Quinidine

Last updated
Quinidine
Quinidine structure.png
Clinical data
Trade names Quinaglute, Quinidex
Other names(2-Ethenyl-4-azabicyclo[2.2.2]oct-5-yl)-(6-methoxyquinolin-4-yl)-methanol
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth, intramuscular injection, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 70–85%
Metabolism 50–90% (by liver)
Elimination half-life 6–8 hours
Excretion By the liver (20% as unchanged quinidine via urine)
Identifiers
  • (S)-(6-Methoxyquinolin-4-yl)[(1S,2R,4S,5R)-5-vinylquinuclidin-2-yl]methanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.254 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H24N2O2
Molar mass 324.424 g·mol−1
3D model (JSmol)
  • O(c4cc1c(nccc1[C@H](O)[C@@H]2N3CC[C@@H](C2)[C@@H](/C=C)C3)cc4)C
  • InChI=1S/C20H24N2O2/c1-3-13-12-22-9-7-14(13)10-19(22)20(23)16-6-8-21-18-5-4-15(24-2)11-17(16)18/h3-6,8,11,13-14,19-20,23H,1,7,9-10,12H2,2H3/t13-,14-,19+,20-/m0/s1 Yes check.svgY
  • Key:LOUPRKONTZGTKE-LHHVKLHASA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Quinidine is a class IA antiarrhythmic agent used to treat heart rhythm disturbances. [1] It is a diastereomer of antimalarial agent quinine, [2] 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, its IV formulation is no longer being manufactured for use in the United States. [3]

Contents

Medical uses

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. [1] [4]

It reduces the recurrence of atrial fibrillation after patients undergo cardioversion, but it has proarrhythmic effects and trials suggest that it may lead to an overall increased mortality in these patients. [5]

Quinidine is also used to treat short QT syndrome. [6]

Eli Lilly has discontinued manufacture of parenteral quinidine gluconate in the US, and its future availability in many countries is uncertain. [7]

Other uses

There is one study supporting the use of a novel combination of dextromethorphan and low dose quinidine in alleviating symptoms of easy laughing and crying (pseudobulbar affect); these are a type of rather severe uncontrollable behaviors which can be present in various neurological pathologies such as amyotrophic lateral sclerosis and multiple sclerosis. The dose of quinidine (10 mg two times daily) is about 1/40th of a relatively low antiarrhythmic dose (400 mg, twice or 3 times daily, as an example; antiarrhythmic doses can sometimes exceed 1500 mg/day). The authors did not observe significant safety risks using the low quinidine dose, but urged caution and also pointed out that quinidine interacts with a large number of other medications in dangerous or unpredictable ways. A meta analysis was published referencing only that one study. [8] [9]

Although intravenous quinidine is sometimes used to treat Plasmodium falciparum malaria, the future availability of this agent is uncertain. [10]

Side effects

Quinidine is 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. [11]

Quinidine can cause thrombocytopenia, granulomatous hepatitis, myasthenia gravis, and torsades de pointes (dangerous heart rhythm), [12] and has been largely phased out in favor of other antiarrhythmics. 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.

Pharmacology

Pharmacodynamics

Quinidine acts as a blocker of voltage-gated sodium channels. [13] [14] Inhibition of the Nav1.5 channel is specifically involved in its antiarrhythmic effects as a class I antiarrhythmic agent. [15] Quinidine also blocks certain voltage-gated potassium channels (e.g., Kv1.4, Kv4.2, hERG, among others), [16] [17] acts as an antimuscarinic and alpha-1 blocker, [18] and is an antimalarial. [15] It is said to be a selective muscarinic acetylcholine M3 receptor antagonist. [19]

Mechanism of action

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).

It seems still efficacious as an IV antimalarial against Plasmodium falciparum. This electrolyte dependent agent also increases action potentials and prolongs the QT interval. 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

Elimination

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

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". [20]

"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." [21]

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, quinidine 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. [20]

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. [22]

Chemistry

Quinidine-based ligands are used in AD-mix-β for Sharpless asymmetric dihydroxylation.

Veterinary use

Quinidine sulfate is used in the treatment of atrial fibrillation in horses. [23] [24]

Related Research Articles

<span class="mw-page-title-main">Cardioversion</span> Conversion of a cardiac arrhythmia to a normal rhythm using an electrical shock or medications

Cardioversion is a medical procedure by which an abnormally fast heart rate (tachycardia) or other cardiac arrhythmia is converted to a normal rhythm using electricity or drugs.

<span class="mw-page-title-main">Antiarrhythmic agent</span> Heart rhythm medication

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

<span class="mw-page-title-main">Dofetilide</span> Antiarrhythmic medication

Dofetilide is a class III antiarrhythmic agent. It is marketed under the trade name Tikosyn by Pfizer, and is available in the United States in capsules containing 125, 250, and 500 μg of dofetilide. It is not available in Europe or Australia.

<span class="mw-page-title-main">Amiodarone</span> Antiarrhythmic medication used for various types of irregular heartbeats

Amiodarone is an antiarrhythmic medication used to treat and prevent a number of types of cardiac dysrhythmias. This includes ventricular tachycardia, ventricular fibrillation, and wide complex tachycardia, atrial fibrillation, and paroxysmal supraventricular tachycardia. Evidence in cardiac arrest, however, is poor. It can be given by mouth, intravenously, or intraosseously. When used by mouth, it can take a few weeks for effects to begin.

<span class="mw-page-title-main">Sotalol</span> Medication

Sotalol, sold under the brand name Betapace among others, is a medication used to treat and prevent abnormal heart rhythms. Evidence does not support a decreased risk of death with long term use. It is taken by mouth or given by injection into a vein.

<span class="mw-page-title-main">Procainamide</span> Medication to treat cardiac arrhythmias

Procainamide (PCA) is a medication of the antiarrhythmic class used for the treatment of cardiac arrhythmias. It is a sodium channel blocker of cardiomyocytes; thus it is classified by the Vaughan Williams classification system as class Ia. In addition to blocking the INa current, it inhibits the IKr rectifier K+ current. Procainamide is also known to induce a voltage-dependent open channel block on the batrachotoxin (BTX)-activated sodium channels in cardiomyocytes.

<span class="mw-page-title-main">Azimilide</span> Chemical compound

Azimilide is a class ΙΙΙ antiarrhythmic drug. The agents from this heterogeneous group have an effect on the repolarization, they prolong the duration of the action potential and the refractory period. Also they slow down the spontaneous discharge frequency of automatic pacemakers by depressing the slope of diastolic depolarization. They shift the threshold towards zero or hyperpolarize the membrane potential. Although each agent has its own properties and will have thus a different function.

<span class="mw-page-title-main">Disopyramide</span> Chemical compound

Disopyramide is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and is classified as a Class 1a anti-arrhythmic agent. Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility. Disopyramide also has general anticholinergic effects which contribute to unwanted adverse effects. Disopyramide is available in both oral and intravenous forms. In 1972, when it was one of the only alternatives to quinidine, it was praised for being more potent and somewhat less toxic. However, a 2012 review of antiarrhythmic drugs noted that disopyramide is among the most toxic agents, with a high burden of side effects and increased mortality when used to treat atrial fibrillation.

<span class="mw-page-title-main">Ibutilide</span> Chemical compound

Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.

<span class="mw-page-title-main">Prajmaline</span> Chemical compound

Prajmaline (Neo-gilurythmal) is a class Ia antiarrhythmic agent which has been available since the 1970s. Class Ia drugs increase the time one action potential lasts in the heart. Prajmaline is a semi-synthetic propyl derivative of ajmaline, with a higher bioavailability than its predecessor. It acts to stop arrhythmias of the heart through a frequency-dependent block of cardiac sodium channels.

<span class="mw-page-title-main">Lorcainide</span> Antiarrythmic agent

Lorcainide is a Class 1c antiarrhythmic agent that is used to help restore normal heart rhythm and conduction in patients with premature ventricular contractions, ventricular tachycardiac and Wolff–Parkinson–White syndrome. Lorcainide was developed by Janssen Pharmaceutica (Belgium) in 1968 under the commercial name Remivox and is designated by code numbers R-15889 or Ro 13-1042/001. It has a half-life of 8.9 +- 2.3 hrs which may be prolonged to 66 hrs in people with cardiac disease.

<span class="mw-page-title-main">Tedisamil</span> Chemical compound

Tedisamil (3,7-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo-3,3,1-nonane) is an experimental class III antiarrhythmic agent currently being investigated for the treatment of atrial fibrillation. Tedisamil blocks multiple types of potassium channels in the heart resulting in slowed heart rate. While the effects of tedisamil have been demonstrated in both atrial and ventricular muscle, repolarization is prolonged more efficiently in the atria. Tedisamil is administered intravenously and has a half-life of approximately 8 –13 hours in circulation. Tedisamil is being developed as an alternative to other antiarrhythmics as incidence of additional arrhythmic events is lower compared to other class III agents. Tedisamil also has significant anti-ischemic properties and was initially investigated as a potential treatment for angina until its antiarrhythmic effects were discovered. Tedisamil is manufactured by Solvay Pharmaceuticals Inc. under the proposed trade name Pulzium.

<span class="mw-page-title-main">Vernakalant</span> Medication for the treatment of atrial fibrillation

Vernakalant, sold under the brand name Brinavess, is a class III antiarrhythmic drug for the acute conversion of atrial fibrillation, a kind of irregular heartbeat, in form of an intravenous infusion. It has been approved for use in the European Union and the United Kingdom since 2010. The US Food and Drug Administration denied approval in 2008 and 2019.

<span class="mw-page-title-main">Pilsicainide</span> Chemical compound

Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991. The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

Sodium channel blockers are drugs which impair the conduction of sodium ions (Na+) through sodium channels.

<span class="mw-page-title-main">Potassium channel blocker</span> Several medications that disrupt movement of K+ ions

Potassium channel blockers are agents which interfere with conduction through potassium channels.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Budiodarone</span> Chemical compound

Budiodarone (ATI-2042) is an antiarrhythmic agent and chemical analog of amiodarone that is currently being studied in clinical trials. Amiodarone is considered the most effective antiarrhythmic drug available, but its adverse side effects, including hepatic, pulmonary and thyroid toxicity as well as multiple drug interactions, are discouraging its use. Budiodarone only differs in structure from amiodarone through the presence of a sec-butyl acetate side chain at position 2 of the benzofuran moiety. This side chain allows for budiodarone to have a shorter half-life in the body than amiodarone which allows it to have a faster onset of action and metabolism while still maintaining similar electrophysiological activity. The faster metabolism of budiodarone allows for fewer adverse side effects than amiodarone principally due to decreased levels of toxicity in the body.

<span class="mw-page-title-main">AZD1305</span> Chemical compound

AZD1305 is an experimental drug candidate that is under investigation for the management and reversal of cardiac arrhythmias, specifically atrial fibrillation and flutter. In vitro studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa).

QT prolongation is a measure of delayed ventricular repolarisation, which means the heart muscle takes longer than normal to recharge between beats. It is an electrical disturbance which can be seen on an electrocardiogram (ECG). Excessive QT prolongation can trigger tachycardias such as torsades de pointes (TdP). QT prolongation is an established side effect of antiarrhythmics, but can also be caused by a wide range of non-cardiac medicines, including antibiotics, antidepressants, antihistamines, opioids, and complementary medicines. On an ECG, the QT interval represents the summation of action potentials in cardiac muscle cells, which can be caused by an increase in inward current through sodium or calcium channels, or a decrease in outward current through potassium channels. By binding to and inhibiting the “rapid” delayed rectifier potassium current protein, certain drugs are able to decrease the outward flow of potassium ions and extend the length of phase 3 myocardial repolarization, resulting in QT prolongation.

References

  1. 1 2 Grace AA, Camm AJ (January 1998). "Quinidine". The New England Journal of Medicine. 338 (1): 35–45. doi:10.1056/NEJM199801013380107. PMID   9414330.
  2. ↑ Shiomi S, Misaka R, Kaneko M, Ishikawa H (November 2019). "Enantioselective total synthesis of the unnatural enantiomer of quinine". Chemical Science. 10 (41): 9433–9437. doi:10.1039/c9sc03879e. PMC   7020653 . PMID   32110303.
  3. ↑ "Artesunate Now First-Line Treatment for Severe Malaria in the United States". CDC Online Newsroom. U.S. Centers for Disease Control and Prevention. 28 March 2019. Retrieved 6 April 2019.
  4. ↑ Bozic B, Uzelac TV, Kezic A, Bajcetic M (2018). "The Role of Quinidine in the Pharmacological Therapy of Ventricular Arrhythmias 'Quinidine'". Mini Reviews in Medicinal Chemistry. 18 (6): 468–475. doi:10.2174/1389557517666170707110450. PMID   28685701.
  5. ↑ Valembois L, Audureau E, Takeda A, Jarzebowski W, Belmin J, Lafuente-Lafuente C (September 2019). "Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation". The Cochrane Database of Systematic Reviews. 2019 (9): CD005049. doi:10.1002/14651858.CD005049.pub5. PMC   6738133 . PMID   31483500.
  6. ↑ Kaufman ES (June 2007). "Quinidine in short QT syndrome: an old drug for a new disease". Journal of Cardiovascular Electrophysiology. 18 (6): 665–666. doi:10.1111/j.1540-8167.2007.00815.x. PMID   17521305. S2CID   42247356.
  7. ↑ "Quinidine Gluconate Injection". FDA: Drug Shortages. U.S. Food and Drug Administration. 1 December 2017. Archived from the original on 22 March 2019.
  8. ↑ 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". British Journal of Clinical Pharmacology. 84 (7): 1445–1456. doi:10.1111/bcp.13604. PMC   6005613 . PMID   29637593.
  9. ↑ Brooks BR, Thisted RA, Appel SH, Bradley WG, Olney RK, Berg JE, et al. (October 2004). "Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial". Neurology. 63 (8): 1364–1370. doi:10.1212/01.wnl.0000142042.50528.2f. PMID   15505150. S2CID   25732335.
  10. ↑ "Quinidine Availability in the United States". U.S. Centers for Disease Control and Prevention. 2019-01-28.
  11. ↑ Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (September 2000). "Increased drug delivery to the brain by P-glycoprotein inhibition". Clinical Pharmacology and Therapeutics. 68 (3): 231–237. doi:10.1067/mcp.2000.109156. PMID   11014404. S2CID   38467170.
  12. ↑ Dubin DB (2000). Rapid interpretation of EKG's: an interactive course (6th ed.). Tampa, Fla: Cover Publishing Company. ISBN   978-0-912912-06-6.
  13. ↑ de Lera Ruiz M, Kraus RL (September 2015). "Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications". Journal of Medicinal Chemistry. 58 (18): 7093–7118. doi: 10.1021/jm501981g . PMID   25927480.
  14. ↑ Roden DM (1 September 2015). "Pharmacology and Toxicology of NaV1.5 Class 1 Antiarrhythmic Drugs". In Abriel H (ed.). Cardiac Sodium Channel Disorders, An Issue of Cardiac Electrophysiology Clinics, E-Book. Elsevier Health Sciences. pp. 695–. ISBN   978-0-323-32641-4.
  15. 1 2 Abbott GW, Levi R (2013). "Antiarrhythmic Drugs". In Hemmings HC, Egan TD (eds.). 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.
  16. ↑ Pearlstein RA, MacCannell KA, Hu QY, Farid R, Duca JS (23 February 2015). "The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof". In Urban L, Patel V, Vaz RJ (eds.). Antitargets and Drug Safety. Wiley. pp. 303–. ISBN   978-3-527-67367-4.
  17. ↑ Archer SL, Rusch NJ (6 December 2012). Potassium Channels in Cardiovascular Biology. Springer Science & Business Media. pp. 343–. ISBN   978-1-4615-1303-2.
  18. ↑ Shibata K, Hirasawa A, Foglar R, Ogawa S, Tsujimoto G (April 1998). "Effects of quinidine and verapamil on human cardiovascular alpha1-adrenoceptors". Circulation. 97 (13): 1227–1230. doi: 10.1161/01.cir.97.13.1227 . PMID   9570190.
  19. ↑ Lavrador M, Cabral AC, Veríssimo MT, Fernandez-Llimos F, Figueiredo IV, Castel-Branco MM (January 2023). "A Universal Pharmacological-Based List of Drugs with Anticholinergic Activity". Pharmaceutics. 15 (1): 230. doi: 10.3390/pharmaceutics15010230 . PMC   9863833 . PMID   36678858.
  20. 1 2 Hollman A (October 1991). "Quinine and quinidine". British Heart Journal. 66 (4): 301. doi:10.1136/hrt.66.4.301. PMC   1024726 . PMID   1747282.
  21. ↑ Bowman IA (March 1987). "Jean-Baptiste Sénac and his treatise on the heart". Texas Heart Institute Journal. 14 (1): 5–11. PMC   324686 . PMID   15227324.
  22. ↑ Sneader W (Jun 20, 2005). Drug Discovery: A History. John Wiley and Sons. p. 95. ISBN   978-0-471-89980-8.
  23. ↑ Kurakane E, Amada A (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.
  24. ↑ Hiraga A, Sugano S (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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.