Pharmacology of Quinine

Introduction/Overview

Quinine, a naturally occurring alkaloid derived from the bark of the Cinchona tree, represents one of the oldest and most historically significant therapeutic agents in medicine. Its use for the treatment of febrile illnesses was documented in South America long before its active principle was isolated in the early 19th century. For centuries, it served as the primary therapy for malaria, a role that has been largely supplanted by more modern synthetic agents. However, quinine retains critical clinical relevance, particularly in the management of severe and complicated malaria caused by Plasmodium falciparum, especially in regions with chloroquine-resistant strains. Furthermore, it finds application in the treatment of nocturnal leg cramps and certain autoimmune disorders, though these uses are often limited by its narrow therapeutic index and potential for serious toxicity. A thorough understanding of its pharmacology is essential for healthcare professionals to utilize it effectively and safely.

Learning Objectives

Upon completion of this chapter, the reader should be able to:

• Describe the chemical classification of quinine and its relationship to other cinchona alkaloids.
• Explain the detailed molecular mechanism of action against Plasmodium species and its effects on human excitable tissues.
• Outline the pharmacokinetic profile of quinine, including factors influencing its absorption, distribution, metabolism, and excretion.
• Identify the approved therapeutic indications for quinine and recognize its significant adverse effect profile, particularly cinchonism and cardiotoxicity.
• Apply knowledge of quinine’s drug interactions and special population considerations to optimize therapy and minimize patient risk.

Classification

Drug Class and Category

Quinine is primarily classified as an antimalarial agent. More specifically, it belongs to the 4-methanolquinoline family of compounds. It is categorized as a blood schizonticide, meaning it acts against the asexual erythrocytic stages of the malaria parasite that are responsible for clinical symptoms. It also possesses gametocytocidal activity against Plasmodium vivax and Plasmodium malariae, but not against mature gametocytes of P. falciparum.

Chemical Classification

Quinine is a natural alkaloid. Its core structure consists of a quinoline ring linked to a quinuclidine ring via a secondary alcohol bridge. This structure is shared with its stereoisomer, quinidine, which is used as a class Ia antiarrhythmic. The key chemical features include:

• A methoxy group at the 6′ position of the quinoline ring.
• A vinyl group attached to the quinuclidine ring.
• The presence of two basic nitrogen atoms.

The molecule exists as a diastereomer, and its stereochemistry is crucial for its antimalarial activity. Quinine is the levorotatory isomer, whereas quinidine is dextrorotatory. This structural similarity explains the shared toxicities, particularly the cardiac effects, between the two compounds.

Mechanism of Action

Antimalarial Action

The primary mechanism of quinine’s antimalarial effect is believed to involve the inhibition of hemozoin polymerization within the parasite’s digestive vacuole. Malaria parasites, during their intraerythrocytic life cycle, digest host hemoglobin as a source of amino acids. This process releases free heme (ferriprotoporphyrin IX), which is highly toxic to the parasite. To detoxify this heme, the parasite normally polymerizes it into an insoluble, crystalline pigment called hemozoin or malaria pigment.

Quinine, being a weak base, accumulates in the acidic digestive vacuole of the parasite. There, it is thought to form a complex with free heme, preventing its sequestration into non-toxic hemozoin. The accumulation of toxic heme, or heme-quinine complexes, leads to membrane damage, oxidative stress, and ultimately parasite death. This mechanism is shared with chloroquine, though differences in parasite resistance profiles suggest additional or alternative targets may be involved. Quinine may also exert effects by raising the pH of the parasite’s digestive vacuole, interfering with protein digestion, and possibly through interactions with parasite DNA.

Effects on Skeletal Muscle

The mechanism underlying quinine’s efficacy in nocturnal leg cramps is not fully elucidated but is thought to involve several actions on skeletal muscle and the motor nervous system. Proposed mechanisms include:

• Reduction of Motor Endplate Excitability: Quinine may decrease the excitability of the motor endplate by prolonging the refractory period, potentially through sodium channel blockade.
• Calcium Channel Antagonism: It may interfere with calcium mobilization from the sarcoplasmic reticulum, reducing muscle contractility.
• Increased Muscle Fiber Refractory Period: A direct effect on the muscle membrane may increase the refractory period, preventing repetitive firing and tetany.

These effects are generally mild at doses used for leg cramps but can become pronounced in overdose, leading to muscle weakness.

Cardiac Electrophysiological Effects

Similar to its stereoisomer quinidine, quinine exerts class Ia antiarrhythmic effects on the heart, though these are typically undesirable side effects. Its actions include:

• Sodium Channel Blockade: It blocks fast voltage-gated sodium channels, slowing the phase 0 depolarization (V_max) of the cardiac action potential, which decreases conduction velocity, particularly in Purkinje fibers and ventricular muscle.
• Potassium Channel Blockade: It prolongs the action potential duration (APD) and effective refractory period (ERP) by blocking repolarizing potassium currents (e.g., I_Kr). This is reflected as a prolongation of the QT interval on the electrocardiogram.
• Anticholinergic (Vagolytic) Effects: It possesses mild antimuscarinic properties, which can increase sinoatrial (SA) nodal automaticity and atrioventricular (AV) nodal conduction velocity.

The net electrophysiological effect is a depression of conduction and increased refractoriness, which can be proarrhythmic, especially in the setting of QT prolongation leading to torsades de pointes.

Pharmacokinetics

Absorption

Quinine is readily absorbed from the gastrointestinal tract, with oral bioavailability ranging from 76% to 88% in healthy individuals. Absorption occurs primarily in the small intestine. The presence of food may slow the rate of absorption but does not significantly alter the overall extent. Peak plasma concentrations (C_max) are typically achieved within 1 to 3 hours after an oral dose. In severe malaria, gastrointestinal absorption may be erratic and reduced due to ileus and vomiting, necessitating intravenous administration initially.

Distribution

Quinine is distributed widely throughout the body. Its volume of distribution is approximately 1.5 to 2.0 L/kg, indicating extensive tissue binding. It concentrates in tissues such as the liver, spleen, kidney, and lung, and crosses the placenta. Protein binding is concentration-dependent, ranging from approximately 70% at therapeutic concentrations to over 90% at lower concentrations, primarily to alpha-1 acid glycoprotein (AAG), an acute-phase reactant. In malaria, AAG levels are elevated, which may increase the bound fraction and potentially alter free drug concentrations. Quinine achieves concentrations in cerebrospinal fluid (CSF) that are approximately 2-7% of plasma levels, which is sufficient for activity against cerebral malaria.

Metabolism

Quinine undergoes extensive hepatic metabolism, primarily via the cytochrome P450 system. The major isoform involved is CYP3A4. The main metabolites are 3-hydroxyquinine and 2′-quinone, which are formed through oxidation. 3-Hydroxyquinine retains some antimalarial activity, estimated at approximately 20-30% that of the parent compound. Other minor metabolic pathways include O-demethylation and formation of N-oxide derivatives. First-pass metabolism accounts for approximately 20% of an oral dose. The metabolism is saturable at higher concentrations, leading to non-linear pharmacokinetics.

Excretion

Elimination of quinine occurs predominantly via hepatic metabolism, with less than 20% of an administered dose excreted unchanged in the urine. Renal clearance of unchanged drug is low, approximately 1-3 mL/min/kg. The elimination half-life (t_1/2) in healthy adults is approximately 11 hours but can be prolonged in patients with severe malaria, often to 16-18 hours, due to a combination of reduced hepatic metabolism, increased volume of distribution, and possibly reduced renal clearance. Acidification of urine increases the renal excretion of quinine, as it is a weak base (pKa ≈ 8.5 and 4.2), but this maneuver is not used clinically due to risks.

Dosing Considerations

Dosing is highly indication-specific. For severe malaria, a loading dose is typically administered intravenously to achieve therapeutic concentrations rapidly, followed by maintenance doses. The therapeutic range for antimalarial activity is narrow, generally considered to be a free plasma concentration of 2-5 mg/L. Monitoring of plasma levels may be considered in severe cases, especially with renal or hepatic impairment, or to assess toxicity. For nocturnal leg cramps, doses are significantly lower (200-300 mg at bedtime).

Therapeutic Uses/Clinical Applications

Approved Indications

1. Severe and Complicated Falciparum Malaria: This remains the primary and most critical indication for quinine. It is a first-line agent, often in combination with a second drug such as clindamycin or doxycycline, for the treatment of severe malaria (e.g., cerebral malaria, severe anemia, renal failure, acute respiratory distress syndrome) in areas with chloroquine-resistant P. falciparum. Intravenous administration is required initially, transitioning to oral therapy once the patient can tolerate it.

2. Uncomplicated Chloroquine-Resistant Falciparum Malaria: Quinine, in combination with a second agent like tetracycline, doxycycline, or clindamycin, is used for oral treatment of uncomplicated cases. The combination is essential to improve efficacy and reduce the risk of recrudescence and development of resistance.

3. Nocturnal Leg Cramps: Quinine sulfate is approved for the prevention and treatment of nocturnal recumbent leg cramps. However, due to its risk profile, its use is typically reserved for cases that are frequent and disabling, and after non-pharmacological measures have failed. Regulatory agencies in many regions have issued warnings restricting this use.

Off-Label Uses

1. Babesiosis: Quinine, in combination with clindamycin, is considered an alternative regimen for the treatment of babesiosis, a tick-borne parasitic infection caused by Babesia species, particularly in severe cases or when first-line therapy with atovaquone plus azithromycin is not suitable.

2. Autoimmune Disorders: Historically, quinine and related antimalarials like hydroxychloroquine have been used for conditions such as lupus erythematosus and rheumatoid arthritis, primarily for their immunomodulatory effects. However, hydroxychloroquine is now preferred due to a better safety profile.

3. Myotonia Congenita: It has been used to alleviate symptoms of myotonia due to its membrane-stabilizing properties, though other agents are typically preferred.

Adverse Effects

The use of quinine is limited by a high incidence of adverse effects, collectively known as cinchonism, and by potentially life-threatening toxicities.

Common Side Effects (Cinchonism)

Cinchonism is a dose-related syndrome that can occur even at therapeutic levels. Symptoms include:

• Gastrointestinal: Nausea, vomiting, abdominal pain, and diarrhea.
• Neurological: Tinnitus, hearing impairment (high-frequency loss), headache, vertigo, blurred vision, and disturbed color perception.
• General: Sweating, flushing, and warmth of the skin.

Mild cinchonism is common and often does not require discontinuation of therapy. Tinnitus may serve as a clinical indicator of approaching toxic concentrations.

Serious and Rare Adverse Reactions

1. Hematological Toxicity:

• Hemolytic Anemia: Quinine is a known cause of drug-induced immune hemolytic anemia. It acts as a hapten, binding to platelet or red cell membranes and inducing antibody formation (quinine-dependent antibodies). This can lead to severe intravascular hemolysis, hemoglobinuria, and renal failure, a syndrome historically termed “blackwater fever.”
• Thrombocytopenia: Quinine-induced immune thrombocytopenia (QIIT) is a well-documented, potentially fatal reaction. Antibodies target platelet glycoproteins in the presence of quinine, leading to rapid platelet destruction. Bleeding complications can ensue.
• Agranulocytosis: Rare cases of neutropenia and agranulocytosis have been reported.

2. Cardiotoxicity: Due to its class Ia antiarrhythmic properties, quinine can cause significant cardiac effects.

• QT Interval Prolongation and Torsades de Pointes: This polymorphic ventricular tachycardia is a life-threatening risk, particularly with high doses, rapid intravenous infusion, or in patients with underlying heart disease, electrolyte disturbances (hypokalemia, hypomagnesemia), or concomitant use of other QT-prolonging drugs.
• Conduction Abnormalities: Sinus bradycardia, atrioventricular block, and widening of the QRS complex can occur, which may progress to ventricular fibrillation or asystole in overdose.
• Hypotension: Rapid intravenous administration can cause severe hypotension due to peripheral vasodilation and negative inotropic effects.

3. Hypoglycemia: This is a particularly important adverse effect in the treatment of severe malaria. Quinine stimulates pancreatic beta cells to release insulin. In malaria, this effect is potentiated because the disease itself can cause hypoglycemia due to increased glucose consumption by host and parasite, impaired gluconeogenesis, and hyperinsulinemia. Hypoglycemia requires vigilant monitoring and management with glucose infusion.

4. Ocular Toxicity: While less common than with chloroquine, quinine overdose can cause a syndrome known as “quinine amblyopia.” This involves sudden onset of blurred vision, constricted visual fields, photophobia, and, in severe cases, permanent blindness due to retinal ganglion cell toxicity and retinal vascular spasm.

5. Allergic Reactions: Skin rashes, urticaria, angioedema, and anaphylaxis can occur.

Black Box Warnings

In several jurisdictions, quinine sulfate carries a black box warning, the strongest safety alert, for its use in the treatment of nocturnal leg cramps. The warning highlights the risks of serious and life-threatening hematological reactions, including thrombocytopenia and hemolytic anemia, as well as other severe hypersensitivity reactions. These risks may occur following a single dose. Consequently, its use for leg cramps is not recommended as first-line therapy and is strictly contraindicated in patients with a previous history of quinine-induced thrombocytopenia or hypersensitivity.

Drug Interactions

Major Drug-Drug Interactions

Quinine is a potent inhibitor of the cytochrome P450 enzyme CYP2D6 and a moderate inhibitor of CYP3A4. It is also a substrate of CYP3A4. These properties underlie many of its significant interactions.

• Enzyme Inhibitors: Drugs that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir, clarithromycin, grapefruit juice) can decrease quinine metabolism, leading to increased plasma concentrations and a heightened risk of toxicity, including cinchonism, cardiotoxicity, and hypoglycemia.
• Enzyme Inducers: Drugs that induce CYP3A4 (e.g., rifampin, phenytoin, phenobarbital, carbamazepine, St. John’s wort) can accelerate quinine metabolism, potentially leading to subtherapeutic levels and treatment failure in malaria.
• CYP2D6 Substrates: Quinine’s inhibition of CYP2D6 can increase levels of drugs metabolized by this pathway. This includes many antidepressants (e.g., tricyclic antidepressants, fluoxetine, paroxetine), antipsychotics (e.g., haloperidol, risperidone), beta-blockers (e.g., metoprolol, timolol), and codeine. Inhibition of CYP2D6 can prevent the conversion of codeine to its active metabolite, morphine, reducing its analgesic effect.
• Drugs Prolonging the QT Interval: Concomitant use with other QT-prolonging agents (e.g., class Ia and III antiarrhythmics, macrolide antibiotics, some antipsychotics, methadone) is contraindicated or requires extreme caution due to an additive risk of torsades de pointes.
• Neuromuscular Blocking Agents: Quinine may potentiate the effects of both depolarizing (succinylcholine) and non-depolarizing (e.g., pancuronium) neuromuscular blockers, potentially leading to prolonged apnea.
• Digoxin: Quinine can increase serum digoxin concentrations by reducing its renal and non-renal clearance, potentially leading to digoxin toxicity. Close monitoring of digoxin levels is required.
• Warfarin: Quinine may potentiate the anticoagulant effect of warfarin by inhibiting its metabolism (CYP2C9) and possibly through an additive effect on vitamin K-dependent clotting factor synthesis. Prothrombin time (INR) should be monitored closely.
• Antacids: Aluminum-containing antacids may delay or reduce the absorption of quinine.

Contraindications

Absolute contraindications to quinine use include:

• Known hypersensitivity or allergy to quinine, quinidine, or other cinchona alkaloids.
• History of quinine-induced thrombocytopenia, hemolytic anemia, or other severe hematological reactions.
• Myasthenia gravis (due to potential exacerbation of muscle weakness).
• Optic neuritis (risk of exacerbating visual impairment).
• Prolonged QT interval or congenital long QT syndrome, and concomitant use with other drugs that prolong the QT interval.
• Severe heart failure or cardiomyopathy.
• For the indication of leg cramps: pregnancy, G6PD deficiency, and atrial fibrillation or other cardiac arrhythmias requiring treatment.

Special Considerations

Pregnancy and Lactation

Pregnancy: Quinine crosses the placenta. Its use in pregnancy, particularly for malaria, requires careful risk-benefit assessment. For severe falciparum malaria in pregnancy, quinine remains a recommended treatment as the benefits of treating a life-threatening infection outweigh the fetal risks. It may be associated with an increased risk of congenital malformations when used in the first trimester, though data are confounded by the effects of malaria itself. It can stimulate uterine contractions and may induce labor at high doses or in sensitive individuals. Hypoglycemia is a greater risk in pregnant women. Lactation: Quinine is excreted in breast milk in small amounts. While not contraindicated, the infant should be monitored for signs of cinchonism, particularly if the mother is on prolonged therapy. The benefits of antimalarial treatment in a lactating mother usually outweigh the potential risk to the infant.

Pediatric and Geriatric Considerations

Pediatrics: Quinine is used in children for severe malaria. Dosing is based on body weight. Children may be more susceptible to hypoglycemia. Careful monitoring of blood glucose is essential. The safety and efficacy for leg cramps have not been established in children. Geriatrics: Older patients may have reduced hepatic and renal function, potentially leading to increased drug accumulation. They are also more likely to have underlying cardiac conditions or be on concomitant medications that increase the risk of QT prolongation, arrhythmias, and drug interactions. A lower dose or extended dosing interval may be required, and vigilant monitoring for toxicity is necessary.

Renal and Hepatic Impairment

Renal Impairment: Since only a small fraction of quinine is excreted unchanged, dosage adjustment is not routinely required in mild to moderate renal impairment. However, in severe renal failure or end-stage renal disease, accumulation of active metabolites may occur. Furthermore, patients with renal impairment are at increased risk for QT prolongation due to electrolyte imbalances. Plasma concentration monitoring may be advisable in severe cases. Quinine is not effectively removed by hemodialysis or peritoneal dialysis. Hepatic Impairment: Quinine is extensively metabolized by the liver. In patients with significant hepatic impairment (e.g., cirrhosis), metabolism may be reduced, leading to increased plasma levels and prolonged half-life. Dose reduction is recommended, and plasma level monitoring is particularly useful to guide therapy and avoid toxicity.

Summary/Key Points

• Quinine is a natural cinchona alkaloid with a narrow therapeutic index, historically vital as an antimalarial and now reserved primarily for severe/complicated falciparum malaria and, with restrictions, for nocturnal leg cramps.
• Its antimalarial mechanism involves accumulation in the parasite’s digestive vacuole, complexation with toxic heme, and inhibition of hemozoin formation.
• Pharmacokinetically, it is well-absorbed orally, widely distributed, extensively metabolized by CYP3A4 in the liver, and has a half-life of approximately 11-18 hours, prolonged in severe malaria.
• Therapeutic use mandates awareness of “cinchonism” (tinnitus, GI upset) and serious risks: life-threatening hematological toxicity (thrombocytopenia, hemolytic anemia), cardiotoxicity (QT prolongation, torsades de pointes), and profound hypoglycemia, especially in malaria treatment.
• It is a potent inhibitor of CYP2D6 and interacts significantly with many drugs, notably those metabolized by CYP2D6 or CYP3A4, and all QT-prolonging agents.
• Special caution is required in pregnancy, geriatric patients, and those with hepatic impairment. Its use for leg cramps is heavily restricted due to a black box warning for hematological toxicity.

Clinical Pearls

• In severe malaria, always administer a loading dose of intravenous quinine (unless the patient has received quinine, quinidine, or mefloquine in the previous 24-48 hours) to achieve therapeutic levels rapidly.
• Monitor for hypoglycemia every 4-6 hours during intravenous infusion, particularly in pregnant women and children.
• Patient complaints of tinnitus may serve as a useful, though non-specific, clinical sign of approaching toxic plasma concentrations.
• Any patient developing unexplained bleeding, bruising, or pallor during quinine therapy should be evaluated immediately for thrombocytopenia or hemolytic anemia.
• For nocturnal leg cramps, quinine should be a last-resort option after non-pharmacological measures. Treatment should be initiated at the lowest possible dose and periodically re-evaluated for continued necessity.

References

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