CRYSTALS WITH 2.5 MOL WATER OF CRYSTALLIZATION; CRYSTALS FROM DILUTE ALCOHOL
稳定性/保质期：
Quinidine gluconate, quinidine polygalacturonate, and quinidine sulfate darken on exposure to light and should be stored in well-closed, light resistant containers. Solutions of quinidine salts slowly acquire a brownish tint on exposure to light. Only colorless, clear solutions of quinidine gluconate injection should be used. Quinidine gluconate injection should be stored at 15-30 °C. When diluted to a concentration of 16 mg/ml with 5% dextrose injection, quinidine gluconate injection is stable for 24 hours at room temperature and up to 48 hours when refrigerated. /Quinidine salts/
旋光度：
Specific optical rotation @ 15 °C/D + 230 deg (concn by volume = 1.8 in chloroform); specific optical rotation @ 17 °C/D + 258 deg (alcohol); +322 deg (concn by volume = 1.6 in 2 M HCl); UV absorption spectrum is identical with that of quinine; blue fluorescence in dilute H2SO4.
分解：
When heated to decomposition it emits toxic fumes of oxides of nitrogen.
解离常数：
pK1 @ 20 °C = 5.4; pK2 = 10.0
计算性质
辛醇/水分配系数(LogP)：
2.9
重原子数：
24
可旋转键数：
4
环数：
5.0
sp3杂化的碳原子比例：
0.45
拓扑面积：
45.6
氢给体数：
1
氢受体数：
4
ADMET
代谢
过量自杀患者中检测到了奎尼丁及其3-羟基代谢物的乳酸盐共轭物。
Lactate conjugates of quinidine and its 3-hydroxy metabolite were detected in overdose suicide patient.
Quinidine is metabolized in the liver, principally via hydroxylation to 3-hydroxyquinidine and 2-quinidinone. Some metabolites have antiarrhythmic activity. Approximately 10-50% of a dose is excreted in urine (probably by glomerular filtration) as unchanged drug within 24 hr.
Quinidine metabolites include 3-hydroxyquinidine N-oxide, 2'-oxoquinidinone, desmethylquinidine, and quinidine N-oxide. While metabolism is highly variable between individuals, at least in cases of quinidine-induced torsade de pointes, the metabolites do not appear to contribute to the formation of dysrhythmias.
Quinidine undergoes extensive hepatic oxidative metabolism... One metabolite, 3-hydroxyquinidine, is nearly as potent as quinidine in blocking cardiac sodium channels or prolonging action potentials.
来源:Hazardous Substances Data Bank (HSDB)
代谢
大多数前体药物通过细胞色素P450 IIIA的作用在肝脏中被消除。
Most quindiidne is eliminated hepatically via the action of cytochrome P450 IIIA.
Chronic therapy with quinidine is associated with a low rate of serum enzyme elevations, which are usually mild, asymptomatic and self limited even without alteration in dose. In addition, there have been many reports of acute hypersensitivity reactions to quinidine that include hepatic involvement. The reactions usually arise after 1 to 2 weeks of therapy, but can appear within 24 hours of restarting quinidine or with rechallenge. The clinical features are marked by fatigue, nausea, vomiting, diffuse muscle aches, arthralgias and high fever. Blood testing at an early stage shows increases in serum aminotransferase and alkaline phosphatase levels as well as mild jaundice, which can deepen for a few days even after stopping quinidine. The pattern of serum enzymes elevations is typically cholestatic or mixed. Rash is uncommon and eosinophilia is not typical, despite the presence of other signs of hypersensitivity (fever, arthralgias). Autoantibodies are not typically found. Liver biopsies usually show mild injury and small epithelioid granulomas, as are often found in many organs during systemic hypersensitivity reactions. A similar clinical signature of liver injury occurs with quinine, an optical isomer of quinidine that is used predominantly as an antimalarial agent. In recent years, there have been few reports of liver injury attributed to quinidine, probably because it is now rarely used.
The combination of propranolol and quinidine resulted in increased beta-blockade measured by reduction in exercise heart rate and prolongation of the QTc and PR intervals ... quinidine stereoselectively inhibits the metabolism of propranolol through inhibition of the debrisoquin isozyme. The increased concentration of propranolol produced by quinidine results in increased beta-blockade.
Ethacrynic acid and furosemide /diuretics/ increase lipid solubility and tubular reabsorption of quinidine and thus prolong its therapeutic effects/ ...but will not alkalinize urine... .
Quinidine may potentiate the effects of both nondepolarizing and depolarizing skeletal muscle relaxants such as pancuronium bromide, succinylcholine chloride, and tubocurarine chloride. Neostigmine methylsulfate does not appear to reverse these effects.
Quinidine should be used with caution, if at all, in patients with myasthenia gravis and the dose of anticholinesterase drugs such as neostigmine and pyridostigmine may have to be increased. Since quinidine antagonizes the effect of vagal excitation on the atria and AV node, the administration of cholinergic drugs or any other procedures to enhance vagal activity may fail to terminate paroxysmal supraventricular tachycardia in patients receiving quinidine. The anticholinergic effects of quinidine may be additive with those of anticholinergic drugs.
The volume of distribution of quinidine is 2 to 3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3 or 5 L/kg in patients with cirrhosis of the liver. At concentrations of 2 to 5 mg/L (6.5 to 16.2 umol/L), the fraction of quinidine bound to plasma proteins (mainly to (alpha)1-acid glycoprotein and to albumin) is 80 to 88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50 to 70%. Because (alpha)1-glycoprotein levels are increased in response to stress, serum levels of total quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis.
...Essentially completely absorbed after oral admin; max effects occur within 1-3 hr, and persist for 6-8 more hr. Large fluctuations in plasma concentration... if repeated doses are given at this interval. ...IM admin... gluconate yields peak effects in 30-90 min.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
所有给药的化合物都通过肾脏排泄，大约10-50%在24小时内以未改变的奎尼丁形式出现在尿液中。
...All administered compound is excreted by kidney, and about 10-50% appears in urine as unchanged quinidine, within 24 hr.
The bioavailability of quinidine is 70 to 80% after oral use but varies between individuals and preparations. The sulfate salt is rapidly absorbed in 60 to 90 minutes. Polygalacturonate salts produce peak quinidine concentrations in 5 to 6 hours; gastrointestinal absorption of gluconate salts is intermediate (peak 3-4 hours).
申请人：The Board of Trustees of the University of Illinois
公开号：US20150274638A1
公开（公告）日：2015-10-01
The invention provides a novel, general, and facile strategy for the creation of small molecules with high structural and stereochemical complexity. Aspects of the methods include ring system distortion reactions that are systematically applied to rapidly convert readily available natural products to structurally complex compounds with diverse molecular architectures. Through evaluation of chemical properties including fraction of sp
3
carbons, ClogP, and the number of stereogenic centers, these compounds are shown to be significantly more complex and diverse than those in standard screening collections. This approach is demonstrated with natural products (gibberellic acid, adrenosterone, and quinine) from three different structural classes, and methods are described for the application of this strategy to any suitable natural product.
