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Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent (Ia) in the heart.[1] It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree. The drug causes increased action potential duration, as well as a prolonged QT interval.
As of 2019 it is no longer avaliable in the United States.[2]
Quinidine is occasionally used as a class I antiarrhythmic agent to prevent ventricular arrhythmias, particularly in Brugada Syndrome, although its safety in this indication is uncertain.[3][1]
Quinidine increases the likelihood of maintaining sinus rhythm after conversion from atrial fibrillation, but has pro‐arrhythmic effects and may increase mortality.[4]
It is also used to treat short QT syndrome.[5]
Eli Lilly has discontinued manufacture of parenteral quinidine gluconate in the US, and its future availability in many countries is uncertain.[6]
Other uses[edit]
According to a recent meta-analysis, there is only one small study that has shown that a combination of dextromethorphan and quinidine alleviates symptoms of easy laughing and crying (pseudobulbar affect) in patients with amyotrophic lateral sclerosis and multiple sclerosis.[7][8]
Although intravenous quinidine is sometimes used to treat Plasmodium falciparum malaria, its US manufacturer, Eli Lilly, no longer manufactures quinidine and the future availability of this agent in the US and other countries is uncertain.[9]
Side effects[edit]
Quinidine is also an inhibitor of the cytochrome P450 enzyme 2D6, and can lead to increased blood levels of lidocaine, beta blockers, opioids, and some antidepressants. Quinidine also inhibits the transport protein P-glycoprotein and so can cause some peripherally acting drugs such as loperamide to have central nervous system side effects, such as respiratory depression, if the two drugs are coadministered.[10]
Quinidine can cause thrombocytopenia, granulomatous hepatitis, myasthenia gravis, and torsades de pointes, so is not used much today. Torsades can occur after the first dose. Quinidine-induced thrombocytopenia (low platelet count) is mediated by the immune system, and may lead to thrombocytic purpura.
Quinidine intoxication can lead to a collection of symptoms collectively known as cinchonism, with tinnitus (ringing in the ears) being among the most characteristic and common symptoms of this toxicity syndrome. Quinidine toxicity can also invoke episodes of Torsades de Pointes - a rapid and dangerous ventricular rhythm.[11]
Pharmacology[edit]
Pharmacodynamics[edit]
Quinidine acts as a blocker of voltage-gated sodium channels.[12][13] Inhibition of the Nav1.5 channel is specifically involved in its antiarrhythmic effects as a class I antiarrhythmic agent.[14] Quinidine also blocks certain voltage-gated potassium channels (e.g., Kv1.4, Kv4.2, hERG, among others),[15][16] acts as an antimuscarinic and alpha-1 blocker,[17] and is an antimalarial.[14]
Mechanism of action[edit]
Like all other class I antiarrhythmic agents, quinidine primarily works by blocking the fast inward sodium current (INa). Quinidine's effect on INa is known as a 'use dependent block'. This means at higher heart rates, the block increases, while at lower heart rates, the block decreases. The effect of blocking the fast inward sodium current causes the phase 0 depolarization of the cardiac action potential to decrease (decreased Vmax). Understood as a stereoisomer of Quinine, derived from Cinchona bark; Quinidine makes sense. It seems still efficacious as an IV antimalarial against Plasmodium Falciparum. This electrolyte dependent agent also increases action potentials and prolongs the QT interval. US Agent Eli Lilly has abandoned all patents bound to quinidine. Quinidine also blocks the slowly inactivating, tetrodotoxin-sensitive Na current, the slow inward calcium current (ICa), the rapid (IKr) and slow (IKs) components of the delayed potassium rectifier current, the inward potassium rectifier current (IKI), the ATP-sensitive potassium channel (IKATP) and Ito.
At micromolar concentrations, quinidine inhibits Na+/K+-ATPase by binding to the same receptor sites as the digitalis glycosides such as ouabain.
The effect of quinidine on the ion channels is to prolong the cardiac action potential, thereby prolonging the QT interval on the surface ECG.
Other ECG effects include a wide notched P wave, wide QRS complex, depressed ST segment, and U waves. These are the results of both slowed depolarization and repolarization.
Pharmacokinetics[edit]
Elimination[edit]
The elimination half-life of oral quinidine is 6 to 8 hours, and it is eliminated by the cytochrome P450 system in the liver. About 20% is excreted unchanged via the kidneys.
History[edit]
The effects of cinchona bark (the botanical source from which quinidine is extracted) had been commented on long before the understanding of cardiac physiology arose. Jean-Baptiste de Sénac, in his 1749 work on the anatomy, function, and diseases of the heart, had this to say,
"Long and rebellious palpitations have ceded to this febrifuge".[18]
"Of all the stomachic remedies, the one whose effects have appeared to me the most constant and the most prompt in many cases is quinquina [Peruvian bark] mixed with a little rhubarb."[19]
Sénac subsequently became physician to Louis XV of France, a counselor of the state, and superintendent of the mineral waters and medicinals in France. As a result of his influence, throughout the 19th century, quinine was used to augment digitalis therapy. It was described as das Opium des Herzens (the opium of the heart).
However, the use of quinidine to treat arrhythmia really only came into its own because a physician listened to the astute observation of one of his patients. In 1912, Karel Frederik Wenckebach saw a man with atrial fibrillation. He was a Dutch merchant, used to good order in his affairs. He would like to have good order in his heart business, also, and asked, "why there were heart specialists if they could not abolish this very disagreeable phenomenon ... he knew himself how to get rid of his attacks. As I did not believe him, he promised to come back next morning with a regular pulse, and he did."
The man had found by chance that when he took one gram of quinine during an attack, it reliably halted it in 25 minutes; otherwise it would last for two to 14 days. Wenckebach often tried quinine again, but he succeeded in only one other patient.[18]
He made passing mention of it in his book on cardiac arrhythmias published in 1914. Four years later, Walter von Frey of Berlin reported in a leading Viennese medical journal that quinidine was the most effective of the four principal cinchona alkaloids in controlling atrial arrhythmias.[20]
Chemistry[edit]
Quinidine-based ligands are used in AD-mix-β for sharpless asymmetric dihydroxylation.
Veterinary use[edit]
Quinidine sulfate is used in the treatment of atrial fibrillation in horses.[21][22]
^"CDC: Artesunate Now First-Line Treatment for Severe Malaria in the United States | CDC Online Newsroom | CDC". www.cdc.gov. 28 March 2019. Retrieved 6 April 2019.
^Bozic B, Uzelac TV, Kezic A, Bajcetic M (2018). "The Role of Quinidine in the Pharmacological Therapy of Ventricular Arrhythmias 'Quinidine'". Mini Rev Med Chem. 18 (6): 468–475. doi:10.2174/1389557517666170707110450. PMID 28685701.
^Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J (March 2015). "Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation". Cochrane Database Syst Rev (3): CD005049. doi:10.1002/14651858.CD005049.pub4. PMID 25820938.
^Kaufman ES (2007). "Quinidine in short QT syndrome: an old drug for a new disease". J. Cardiovasc. Electrophysiol. 18 (6): 665–6. doi:10.1111/j.1540-8167.2007.00815.x. PMID 17521305.
^Kongpakwattana K, Sawangjit R, Tawankanjanachot I, Bell JS, Hilmer SN, Chaiyakunapruk N (July 2018). "Pharmacological treatments for alleviating agitation in dementia: a systematic review and network meta-analysis". Br J Clin Pharmacol. 84 (7): 1445–1456. doi:10.1111/bcp.13604. PMC 6005613. PMID 29637593.
^Brooks, BR; Thisted, RA; Appel, SH; Bradley, WG; Olney, RK; Berg, JE; Pope, LE; Smith, RA; AVP-923 ALS Study Group (2004). "Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial". Neurology. 63 (8): 1364–70. doi:10.1212/01.wnl.0000142042.50528.2f. PMID 15505150.
^Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (2000). "Increased drug delivery to the brain by P-glycoprotein inhibition". Clin. Pharmacol. Ther. 68 (3): 231–7. doi:10.1067/mcp.2000.109156. PMID 11014404.
^Rapid Interpretation of EKG's 6th Ed., Dubin
^de Lera Ruiz M, Kraus RL (2015). "Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications". J. Med. Chem. 58 (18): 7093–118. doi:10.1021/jm501981g. PMID 25927480.
^Hugues Abriel (1 September 2015). Cardiac Sodium Channel Disorders, An Issue of Cardiac Electrophysiology Clinics, E-Book. Elsevier Health Sciences. pp. 695–. ISBN 978-0-323-32641-4.
^ abHugh C. Hemmings; Talmage D. Egan (2013). Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult - Online and Print. Elsevier Health Sciences. pp. 451–. ISBN 978-1-4377-1679-5.
^Laszlo Urban; Vinod Patel; Roy J. Vaz (23 February 2015). Antitargets and Drug Safety. Wiley. pp. 303–. ISBN 978-3-527-67367-4.
^Stephen L. Archer; Nancy J. Rusch (6 December 2012). Potassium Channels in Cardiovascular Biology. Springer Science & Business Media. pp. 343–. ISBN 978-1-4615-1303-2.
^Shibata K, Hirasawa A, Foglar R, Ogawa S, Tsujimoto G (1998). "Effects of quinidine and verapamil on human cardiovascular alpha1-adrenoceptors". Circulation. 97 (13): 1227–30. doi:10.1161/01.cir.97.13.1227. PMID 9570190.
^ abHollman, A (1991). "Plants in Cardiology: Quinine and Quinidine". British Heart Journal. 66 (4): 301. doi:10.1136/hrt.66.4.301. PMC 1024726. PMID 1747282.
^Bowman, IA (1987). "Jean-Baptiste Senac and His Treatise on the Heart". Texas Heart Institute Journal / From the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. 14 (1): 5–11. PMC 324686. PMID 15227324.
^Sneader, Walter (Jun 20, 2005). Drug Discovery: A History. John Wiley and Sons. p. 95. ISBN 978-0-471-89980-8.
^Kurakane, Eiji; Amada, Akio (1982). "Pharmacokinetic Studies on Quinidine Sulfate Orally Administered in Horses". Bulletin of Equine Research Institute. 1982 (19): 59–68. doi:10.11535/jes1977.1982.59.
^Hiraga, Atsushi; Sugano, Shigeru (2015). "History of research in Japan on electrocardiography in the racehorse". Journal of Equine Science. 26 (1): 1–13. doi:10.1294/jes.26.1. PMC 4379327. PMID 25829865.
[dummy-text] Crossroads (UK TV series) From Wikipedia, the free encyclopedia Jump to navigation Jump to search For other uses, see Crossroads (disambiguation). "Crossroads Motel" redirects here. For the album by the Sonny Moorman Group, see Crossroads Motel (album). Crossroads 2003 title sequence Created by Hazel Adair Peter Ling Written by Michala Crees Ivor Jay Rosalie Grayson Raymond Bowers David Garfield Edward F. Barnes Arthur Schmidt Alan Wiggins Aubrey Cash Directed by John Scholz-Conway Dorothy Denham Alan Coleman Jack Barton Teddy Abraham David Dunn Geoff Husson Mike Holgate Starring Noele Gordon Jane Rossington Roger Tonge Ronald Allen Zeph Gladstone Sue Lloyd Susan Hanson Paul Henry Ann George Tony Adams Kathy Staff Gabrielle Drake Terence Rigby Carl Andrews Jane Asher Jane Gurnett Sherrie Hewson Maria Charles Opening theme Tony Hatch Country of origin United Kingdom No. of episodes Original Series: 4510
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