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Quinidine
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Quinidine
Clinical data
Trade namesQuinaglute, Quinidex
Other names(2-Ethenyl-4-azabicyclo[2.2.2]oct-5-yl)-(6-methoxyquinolin-4-yl)-methanol
AHFS/Drugs.comMonograph
Pregnancy
category
  • AU: C
Routes of
administration		By mouth, intramuscular injection, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability70–85%
Metabolism50–90% (by liver)
Elimination half-life6–8 hours
ExcretionBy the liver (20% as unchanged quinidine via urine)
Identifiers
  • (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.254 Edit this at Wikidata
Chemical and physical data
FormulaC20H24N2O2
Molar mass324.424 g·mol−1
3D model (JSmol)
  • O(c4cc1c(nccc1[C@H](O)[C@@H]2N3CC[C@@H](C2)[C@@H](/C=C)C3)cc4)C
  • InChI=1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19+,20-/m0/s1 checkY
  • Key:LOUPRKONTZGTKE-LHHVKLHASA-N checkY
 ☒NcheckY (what is this?)  (verify)

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances.[1] It is a diastereomer of antimalarial agent quinine,[2] originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval. As of 2019, its IV formulation is no longer being manufactured for use in the United States.[3]

Medical uses

[edit]

Quinidine is occasionally used as a class I antiarrhythmic agent to prevent ventricular arrhythmias, particularly in Brugada Syndrome, although its safety in this indication is uncertain.[1][4]

It reduces the recurrence of atrial fibrillation after patients undergo cardioversion, but it has proarrhythmic effects and trials suggest that it may lead to an overall increased mortality in these patients.[5]

Quinidine is also used to treat short QT syndrome.[6]

Eli Lilly has discontinued manufacture of parenteral quinidine gluconate in the US, and its future availability in many countries is uncertain.[7]

Other uses

[edit]

There is one study supporting the use of a novel combination of dextromethorphan and low dose quinidine in alleviating symptoms of easy laughing and crying (pseudobulbar affect); these are a type of rather severe uncontrollable behaviors which can be present in various neurological pathologies such as amyotrophic lateral sclerosis and multiple sclerosis. The dose of quinidine (10 mg two times daily) is about 1/40th of a relatively low antiarrhythmic dose (400 mg, twice or 3 times daily, as an example; antiarrhythmic doses can sometimes exceed 1500 mg/day). The authors did not observe significant safety risks using the low quinidine dose, but urged caution and also pointed out that quinidine interacts with a large number of other medications in dangerous or unpredictable ways. A meta analysis was published referencing only that one study.[8][9]

Although intravenous quinidine is sometimes used to treat Plasmodium falciparum malaria, the future availability of this agent is uncertain.[10]

Side effects

[edit]

Quinidine is an inhibitor of the cytochrome P450 enzyme 2D6, and can lead to increased blood levels of lidocaine, beta blockers, opioids, and some antidepressants. Quinidine also inhibits the transport protein P-glycoprotein and so can cause some peripherally acting drugs such as loperamide to have central nervous system side effects, such as respiratory depression, if the two drugs are coadministered.[11]

Quinidine can cause thrombocytopenia, granulomatous hepatitis, myasthenia gravis, and torsades de pointes (dangerous heart rhythm),[12] and has been largely phased out in favor of other antiarrhythmics. Torsades can occur after the first dose. Quinidine-induced thrombocytopenia (low platelet count) is mediated by the immune system, and may lead to thrombocytic purpura.

Quinidine intoxication can lead to a collection of symptoms collectively known as cinchonism, with tinnitus (ringing in the ears) being among the most characteristic and common symptoms of this toxicity syndrome.

Pharmacology

[edit]

Pharmacodynamics

[edit]

Quinidine acts as a blocker of voltage-gated sodium channels.[13][14] Inhibition of the Nav1.5 channel is specifically involved in its antiarrhythmic effects as a class I antiarrhythmic agent.[15] Quinidine also blocks certain voltage-gated potassium channels (e.g., Kv1.4, Kv4.2, hERG, among others),[16][17] acts as an antimuscarinic and alpha-1 blocker,[18] and is an antimalarial.[15] It is said to be a selective muscarinic acetylcholine M3 receptor antagonist.[19]

Mechanism of action

[edit]

Like all other class I antiarrhythmic agents, quinidine primarily works by blocking the fast inward sodium current (INa). Quinidine's effect on INa is known as a 'use dependent block'. This means at higher heart rates, the block increases, while at lower heart rates, the block decreases. The effect of blocking the fast inward sodium current causes the phase 0 depolarization of the cardiac action potential to decrease (decreased Vmax).

It seems still efficacious as an IV antimalarial against Plasmodium falciparum. This electrolyte dependent agent also increases action potentials and prolongs the QT interval. Quinidine also blocks the slowly inactivating, tetrodotoxin-sensitive Na current, the slow inward calcium current (ICa), the rapid (IKr) and slow (IKs) components of the delayed potassium rectifier current, the inward potassium rectifier current (IKI), the ATP-sensitive potassium channel (IKATP) and Ito.

At micromolar concentrations, quinidine inhibits Na+/K+-ATPase by binding to the same receptor sites as the digitalis glycosides such as ouabain.

The effect of quinidine on the ion channels is to prolong the cardiac action potential, thereby prolonging the QT interval on the surface ECG.

Other ECG effects include a wide notched P wave, wide QRS complex, depressed ST segment, and U waves. These are the results of both slowed depolarization and repolarization.

Pharmacokinetics

[edit]

Elimination

[edit]

The elimination half-life of oral quinidine is 6 to 8 hours, and it is eliminated by the cytochrome P450 system in the liver. About 20% is excreted unchanged via the kidneys.

History

[edit]

The effects of cinchona bark (the botanical source from which quinidine is extracted) had been commented on long before the understanding of cardiac physiology arose. Jean-Baptiste de Sénac, in his 1749 work on the anatomy, function, and diseases of the heart, had this to say:

"Long and rebellious palpitations have ceded to this febrifuge".[20]

"Of all the stomachic remedies, the one whose effects have appeared to me the most constant and the most prompt in many cases is quinquina [Peruvian bark] mixed with a little rhubarb."[21]

Sénac subsequently became physician to Louis XV of France, a counselor of the state, and superintendent of the mineral waters and medicinals in France. As a result of his influence, throughout the 19th century, quinidine was used to augment digitalis therapy. It was described as das Opium des Herzens (the opium of the heart).

However, the use of quinidine to treat arrhythmia really only came into its own because a physician listened to the astute observation of one of his patients. In 1912, Karel Frederik Wenckebach saw a man with atrial fibrillation. He was a Dutch merchant, used to good order in his affairs. He would like to have good order in his heart business, also, and asked, "why there were heart specialists if they could not abolish this very disagreeable phenomenon ... he knew himself how to get rid of his attacks. As I did not believe him, he promised to come back next morning with a regular pulse, and he did."

The man had found by chance that when he took one gram of quinine during an attack, it reliably halted it in 25 minutes; otherwise it would last for two to 14 days. Wenckebach often tried quinine again, but he succeeded in only one other patient.[20]

He made passing mention of it in his book on cardiac arrhythmias published in 1914. Four years later, Walter von Frey of Berlin reported in a leading Viennese medical journal that quinidine was the most effective of the four principal cinchona alkaloids in controlling atrial arrhythmias.[22]

Chemistry

[edit]

Quinidine-based ligands are used in AD-mix-β for Sharpless asymmetric dihydroxylation.

Veterinary use

[edit]

Quinidine sulfate is used in the treatment of atrial fibrillation in horses.[23][24]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Quinidine

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from Grokipedia
Quinidine is a class Ia antiarrhythmic medication and antimalarial agent derived from the bark of the cinchona tree, primarily used to treat certain cardiac arrhythmias such as and flutter, as well as ventricular arrhythmias, and caused by . It is the dextrorotatory stereoisomer of and is available in oral (immediate- and extended-release) and intravenous formulations. As one of the earliest antiarrhythmic drugs, quinidine has a long dating back to its description in , with its cardiac applications introduced in 1918 by Walter Frey, building on the traditional use of bark for fever and since the . It functions by blocking voltage-gated sodium channels to depress phase 0 of the , while also inhibiting channels to prolong the action potential duration and , thereby suppressing abnormal rhythms. Additionally, quinidine is FDA-approved in combination with for treating , a condition involving involuntary emotional outbursts. Despite its efficacy, quinidine's use has declined due to its narrow and potential for serious adverse effects, including prolongation (with a 1-3% risk of ), cinchonism (characterized by and ), gastrointestinal disturbances like and , and reactions. It is contraindicated in patients with certain conditions, such as , , or preexisting , and requires careful monitoring by an interprofessional healthcare team.

Medical uses

Arrhythmia treatment

Quinidine, recognized as the first antiarrhythmic drug derived from bark and introduced in clinical practice over a century ago, was historically pivotal in managing various cardiac rhythm disorders but is now reserved primarily for select cases due to its potential proarrhythmic effects. As a class IA antiarrhythmic agent, it is indicated for restoring and maintaining in primary conditions including and , where it facilitates pharmacological and reduces relapse rates. It also suppresses and premature ventricular contractions, as well as terminating . Quinidine was historically a second- or third-line option for rhythm control in per the 2014 AHA/ACC/HRS guidelines (class IIb recommendation), particularly in patients without structural heart disease after failure of preferred agents such as or . However, the 2023 ACC/AHA/ACCP/HRS guideline does not recommend quinidine for this purpose, favoring safer alternatives. For ventricular arrhythmias, it remains positioned as an alternative therapy in nonischemic or idiopathic cases without significant structural abnormalities per the 2017 AHA/ACC/HRS guideline, emphasizing its role when first-line interventions prove inadequate. These recommendations underscore quinidine's utility in scenarios where its blockade helps stabilize membrane potentials, though monitoring for QT prolongation remains essential. In rare inherited arrhythmia syndromes, quinidine stands out as one of the few effective pharmacological options for and , where it suppresses recurrent ventricular arrhythmias by modulating sodium and potassium channels to prevent malignant . AHA/ACC/HRS guidelines endorse its use (class IIa recommendation) in these conditions, often as an adjunct to implantable cardioverter-defibrillators or when device therapy is not feasible, with intravenous loading doses of 800 mg recommended for acute management in . Its efficacy in these syndromes highlights quinidine's niche role despite broader limitations in contemporary antiarrhythmic practice.

Antimalarial and other uses

Quinidine was historically an alternative treatment for severe malaria, particularly in cases of cerebral malaria, when other intravenous options were unavailable. It demonstrated efficacy against chloroquine-resistant strains but is no longer available as an intravenous formulation in the United States since its discontinuation in 2019; current CDC guidelines recommend intravenous artesunate as the preferred treatment for severe . Globally, contemporary guidelines position quinidine as a backup option for severe malaria due to its narrower and the superiority of artemisinin-based combination therapies (ACTs), which offer faster parasite clearance and fewer adverse effects; its use has declined with the widespread adoption of ACTs and improved access to intravenous artesunate. The antimalarial action of quinidine, a quinoline derivative, primarily involves interference with the parasite's heme detoxification process. During hemoglobin digestion in the erythrocyte, the malaria parasite releases toxic free , which it detoxifies by forming β-hematin (hemozoin). Quinidine inhibits this , leading to accumulation of toxic and subsequent parasite death. Beyond malaria, quinidine has been used historically in the suppression of , a tick-borne parasitic , particularly in severe cases where standard regimens like atovaquone plus are insufficient; however, parenteral formulations are no longer available in the United States, limiting its current role. In rare instances, it has been employed off-label for , a nondystrophic myotonia, leveraging its blocking effects to reduce muscle stiffness and delayed relaxation. Quinidine is also FDA-approved in combination with dextromethorphan (as Nuedexta) for the treatment of , a characterized by involuntary emotional outbursts.

Adverse effects

Common side effects

The most common adverse reactions to quinidine therapy are gastrointestinal disturbances, affecting 20-35% of patients overall. is the most frequent, occurring in up to 35% of users, followed by , , , and anorexia in 20-30%. These symptoms are typically dose-related and may be accompanied by a bitter in the , a hallmark of mild cinchonism induced by quinidine's structural similarity to . Other mild side effects include (reported in about 7% of patients), or (up to 15%), , , and mild manifesting as transient upon standing. These effects generally arise from the drug's impact on the and cardiovascular tone and are reversible. Management of common side effects focuses on symptomatic relief and optimization of dosing; gastrointestinal symptoms often improve with dose reduction, administration with food or antacids, or use of antidiarrheal agents like . In many cases, switching to the extended-release quinidine gluconate formulation reduces the incidence of gastrointestinal upset compared to the immediate-release salt, due to more stable plasma concentrations. Patients should monitor for these effects, as they usually subside with adjustment but warrant medical consultation if persistent.

Serious side effects

Quinidine is associated with serious proarrhythmic effects, primarily due to prolongation of the , which can lead to in 2% to 8% of patients and . The risk is heightened in women and in the presence of electrolyte imbalances such as or hypomagnesemia. Hematologic toxicities represent another category of severe adverse reactions, including with an incidence of approximately 1.8 cases per 1,000 patient-years, and rare cases of (particularly in patients with ) and . These effects can lead to severe , infection, or . Other serious reactions encompass hypersensitivity-mediated conditions such as drug-induced lupus-like syndrome (incidence up to 2%), with and elevated liver enzymes, and exacerbation of due to interference with neuromuscular transmission. Due to these risks, the U.S. includes a black box warning for quinidine regarding increased mortality from proarrhythmia, particularly in patients with or structural heart disease. Monitoring involves serial electrocardiograms to assess QTc intervals, with discontinuation recommended if QTc exceeds 500 ms or increases by more than 20% from baseline. Early studies reported sudden death rates of 5% to 10% associated with quinidine use, though contemporary monitoring has reduced this incidence.

Pharmacology

Pharmacodynamics

Quinidine is classified as a class IA antiarrhythmic agent, primarily exerting its effects by blocking voltage-gated sodium (Na⁺) channels in a use-dependent manner, which depresses phase 0 of the cardiac action potential and slows conduction velocity in cardiac tissues. This sodium channel inhibition, along with potassium channel blockade, prolongs the action potential duration (APD) and effective refractory period (ERP), particularly in atrial and ventricular myocardium, thereby reducing the likelihood of reentrant arrhythmias. Additionally, quinidine blocks the rapid component of the delayed rectifier potassium (K⁺) current (I_{Kr}), contributing to QT interval prolongation with reverse use-dependence, where the effect is more pronounced at slower heart rates. Beyond its primary interactions, quinidine exhibits mild antagonism of L-type calcium (Ca²⁺) channels, which may contribute to its negative inotropic effects, and peripheral alpha-adrenergic blockade, leading to and potential reflex . At the cellular level, these actions suppress abnormal by decreasing the slope of phase 4 depolarization in pacemaker cells and interrupt reentrant circuits by increasing refractoriness in the atrioventricular (AV) node and accessory pathways. The overall mechanism enhances AV nodal conduction delay and refractoriness, stabilizing cardiac rhythm in conditions involving supraventricular or ventricular tachyarrhythmias. In its antimalarial role, quinidine accumulates in the acidic food of Plasmodium parasites, where it forms a complex with free released from digestion, inhibiting the of toxic into non-toxic hemozoin crystals and leading to parasite death through heme-mediated . This mechanism is analogous to that of , its stereoisomer. Therapeutic plasma concentrations for antiarrhythmic effects typically range from 2 to 6 mcg/mL, with levels above this threshold increasing the risk of toxicity, such as due to excessive QT prolongation.

Pharmacokinetics

Quinidine exhibits good oral absorption, with an absolute of 70% to 80%. The gluconate formulation demonstrates slightly higher and more consistent compared to the salt, which can vary from 45% to 100%. Peak plasma concentrations occur within 1 to 3 hours after administration of the salt and 3 to 5 hours for the gluconate salt, with absorption rate increased by approximately 27% when taken with food. Following absorption, quinidine distributes widely throughout the body, with a of 2 to 3.5 L/kg in healthy adults; this value decreases to about 0.5 L/kg in patients with and increases to 3 to 5 L/kg in . Approximately 80% to 90% of quinidine is bound to plasma proteins, primarily alpha-1-acid , though binding is reduced (to 50% to 70%) in pregnant women, infants, and neonates. The drug readily crosses the placental barrier, achieving detectable levels in fetal serum, and is excreted into , necessitating caution during and . Quinidine undergoes extensive hepatic metabolism, primarily via the 3A4 enzyme, accounting for 60% to 80% of its clearance. The major metabolite is 3-hydroxyquinidine, which possesses active antiarrhythmic properties with roughly 50% of the potency of the parent compound and achieves serum concentrations approaching those of quinidine. While may contribute to minor oxidative pathways, such as N-oxidation, it is not the primary enzyme involved. exhibits some variability, though not primarily driven by CYP2D6 polymorphism. Elimination of quinidine occurs mainly through hepatic , with only 10% to 20% excreted unchanged in the under normal conditions; renal clearance is approximately 1 mL/min/kg and increases in acidic (pH <7). The terminal elimination averages 6 to 8 hours in healthy adults but is prolonged to 16 to 30 hours in patients with renal or hepatic impairment and reduced to 3 to 4 hours in children. Steady-state plasma concentrations are typically reached within 24 to 48 hours of initiating therapy, though this may extend to 5 to 7 days in some cases due to interindividual variability in clearance.

Contraindications and interactions

Contraindications

Quinidine is absolutely contraindicated in patients with known to quinidine or , as this can precipitate severe allergic reactions including . It is also contraindicated in individuals with a history of quinidine- or quinine-induced , due to the high risk of recurrent severe hematologic toxicity that can be life-threatening. Additionally, quinidine must not be used in patients with , where its effects can exacerbate muscle weakness and respiratory compromise. Patients with congenital or a history of face an absolute prohibition, as quinidine's potent QT-prolonging properties substantially increase the risk of sudden cardiac death. Use in patients with preexisting prolonged (greater than 450 ms) is relatively contraindicated, requiring close ECG monitoring to mitigate the risk of . Complete atrioventricular (AV) block or other rhythms dependent on junctional or idioventricular pacemakers without a functioning artificial pacemaker represent another absolute , given the potential for progression to . Relative contraindications include sick sinus syndrome, where quinidine may cause profound sinus node depression and , potentially leading to hemodynamic instability. It should be avoided in cases of , uncorrected , or hypomagnesemia, as these conditions heighten the risk of arrhythmogenic effects and toxicity through altered electrophysiologic properties. Decompensated (New York Heart Association class III or IV) warrants relative contraindication due to quinidine's negative inotropic effects, which can worsen and precipitate . In patients with renal or hepatic impairment, quinidine is relatively contraindicated without dose adjustment, as reduced clearance can lead to accumulation and amplified adverse cardiac risks. Special considerations apply to certain populations. Quinidine is classified as pregnancy category C and should be avoided unless benefits outweigh risks, owing to placental transfer and potential fetal , including . Caution is advised in elderly patients due to increased susceptibility from , age-related declines in renal function, and higher baseline risk. The rationale for these contraindications stems from the fact that quinidine's benefits in arrhythmia suppression are outweighed by the potential for severe harm, including , , or exacerbation of underlying conditions, in at-risk individuals. For with contraindications requiring antiarrhythmic therapy, alternatives such as beta-blockers (e.g., metoprolol) or (e.g., verapamil) may be considered for similar indications, depending on the specific and profile.

Drug interactions

Quinidine, as an inhibitor of and to a lesser extent , can significantly elevate plasma levels of coadministered drugs metabolized by these enzymes, potentially leading to toxicity. For instance, concurrent use with approximately doubles serum digoxin concentrations in 90% of patients, necessitating a 50% reduction in digoxin dosage to prevent adverse effects such as arrhythmias. Similarly, quinidine increases levels, heightening the risk of bleeding through enhanced anticoagulation effects. With , quinidine blocks its conversion to active via CYP2D6 inhibition, thereby reducing analgesic efficacy. Tricyclic antidepressants (e.g., amitriptyline) experience elevated levels and prolonged effects, increasing risks of and cardiotoxic side effects. Combination with other QT-prolonging agents poses a major risk of additive prolongation of the , potentially inducing . Drugs such as , , fluoroquinolones (e.g., ), and antipsychotics (e.g., ) should generally be avoided or used with extreme caution, including close ECG monitoring. Verapamil and substantially increase quinidine plasma levels by inhibiting its and clearance, which may necessitate dosage adjustments to avoid quinidine . Antacids, particularly those containing aluminum , reduce quinidine absorption by up to 30-50%, delaying onset and decreasing ; administration should be separated by at least 2 hours. inhibits CYP3A4-mediated of quinidine, leading to higher serum concentrations and enhanced risk of side effects. Moderate alcohol consumption may potentiate quinidine-induced through additive vasodilatory effects. Agents that alkalinize urine, such as , decrease quinidine renal excretion, elevating its levels and risk; such combinations should be avoided. Overall, quinidine is involved in 632 known drug interactions, classified as 219 major, 394 moderate, and 19 minor according to interaction databases. of quinidine levels (target 2-5 mcg/mL) and ECG is essential for safe coadministration. Caution is advised with treatments like due to synergistic QT prolongation.

History

Discovery and early use

Quinidine, an derived from the bark of the tree (also known as Peru bark), originates from the Andean regions of , where indigenous peoples, including the Quechua, had been using infusions of the bark to treat fevers and chills since the early 1600s. The bark's febrifugal properties were first documented in European records around 1630 in , highlighting its role in for managing intermittent fevers long before scientific isolation of its active components. By the mid-17th century, Spanish Jesuit missionaries introduced bark to , where it gained recognition as a treatment for following endorsements from figures like Cardinal Juan de Lugo in the 1660s. This adoption accelerated in the 1740s, when formally named the genus in 1742, solidifying its place in European pharmacopeias and establishing the bark's dual potential for antimalarial and other therapeutic uses, including early hints at cardiovascular effects. The isolation of quinidine from bark occurred in the early , building on the 1820 extraction of by French chemists Pierre-Joseph Pelletier and Joseph-Bienaimé Caventou, who separated key alkaloids from the bark. Quinidine, the dextrorotatory stereoisomer of , was first isolated and named in 1833 by Henry and Delondre from the mother liquor remaining after quinine . It was further described in 1848 by Van Heijningen. Quinidine's antiarrhythmic properties were recognized in the early , with German pharmacologist Walter Frey and colleagues, including Richard Wasicky, demonstrating its efficacy in suppressing in experimental models between 1912 and 1914. This led to the first clinical applications in the late , when Frey reported successful restoration of in patients with using quinidine sulfate starting in 1918. Initial formulations, primarily the sulfate salt, became standard in the for oral and parenteral use in cardiac rhythm disorders, while the gluconate salt emerged in the 1930s for improved solubility in injectable forms. Widespread adoption followed , as quinidine served as a primary antiarrhythmic before the rise of synthetic alternatives like in the 1950s.

Modern developments

The use of quinidine declined significantly in the late following the Cardiac Arrhythmia Suppression Trial (CAST) in 1989, which demonstrated increased mortality associated with class I antiarrhythmic drugs like encainide and in post-myocardial patients with ventricular arrhythmias, prompting broader caution for similar agents including quinidine. A 1990 meta-analysis of randomized controlled trials further revealed that quinidine, while effective in maintaining after cardioversion for , was linked to a threefold increase in mortality compared to or no therapy (2.9% vs. 0.8% death rate). These findings restricted quinidine's role to niche indications, such as and , where its benefits in preventing ventricular arrhythmias outweigh risks in select patients. Regulatory actions in the 1990s emphasized quinidine's proarrhythmic potential, with FDA labels highlighting risks of QT prolongation, torsades de pointes, and excess mortality in non-life-threatening arrhythmias based on the aforementioned meta-analyses. By the early 2000s, quinidine was withdrawn from markets in several countries due to availability of safer alternatives and these safety concerns; for instance, it became unavailable in the UK around 2008 and is not marketed in most European nations, though it remains accessible as a generic in the United States. In the 2010s, research reaffirmed quinidine's value for rare arrhythmias, with a 2019 JACC review underscoring its efficacy in reducing life-threatening events in Brugada syndrome through multichannel blockade, particularly when implantable cardioverter-defibrillators are not feasible. As of 2025, ongoing studies explore its role in electrical storm and short-coupled premature ventricular contractions. Formulations have evolved to include extended-release tablets for better tolerability in arrhythmia management, and a fixed-dose combination with dextromethorphan (Nuedexta) was FDA-approved in 2010 for pseudobulbar affect, leveraging low-dose quinidine to inhibit CYP2D6 metabolism. In 2019, the intravenous formulation of quinidine was discontinued in the United States, limiting its use for acute settings and prompting alternatives like IV for arrhythmias. Although intravenous quinidine was discontinued in the in 2019 and replaced by artesunate, it may persist as an alternative for severe in some resource-limited global settings where other intravenous antimalarials are unavailable, with careful cardiac monitoring. In , it remains a standard treatment for in horses, with recent pharmacokinetic studies optimizing dosing regimens for Thoroughbreds as of 2024.

Chemistry

Chemical structure

Quinidine is a cinchona alkaloid with the molecular formula C20_{20}H24_{24}N2_{2}O2_{2} and a molecular weight of 324.42 g/mol. Its core structure consists of a methoxy-substituted quinoline ring connected via a chiral carbon bearing a hydroxy group to a quinuclidine moiety featuring a vinyl group on the quinuclidine ring. Specifically, the IUPAC name is (S)-(6-methoxyquinolin-4-yl)[(2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol, highlighting the bicyclic 1-azabicyclo[2.2.2]octane (quinuclidine) system. Quinidine is the (9S)- and exists as a of , differing in configuration at the C8 and C9 positions; quinidine has the 8R,9S configuration, while is 8S,9R. This stereochemical distinction makes quinidine the pseudo-enantiomer of , with both sharing the 3R configuration at the quinuclidine C3. Quinidine is optically active and dextrorotatory in solution, with a of approximately +235° to +265° (c=1, ). Due to its poor solubility, quinidine is commonly administered as salts such as the sulfate dihydrate or gluconate to enhance for pharmaceutical use. The contains two basic atoms—the with a pKa of approximately 4.3 and the with a pKa of approximately 8.6—contributing to its behavior and salt formation.

Physical and chemical properties

Quinidine base appears as a white to off-white crystalline powder that is odorless and has a bitter taste. The base exhibits poor in , approximately 0.05 g per 100 mL at 20°C, but is more soluble in organic solvents such as (at least 10.32 mg/mL) and . In contrast, the gluconate salt form is highly water-soluble, with about 111 g per liter at 25°C, facilitating its use in formulations requiring aqueous dissolution. The sulfate salt shows moderate water , dissolving 1 g in approximately 90 mL of at ambient . The of quinidine base is 168–172°C, while the sulfate salt melts at around 212°C with . Quinidine is light-sensitive and darkens upon exposure to light, remaining stable under neutral conditions but subject to in strong acidic or basic environments; its , which is pH-dependent, influences and behavior. Analytical characterization includes UV absorbance with a maximum near 235–250 nm and chiral (HPLC) for separating enantiomers. For storage, quinidine should be protected from and , ideally kept sealed in a dry place at 2–8°C, with a typical of 2–5 years depending on the formulation and packaging.

Veterinary use

Use in

Quinidine is primarily indicated in equine for the treatment of (AF), a common in performance horses such as Standardbreds and Thoroughbreds, where it facilitates conversion to normal in approximately 60-80% of cases. This condition often arises in high-performance breeds due to the demands of racing or intense exercise, leading to irregular heart rhythms that can impair and athletic performance. Standard dosing regimens for quinidine sulfate involve at 22 mg/kg every 6 hours, often preceded by pretreatment to control ventricular rate and enhance conversion success. For intravenous administration, quinidine gluconate is preferred for its rapid onset, typically given as 0.5-2 mg/kg boluses every 5-10 minutes until a total dose of up to 11 mg/kg is reached or conversion occurs. Oral quinidine is commonly used for therapy following initial conversion, while the gluconate form is reserved for acute interventions requiring quick action. Efficacy is particularly high in and horses with recent-onset , where success rates exceed 70% when administered promptly, though outcomes depend on AF duration and absence of underlying structural heart disease. Treatment requires continuous monitoring via (ECG) or to assess rhythm conversion, detect adverse effects like , and guide dose adjustments. Gastrointestinal side effects, including , are a notable with oral quinidine, prompting recent to refine regimens. A 2024 population study proposed optimized dosing—such as 30 mg/kg initially followed by 12 mg/kg every 3 hours for three days—to achieve therapeutic levels while minimizing toxicity and colic incidence in racehorses.

Use in other animals

Quinidine, a class Ia antiarrhythmic agent, is employed in veterinary practice to manage supraventricular tachyarrhythmias, particularly , in various non-equine species, though its application is less common and more limited compared to . In dogs, it is primarily used to facilitate synchronized of rather than for rate control or ventricular arrhythmias, with reported success in converting persistent cases to . Typical dosages include 6–20 mg/kg orally every 6–8 hours for quinidine or 6–20 mg/kg intramuscularly or orally every 6–8 hours for quinidine gluconate; intravenous administration of at 5–10 mg/kg every 6 hours is also an option under close monitoring. Quinidine is contraindicated in cats due to heightened risk of toxicity, including severe cardiotoxicity and gastrointestinal upset, and alternative therapies such as electrical are preferred for feline associated with underlying cardiac failure. In , quinidine gluconate has been used intravenously or orally to treat , a condition often linked to in lactating cows, with case reports demonstrating conversion to normal when therapeutic plasma levels are achieved, though subtherapeutic dosing may necessitate repeated administration. For pigs, oral quinidine sulfate at 10 mg/kg every 8 hours has effectively terminated in breeding sows presenting with anorexia and abnormal cardiac , restoring normal rhythm without reported complications in documented cases. Use in other ruminants, such as sheep or , lacks substantial clinical documentation, with pharmacokinetic studies indicating similar elimination rates to dogs but no established therapeutic protocols for arrhythmias. Across species, monitoring for adverse effects like , (affecting up to 25% of dogs), and proarrhythmic ventricular ectopy is essential, particularly in animals with preexisting myocardial disease.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK542193/
  2. https://www.mayoclinic.org/drugs-supplements/quinidine-oral-route-injection-route-intramuscular-route/description/drg-20065770
  3. https://pubchem.ncbi.nlm.nih.gov/compound/Quinidine
  4. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a08a0f0b-6cf5-4fa4-a861-0b054d6fddfc
  5. https://pubmed.ncbi.nlm.nih.gov/2281676/
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