Continuing Education Activity

Quinidine is one of the oldest known antiarrhythmics; an interprofessional approach is necessary when using this drug, including specialties such as cardiology, rheumatology, infectious disease, intensive care, and nursing. Quinidine is a medication used in the management and treatment of specific arrhythmias and malaria. It comes under the "class 1a antiarrhythmic" class of drugs. This activity reviews the indications, action, and contraindications for quinidine as a valuable agent in the management of certain arrhythmias and malaria. This activity will highlight the mechanism of action, adverse event profile, and other key factors pharmacodynamics, pharmacokinetics, monitoring, relevant interactions pertinent for members of the interprofessional team in the management of patients with certain arrhythmias, their related conditions, and malaria.

Objectives:

• Identify the mechanism of action of quinidine.
• Describe the adverse effects of quinidine.
• Outline the appropriate monitoring of quinidine.
• Review interprofessional team strategies for improving care coordination and communication to advance quinidine and improve outcomes.

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Note: The use of quinidine for the above indications has mostly been replaced by better pharmacological therapies such as amiodarone and procainamide.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 the 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 receive counsel 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 is approximately 2 hours, and extended-release preparations have around 3 to 4 hours.
• Bioavailability - Sustained release quinidine gluconate has 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 demonstrated 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. The elderly population shows reduced clearance of quinidine, and increased drug half-life, 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 EKGs 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 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 drugs 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. As all these interactions and responsibilities demonstrate, an interprofessional healthcare team approach is necessary for effective and safe therapy with quinidine. [Level 5]