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 N
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.

The effects of quinidine on atrial fibrillation are said to have been discovered by a Danish Merchant seaman with AF who took quinine for malaria prophylaxis during trips to India.  He noted his pulse was regular while in India but irregular at home.^{[citation needed]}

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.^[1]

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.^[2] 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.

References

1. ^ 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. 
2. ^ "From the Centers for Disease Control and Prevention. Availability and use of parenteral quinidine gluconate for severe or complicated malaria". JAMA 285 (6): 730. February 2001. doi:10.1001/jama.285.6.730. PMID 11236771. http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=11236771. 

External links

• MedlinePlus
• Poisons Information Monograph

See also

• Antiarrhythmic agents
• Cardiac action potential