosage: Malaria (Adult): 600-648mg every 8 hours for 7 days; Nocturnal leg cramps: 200-300mg at bedtime. Pediatric and special adjustments needed.
• Monitoring Parameters: Blood glucose, complete blood count, liver function tests, electrocardiogram (ECG), hearing and vision assessments.

Popular Combinations

• Malaria: Quinine + clindamycin (recommended for pregnant women)
• Malaria: Quinine + doxycycline

Precautions

• Patients with G6PD deficiency, cardiac conditions (especially QT prolongation risk), hepatic/renal impairment, and pregnant/breastfeeding women require close monitoring.
• Alcohol may worsen side effects.
• Quinine may impair ability to operate machinery or drive.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Quinine?

A: For malaria in adults, 600-648 mg orally every 8 hours for 7 days. For nocturnal leg cramps, 200-300 mg orally at bedtime. Pediatric dosing is 10 mg/kg every 8 hours for malaria. Dose adjustments are necessary for renal/hepatic impairment.

Q2: What are the serious side effects of quinine?

A: Severe hypoglycemia, hemolytic anemia (especially with G6PD deficiency), thrombocytopenia, cardiac arrhythmias (QT prolongation), TTP/HUS, cinchonism, severe allergic reactions.

Q3: Can quinine be used during pregnancy?

A: Yes, but only if absolutely necessary for the treatment of malaria. It is not recommended for leg cramps during pregnancy. Risks vs. benefits must be carefully weighed.

Q4: How does quinine interact with other medications?

A: Quinine interacts with drugs metabolized by CYP3A4, digoxin, warfarin, QT prolonging agents, and antacids.

Q5: What is cinchonism?

A: A syndrome associated with quinine toxicity characterized by tinnitus, headache, nausea, disturbed vision, delirium, and other symptoms.

Q6: How should quinine be administered?

A: Oral quinine should be taken with food to minimize gastrointestinal upset. Intravenous quinine must be diluted and infused slowly. It should never be given as a bolus injection.

Q7: Can quinine be used to treat all types of malaria?

A: Quinine is primarily used for Plasmodium falciparum malaria, especially chloroquine-resistant strains. It is effective against other Plasmodium species but may not be the first-line treatment.

Q8: Is there a risk of developing resistance to quinine?

A: Yes, resistance to quinine has been reported. Therefore, combination therapy with other antimalarials may be recommended.

Q9: What should be monitored in patients taking quinine?

A: Blood glucose levels, complete blood count, liver function tests, electrocardiogram (ECG), hearing and vision should be monitored regularly in patients taking quinine.

Q10: What are the contraindications to quinine use?

A: Contraindications include hypersensitivity to quinine, G6PD deficiency, history of TTP/HUS, myasthenia gravis, optic neuritis, prolonged QT interval, and prior episodes of blackwater fever.