VA Class:CV300

AHFS Class:

• Class Ia Antiarrhythmics 24:04.04.04

Generic Name(s):

• quiNIDine Gluconate

• quiNIDine Sulfate

Quinidine is a class Ia antiarrhythmic agent that exhibits antimalarial activity.119,163,167,168,169,170

Arrhythmias

Quinidine is used to convert and prevent recurrence of atrial fibrillation or atrial flutter.119,163,167,169,170,301 The drug also has been used in the management of other supraventricular and ventricular arrhythmias such as paroxysmal atrial fibrillation, paroxysmal atrial tachycardia, paroxysmal AV junctional rhythm, paroxysmal ventricular tachycardia, and atrial or ventricular premature contractions. However, pooled analysis of data from several randomized controlled studies in patients with atrial flutter and fibrillation indicates that quinidine appears to be associated with a mortality rate more than 3 times higher compared with that associated with placebo.119,149,163,167,168,169,170 In addition, pooled analysis of data from several other randomized controlled studies in patients with non-life-threatening ventricular arrhythmias indicates that mortality rate associated with quinidine was consistently higher than that associated with other antiarrhythmic drugs (e.g., flecainide, mexiletine, propafenone, tocainide);145,163,167,168,169,170 the risk of mortality appeared to be increased in patients with structural heart disease, particularly those with left ventricular dysfunction.145

Supraventricular Tachyarrhythmias

Atrial Fibrillation or Flutter

Quinidine is used to convert atrial fibrillation or atrial flutter to normal sinus rhythm in patients whose symptoms are not adequately controlled by measures to reduce ventricular rate; the drug also is used to prevent recurrence of these arrhythmias following conversion.119,163,167,169,170,301 Quinidine was one of the first antiarrhythmic agents available for the treatment of atrial fibrillation and flutter; however, the drug is now infrequently used because of its propensity for adverse effects (e.g., QT-interval prolongation, torsades de pointes) and association with increased mortality.301 Experts currently consider quinidine an alternative agent for the treatment of atrial fibrillation when other antiarrhythmic drugs cannot be used.301

The use of quinidine to prevent recurrence of atrial fibrillation or flutter is controversial. Although the drug may maintain normal sinus rhythm for long periods in patients with recent onset of atrial fibrillation or flutter without congestive heart failure, atrial enlargement, or left ventricular hypertrophy, patients who have had long-standing atrial fibrillation are likely to have recurrence of fibrillation even with quinidine maintenance therapy. Generally, quinidine should not be used prophylactically for atrial fibrillation unless the ventricular rate is inadequately controlled by alternative measures.

If quinidine is used for conversion of atrial fibrillation/flutter, appropriate measures should be taken to ensure that the patient is adequately anticoagulated since conversion to normal sinus rhythm may be associated with embolism, particularly when the arrhythmia has been present for more than 48 hours.301 (See Uses: Cardioversion of Atrial Fibrillation/Flutter, in Heparin 20:12.04.16.) The possibility of additive hypoprothrombinemic effects should be considered if oral anticoagulants and quinidine are administered concomitantly. (See Drug Interactions: Coumarin Anticoagulants.)

Paroxysmal Atrial Tachycardia and AV Junctional Rhythm

Quinidine has been used in the treatment of paroxysmal atrial tachycardia or paroxysmal AV junctional rhythm. If treatment of paroxysmal atrial tachycardia is necessary, however, measures to increase vagal tone (such as carotid sinus massage or Valsalva maneuver) and/or IV adenosine are the treatments of choice.300 Paroxysmal AV junctional rhythm is rarely treated unless there is an extremely rapid ventricular rate; if treatment is necessary, measures to increase vagal tone, IV adenosine, IV amiodarone, calcium-channel blocking agents (e.g., diltiazem, verapamil), β-adrenergic blockers, or electrical cardioversion are used.

Atrial Premature Complexes

Although quinidine can be used for the treatment of atrial premature complexes, these arrhythmias are usually treated with a cardiac glycoside.

Ventricular Arrhythmias

Quinidine is used to suppress and prevent the recurrence of ventricular arrhythmias (e.g., sustained ventricular tachycardia) that in the judgment of the physician are life-threatening. The manufacturers and many clinicians state that because of the drug's arrhythmogenic potential and the lack of evidence for improved survival for class I antiarrhythmic agents,146,147 use of quinidine for less severe ventricular arrhythmias is not recommended and treatment of patients with asymptomatic ventricular premature contractions (VPCs) should be avoided.

Parenteral lidocaine is the drug of choice for treatment of VPCs; although quinidine decreases the frequency of VPCs associated with acute myocardial infarction, usual doses may decrease myocardial contractility in these patients. Like other antiarrhythmic drugs, quinidine has not been shown to decrease mortality rate in patients with VPCs associated with acute myocardial infarction. Quinidine generally is not used to treat cardiac glycoside-induced ventricular arrhythmias. (See Cautions: Precautions and Contraindications.)

Malaria

Treatment of Severe Malaria

IV quinidine gluconate is used for initial treatment of severe, life-threatening malaria caused by Plasmodium falciparum or other Plasmodium species†.102,104,105,119,122,124,126,134,142,143,144,153 Severe malaria usually is caused by P. falciparum ;143 P. knowlesi also can cause severe malaria, but other species ( P. ovale , P. malariae , P. vivax ) are less likely to cause severe disease.143

Severe malaria can be a rapidly progressive, fatal illness.143 Because most deaths occur within the first 24-48 hours of illness, initial aggressive treatment with a parenteral antimalarial regimen is indicated as soon as possible after a diagnosis has been made (regardless of Plasmodium species involved) and whenever severe malaria is suspected based on possible exposure and symptoms.143,144 Manifestations of severe malaria include impaired consciousness/coma, severe normocytic anemia (hemoglobin less than 7 g/dL), renal failure, pulmonary edema, acute respiratory distress syndrome, hypotension, circulatory shock, disseminated intravascular coagulation, spontaneous bleeding, acidosis, hemoglobinuria, jaundice, repeated generalized seizures, and/or parasite density (parasitemia) greater than 5%.143,144

For treatment of severe malaria in adults or children, the US Centers for Disease Control and Prevention (CDC) recommends an initial regimen of IV quinidine gluconate in conjunction with doxycycline, tetracycline, or clindamycin (oral or IV as tolerated).143,144 After at least 24 hours of continuous IV infusion of quinidine gluconate (or 3 intermittent IV doses) and when parasitemia is reduced to less than 1% and the patient can tolerate oral therapy, IV quinidine gluconate can be discontinued and oral quinine sulfate therapy initiated to complete 7 or 3 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (7 days if malaria was acquired in Southeast Asia or 3 days if malaria was acquired elsewhere).143,144 Oral antimalarials are not recommended for initial treatment of severe malaria.143

Although CDC previously recommended that exchange transfusions be considered an adjunct procedure for treatment of severe malaria in certain severely ill patients, CDC no longer recommends use of such transfusions in patients with severe malaria.143 Exchange transfusions have been used in treatment of severe malaria because they were thought to provide beneficial effects through removal of infected erythrocytes, improvement in blood rheology, and reduction of toxic factors (e.g., parasite-derived toxins, harmful metabolites, cytokines).143 However, clinical benefits have not been documented by a randomized clinical trial and survival benefits were not demonstrated in an analysis done by CDC involving cases of severe malaria treated with exchange transfusions.143 In addition, the risks of exchange transfusions include fluid overload, febrile and allergic reactions, metabolic disturbances (e.g., hypocalcemia), erythrocyte alloantibody sensitization, transmissible infection, and line sepsis.143

In the past, IV quinine hydrochloride was considered the drug of choice for treatment of severe malaria, but was available in the US only from the Parasitic Diseases Drug Service of CDC100,104,105,111 and delivery of emergency supplies for specific patient needs was problematic.105,126 Evidence of the clinical efficacy and toxicity of IV quinidine gluconate over a 2-year period in the US124,126 and experience of an expert panel convened by the World Health Organization (WHO)126,130 supported a recommendation for use of quinidine gluconate for treatment of severe P. falciparum malaria. On an equimolar basis, quinidine is more active than quinine against P. falciparum and has been shown to be highly effective clinically; in addition, slow IV infusion of quinidine gluconate generally is well-tolerated, even in critically ill patients, patients with underlying cardiac disease, and children.107,108,122,124,125,126 For these reasons, IV quinine dihydrochloride is no longer available for use in the US, either commercially or from CDC,125,126 and IV quinidine gluconate has been the only parenteral cinchona alkaloid antimalarial agent commercially available in the US since 1991.126,143,153

There have been several reports of fatal cases of P. falciparum malaria in the US and Canada in which delays in obtaining IV quinidine gluconate appeared to contribute to the deaths.142,153,154 As newer antiarrhythmics have replaced quinidine for many cardiac uses, some health-care facilities no longer have IV quinidine gluconate readily available for use.142,143,148,153 In addition, the number of clinicians with experience in using IV quinidine has decreased.143,153 Although most patients with malaria in the US respond to oral antimalarial agents and recover fully, a small number of fatal cases continue to occur each year, often in association with substantial delays in seeking medical attention and/or in initiating appropriate treatment.142

Because of the potentially fatal consequences of delays in initiating appropriate therapy in patients with severe malaria, CDC, the US Food and Drug Administration (FDA), the manufacturer of parenteral quinidine gluconate, and other experts have alerted institutional pharmacy services regarding the essential role that ready availability of IV quinidine gluconate plays in treatment of severe and complicated malaria, and that this be weighed in any formulary decision that might affect availability of the drug.142,143,148,153 CDC and other experts encourage institutions within close geographic proximity to coordinate their respective formulary decisions so that IV quinidine gluconate remains readily available within the area (either by keeping IV quinidine gluconate on their formulary or knowing which neighboring hospitals or other health-care facilities maintain the drug on their formulary).142,143,148 In hospitals where IV quinidine gluconate is not maintained on formulary, health-care professionals (e.g., pharmacists) who require the drug for patients with severe P. falciparum malaria should contact local or regional distributors of the drug or the manufacturer.143,153

If IV quinidine gluconate is unavailable locally and cannot be obtained quickly or cannot be used because of adverse effects or contraindications or if parasitemia is high and has not responded to quinidine gluconate, IV artesunate is available from CDC under an investigational new drug (IND) protocol for initial treatment of severe malaria.143,144,171,172 WHO recommends artesunate as the drug of choice for treatment of severe malaria.161

Clinicians who desire assistance with the diagnosis or treatment of malaria or assistance obtaining IV quinidine gluconate or IV artesunate for treatment of severe malaria should contact the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143,144,171,172

Treatment of Uncomplicated Malaria

Oral quinidine sulfate has been used for treatment of uncomplicated P. falciparum malaria† in Thailand where this organism generally is resistant to chloroquine and/or the fixed combination of sulfadoxine and pyrimethamine (no longer commercially available in the US).102,108,109,110 Although quinidine appears to be more active than quinine in vitro on a weight basis against P. falciparum and it has been suggested that oral quinidine may be more effective than oral quinine for treatment of P. falciparum malaria,102,103,104,112 CDC and other experts recommend oral quinine sulfate (not oral quinidine sulfate) for treatment of uncomplicated P. falciparum malaria.134,143,144 Oral quinidine sulfate is not included in CDC recommendations for treatment of uncomplicated or severe malaria.143,144

Pseudobulbar Affect

Quinidine sulfate is used orally in fixed combination with dextromethorphan hydrobromide (Nuedexta^®) in the treatment of pseudobulbar affect (PBA).174 Quinidine, a specific inhibitor of the hepatic cytochrome P-450 (CYP) isoenzyme 2D6, is used in the fixed combination to increase the systemic bioavailability of dextromethorphan.174 (See Dextromethorphan Hydrobromide and Quinidine Sulfate 28:92.)

Administration

Quinidine gluconate168,169 and quinidine sulfate163,167,170 are administered orally. Quinidine gluconate also is administered by IV infusion;119 IM administration is not recommended because absorption kinetics of the drug may vary depending on the patient's peripheral perfusion.119

Oral Administration

Quinidine gluconate is administered orally as extended-release tablets.168,169

Quinidine sulfate is administered orally as conventional167,170 or extended-release tablets.163

In the management of arrhythmias, extended-release tablets of quinidine are used primarily for maintenance therapy. If necessary, extended-release tablets of quinidine may be broken in half in order to titrate dosa however, extended-release tablets should not be chewed or crushed.168,169

Adverse GI effects of quinidine may be minimized by administering oral doses of the drug with food or antacids; however, the possibility that food and antacids may delay absorption and that antacids which increase urine pH may decrease quinidine excretion should be considered.

Because grapefruit juice may delay the absorption and inhibit the metabolism of quinidine to 3-hydroxyquinidine in the gut,156,157 grapefruit juice should be avoided in patients receiving quinidine.156,163,168,169 If grapefruit juice is ingested concomitantly, the patient should be monitored for evidence of the interaction.156,157 (See Cautions: Precautions and Contraindications.)

To determine possible idiosyncrasy to quinidine, a test dose of 200 mg of quinidine sulfate should be administered orally several hours before full dosage is begun. For children, the test dose for idiosyncrasy to quinidine is 2 mg/kg (up to 200 mg) of quinidine sulfate orally.164

IV Administration

For the treatment of arrhythmias, quinidine gluconate is administered by IV infusion.119

For the treatment of severe Plasmodium falciparum malaria, quinidine gluconate is administered by continuous or intermittent IV infusion.102,104,111,119,122,123,124,125,134,143,144

Dosage

Dosage of quinidine gluconate or quinidine sulfate for the treatment of arrhythmias usually is expressed in terms of the salt.119,167,168,169 Dosage of quinidine gluconate for the treatment of malaria is expressed in terms of the base or salt.119,143,144

On a molar basis, approximately 267 mg of quinidine gluconate is equivalent to 200 mg of quinidine sulfate.

Dosage of quinidine must be carefully adjusted according to individual requirements and response, and the general condition and cardiovascular status of the patient.

Quinidine therapy should be initiated or quinidine dosage adjusted in a setting where facilities and personnel for patient monitoring and resuscitation are continuously available, especially if the drug is used in patients with known structural heart disease or other risk factors for toxicity.163,167,168,169,170

ECG monitoring of cardiac function and determination of plasma quinidine concentrations are recommended during quinidine therapy, especially when the drug is given IV or when more than 2 g of oral quinidine sulfate is administered daily, and in patients with an increased risk of adverse reactions to quinidine, such as patients with severe heart disease, hypotension, or hepatic or renal disease.

Quinidine should be used for conversion of atrial fibrillation/flutter only after alternative measures (e.g., use of other drugs to control ventricular rate) have been inadequate.163,167,168,169,170 Quinidine should be discontinued if sinus rhythm is not restored within a reasonable amount of time.119,163,167,168,169,170

Quinidine should be discontinued if QRS complex widens to 130% of its pretreatment duration, QT_c interval widens to 130% of its pretreatment duration and is greater than 500 milliseconds, P waves disappear, or the patient develops clinically important tachycardia, symptomatic bradycardia, or hypotension.119,163,167,168,169,170

Arrhythmias

Oral Quinidine Sulfate

If oral quinidine sulfate (conventional tablets) is used for conversion of atrial fibrillation/flutter in adults, the manufacturers recommend that 400 mg of quinidine sulfate (332 mg of quinidine) be given every 6 hours initially.167,170 The dose may be cautiously increased if conversion is not attained after 4 or 5 doses.167,170

Alternatively, if oral quinidine sulfate (extended-release tablets) is used for conversion of atrial fibrillation/flutter in adults, the manufacturer recommends that 300 mg of quinidine sulfate (249 mg of quinidine) be given every 8-12 hours initially.163 The dose may be cautiously increased if conversion is not attained, quinidine serum concentrations are within the therapeutic range, and the drug is well tolerated.163

If successful conversion of atrial fibrillation does not occur when quinidine serum concentrations are in the therapeutic range, further increases in dosage are generally unsuccessful and increase the possibility of toxicity.

For reduction in frequency of relapse into atrial fibrillation/flutter, the initial adult dosage of oral quinidine sulfate (conventional tablets) recommended by the manufacturers is 200 mg of quinidine sulfate (166 mg of quinidine) every 6 hours.167,170 The dose may be cautiously increased if the drug is well tolerated, serum quinidine concentrations are within the therapeutic range, and the average time between arrhythmic episodes has not been satisfactorily increased.167,170

Alternatively, if oral quinidine sulfate (extended-release tablets) is used for reduction in frequency of relapse into atrial fibrillation/flutter, the initial dosage recommended by the manufacturer is 300 mg of quinidine sulfate (249 mg of quinidine) every 8-12 hours.163 The dose may be cautiously increased if the drug is well tolerated, serum quinidine concentrations are within the therapeutic range, and average time between arrhythmic episodes has not been satisfactorily increased.163

Quinidine sulfate (conventional or extended-release tablets) should be used for reduction in frequency of relapse into atrial fibrillation/flutter only if alternative measures have been inadequate and if potential benefits of such prophylaxis outweigh risks;163,167,170 the mortality risk should be considered.163,167,170

The manufacturers of oral quinidine sulfate (conventional and extended-release tablets) state that dosage regimens for suppression of life-threatening ventricular arrhythmias have not been adequately studied, but regimens similar to those used in the management of atrial fibrillation/flutter have been described.163,167,170 Whenever possible, such therapy should be guided by results of programmed electrical stimulation and/or Holter monitoring with exercise.163,167,170

Oral Quinidine Gluconate

If oral quinidine gluconate (extended-release tablets) is used for conversion of atrial fibrillation/flutter in adults, the manufacturers recommend an initial dosage of 648 mg of quinidine gluconate (403 mg of quinidine) every 8 hours.168,169 The dose may be cautiously increased if conversion is not attained after 3 or 4 doses.168,169 Alternatively, the manufacturers state that adults can receive an oral regimen of 324 mg of quinidine gluconate (202 mg of quinidine) every 8 hours for 2 days, then 648 mg of quinidine gluconate (403 mg of quinidine) every 12 hours for 2 days, and then 648 mg of quinidine gluconate (403 mg of quinidine) every 8 hours for up to 4 days.168,169 If the 648-mg dose is not tolerated, a lower dosage can be continued for the last 4 days.168,169

If oral quinidine gluconate (extended-release tablets) is used for reduction in frequency of relapse into atrial fibrillation/flutter, the manufacturers recommend that adults receive an initial dosage of 324 mg of quinidine gluconate (202 mg of quinidine) every 8 or 12 hours.168,169 The dose may be cautiously increased if the drug is well tolerated, serum quinidine concentrations are within the therapeutic range, and the average time between arrhythmic episodes has not been satisfactorily increased.168,169 Quinidine gluconate should be used for such prophylaxis only if alternative measures have been inadequate and if potential benefits outweigh risks;168,169 the mortality risk should be considered.168,169

The manufacturers of oral quinidine gluconate (extended-release tablets) state that dosage regimens for suppression of life-threatening ventricular arrhythmias have not been adequately studied, but regimens similar to those used in the management of atrial fibrillation/flutter have been described.168,169 Whenever possible, such therapy should be guided by results of programmed electrical stimulation and/or Holter monitoring with exercise.168,169

IV Quinidine Gluconate

For IV treatment of symptomatic atrial fibrillation/flutter in adults, 800 mg of quinidine gluconate (10 mL of the commercially available injection containing 80 mg/mL) is diluted in 40 mL of 5% dextrose injection to provide a solution containing 16 mg/mL.119 The 16 mg/mL solution is infused at an initial rate of up to 0.25 mg/kg per minute (i.e., 1 mL/kg per hour).119

Blood pressure and ECG should be monitored continuously during IV infusion and the rate of administration adjusted so the arrhythmia is abolished without disturbing the normal mechanism of the heart beat. If the QRS complex widens to 130% of its pretreatment duration, the QT_c interval widens to 130% of its pretreatment duration and is longer than 500 milliseconds, if disappearance of the P wave, severe hypotension, substantial tachycardia, or symptomatic bradycardia occurs, or if normal sinus rhythm is restored or severe adverse effects appear, IV administration of the drug should be discontinued.

Generally, the total IV dosage in the treatment of atrial fibrillation/flutter is less than 5 mg/kg, although 10 mg/kg may be required in some patients.119 If conversion to sinus rhythm has not occurred after infusion of quinidine gluconate 10 mg/kg, the infusion should be discontinued and other means of cardioversion should be considered.119

While dosing regimens using IV quinidine gluconate for the management of life-threatening ventricular arrhythmias have not been systematically evaluated, regimens similar to that used in the management of atrial fibrillation/flutter have been described.119

Malaria

Oral Quinidine Sulfate

For treatment of uncomplicated Plasmodium falciparum malaria† in adults, 300-600 mg or 10 mg/kg of quinidine sulfate has been administered orally every 8 hours for 5-7 days.102,103,108,109,110

Oral quinidine sulfate is not included in US Centers for Disease Control and Prevention (CDC) recommendations for treatment of uncomplicated or severe malaria.143,144 (See Uses: Malaria.)

IV Quinidine Gluconate

For treatment of severe malaria caused by P. falciparum or other Plasmodium species†, CDC states that IV quinidine gluconate in conjunction with doxycycline, tetracycline, or clindamycin (oral or IV as tolerated) should be initiated as soon as possible after a diagnosis of severe malaria has been made (regardless of Plasmodium species involved) and whenever severe malaria is suspected based on possible exposure and symptoms.143,144 Several dosage regimens (intermittent or continuous IV infusion) of quinidine gluconate have been employed for treatment of severe P. falciparum malaria.102,104,111,119,122,123,124,125,134,144 Because most deaths from severe malaria occur within the first 24-48 hours of illness, an initial loading dose of IV quinidine gluconate usually is used to rapidly provide therapeutic plasma concentrations of the drug.143,144

When a continuous IV infusion regimen is used, an initial loading dose of 6.25 mg/kg of quinidine (10 mg/kg of quinidine gluconate)119,134,141,143,144,153 diluted in approximately 5 mL/kg of 0.9% sodium chloride injection119 should be given by IV infusion over 1-2 hours,119,134,143,144,153 followed by a continuous maintenance infusion of 12.5 mcg/kg of quinidine per minute (20 mcg/kg of quinidine gluconate per minute)119,134,143,144,153 given for at least 24 hours and until parasitemia is reduced to less than 1% and oral quinine sulfate can be substituted.119,122,123,124,134,141,143,144

Alternatively, if an intermittent IV infusion regimen is used, an initial loading dose of 15 mg/kg of quinidine (24 mg/kg of quinidine gluconate)119,143,144,153 should be diluted in 250 mL of 0.9% sodium chloride injection119 and infused over 4 hours, followed 4 hours later (i.e., 8 hours after the beginning of the loading-dose infusion) by maintenance doses of 7.5 mg/kg of quinidine (12 mg/kg of quinidine gluconate) given by IV infusion over 4 hours at 8-hour intervals until 3 maintenance doses have been administered and parasitemia is reduced to less than 1% and oral quinine sulfate can be substituted.119,143,144,153

The IV infusion rate should be decreased or the flow interrupted if corrected QT interval exceeds 0.6 seconds, corrected QT interval exceeds baseline by more than 25%, QRS widening exceeds 50% of baseline, or clinically important hypotension unresponsive to fluid expansion develops.111,123,124,128,143 Some clinicians state that the initial loading dose of quinidine gluconate should not exceed 375 mg of quinidine (600 mg of quinidine gluconate) when administered by a continuous IV infusion regimen.134

Blood pressure and ECG should be continuously monitored and blood glucose periodically monitored in patients receiving quinidine for the treatment of malaria, and dosage adjusted accordingly .102,104,111,134,141,143,144 Clinicians should also consider that the risk of serious ventricular arrhythmias associated with quinidine is increased by bradycardia, hypokalemia, and hypomagnesemia.143,153 When deciding whether a patient should receive an initial loading dose of quinidine gluconate, clinicians should consider whether the patient has been receiving drugs that can prolong the QT interval (e.g., halofantrine [an antimalarial drug not commercially available in the US], mefloquine, quinine).134,143,144,153 A loading dose of quinidine gluconate should not be administered if the patient has received more than 40 mg/kg of quinine in the previous 48 hours or has received mefloquine in the previous 12 hours.143,144 Because clinical experience on which to base therapeutic decisions regarding quinidine gluconate is limited, these recommendations for administration of an initial loading dose are based on clinical experience with the use of initial loading doses of quinine.143 Both loading dose and infusion rate should be calculated carefully to prevent acute cardiac events.153 Consultation with a cardiologist and a clinician with experience using quinidine gluconate for treatment of severe malaria is advised.144,153

After at least 24 hours of continuous IV quinidine gluconate infusion (or 3 intermittent doses) and if parasitemia is reduced to less than 1% and the patient can tolerate oral therapy, IV quinidine gluconate therapy can be discontinued and oral quinine sulfate therapy initiated to complete a total of 7 or 3 days of total quinidine and quinine therapy as determined by the geographic origin of the infecting parasite (7 days if acquired in Southeast Asia or 3 days if acquired elsewhere).122,123,141,143,144

The initial IV quinidine gluconate regimen followed by oral quinine sulfate is used in conjunction with a 7-day regimen of doxycycline, tetracycline, or clindamycin administered IV or orally as tolerated.143,144 Adults intolerant of oral therapy may receive IV therapy with doxycycline hyclate (100 mg every 12 hours) or clindamycin (10 mg/kg loading dose followed by 5 mg/kg every 8 hours) until they can be switched to oral therapy.143,144 Rapid IV administration of doxycycline hyclate or clindamycin should be avoided.143,144 Adults who tolerate oral therapy may receive a 7-day course of therapy with doxycycline (100 mg every 12 hours), tetracycline (250 mg every 6 hours), or clindamycin (20 mg/kg daily given in 3 equal doses).143,144

Additional information on the management of malaria can be obtained by contacting the CDC Malaria Hotline at 770-488-7788 or 855-856-4713 from 9:00 a.m. to 5:00 p.m. Eastern Standard Time or the CDC Emergency Operation Center at 770-488-7100 after hours and on weekends and holidays.143,144

Pediatric Dosage

Arrhythmias

Oral Quinidine Sulfate

Although safety and efficacy for use as an antiarrhythmic agent in children have not been established in well-controlled clinical trials,163,167,170 some clinicians recommend that children with arrhythmias† receive oral quinidine sulfate in a dosage of 15-60 mg/kg daily given in divided doses every 6 hours.164,165 Other clinicians recommend that children with arrhythmias receive 30 mg/kg daily or 900 mg/m² daily, given in 5 divided doses.

Oral Quinidine Gluconate

Although safety and efficacy for use as an antiarrhythmic agent in children have not been established in well-controlled clinical trials,168,169 some clinicians recommend that children with arrhythmias† receive oral quinidine gluconate in a dosage of 20-60 mg/kg daily given in divided doses every 8 hours.165

IV Quinidine Gluconate

Although safety and efficacy for use as an antiarrhythmic agent in children have not been established in well-controlled clinical trials,119 some clinicians have recommended parenteral quinidine gluconate dosages of 30 mg/kg daily or 900 mg/m² daily, given in 5 divided doses.

Malaria

IV Quinidine Gluconate

For treatment of severe malaria caused by P. falciparum or other Plasmodium species† in pediatric patients†, CDC and other clinicians recommend that quinidine gluconate be given in the same dosage regimen recommended for adults.122,124,134,143,144 (See IV Quinidine Gluconate under Dosage: Malaria, in Dosage and Administration.) In addition, the appropriate pediatric dosages of oral quinine sulfate and IV or oral doxycycline, tetracycline, or clindamycin should be used in conjunction with IV quinidine gluconate.143,144 (See the dosage sections in Doxycycline and Tetracycline Hydrochloride in 8:12.24 and the dosage section in Clindamycin in 8:12.28.20.)

Dosage in Renal Impairment

For the treatment of severe malaria, the initial loading dose and continuous IV infusion rate of quinidine gluconate do not need to be reduced in patients with renal failure.143 If renal failure persists or clinical improvement does not occur in such patients, the maintenance infusion rate should be reduced by one-third to one-half on the third day of the quinidine gluconate infusion.143

Quinidine has numerous adverse effects which may necessitate cessation of therapy in many patients.

GI Effects

Adverse GI effects such as diarrhea, anorexia, abdominal pain and cramps, colic, nausea, bitter taste, esophagitis, and vomiting occur commonly with quinidine therapy and are the most frequent reasons for discontinuance of the drug. Adverse GI effects may be less severe with extended-release preparations than with other oral dosage forms, but there are no well-controlled clinical trials to date comparing adverse effects of quinidine salts after administration of doses that produce similar plasma concentrations.

Dermatologic and Sensitivity Reactions

Idiosyncratic and hypersensitivity reactions to quinidine may occur, and the reaction of the patient to a test dose or the first dose of the drug should be observed carefully. (See Dosage and Administration: Administration.) Observation of the patient for hypersensitivity should be continued for the first weeks of therapy. Symptoms of cinchonism such as tinnitus, headache, vertigo, fever, dizziness, lightheadedness, tremor, nausea, and disturbed vision may occur in sensitive patients after a single dose of quinidine. Dosage should be decreased if signs of cinchonism appear.

Other hypersensitivity reactions to quinidine include fever, thrombocytopenic purpura, hypoprothrombinemia, hemorrhage, acute hemolytic anemia, agranulocytosis, aplastic anemia, leukopenia, acute asthmatic episode, angioedema, vascular collapse, respiratory arrest, and anaphylactic shock. Quinidine may cause hemolysis in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

Skin reactions to quinidine are rare and include morbilliform and scarlatiniform eruptions, urticaria, rash, pruritus, exfoliative dermatitis, eczema, severe exacerbation of psoriasis, lichenoid reactions, flushing, pigmentary abnormalities, photodermatitis (photosensitivity), and contact dermatitis.

Quinidine has produced a systemic lupus erythematosus-like syndrome characterized by polyarthritis, fever, pleuritic chest pain, lupus nephritis, and the presence of antinuclear antibodies (ANA) in the blood.113,114,120

Hepatotoxicity, including granulomatous hepatitis, increased serum AST (SGOT) and alkaline phosphatase concentrations, and jaundice, has been reported with quinidine. Quinidine-induced hepatotoxicity appears to be the result of hypersensitivity to the drug. The possibility of quinidine-induced hepatotoxicity should be considered in any patient who develops unexplained fever and/or elevation of hepatic enzymes, particularly during the initial stages of therapy.

Cardiovascular Effects

Paradoxically, an extremely rapid ventricular rate may occur when quinidine is used in the treatment of atrial flutter or fibrillation, due to a reduction in the degree of AV nodal block to a 1:1 ratio. The anticholinergic action of the drug on the AV node may also increase the heart rate. This tachycardia may be prevented by prior digitalization. If cessation of atrial fibrillation or flutter is accompanied by depression of the normal pacemaker, an idioventricular rhythm (including ventricular tachycardia and fibrillation) may result. Conversion of atrial fibrillation also may be associated with embolism. Therefore, anticoagulant therapy may be necessary before administration of quinidine for conversion of atrial fibrillation to normal sinus rhythm. (See Atrial Fibrillation or Flutter under Arrhythmias: Supraventricular Tachyarrhythmias, in Uses and see Drug Interactions: Coumarin Anticoagulants.)

The risk of fibrillation increases with increasing dosage and may be accompanied by ECG signs of toxicity. Quinidine-induced cardiotoxicity is evidenced by conduction defects (50% widening of the QRS complex), ventricular tachycardia or flutter, frequent ventricular premature contractions, and complete AV block. When these ECG signs appear, quinidine should be discontinued and the patient should be monitored closely. Lidocaine may be effective in treating quinidine-induced ventricular premature contractions, tachycardia, or fibrillation. Adverse cardiac effects occur most commonly when quinidine is administered IV. Large IV doses of the drug may cause heart block and asystole, and death has occurred during IV administration of quinidine in seriously ill patients.

In usual doses, quinidine may cause syncope, probably due to ventricular tachycardia or fibrillation. These syncopal episodes may subside spontaneously, but occasionally they are fatal. If quinidine-induced syncope occurs, the drug should be discontinued. Quinidine also may cause bradycardia.

Severe hypotension may occur following IV administration or oral overdosage of quinidine. Vascular collapse, respiratory distress, and respiratory arrest may occur. Quinidine-induced hypotension is reportedly related to the dose and rate of administration of the drug.102,107,119 Rapid IV injection of as little as 200 mg of quinidine reportedly may cause a decrease in blood pressure of 40-50 mm Hg.119 Norepinephrine or metaraminol may be used if necessary to treat vascular collapse; artificial respiration and other supportive measures may be required.

While substantial cardiovascular toxicity generally has not occurred, ECG changes, including prolonged QT interval, widened QRS complex, and flattened T waves (without dysrhythmia), have occurred frequently and hypotension and ventricular tachycardia have occurred occasionally in patients receiving IV quinidine gluconate for the treatment of Plasmodium falciparum malaria.102,104,108,124

Other Adverse Effects

Adverse nervous system effects of quinidine include headache, vertigo, faintness, apprehension, excitement, confusion, dementia, cold sweat, delirium, ataxia, and mental depression. Hearing disturbances such as tinnitus, decreased auditory acuity, and transitory deafness have occurred. Vision disturbances have included mydriasis, blurred vision, disturbed color perception, photophobia, diplopia, night blindness, reduced visual fields, scotomata, and optic neuritis. Increased serum skeletal muscle creatine kinase (CK, creatine phosphokinase, CPK), myalgia, and arthralgia also have been reported. Quinidine can decrease blood glucose concentrations, possibly by inducing insulin secretion, and has been associated with severe hypoglycemia in at least one patient with cerebral malaria and acute renal failure.121

Precautions and Contraindications

Quinidine is contraindicated in patients with an AV junctional or idioventricular pacemaker, including those in complete AV block.119,163,167,168,169,170 The drug is contraindicated in patients with a history of quinidine- or quinine-associated thrombocytopenic purpura119,163,167,168,169,170 and in patients with myasthenia gravis or other conditions that might be adversely affected by anticholinergic effects.119,163,167,168,169,170 Quinidine also is contraindicated in patients with known hypersensitivity to the drug.119,163,167,168,169,170

Since pooled analysis of data from several randomized, controlled studies in patients with non-life-threatening ventricular arrhythmias indicates that the mortality rate associated with quinidine therapy was consistently higher than that associated with various other antiarrhythmic agents (e.g., flecainide, mexiletine, propafenone, tocainide),163,167,168,169,170 quinidine should only be used for life-threatening ventricular arrhythmias.145 Use of the drug for less severe ventricular arrhythmias is not recommended and treatment of patients with asymptomatic ventricular premature contractions should be avoided.145 In addition, pooled analysis of data from several randomized, controlled studies in patients with atrial flutter and fibrillation indicates that quinidine therapy may be associated with a mortality rate more than 3 times higher compared with that associated with placebo.149,163,167,168,169,170 The mortality risk should be considered when initiating quinidine therapy.149,163,167,168,169,170 Quinidine should be used with extreme caution, if at all, in patients with incomplete AV nodal block, since complete heart block and asystole may result. Parenteral quinidine is especially hazardous in the presence of AV block, in the absence of atrial activity, and in patients with extensive myocardial injury. The possibility that potentially serious cardiac arrhythmias, including torsades de pointes, could occur if quinidine were used concomitantly with other drugs that prolong the QT_c interval also should be considered.119 Hypokalemia, hypoxia, and disorders of acid-base balance must be eliminated as potentiating factors in patients who require large doses of antiarrhythmic agents to control ventricular arrhythmias.

Quinidine should be used with extreme caution in patients with cardiac glycoside intoxication, since cardiac glycoside intoxication may cause serious impairment of cardiac conduction and produce arrhythmias which may contraindicate use of quinidine. Conversely, quinidine may cause unpredictable, abnormal rhythms and decrease contractility in the presence of cardiac glycoside intoxication.

Since quinidine-induced decreases in cardiac contractility and blood pressure may aggravate congestive heart failure or preexisting hypotension, the drug should be used cautiously, if at all, in patients with these conditions.

Rapid IV infusion of quinidine gluconate may cause peripheral vascular collapse and severe hypotension.119 (See Dosage and Administration.) If hypotension or congestive heart failure is caused or aggravated by an arrhythmia treatable with quinidine, the drug may be useful, but the potential risks and benefits must be considered.

Concomitantly administered grapefruit juice may delay absorption of quinidine and inhibit metabolism of the drug to 3-hydroxyquinidine by cytochrome P-450 (CYP) isoenzyme 3A4 in the gut;156,157 in one study, the delay in quinidine absorption tended to delay the effects of the drug on the QT_c interval.157 Although the clinical importance of this interaction is unknown,156 the manufacturers of extended-release tablets recommend avoiding concomitant ingestion of grapefruit juice and quinidine.163,168,169 Some experts state that the clinical significance of resultant pharmacokinetic interactions appears to be limited and that no specific action other than being alert for evidence of the interaction is indicated.156

Quinidine should be used with caution in patients with preexisting asthma, muscle weakness, or infection with fever, since hypersensitivity reactions to the drug may be masked. The drug should also be used with caution in patients with hepatic and/or renal (particularly if renal tubular acidosis is present) insufficiency, since systemic accumulation of quinidine potentially may result.

Patients receiving chronic quinidine therapy should be instructed to notify their physician if rash, fever, unusual bleeding or bruising, ringing in the ears, or visual disturbance occurs. During long-term administration of quinidine, complete blood counts (CBCs) and liver (particularly during the initial 4-8 weeks of therapy) and renal function tests should be performed periodically. The drug should be discontinued if blood dyscrasias or signs of hepatic or renal dysfunction occur.

Since prolongation of the QT interval, ventricular arrhythmias, hypotension, and hypoglycemia may occur when quinidine is administered parenterally for the treatment of severe P. falciparum malaria, therapy preferably should be undertaken in an intensive care facility where central hemodynamic and ECG monitoring is available.119,143,153 In addition, careful monitoring of hydration status,126 blood glucose,143 and parasitemia is required.119

Pediatric Precautions

Safety and efficacy of quinidine as an antiarrhythmic agent in children have not been determined.119,163,167,168,169,170 Quinidine has been used in children with arrhythmias†.165

Study and experience in children with malaria suggest that safety and efficacy of IV quinidine gluconate are similar to those in adults.119

Geriatric Precautions

Safety and efficacy of quinidine have not been systematically studied in geriatric patients,119,167,168,169,170 and clinical studies did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults.119 Other reported clinical experience has not identified differences in responses between geriatric adults and younger patients.119

When used in geriatric patients, quinidine dosage should be selected with caution, usually initiating therapy at the low end of the dosage range and taking into consideration the greater frequency of decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy in this age group.119

Mutagenicity and Carcinogenicity

Animal studies to determine the carcinogenic or mutagenic potential of quinidine have not been performed to date.119,163,167,168,169,170

Pregnancy, Fertility, and Lactation

Pregnancy

Animal reproduction studies have not been performed to date with quinidine. It is not known whether quinidine can cause fetal harm when administered to pregnant women. Another cinchona alkaloid, quinine , has caused fetal blindness and has been implicated in congenital deafness. Quinidine should be used during pregnancy only when clearly needed.119,163,166,167,168,169,170 The safety of quinidine during labor and delivery is not known, but the drug exhibits oxytocic properties; the clinical importance remains to be established.

Fertility

There is no evidence to date of quinidine-induced impairment of fertility.

Lactation

Since quinidine is distributed into milk,119,163,166,167,168,169,170 the drug should be avoided, if possible, in nursing women.119,163,167,168,169,170

Drugs or Foods Affecting or Metabolized by Hepatic Microsomal Enzymes

Quinidine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 and pharmacokinetic interactions with drugs that are inhibitors, inducers, or substrates of CYP3A4 are possible.119,163,167,168,169,170

Quinidine inhibits CYP2D6 and therapeutic serum quinidine concentrations may effectively convert CYP2D6 extensive metabolizers into CYP2D6 poor metabolizers.119,163,167,168,169,170 Quinidine should be used with caution concomitantly with drugs that are metabolized by CYP2D6 (e.g., mexiletine, some phenothiazines, polycyclic antidepressants).119,163,167,168,169,170 Reduced dosage of such drugs may be necessary to obtain clinical benefit without toxicity.119,163,167,168,169,170 Quinidine is used in fixed combination with dextromethorphan (Nuedexta^®) to inhibit the CYP2D6-mediated metabolism of dextromethorphan and thereby increase its systemic bioavailability in patients with pseudobulbar affect (PBA).174 (See Dextromethorphan Hydrobromide and Quinidine Sulfate 28:92.) If quinidine is used concomitantly with some prodrugs that require CYP2D6 for conversion to an active metabolite (e.g., codeine, hydrocodone), it may not be possible to achieve the desired clinical benefits of the drugs.119,163,167,168,169,170

Alkalinizing Agents

Quinidine toxicity may result when the drug is administered with agents which increase urine pH; therefore, patients receiving quinidine should be monitored closely during initiation of therapy with drugs such as carbonic anhydrase inhibitors (e.g., acetazolamide), thiazide diuretics, some antacids, or sodium bicarbonate.

Anticonvulsants

Anticonvulsants such as phenytoin and phenobarbital may increase the rate of metabolism and decrease the elimination half-life of quinidine, and caution should be used when therapy with these anticonvulsants is initiated or discontinued in patients receiving quinidine.

Cardiovascular Drugs

Cardiac Glycosides

Concomitant administration of quinidine and digoxin produces increased plasma concentrations of digoxin (in 90% or more of patients) which may result in GI and cardiac toxicity. Although variability exists in the magnitude of the increase, plasma digoxin concentrations usually increase twofold to threefold when quinidine therapy is initiated in patients digitalized with digoxin. Plasma digoxin concentrations may begin to increase within a few hours after initiation of quinidine therapy, but at least 5-7 days are usually required to achieve a new steady-state plasma digoxin concentration. The magnitude of the effect appears to depend on the serum quinidine concentration. Both the clearance (principally renal clearance) and volume of distribution of digoxin are generally decreased, but serum half-life of the drug may be unaffected. When quinidine therapy is initiated in a patient receiving digoxin, serum digoxin concentrations should be carefully monitored and digoxin dosage reduced as needed; the patient should be observed closely for signs of toxicity. Many clinicians recommend that digoxin dosage be reduced by one-half when quinidine therapy is initiated; however, because of the variability in magnitude of the interaction, additional dosage adjustments are likely to be necessary. If severe toxicity occurs or if digoxin dosage adjustment is difficult, an alternative antiarrhythmic agent (if possible, one that does not interact with digoxin) should be used instead of quinidine (e.g., procainamide). If digoxin therapy is initiated in a patient receiving quinidine, lower than usual dosages of digoxin may be sufficient to produce desired plasma concentrations of the cardiac glycoside. If quinidine is discontinued in a patient stabilized on therapy with both drugs, the patient should be observed for signs of decreased response to digoxin and dosage of the cardiac glycoside adjusted as necessary.

Calcium-Channel Blocking Agents

A substantial hypotensive effect has occurred when verapamil was used concomitantly with quinidine in patients with arrhythmia or hypertrophic cardiomyopathy.116,117 Pending further accumulation of data on the safety of combined therapy, concomitant use of verapamil and quinidine in such patients should probably be avoided.116 For additional information, see Drug Interactions: Antiarrhythmic Agents, in Verapamil Hydrochloride 24:28.92.

Nifedipine may decrease serum quinidine concentrations in some patients.119,129,132,136,137,139 Reductions or increases in serum quinidine concentrations occasionally have been observed following initiation or discontinuance, respectively, of nifedipine.137,139 Such changes can be substantial and may manifest as therapeutic resistance to usual quinidine dosages during concomitant therapy and/or altered ECGs (e.g., prolongation in corrected QT interval following discontinuance of nifedipine).129,132,136,139 While it had been postulated that alterations in quinidine pharmacokinetics during concomitant nifedipine therapy may have resulted from changes in hemodynamics induced by the latter drug (e.g., reduced peripheral vascular resistance with resultantly increased quinidine volume of distribution) in some patients (e.g., those with left ventricular dysfunction),129,132,136,139 subsequent study failed to confirm left ventricular dysfunction as a predictor of this interaction.132,137 Therefore, the mechanism of this interaction remains to be established, and possible identification of patients at risk requires further study.132,137 The possibility of this interaction should be considered in any patient exhibiting unpredictably low serum quinidine concentrations during concomitant nifedipine therapy.132,137 Serum quinidine concentrations should be monitored whenever nifedipine is initiated or discontinued in patients maintained on the antiarrhythmic, and quinidine dosage adjusted accordingly.129,132,136,137,139

Amiodarone

Serum quinidine concentrations may increase following initiation of amiodarone therapy in patients currently receiving quinidine, with subsequent toxicity occurring in some patients. Administration of amiodarone hydrochloride (1200 mg daily for 5-7 days then reduced to 600 mg daily) to a limited number of patients receiving quinidine gluconate or sulfate (average dose of about 3 g daily) resulted in an increase in serum quinidine concentrations of about 33%. Serum quinidine concentrations may begin to increase within a couple days after initiation of amiodarone therapy. The mechanism of the interaction is not fully established, but it has been suggested that amiodarone may inhibit hepatic clearance or decrease renal clearance of quinidine and/or displace quinidine from tissue- and/or protein-binding sites. Although not clearly established, combination therapy with amiodarone and quinidine may also cause marked QT prolongation, predisposing patients to atypical ventricular tachycardia (torsades de pointes). It is generally recommended that quinidine dosage be reduced by 33-50% when amiodarone therapy is initiated in patients currently receiving quinidine or that quinidine therapy be discontinued. Serum quinidine concentrations should be monitored carefully and quinidine dosage reduced as necessary in patients receiving concomitant quinidine and amiodarone therapy; patients should be observed closely for signs of toxicity, including QT prolongation.

Other Antiarrhythmic Agents

When quinidine is administered with other antiarrhythmic drugs such as lidocaine, phenytoin, procainamide, or propranolol, cardiac effects may be additive or antagonistic and toxic effects may be additive. Quinidine also may increase plasma procainamide and N -acetylprocainamide (NAPA) concentrations, possibly via competition for renal excretory mechanisms (e.g., tubular secretion).119,133,138 The pharmacologic effects of quinidine may be additive with those of quinine.

Cholinergic and Anticholinergic Agents

Quinidine should be used with caution, if at all, in patients with myasthenia gravis and the dose of anticholinesterase drugs such as neostigmine and pyridostigmine may have to be increased. Since quinidine antagonizes the effect of vagal excitation on the atria and AV node, the administration of cholinergic drugs or any other procedures to enhance vagal activity may fail to terminate paroxysmal supraventricular tachycardia in patients receiving quinidine. The anticholinergic effects of quinidine may be additive with those of anticholinergic drugs.

Cimetidine

Administration of cimetidine with quinidine may increase serum quinidine concentrations;119,140 however, the mechanism of this interaction has not been elucidated,135,140 and the clinical importance remains to be established.140

Clarithromycin

Torsades de pointes has been reported rarely in patients receiving quinidine and clarithromycin concomitantly.159 If quinidine and clarithromycin are used concomitantly, ECGs and serum quinidine concentrations should be monitored.159

Coumarin Anticoagulants

Patients who receive quinidine and coumarin anticoagulants should be closely observed for additive hypoprothrombinemic effects, since hypoprothrombinemic hemorrhage has reportedly occurred in patients receiving quinidine and chronic anticoagulant therapy.

Hypotensive Agents

Since quinidine may reduce blood pressure, patients receiving antihypertensive drugs and quinidine parenterally or in high oral doses should be observed for possible additive hypotensive effects. Additive cardiac depressant effects are possible when quinidine and phenothiazines or reserpine are administered concomitantly.

Ketoconazole

Concomitant use of ketoconazole results in increased plasma concentrations of quinidine.119,163,167,168,169,170

Neuromuscular Blocking Agents

Quinidine may potentiate the effects of both nondepolarizing and depolarizing skeletal muscle relaxants such as pancuronium bromide, succinylcholine chloride, and tubocurarine chloride. Neostigmine methylsulfate does not appear to reverse these effects. The use of quinidine should be avoided immediately after surgery when the effects of neuromuscular blocking agents may be present. If quinidine must be used, respiratory support may be needed.

Acute Toxicity

Manifestations

Overdosage of quinidine has produced ataxia, respiratory depression or distress, apnea, vomiting, diarrhea, severe hypotension, syncope, anuria, absence of P waves, broadening of the QRS complex, PR and QT intervals, ventricular arrhythmias, extrasystoles, heart block, heart failure, coma, death, irritability, lethargy, thrashing, twitching, hallucinations, paresthesia, and generalized seizures. Signs of cinchonism may also occur. (See Cautions: Dermatologic and Sensitivity Reactions.)

Treatment

Management of quinidine overdosage includes symptomatic treatment, ECG and blood pressure monitoring, and cardiac pacing if indicated. Administration of drugs that delay elimination of quinidine (e.g., cimetidine, carbonic anhydrase inhibitors, thiazide diuretics) should be avoided, unless absolutely necessary.119 If ingestion of the drug is recent, gastric lavage, emesis, and/or administration of activated charcoal may reduce absorption. Artificial respiration and other supportive measures may be required.

IV infusion of (1/6) M sodium lactate injection reportedly reduces the cardiotoxic effects of quinidine. Since marked CNS depression may occur even in the presence of seizures, CNS depressants should not be administered. Hypotension may be treated, if necessary, with metaraminol or norepinephrine after adequate fluid volume replacement. Tachyarrhythmias may be treated with phenytoin or lidocaine. Hemodialysis or forced diuresis may be effective in the treatment of quinidine overdosage in adults and children, but is rarely warranted. Peritoneal dialysis is not effective.

Pharmacology

Antiarrhythmic and Electrophysiologic Effects

Quinidine is an antiarrhythmic agent whose cardiac actions appear to be similar to those of procainamide. Quinidine is regarded as a myocardial depressant because it decreases myocardial excitability and conduction velocity, and may depress myocardial contractility. Quinidine, like disopyramide and procainamide, also possesses anticholinergic properties that may modify the direct myocardial effects of the drug.

Like other class I antiarrhythmic agents, quinidine is believed to combine with fast sodium channels in their inactive state and thereby inhibit recovery after repolarization in a time- and voltage-dependent manner, which is associated with subsequent dissociation of the drug from the sodium channels. Quinidine exhibits electrophysiologic effects characteristic of class IA antiarrhythmic agents. The electrophysiologic characteristics of the subgroups of class I antiarrhythmic agents may be related to quantitative differences in their rates of attachment to and dissociation from transmembrane sodium channels, with class IA agents exhibiting intermediate rates of attachment and dissociation.

Like lidocaine and procainamide, quinidine suppresses automaticity in the His-Purkinje system. In usual doses, quinidine may decrease the automaticity of ectopic pacemakers, but the extent of this effect also depends upon the anticholinergic effect of the drug on the sinoatrial (SA) node, atria, and atrioventricular (AV) node. Extremely high concentrations of quinidine may increase myocardial automaticity. The drug decreases conduction velocity in the atria, ventricles, and His-Purkinje system, and may decrease or cause no change in conduction velocity through the AV node. Quinidine probably suppresses atrial fibrillation or flutter by prolonging the effective refractory period (ERP) and increasing the action potential duration in atrial and ventricular muscle and in the His-Purkinje system. Because prolongation of the ERP is greater than the increase in the duration of the action potential, the cardiac tissue remains refractory even after restoration of the resting membrane potential. Quinidine shortens the ERP of the AV node, and the anticholinergic action of the drug may also increase the conductivity of the AV node. The effects of quinidine on refractoriness and the action potential duration of atrial fibers may be modified by the anticholinergic effects of the drug. Quinidine decreases cardiac excitability, both in diastole and in the relative refractory period, by increasing the threshold potential for electrical excitation. At therapeutic plasma concentrations, quinidine causes prolongation of the QRS complex and QT interval.

Cardiovascular Effects

In therapeutic doses, quinidine may produce sinus tachycardia via its anticholinergic effects. Quinidine has a direct negative inotropic effect, but therapeutic plasma concentrations of the drug do not usually depress contractility in the normal heart. Quinidine may reduce peripheral resistance and blood pressure by blockade of α-adrenergic receptors and by its effects on myocardial contractility; decreased blood pressure is most likely to occur with high plasma concentrations of the drug. At high plasma concentrations, quinidine may produce sinus tachycardia because of reflex sympathetic response to the drug's hypotensive effect.

Other Effects

Like quinine, quinidine has antimalarial activity.102,103,104,112,119 In patients with malaria, quinidine acts principally as an intraerythrocytic schizonticide; the drug has little effect on sporozoites or preerythrocytic parasites.119 Quinidine is gametocidal against Plasmodium vivax and P. malariae , but not P. falciparum .119 In vitro on a weight basis, quinidine appears to be more active than quinine against Plasmodium falciparum .102,103,104,112

Quinidine also exhibits some antipyretic and oxytocic properties. Quinidine has a very weak curare-like action on the myoneural junction and also causes depression of skeletal muscle action potential.

Pharmacokinetics

Absorption

Quinidine salts are almost completely absorbed from the GI tract. The amount of quinidine that reaches the circulation after oral administration is variable and depends on the amount of drug metabolized on the first pass through the liver. Extended-release formulations of quinidine gluconate and quinidine sulfate are absorbed more slowly than conventional tablets of quinidine sulfate.

Following oral administration of quinidine sulfate conventional tablets, absolute bioavailability is about 70% (range 45-100%) and peak serum concentrations are attained in about 2 hours.167,170

Following oral administration of quinidine gluconate extended-release tablets or quinidine sulfate extended-release tablets, absolute bioavailability is 70-80% and peak serum concentrations are attained within 3-6 hours.163,168,169

In patients with congestive heart failure, the rate and extent of quinidine absorption is reduced but these patients have higher plasma concentrations of quinidine due to a decreased volume of distribution.

In healthy fasting individuals, mean peak plasma quinidine concentrations of 0.43-1.14 mcg/mL are attained 1-2 hours following oral administration of a single 200-mg dose of quinidine sulfate. Plasma concentrations of quinidine generally reach steady-state after oral administration of 4-6 doses (200-300 mg) of quinidine sulfate at 2-hour intervals. If higher plasma concentrations are necessary after this time, the size of the individual dose must be increased.

Immediately following IV infusion over 4 hours of a single 24-mg/kg dose of quinidine gluconate in patients with Plasmodium falciparum malaria, plasma quinidine concentrations average 9.4 mcg/mL.102

Plasma quinidine concentrations necessary to produce a therapeutic cardiovascular effect depend on the type of cardiac arrhythmia, the severity and duration of the arrhythmia, and the sensitivity of the patient to the drug. In the past when nonspecific assay methods were used to determine plasma quinidine concentrations, therapeutic plasma concentrations of quinidine were reportedly approximately 2-7 mcg/mL. Toxicity was generally associated with plasma quinidine concentrations greater than 5 mcg/mL. However, more specific assay methods are currently available and plasma quinidine concentrations are lower when these methods are used.119 Therefore, clinicians interpreting plasma quinidine concentrations should be aware of the method of analysis used.119 Therapeutic plasma concentrations of quinidine when these more specific assays are used have not been definitely established, but effective reduction of ventricular premature contractions has been reported with plasma quinidine concentrations less than 1 mcg/mL. After oral administration of 400-600 mg of quinidine sulfate, the onset of cardiovascular effects usually occurs in 1-3 hours and therapeutic cardiovascular effects persist for 6-8 hours.

Concomitant administration of antacids may delay oral absorption of quinidine. However, concomitant administration of oral quinidine gluconate and an aluminum hydroxide antacid does not have a clinically important effect on the rate and extent of absorption of quinidine.169

When quinidine sulfate conventional tablets are administered with food, the rate of absorption is decreased but the extent of absorption is not affected.167,170 When quinidine gluconate extended-release tablets are administered with food, the rate of absorption is increased 27% and the extent of absorption is increased 17%.168,169

Distribution

Quinidine is rapidly distributed into all body tissues except the brain. The volume of distribution of the drug reportedly averages 2 L/kg in healthy adults106 and 0.9-1.8 L/kg in patients with malaria.102,103

Quinidine is concentrated in heart, liver, kidneys, and skeletal muscle. Quinidine also is distributed into erythrocytes, where it is bound to hemoglobin. In one study in patients with cerebral P. falciparum malaria who received IV quinidine gluconate, CSF concentrations of quinidine were 7-17% of plasma concentrations.102

Quinidine is about 80-88% bound to plasma proteins in adults and older children.119,163,167,168,169,170 Protein binding is lower in pregnant women, infants, and neonates, and may be as low as 50-70% in neonates and infants.119,163,167,168,169,170

Quinidine crosses the placenta119,163,166,167,168,169,170 and is distributed into milk.119,163,166,167,168,169,170

Elimination

Quinidine generally has a plasma half-life of 6-8 hours in healthy individuals, but half-life may range from 3-16 hours or longer.119,163,167,168,169,170 In children, the elimination half-life of quinidine is 3-4 hours.119,163,167,168,169,170 In one study in patients with P. falciparum malaria, the elimination half-life of the drug averaged 12.8 hours (range: 6.6-24.8 hours).102

Quinidine is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.2,119,163,167,168,169,170 Quinidine is metabolized in the liver, principally via hydroxylation to 3-hydroxyquinidine and 2-quinidinone. Some metabolites have antiarrhythmic activity.119,163,167,168,169,170 Animal studies indicate that the major metabolite, 3-hydroxyquinidine, has at least half of the antiarrhythmic activity of quinidine.119,163,167,168,169,170

Approximately 10-50% of a dose is excreted in urine (probably by glomerular filtration) as unchanged drug within 24 hours. The rate of renal excretion of quinidine increases when the pH of urine is 6 or less; the rate of excretion decreases and plasma quinidine concentrations increase when urine is alkaline. Less than 5% of the orally administered drug is excreted in feces. Small amounts of quinidine are removed by hemodialysis; the drug is not removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Quinidine is an alkaloid obtained from various species of Cinchona or their hybrids, from Remijia pedunculata, or prepared from quinine. Quinidine is the dextrorotatory isomer of quinine and contains 2 basic nitrogen atoms with pK_a values of 4 and 8.6. Commercially available quinidine salts contain not more than 20% of the respective dihydroquinidine salt, 1% of the respective quinine salt, and 1% of the respective dihydroquinine salt as impurities. The gluconate and sulfate derivatives of quinidine are used as antiarrhythmic agents.

Quinidine gluconate occurs as a white powder and is freely soluble in water and slightly soluble in alcohol. Commercially available quinidine gluconate injection has a pH of 5.5-7. Quinidine sulfate occurs as fine, needle-like, white crystals that frequently cohere in masses or as a fine, white powder and is slightly soluble in water and soluble in alcohol. The gluconate and sulfate derivatives of quinidine have a very bitter taste.

Stability

Quinidine gluconate extended-release tablets should be stored at 20-25°C in tight, light-resistant containers.168,169

Quinidine sulfate conventional or extended-release tablets should be stored at 20-25°C in tight containers.163,167,170 The tablets should be protected from light and moisture.163,167,170

Quinidine gluconate injection should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.119 When diluted to a concentration of 16 mg/mL with 5% dextrose injection, quinidine gluconate injection is stable for 24 hours at room temperature and up to 48 hours when refrigerated at 4°C.119

Quinidine gluconate and quinidine sulfate darken on exposure to light. Solutions of quinidine salts slowly acquire a brownish tint on exposure to light. Only colorless, clear solutions of quinidine gluconate injection should be used.

Quinidine gluconate injection has been reported to be physically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Only references cited for selected revisions after 1984 are available electronically.

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