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Quinidine
Quinidine M Tsai-Turton, Food and Drug Administration, Silver Spring, MD, USA Ó 2014 Elsevier Inc. All rights reserved. This article is a revision of the previous edition article by Dennis J. Naas, volume 3, pp 593–594, Ó 2005, Elsevier Inc.
l
Chemical Abstracts Service Registry Number: 56-54-2 Synonyms: Chinidin; Conquinine; (9S)-60 -Methoxycinchonan-9-ol; a-(6-Methoxy-4-quinolyl)-5-vinyl-2-quinuclidinemethanol; b-Quinine l Molecular Formula: C20H24N2O2 l Chemical Structure: l
quinidine can still be used to treat malaria, although quinine is preferred.
Exposure Routes and Pathways Ingestion is the most common route of exposure in both accidental and intentional poisonings. Quinidine is also available in intravenous and intramuscular forms. Oral products include the sulfate, gluconate, and polygalacturonate salts. Intravenous quinidine is available as the gluconate but its clinical usefulness is limited to hypotension.
Toxicokinetics
Background Quinidine is an optical isomer of quinine, originally extracted from the bark of the Cinchona tree and similar plant species. It has a long history of use, initially by Peruvians who are often credited with the discovery of some of its pharmaceutical properties. It is now also produced by chemical synthesis. Quinidine was first isolated by Pasteur in 1853 for treating fevers. The bark was brought back to Europe from Peru by Spanish missionaries in 1630 where its value to treat malaria was discovered. The use of quinidine for arrhythmias was not discovered until 1912 when Professor Karel F. Wenckebach learned from his patient, who found by chance that quinine reliably halted the irregular pause in his cardiac rhythm in 25 min. In 1918, W. Frey in Berlin studied all four cinchona alkaloids and found that quinidine was the most effective for treating atrial fibrillation. In 1920, Thomas Lewis proved his hypothesis (circus movement) that quinidine restored normal rhythm. The circus movement (i.e., entrapped circuit wave) is the mechanism responsible for atrial flutter when the diagnosis of an arrhythmia was made based on the classic description by Lewis.
Uses Quinidine is used to control atrial fibrillation and atrial flutter. It is also approved to treat premature ventricular contractions and to treat paroxysmal atrial tachycardia or paroxysmal atrioventricular junctional rhythm. In addition,
16
Quinidine is well absorbed and undergoes some first-pass (hepatic oxidative) metabolism. The bioavailability for an oral dose is 70–80%. Peak plasma effects occur in 1–3 h (Tmax). Sustained-release preparations produce peak plasma levels in 5 or 6 h. Quinidine is up to 90% bound to protein, but it is lower in pregnant women and in infants/neonates (as low as 50–70%). The volume of distribution (Vd) is 2–3 l kg1. Congestive heart failure can lower the Vd to 0.5 l kg1, whereas liver cirrhosis can increase the Vd to 3–5 l kg1. Up to 80% of quinidine undergoes hepatic hydroxylation. The remainder (w20% of a therapeutic dose) is eliminated unchanged in the urine. Quinidine generally has a plasma half-life of 6–8 h in healthy individuals, but the half-life may range from 3 to 16 h or longer in malaria patients and those with chronic liver disease. In addition, quinidine crosses the placenta and is distributed in milk (at slightly lower levels than those in maternal serum).
Mechanism of Action This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking fast active/opened sodium channels (inhibiting depolarization) and potassium channels (prolonging repolarization) across cellular membranes. It prolongs the cellular action potential (thereby prolonging the QT interval on the electrocardiograph (ECG)) and decreases automaticity (as well as myocardial excitability, conduction velocity, and contractility). Other ECG effects include a wide notched P wave, wide QRS complex, depressed ST segment, and U waves. Theses are all the results of both slowed depolarization and repolarization. In addition, quinidine processes antimuscarinic actions (i.e., anticholinergic effects, increased heart rate, and increased atrioventricular conduction) and a-adrenergic antagonist actions (i.e., decreased blood pressure/reflex and increased heart rate, cause of vasodilation and hypotension).
Encyclopedia of Toxicology, Volume 4
http://dx.doi.org/10.1016/B978-0-12-386454-3.00055-5
Quinidine
Acute and Short-Term Toxicity Animal Lethal dose 50% (LD50) values of 263 mg kg1 (oral) and 23 mg kg1 (intravenous) were reported in rats. AN LD50 of 173 mg kg1 (intraperitoneal) was reported in mice.
17
hemolytic anemia and drug-induced hepatitis. Allergic contact dermatitis has also been reported in pharmaceutical workers since quinidine is structurally related to quinine and chloroquine, which also can cause such allergic reaction.
Reproductive and Developmental Toxicity Human Acute overdose of quinidine can result in both cardiovascular and neurologic effects. The most serious quinidine toxicities are ventricular dysrhythmias and hypotension. When acutely overdosed, treatment is primarily supportive. Adverse cardiovascular effects may develop as a result of myocardial depression and depression of atrial/atrioventricular/ventricular conduction. Myocardial depression and vasodilation can lead to hypotension. A transient (proarrhythmic effect) torsade de pointes (i.e., bursts of atypical ventricular tachycardia) can lead to syncope (fainting). Ventricular tachycardia and ventricular fibrillation may also occur. ECG changes (i.e., a widening of the QT, PR, and QRS complexes; ST depression; and T inversion) are evident with these adverse cardiovascular effects. In addition, possible adverse central nervous system (CNS) effects can occur, including lethargy, seizures, and coma. Other adverse acute effects such as apnea can also occur. However, signs of quinidine toxicity are expected to occur in adults ingesting a gram or more. Therapeutic plasma levels of quinidine range from 1 to 4 mg ml1. Cardiac toxicity can occur with levels of at least 14–16 mg ml1.
Chronic Toxicity Animal Similar to what would be expected in humans, cardiovascular toxicity can be seen in animals treated with quinidine. It can also induce CNS symptoms (i.e., neurotoxicity and respiratory depression).
Human Gastrointestinal symptoms (i.e., upper gastrointestinal distress) are commonly associated with chronic toxicity of quinidine. Symptoms, such as nausea, vomiting, heartburn/esophagitis, and diarrhea, are generally seen at therapeutic levels (at oral doses of 200–400 mg 3–4 times a day for quinidine sulfate in adults). Another toxic syndrome, cinchonism, is associated with chronic toxicity of quinidine. Clinical manifestations include headache, fever, visual disturbances, mydriasis, decreased hearing or tinnitus, nausea, vomiting, hot flushed skin, rash, and CNS impairment (lethargy, memory impairment, delirium, hallucinations) and may present without cardiovascular toxicity, other than QT prolongation. Cinchonism can occur when quinidine plasma levels are at least 5 mg ml1. In addition, amblyopia, vision loss, can occur when levels are at least 10 mg ml1. As an oral medication, other side effects have been reported after ingestion of therapeutic doses including immune
Reproductive studies have not been conducted in animals. There are no adequate and well-controlled studies of adverse reproductive or developmental effects in humans. However, it has been shown that quinidine can be present in human milk at levels slightly lower than those in maternal serum. The pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied.
Genotoxicity Very limited published literature show that quinidine is not mutagenic by Ames assays.
Ecotoxicology No studies were found in the published literature that examine health effects in aquatic or terrestrial organisms. Quinidine is soluble in water and light sensitive. It also degrades with excess heat. One quinidine material safety data sheet (MSDS) reports that possibly hazardous short-term degradation products are not likely but long-term degradation products may arise. The product itself and its products of degradation, however, are not toxic to the environment. With an octanol/water partition coefficient (Kow) of 3.44, quinidine would not be expected to bioconcentrate or bioaccumulate significantly in lipid tissues of animals exposed to this compound.
Exposure Standards and Guidelines The Comprehensive Environmental Responses, Compensation, and Liability Act (CERCLA) reportable quantities: The National Response Center (NRC) requires to be notified if there is a release of quinidine in an amount equal or greater than its reportable quantity of 5000 lb or 2270 kg. No other exposure limits are listed by other federal agencies (i.e., National Institute for Occupational Safety and Health (NIOSH) and Occupational Safety and Health Administration (OSHA)).
Clinical Management Basic and advanced life-support measures should be used as needed. Induction of emesis is not recommended due to the potential for a decreased level of consciousness, seizures, and arrhythmias. Gastric lavage followed by activated charcoal is recommended. Repeated doses of activated charcoal may enhance elimination. Serum electrolytes should be monitored in all serious
18
Quinidine
exposures. Intravenous administration of sodium bicarbonate may decrease toxicity. Hypotension can be treated with fluids and vasopressors if needed. Ventricular dysrhythmias can be treated with class IB antiarrhythmics such as phenytoin or lidocaine. Persistent bradycardia and third-degree heart block are indications for insertion of a temporary pacemaker. Seizures can be treated with diazepam. If seizures are uncontrolled, phenobarbital or phenytoin can be administered.
Dart, R.C. (Ed.), 2003. Medical Toxicology, third ed. Lippincott Williams & Wilkins, Philadelphia, PA. Hellgren, U., Ericsson, O., AdenAbdi, Y., Gustafsson, L.L. (Eds.), 1995. Handbook of Drugs for Tropical Parasitic Infections, second ed. Taylor & Francis, London. Hollman, A., 1991. Quinine and quinidine. Br. Heart J. 66 (4), 301. Klaassen, C. (Ed.), 2008. Cassarett and Doull’s Toxicology, The Basic Science of Poisons, seventh ed. McGraw-Hill, New York. Nelson, L., Lewin, N., Howland, M.A., Hoffman, R. (Eds.), 2010. Goldfrank’s Toxicologic Emergencies, ninth ed. McGraw-Hill, New York.
Relevant Websites See also: Cardiovascular System; Quinine.
Further Reading Brunton, L., Chabner, B., Knollman, B. (Eds.), 2010. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, twelfth ed. McGraw-Hill, New York. Cygankiewicz, I., 2007. Sir Thomas Lewis (1881–1945). Cardiol. J. 14 (6), 605–606.
http://www.inchem.org/ – International Programme on Chemical Safety: Quinidine. http://chem.sis.nlm.nih.gov/chemidplus/ – National Library of Medicine ChemIDplus: Quinidine. http://www.sciencelab.com/ – Sciencelab.com: MSDS sheet for quinidine gluconate. http://www.toxnet.nlm.nih.gov/ – TOXNET Toxicology Data Network: Quinidine.
l
Chemical Abstracts Service Registry Number: 56-54-2 Synonyms: Chinidin; Conquinine; (9S)-60 -Methoxycinchonan-9-ol; a-(6-Methoxy-4-quinolyl)-5-vinyl-2-quinuclidinemethanol; b-Quinine l Molecular Formula: C20H24N2O2 l Chemical Structure: l
quinidine can still be used to treat malaria, although quinine is preferred.
Exposure Routes and Pathways Ingestion is the most common route of exposure in both accidental and intentional poisonings. Quinidine is also available in intravenous and intramuscular forms. Oral products include the sulfate, gluconate, and polygalacturonate salts. Intravenous quinidine is available as the gluconate but its clinical usefulness is limited to hypotension.
Toxicokinetics
Background Quinidine is an optical isomer of quinine, originally extracted from the bark of the Cinchona tree and similar plant species. It has a long history of use, initially by Peruvians who are often credited with the discovery of some of its pharmaceutical properties. It is now also produced by chemical synthesis. Quinidine was first isolated by Pasteur in 1853 for treating fevers. The bark was brought back to Europe from Peru by Spanish missionaries in 1630 where its value to treat malaria was discovered. The use of quinidine for arrhythmias was not discovered until 1912 when Professor Karel F. Wenckebach learned from his patient, who found by chance that quinine reliably halted the irregular pause in his cardiac rhythm in 25 min. In 1918, W. Frey in Berlin studied all four cinchona alkaloids and found that quinidine was the most effective for treating atrial fibrillation. In 1920, Thomas Lewis proved his hypothesis (circus movement) that quinidine restored normal rhythm. The circus movement (i.e., entrapped circuit wave) is the mechanism responsible for atrial flutter when the diagnosis of an arrhythmia was made based on the classic description by Lewis.
Uses Quinidine is used to control atrial fibrillation and atrial flutter. It is also approved to treat premature ventricular contractions and to treat paroxysmal atrial tachycardia or paroxysmal atrioventricular junctional rhythm. In addition,
16
Quinidine is well absorbed and undergoes some first-pass (hepatic oxidative) metabolism. The bioavailability for an oral dose is 70–80%. Peak plasma effects occur in 1–3 h (Tmax). Sustained-release preparations produce peak plasma levels in 5 or 6 h. Quinidine is up to 90% bound to protein, but it is lower in pregnant women and in infants/neonates (as low as 50–70%). The volume of distribution (Vd) is 2–3 l kg1. Congestive heart failure can lower the Vd to 0.5 l kg1, whereas liver cirrhosis can increase the Vd to 3–5 l kg1. Up to 80% of quinidine undergoes hepatic hydroxylation. The remainder (w20% of a therapeutic dose) is eliminated unchanged in the urine. Quinidine generally has a plasma half-life of 6–8 h in healthy individuals, but the half-life may range from 3 to 16 h or longer in malaria patients and those with chronic liver disease. In addition, quinidine crosses the placenta and is distributed in milk (at slightly lower levels than those in maternal serum).
Mechanism of Action This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking fast active/opened sodium channels (inhibiting depolarization) and potassium channels (prolonging repolarization) across cellular membranes. It prolongs the cellular action potential (thereby prolonging the QT interval on the electrocardiograph (ECG)) and decreases automaticity (as well as myocardial excitability, conduction velocity, and contractility). Other ECG effects include a wide notched P wave, wide QRS complex, depressed ST segment, and U waves. Theses are all the results of both slowed depolarization and repolarization. In addition, quinidine processes antimuscarinic actions (i.e., anticholinergic effects, increased heart rate, and increased atrioventricular conduction) and a-adrenergic antagonist actions (i.e., decreased blood pressure/reflex and increased heart rate, cause of vasodilation and hypotension).
Encyclopedia of Toxicology, Volume 4
http://dx.doi.org/10.1016/B978-0-12-386454-3.00055-5
Quinidine
Acute and Short-Term Toxicity Animal Lethal dose 50% (LD50) values of 263 mg kg1 (oral) and 23 mg kg1 (intravenous) were reported in rats. AN LD50 of 173 mg kg1 (intraperitoneal) was reported in mice.
17
hemolytic anemia and drug-induced hepatitis. Allergic contact dermatitis has also been reported in pharmaceutical workers since quinidine is structurally related to quinine and chloroquine, which also can cause such allergic reaction.
Reproductive and Developmental Toxicity Human Acute overdose of quinidine can result in both cardiovascular and neurologic effects. The most serious quinidine toxicities are ventricular dysrhythmias and hypotension. When acutely overdosed, treatment is primarily supportive. Adverse cardiovascular effects may develop as a result of myocardial depression and depression of atrial/atrioventricular/ventricular conduction. Myocardial depression and vasodilation can lead to hypotension. A transient (proarrhythmic effect) torsade de pointes (i.e., bursts of atypical ventricular tachycardia) can lead to syncope (fainting). Ventricular tachycardia and ventricular fibrillation may also occur. ECG changes (i.e., a widening of the QT, PR, and QRS complexes; ST depression; and T inversion) are evident with these adverse cardiovascular effects. In addition, possible adverse central nervous system (CNS) effects can occur, including lethargy, seizures, and coma. Other adverse acute effects such as apnea can also occur. However, signs of quinidine toxicity are expected to occur in adults ingesting a gram or more. Therapeutic plasma levels of quinidine range from 1 to 4 mg ml1. Cardiac toxicity can occur with levels of at least 14–16 mg ml1.
Chronic Toxicity Animal Similar to what would be expected in humans, cardiovascular toxicity can be seen in animals treated with quinidine. It can also induce CNS symptoms (i.e., neurotoxicity and respiratory depression).
Human Gastrointestinal symptoms (i.e., upper gastrointestinal distress) are commonly associated with chronic toxicity of quinidine. Symptoms, such as nausea, vomiting, heartburn/esophagitis, and diarrhea, are generally seen at therapeutic levels (at oral doses of 200–400 mg 3–4 times a day for quinidine sulfate in adults). Another toxic syndrome, cinchonism, is associated with chronic toxicity of quinidine. Clinical manifestations include headache, fever, visual disturbances, mydriasis, decreased hearing or tinnitus, nausea, vomiting, hot flushed skin, rash, and CNS impairment (lethargy, memory impairment, delirium, hallucinations) and may present without cardiovascular toxicity, other than QT prolongation. Cinchonism can occur when quinidine plasma levels are at least 5 mg ml1. In addition, amblyopia, vision loss, can occur when levels are at least 10 mg ml1. As an oral medication, other side effects have been reported after ingestion of therapeutic doses including immune
Reproductive studies have not been conducted in animals. There are no adequate and well-controlled studies of adverse reproductive or developmental effects in humans. However, it has been shown that quinidine can be present in human milk at levels slightly lower than those in maternal serum. The pharmacokinetics and pharmacodynamics of quinidine in human infants have not been adequately studied.
Genotoxicity Very limited published literature show that quinidine is not mutagenic by Ames assays.
Ecotoxicology No studies were found in the published literature that examine health effects in aquatic or terrestrial organisms. Quinidine is soluble in water and light sensitive. It also degrades with excess heat. One quinidine material safety data sheet (MSDS) reports that possibly hazardous short-term degradation products are not likely but long-term degradation products may arise. The product itself and its products of degradation, however, are not toxic to the environment. With an octanol/water partition coefficient (Kow) of 3.44, quinidine would not be expected to bioconcentrate or bioaccumulate significantly in lipid tissues of animals exposed to this compound.
Exposure Standards and Guidelines The Comprehensive Environmental Responses, Compensation, and Liability Act (CERCLA) reportable quantities: The National Response Center (NRC) requires to be notified if there is a release of quinidine in an amount equal or greater than its reportable quantity of 5000 lb or 2270 kg. No other exposure limits are listed by other federal agencies (i.e., National Institute for Occupational Safety and Health (NIOSH) and Occupational Safety and Health Administration (OSHA)).
Clinical Management Basic and advanced life-support measures should be used as needed. Induction of emesis is not recommended due to the potential for a decreased level of consciousness, seizures, and arrhythmias. Gastric lavage followed by activated charcoal is recommended. Repeated doses of activated charcoal may enhance elimination. Serum electrolytes should be monitored in all serious
18
Quinidine
exposures. Intravenous administration of sodium bicarbonate may decrease toxicity. Hypotension can be treated with fluids and vasopressors if needed. Ventricular dysrhythmias can be treated with class IB antiarrhythmics such as phenytoin or lidocaine. Persistent bradycardia and third-degree heart block are indications for insertion of a temporary pacemaker. Seizures can be treated with diazepam. If seizures are uncontrolled, phenobarbital or phenytoin can be administered.
Dart, R.C. (Ed.), 2003. Medical Toxicology, third ed. Lippincott Williams & Wilkins, Philadelphia, PA. Hellgren, U., Ericsson, O., AdenAbdi, Y., Gustafsson, L.L. (Eds.), 1995. Handbook of Drugs for Tropical Parasitic Infections, second ed. Taylor & Francis, London. Hollman, A., 1991. Quinine and quinidine. Br. Heart J. 66 (4), 301. Klaassen, C. (Ed.), 2008. Cassarett and Doull’s Toxicology, The Basic Science of Poisons, seventh ed. McGraw-Hill, New York. Nelson, L., Lewin, N., Howland, M.A., Hoffman, R. (Eds.), 2010. Goldfrank’s Toxicologic Emergencies, ninth ed. McGraw-Hill, New York.
Relevant Websites See also: Cardiovascular System; Quinine.
Further Reading Brunton, L., Chabner, B., Knollman, B. (Eds.), 2010. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, twelfth ed. McGraw-Hill, New York. Cygankiewicz, I., 2007. Sir Thomas Lewis (1881–1945). Cardiol. J. 14 (6), 605–606.
http://www.inchem.org/ – International Programme on Chemical Safety: Quinidine. http://chem.sis.nlm.nih.gov/chemidplus/ – National Library of Medicine ChemIDplus: Quinidine. http://www.sciencelab.com/ – Sciencelab.com: MSDS sheet for quinidine gluconate. http://www.toxnet.nlm.nih.gov/ – TOXNET Toxicology Data Network: Quinidine.