Quinidine

Quinidine

Systematic (IUPAC) name
(9S)-6'-methoxycinchonan- 9-ol
Clinical data
AHFS/Drugs.com	monograph
Pregnancy cat.	?
Legal status	?
Routes	Oral
Pharmacokinetic data
Bioavailability	70-80%
Metabolism	50-90% Hepatic
Half-life	6-8h
Excretion	Renal
Identifiers
CAS number	56-54-2 Y
ATC code	C01BA01
PubChem	CID 441074
DrugBank	APRD00136
ChemSpider	389880 Y
UNII	ITX08688JL Y
ChEBI	CHEBI:28593 Y
ChEMBL	CHEMBL97 N
Synonyms	(2-ethenyl- 4-azabicyclo [2.2.2] oct- 5-yl)- (6-methoxyquinolin- 4-yl)- methanol,
Chemical data
Formula	C20H24N2O2
Mol. mass	324.417 g/mol
SMILES	eMolecules & PubChem
InChI 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 Y Key:LOUPRKONTZGTKE-LHHVKLHASA-N Y
N(what is this?)  (verify)

Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent (Ia) in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.

Mechanism

Like all other class I antiarrhythmic agents, quinidine primarily works by blocking the fast inward sodium current (I_Na). Quinidine's effect on I_Na is known as a use dependent block. This means that 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 V_max).

Quinidine also blocks the slowly inactivating tetrodotoxin-sensitive Na current, the slow inward calcium current (I_Ca), the rapid (I_Kr) and slow (I_Ks) components of the delayed potassium rectifier current, the inward potassium rectifier current (I_KI), the ATP-sensitive potassium channel (I_KATP) and I_to.

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.

History

The effects of cinchona bark (the botanical source from which quinidine is extracted) had been commented on long before our 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".

"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."

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 nineteenth century quinine was used to augment digitalis therapy. It was described as "das opium des herzens" (the opium of the heart).

But the use of quinidine to treat arrhythmias really only came into its own because a physician listen 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 2-14 days. Wenckebach often tried quinine again but he succeeded in only one other patient.

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 principle cinchona alkaloids in controlling atrial arrhythmias.

Elimination

The 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.

Side effects

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 anti-depressants. Quinidine also inhibits the transport protein P-glycoprotein and so can cause some peripherally acting drugs such as loperamide to have CNS side effects such as respiratory depression if the two drugs are co-administered.

Quinidine can cause thrombocytopenia, granulomatous hepatitis, myasthenia gravis, and torsades de pointes and for that reason 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.

Other uses

Intravenous quinidine is also indicated for treatment of Plasmodium falciparum malaria. However, quinidine is not considered the first line therapy for P. falciparum. The recommended treatments for plasmodium falciparum according to the Toronto Notes 2008 are quinine (not to be confused with "quinidine") + doxycycline combination or atovaquone/proguanil (Malarone TM).

Quinidine sulfate is used in the treatment of atrial fibrillation in horses.

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

External links

• MedlinePlus
• Poisons Information Monograph

See also

• Antiarrhythmic agents
• Cardiac action potential