Quinidine


Article Author:
Ashish Jain


Article Editor:
Jitendra Sisodia


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
5/21/2019 7:48:01 PM

Indications

Quinine is a derivate of the bark of the South American cinchona tree. Quinidine is a stereoisomer of quinine; it is a "class 1a antiarrhythmic drug" and also an antimalarial agent.

As an "Antiarrhythmic"[1]:

  • Atrial fibrillation (AFib) (safe and efficacious in combination with verapamil for the treatment of atrial fibrillation
  • Atrial flutter 
  • Paroxysmal supraventricular tachycardia (PSVT)
  • AVNRT ( AV nodal reentrant tachycardia)
  • AVRT (Atrioventricular reentrant tachycardia)
  • WPW (Wolf Parkinson White syndrome)
  • Ventricular tachycardia (VT)
  • Brugada syndrome
  • Short QT interval.

Note: The use of quinidine for the above indications has mostly been replaced by better pharmacological therapies such as amiodarone and procainamide.

Plasmodium Falciparum Malaria, Quinidine gluconate is acknowledged as an effective treatment of severe and complicated Malaria both alone as a therapy or in combination with exchange transfusion. EKG monitoring for prolongation of QT interval and QRS changes along with CBC, liver and renal function testing should be done on a routine basis when giving Quinidine as an IV infusion or for a prolonged period.

Mechanism of Action

Antiarrhythmic- Class 1a antiarrhythmic agents (example - quinidine, procainamide, disopyramide, ajmaline) work by inhibiting the fast inward sodium current, depressing the phase 0 of the action potential hence dampening the excitability of cardiac muscles which in turn prolongs the action potential and decreases automaticity. Quinidine's effect on fast inward sodium current is known as a 'use-dependent block' - this means at higher heart rates, the block increases, while at lower heart rates, the block decreases.[2] Quinidine has also been shown to decrease potassium efflux during repolarization, inhibition of slow delayed rectifier potassium current and shows a "reverse use dependence" pattern (less current suppression at more frequent depolarizations) and calcium transport across cell membranes.[3] 

Antimalarial-  It works as an antimalarial agent by having activity against the erythrocytic stage of the Plasmodium species, and it acts by building up in the parasites food vacuole, it forms a complex with heme which prevents crystallization in the parasites food vacuole. Cytotoxic-free heme accumulates secondary to inhibited heme polymerase activity.

Quinidine also has anticholinergic activity.

Administration

Quinidine is available as both parenteral and oral preparations.

  • Parenteral (Only gluconate preparations) - quinidine is available in the form of injections, given via intravenous route
  • Oral (All salts) -  quinidine is available as tablets ( also in extended release preparations) - for the extended-release preparations, patients should be educated to swallow the whole pill and not to chew, crush or break the tablet

 Pharmacodynamics and Pharmacokinetics[4]:

  • Distribution: Volume of distribution "Vd" is increased with cirrhosis and decreased with congestive heart failure
  • Metabolism: Hepatic metabolism by a series of hydroxylation reaction by cytochrome P450 enzymes, (60% to 80%), gets converted into active compounds, the most important with antiarrhythmic activity being  3-hydroxy-quinidine (3HQ); dose adjustment necessary per hepatic impairment.
  • Excretion: less than 20% of the drug gets excreted in the urine in an unchanged form, and dose adjustment may be needed only in severe renal impairment
  • Half-life elimination: Increases with age and conditions such as cirrhosis, and congestive heart failure
  • Time to peak: Oral preparation have approximately 2 hours, and extended-release preparations have around 3 to 4 hours
  • Bioavailability - Sustained release quinidine gluconate have shown to have higher serum concentrations than sustained-release quinidine sulfate

Adverse Effects

  • Cardiovascular[5][6]:
    • Quinidine is one of the most common drugs to cause a prolongation of QT interval, which sometimes can progress to a pleomorphic tachyarrhythmia torsades de pointes occurring in 1 to 3% of patients
    • Cardiac adverse effects tend to be more in the setting of lower heart rates and hypokalemia
    • The prolongation of QT interval is more pronounced in females as compared to males, and a new onset severe QT prolongation tends to be an indicator of drug toxicity
    • Palpitations, angina pectoris, cardiac arrhythmia - new or worsened, and syncope are all signs
  • Central nervous system[7]:
    • Quinidine crosses blood-brain barrier both by passive diffusion and active transport system, dizziness, fatigue, headache, disturbed sleep, nervousness, ataxia 
  • Dermatologic:
    • Skin rash 
  • Gastrointestinal:
    • Hepatotoxicity, diarrhea, digestive distress, nausea and vomiting, esophagitis
  • Neuromuscular & skeletal:
    • Weakness, tremor, Lupus-like syndrome
  • Ophthalmic:
    • Visual disturbance 
  • Hypokalemia or hypomagnesemia can precipitate drug toxicity.
  • Hemolysis may occur in patients suffering from G6PD deficiencies. 
  • Miscellaneous:
    • Fever, hypersensitivity reactions in people allergic to the drug.
    • Cinchonism (quinidine is a stereoisomer of quinine which derives from the bark of cinchona tree) which can present as tinnitus, high-frequency hearing loss, blurring of vision, diplopia, photophobia, confusion, headache, delirium, decreased hearing to profound deafness, lupus-like syndrome, Sjogren syndrome

Contraindications

  • Thrombocytopenia
  • Thrombocytopenic purpura
  • Hypersensitivity to quinine, mefloquine, quinidine, or to any component used in the drug preparation
  • Heart block greater than a 1st degree
  • Concurrent, amprenavir, cisapride, or ritonavir along with drugs responsible for the prolongation of QT interval such as fluoroquinolones.
  • Congenital long QT interval
  • AV block as the concurrent use of the drug can progress to complete block

Precautions[8][9][10]:

  1. Patients who are on digoxin were seen to have higher plasma quinidine levels and a shorter half-life on low doses when compared with patients who are not on quinidine. 
  2. Children require a larger dose of quinidine as compared to adults.
  3. In the elderly population clearance of quinidine is shown to be decreased, and drug half-life increases, which can predispose to toxicity. Hence appropriate drug dose adjustment is necessary.
  4. Quinidine should be dose adjusted in patients with congestive heart failure as normal dosing of the drug may lead to abnormally high serum concentrations.
  5. Pregnancy- Quinidine is an "FDA pregnancy risk category C" and is not safe during pregnancy, it can only be given when potential maternal benefit justifies the possible risk to the fetus
  6. Quinidine, although concentrations lower than maternal plasma, do pass in breast milk, breastfeeding neonates can develop serum quinidine concentration lower than maternal serum concentration. Neonates can develop toxicity with lower plasma quinidine levels.
  7. Myasthenia Gravis - Anticholinergic activity of quinidine can potentially worsen the condition of the patient. Quinidine can also interact with drugs used for the treatment of the disease.
  8. Asthma and other allergic conditions- It should be used with caution in patients with asthma and other allergic conditions because these conditions can hide the hypersensitivity of the drug.

Safe Practice:

  1. Quinidine can sometimes be confused with clonidine and quinine.
  2. Dose modulation may be necessary for patients with hepatic and renal disorders.
  3. To be used in caution with drugs that prolong QT interval such as thiazide diuretics, ondansetron, opioids, fluoroquinolones, risperidone, sotalol, antihistaminics, tricyclic antidepressants, macrolides (erythromycin), SSRIs

Monitoring

  1. Quinidine is an inhibitor of CYP450 and can interact with drugs metabolized by this enzyme system.
  2. Quinidine has shown to decrease digoxin's total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent.[11] This action is explainable by quinidine's property of displacing digoxin from protein binding sites. Reduction in renal clearance may be due to inhibition of renal secretion of digoxin by quinidine.[12]
  3.  Erythromycin has shown to decrease quinidine clearance, increase serum concentrations and possibly predispose to quinidine toxicity, hence when given concurrently with quinidine; it is advisable to monitor patients serum potassium, magnesium and timely EKG's for possible toxicity.[13]
  4. Phenobarbital and phenytoin have shown to decrease the half-life of quinidine by half, possibly by increasing its metabolism by induction of CYP450 class of enzymes.[14]
  5. Cimetidine competes for the renal tubular secretion of quinidine in its unchanged form and its metabolites hence increasing its concentration in plasma.[15]

Toxicity

Quinidine is well known for its toxicity causing QT prolongation and in severe cases a pleomorphic arrhythmia a.k.a "Torsades de Pointes." This condition can be fatal and times and the management of the situation includes discontinuation of the drug, institution of cardiac and electrolyte (potassium and magnesium) monitoring, management of hypoxia. Prompt management of torsades de pointes can be done by giving magnesium sulfate and terminating prolonged episodes by electrical cardioversion, in refractory cases isoproterenol or transvenous pacing is an option.[16]

Enhancing Healthcare Team Outcomes

Quinidine is one of the oldest drug known for the management of arrhythmias, and still has utility in the management of early repolarization syndrome, Brugada syndrome and idiopathic ventricular fibrillation, and certain infections such as Plasmodium falciparum malaria. A team approach is necessary amongst physicians, nurses, cardiologist, rheumatologist, a pharmacist for early detection and management of the drug toxicity which can be fatal at times (cardiology - as an antiarrhythmic/proarrhythmic, rheumatologist - known to cause lupus-like syndrome, infectious disease specialist - used in severe malaria), nurses for adverse effect monitoring and proper drug administration, pharmacists for correct drug dosing. The choice of the patient for the treatment is also essential for deciding therapy with quinidine, such as dose adjustment may be required in neonates, elderly, patients with CHF, hepatic or renal dysfunction and patients who are on other drugs such as digoxin and the ones known to prolong the QT interval. While inpatient consults with the cardiologist and intensivist about ICU care and monitoring while in the hospital are indicated.


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Quinidine - Questions

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After starting a medication for abnormal heart rhythm, a 56-year-old African American male came to the provider with the complaints of dark-colored urine, fatigue, and abdominal pain. He has a history of serious illness. Examination showed scleral icterus and no tenderness or organomegaly on palpation of the abdomen. Labs showed a low hemoglobin level, elevated lactate dehydrogenase levels, and peripheral blood smear showed "bite cells." Which of the following drugs has the patient most likely been taking?



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A 27-year old female, G1P0L0 at 11 weeks gestation and no significant past medical history has complaints of fever with chills, myalgia, and fatigue, and dark yellow urine. She just returned from a trip to Nigeria. Her vitals are within the normal range. Examination showed scleral icterus and splenomegaly. Labs show hemoglobin of 11.7 and mild elevation of bilirubin and LDH. She was diagnosed with malaria. What is the status of Quinidine as a treatment option for this patient?



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A 59-year-old woman, with the past medical history of diabetes mellitus type 2 and coronary artery disease has a chief complaint of dizziness and palpitations. On examination, she was found to have an irregularly irregular pulse and a heart rate of 104. Her other vitals were within the normal range. She was given a medication which is known to cause blockage of fast sodium channels (class 1 antiarrhythmic) which of the drugs mentioned in the answer options could have been given to the patient?



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If a patient has a known allergy to quinidine, which of the following medications should be avoided in the future as a part of medical management?.



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A 9-year-old African American male was evaluated for an episode of syncope, and on the basis of EKG, he was diagnosed with Brugada syndrome. The appropriate medication was started. He started complaining of back pain and abdominal pain and passage of extremely dark urine. Examination showed scleral icterus and splenomegaly, a peripheral blood smear showed "bite cells," and his serum creatinine and blood urea nitrogen levels were markedly increased. Which of the following drugs as given in the options can be responsible for the patient's condition?



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A 5-year-old Asian boy is brought to the provider because of high-grade fever with chills, body aches, and generalized fatigue for 4 to 5 days. The fever occurs in paroxysms of 48 to 78 hours. He returned from a vacation to Zimbabwe a week back. He took the appropriate medications and immunizations before his visit. On examination, he is hyperthermic and tachycardic. Examination shows scleral icterus and splenomegaly. Laboratory studies showed low hemoglobin and high bilirubin and lactate dehydrogenase levels. Peripheral blood smear showed intracellular parasites in red blood cells. Which of the following drugs in the option can be used for the management of this boys condition?



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A 62-year-old female came to the provider with the chief complaints of palpitations, an EKG was done which showed atrial fibrillation and she was given medications for the same. Following treatment, she now complains of a ringing sensation in her ears (tinnitus), which of the following drugs can be responsible for this condition?



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Quinidine was prescribed to a patient with atrial flutter, To what class of medications does this drug belong?



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A 23-year-old Asian male has a chief complaint of syncope. He has had previous episodes of syncope, but according to him, the episodes have increased in the past year. Otherwise, he does not complain of chest pain, shortness of breath or any other significant clinical complaints. He has no significant past or social history. He said that his father died young at the age of 35 years without any known cause. An EKG was done, and it showed pseudo right bundle branch block and ST elevation in lead V1-V2. Troponins were normal in range. The appropriate medication was given, following therapy he started complaining of a ringing sensation in his years and blurring of vision. Which of the following drugs given in the options can be responsible for these adverse effects?



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What kind of medication is quinidine?



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A 38-year-old male enters the pharmacy with a new prescription and wants to know about the side effects of the drug he will receive. If one of the side effects is diarrhea, which of the following drugs is the likely medication he was prescribed?



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Quinidine - References

References

Yang F,Hanon S,Lam P,Schweitzer P, Quinidine revisited. The American journal of medicine. 2009 Apr;     [PubMed]
Starmer CF,Grant AO,Strauss HC, Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophysical journal. 1984 Jul;     [PubMed]
Yao JA,Trybulski EJ,Tseng GN, Quinidine preferentially blocks the slow delayed rectifier potassium channel in the rested state. The Journal of pharmacology and experimental therapeutics. 1996 Nov;     [PubMed]
Taggart WV,Holyoak W, Steady-state bioavailability of two sustained-release quinidine preparations: quinidine gluconate versus quinidine sulfate. Clinical therapeutics. 1983;     [PubMed]
Roden DM,Thompson KA,Hoffman BF,Woosley RL, Clinical features and basic mechanisms of quinidine-induced arrhythmias. Journal of the American College of Cardiology. 1986 Jul;     [PubMed]
Benton RE,Sale M,Flockhart DA,Woosley RL, Greater quinidine-induced QTc interval prolongation in women. Clinical pharmacology and therapeutics. 2000 Apr;     [PubMed]
Ochs HR,Greenblatt DJ,Lloyd BL,Woo E,Sonntag M,Smith TW, Entry of quinidine into cerebrospinal fluid. American heart journal. 1980 Sep;     [PubMed]
Burckart GJ,Marin-Garcia J, Quinidine dosage in children using population estimates. Pediatric cardiology. 1986;     [PubMed]
Ochs HR,Greenblatt DJ,Woo E,Smith TW, Reduced quinidine clearance in elderly persons. The American journal of cardiology. 1978 Sep;     [PubMed]
Crouthamel WG, The effect of congestive heart failure on quinidine pharmacokinetics. American heart journal. 1975 Sep;     [PubMed]
Leahey EB Jr,Bigger JT Jr,Butler VP Jr,Reiffel JA,O'Connell GC,Scaffidi LE,Rottman JN, Quinidine-digoxin interaction: time course and pharmacokinetics. The American journal of cardiology. 1981 Dec;     [PubMed]
Hager WD,Fenster P,Mayersohn M,Perrier D,Graves P,Marcus FI,Goldman S, Digoxin-quinidine interaction Pharmacokinetic evaluation. The New England journal of medicine. 1979 May 31;     [PubMed]
Spinler SA,Cheng JW,Kindwall KE,Charland SL, Possible inhibition of hepatic metabolism of quinidine by erythromycin. Clinical pharmacology and therapeutics. 1995 Jan;     [PubMed]
Data JL,Wilkinson GR,Nies AS, Interaction of quinidine with anticonvulsant drugs. The New England journal of medicine. 1976 Mar 25;     [PubMed]
Hardy BG,Schentag JJ, Lack of effect of cimetidine on the metabolism of quinidine: effect on renal clearance. International journal of clinical pharmacology, therapy, and toxicology. 1988 Aug;     [PubMed]
Thomas SH,Behr ER, Pharmacological treatment of acquired QT prolongation and torsades de pointes. British journal of clinical pharmacology. 2016 Mar;     [PubMed]

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