第四章循环系统药物CirculatorySystemA

1、Chapter 7i 一Antihyperlipoproteinemics降血脂药lipoprotein* Cholesterol and Cholesterol ester 胆固醇* triglycerides,甘油三脂#Phospholipids,磷脂Cholesterol: cell membranes, androgens, estrogens and progesteronelipoprotein* CM（乳麋微粒）：Chylomicrons *VLDL（极低密度脂蛋白）：very low-density lipoprotein* LDL（低密度脂蛋白）:low-density li

2、poprotein*HDL（高密度脂蛋白）:high-density lipoproteinhyperlipidemiaHypercholesterolemia (LDL)240mg/dl5*Hypertriglyceridemia( VLDL)140mg/dlStrongly associated with atherosclerotic (动脉粥梓硬化)lesions and coronary(冠状 动脉)heart disease, 50%*CHD related cigarette smoking, physical inactivity and obesity.Classified

3、by structure* The treatment of Hypercholesterolemia* 1, Bile acid sequestrants （胆汁酸结合树脂）* 2, HMG CoA reductase inhibitors （ HMG CoA还原酶抑制剂）ManufacturerAntihyp erlipidemic drugs in the top 200Rank in2001Generic nameTrade name2AstorvastatinLipitor21SimvastatinZocor47PravastatinPravacol68Fluvastatin sod

4、iumLescol115GemfibrozilLopid157CerivastatinBay col176fenofibrateTricorPfizerMerckBMSBile acid sequestrantsQuaternaryAmmonium1973W落一 _H-C塚CHC%-仝舞一 CH2_HC CH2N(CH3)3P考来烯胺Secondary Tertiary Amines 1977第cholestryramineCholestyramineNHRN i RNHCH2 HC-OHch2. HN. /Colestipol:R = H or epichlorhydrinRR 了；j/.

5、RHNch2HC-OHch2N.八ch2HC-OHch2 1,000,000* Cholestyramine （考来烯胺），1624grams/D , a powder（ a slurry）* Colestipol （考来替泊）,530 grams/D, granules（#i齐U） and tablet* Tablet should not to be chewed, crushed, cutMetabolism*Not orally absorbed and metabolized by gastrointestinal enzymes: onset of action 1 2 days,

6、 1 month* Excreted in the feces as an insoluble complex with bile acidsIndications and adverse effects* Hypercholesterolemia : 50% reduction of plasma LDL levels* One of the safest drugs to use* Gastrointestinal symptoms Constipation（便秘）,bloating（ifi胀），abdominal discomfort2, HMG CoA reductase inhibi

7、torsHOCholesterolC27 steroidHMG CoA reductase inhibitors* 3 -hydroxy- 3 -methylglutary 1 CoA reductase* HMG-CoA reductase , A primary control site* HMG-CoA还原酶抑制剂HMG- Co A ReductaseMevalonic acidHMG-CoA : 3-hydroxy-3-methylglutary CoAHMG-CoA ReductaseHMG-CoA Reductase InhibitorHistorical Overview* 19

8、76，Endo and Kuroda, Mevastatin （美伐他丁, Compatin） from Penicillium,affinity for the enzyme 10,000 times grater than that of HMG CoADiscontinuance of Mevastatin#Pre-clinical trail:* Reports of altered intestinal morphology（形态）HOHch30ch3Lovastatin* Lovastatin isolated from Monascus ruber （红曲霉菌）and Asper

9、gillus terreus（土 霉菌）* Over 2-fold potent than MevastatinLovastatinHO* Merck* Received FDA approval o*1987, markedLovacor ch3Hch3*2001/6, patentSimvastadin*辛伐他丁* Merk，* 8& Zocor*97，3 billion; 2000, 5.3 billion;* 2005,12,patentPravastadin*普伐他丁* 1989, Pravachol（普 拉固）* BMS* 97, 0.6 billions* 2001, 3.4 b

10、illions; tops , 47 6hydroxylPhysicochemical Properties* Lovastatin* White crystal powder* insoluble in water* Highest lipid solubility chloroform, acetonePhysicochemical PropertiesSimvastadinPravastadinMetabolismPro-drugHOhydrolysis-oH-OHch3ch3R HExtensive first-pass metabolismLow oral bioavailabil让

11、y592-OHMechanism of actionCOO-OHHRTherapeutic applications* Hypercholesterolemia* Reduce plasma LDL levels* Reduce the morality（死亡率）of coronary heart disease and stroke* Gastrointestinal disturbances* Rhabdomyolysis横纹肌溶解Structure-Activity RelationshipSynthetic agents* Simplify the structure of Lovas

12、tatin* Replacement of the bicyclic ring with various substituted, aromatic ring systemsFluvastatin* 94, Novas,Switzerland*氟伐他丁* Lescol,来适可*2001,68Atorvastatin589592*阿托伐他丁, Lipitor* Pfizer* 1997*2000, 5 billion dollars*2001,2*2004, 1, more than 6 billion dollarsCerivastatin*拜斯汀,Bay col# Bayer&Smithkl

13、ine BeechamProperties of synthetic vastatin FluvastatinAtorvastatinCerivastatinAcidic drugs; 3,5 -dihydroxy carboxy late significantlyimproves water solubilityProperties of synthetic vastatin*Log P* Oral bioavailability#Metaboloism* EliminationAdverse effects* Gastrointestinal disturbances* Cerivast

14、atin,拜斯汀 *2001, 157, 31 deaths* Rhabdomyolysis横纹 肌溶解* It was voluntarily withdraw in 2001Structure-activity Relationship* A一3,5 -dihydroxy carboxy late ； stereochemistry must be same as the lovastatin;* C一ethyl group or double bond ；* B一aromatic ring3, Fibrates苯氧乙酸类Ooocch* 1962，a random screen test*

15、 Clofibrate,氯贝丁酯* 1967, approved for therapeutic use* 197& World Health Organization trialStructure modifications* 1981,Gemfibrozil （吉非贝齐）* Lopid*2001, 115GemfibrozilAn acidic drugHighly lipid solubilityGemfibrozil,吉非贝齐T/2=l5 hr, 25 days to cause an initial decrease in plasma triglyceride levels, re

16、nal elimination596Fenofibrate* 199&非诺贝特,lipid-soluble* Tricor*2001, 176FenofibrateT 1/2=20-22 hr, 68 weeks to determine efficacy, renal elimination67mg dose of micronized Fenofibrate = 1 OOmg dose of nomicronized FenofibrateTherapeutic Application* to treat hypertriglyceridemia* Gastrointestinal com

17、plains* Caution: combined with HMGRIs; an increase in overall mortalitySpacer groupPropyl spacer迷己 Structure-Activity Relationship厂0Aromatic ring/CI, Longer half-livesP595Pheoxyisobutyric acid4, Nicotinic AcidNicotineNicotinic Acid, 1867Nicotinic AcidC33WTo prevent pellagra（糙皮病） 1955, Altschul, high

18、 doseNicotinic Acid* White, crystalline powder,mp.236.6 C；* Freely soluble in alkaline solutionNicotinic Acid* Hypercholesterolemia, Hypertriglyceridemia, familial combined hyperlipidemia# vasodilation（皮肤血管扩张，flushing and pnwitus（瘙痒症）；gastrointestinal intolerance （20-50%）.Objects* To learn how many classes are Antihyperlipoproteinemics divided ?* To ma