pharmacological effects of statins
DESCRIPTION
Pharmacological Effects of Statins. Overview. Lipids and Lipoproteins Pharmacology of Statins How Do we Choose a Statin?. Lipids and Lipoproteins. Triglycerides Source: sugars, alcohol Essential energy source Energy storage. Cholesterol Source: fats, dietary cholesterol - PowerPoint PPT PresentationTRANSCRIPT
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Pharmacological Effects
of Statins
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OverviewOverview• Lipids and Lipoproteins
• Pharmacology of Statins
• How Do we Choose a Statin?How Do we Choose a Statin?
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Lipids and LipoproteinsLipids and Lipoproteins
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LipidsLipids
TriglyceridesTriglycerides• Source: sugars,
alcohol• Essential energy
source• Energy storage
CholesterolCholesterol• Source: fats, dietary
cholesterol• Bile acid formation• Hormone synthesis• Cell membrane
component
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Lipids vs. LipoproteinsLipids vs. Lipoproteins
• Lipids need to get to site of action for use– Not water soluble not readily carried by
bloodstream
• Special transport “vehicle” necessary for delivery of lipids to tissues for use
• Lipoprotein = Proteins + TG +
Cholesterol + Phospholipids
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Structure of Lipoproteins
Free cholesterol
PhospholipidTriglyceride
Cholesteryl esterApolipoprotein
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ApolipoproteinsApolipoproteins
• Protein components of lipoproteins• Several functions
– Structural stability– Receptor binding (function as ligands in lipoprotein-
receptor interactions)– Regulate enzyme activity
• lecithin cholesterol acyltransferase (LCAT)• lipoprotein lipase (LPL)• hepatic triglyceride lipase (HTGL)
• Concentrations may related to CHD risk• Possible site of genetic variation
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ChylomicronsChylomicrons• Formed in intestines
• Metabolized via LPL (lipoprotein lipase; a triglyceride hydrolase) into remnants which are taken-up by liver
• Primary function is transport of exogenous fatty acids and cholesterol
Major LipoproteinsMajor Lipoproteins
apoB-48apoE
apoA-I, A-IV
apoC-I, C-II, C-III
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VLDLVLDL• Formed in the liver
• Metabolized by LPL into IDL
• Primary function is TG and cholesterol transport
IDLIDL• Formed via VLDL
• Metabolized by LPL into LDL
• Primary function is TG and cholesterol transport
Major LipoproteinsMajor Lipoproteins
apoB-100
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LDLLDL• Formed via IDL
• Metabolized by tissue and hepatic uptake
• Function is cholesterol transport
HDLHDL• Formed primarily via
metabolism of chylomicrons and VLDL
• Primary function is reverse cholesterol transport
Major LipoproteinsMajor Lipoproteins
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Lipoprotein(a); Lp(a)Lipoprotein(a); Lp(a)
SS
LDLLDL
apoB-100
Plasminogen-like domain
apo(a)
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Exogenous PathwayExogenous PathwayFood particles
Intestines
Free Fatty AcidsFree Fatty Acids
Breakdown of Triglyceride
ChylomicronsChylomicrons
BloodstreamBloodstream
LiverLiver
Chylomicron Chylomicron RemnantsRemnants
Bile AcidsBile Acids
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Endogenous PathwayEndogenous Pathway
Free Fatty AcidsFree Fatty Acids
Breakdown of Triglyceride
BloodstreamBloodstream
LiverLiver
IDLIDL
VLDLVLDL
LDLLDL
Body TissuesBody Tissues
HDLHDL
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Possible Causes of Secondary Possible Causes of Secondary DyslipidemiaDyslipidemia
DiseasesDiseases• Diabetes• Hypothyroidism• Nephrotic Syndrome• Obstructive Liver
Disease
DrugsDrugs• Progestins• Corticosteroids• Anabolic steroids -blockers• Thiazide diuretics• Cyclosporin• Sulfonylureas• Isotretinoin• Alcohol
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Benefit of Lowering Cholesterol
Adapted from Gould AL et al. Circulation 1998;97:946–952
Meta-analysis of 38 primary and secondary prevention trials,with more than 98,000 patients in total
Mortality in CHD, p=0.012
Total mortality, p=0.04
Cholesterol reduction (%)
Mo
rtal
ity
(lo
g o
dd
s ra
tio
)
0 4 8 12 16 20 24 28 32–1.0
–0.8
–0.6
–0.4
–0.2
0.0
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Relationship Between Changes in LDL-C and HDL-C Levels and CHD Risk
Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm
1% decreasein LDL-C reduces
CHD risk by1%
1% increasein HDL-C reduces
CHD risk by3%
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Managements of Dyslipidaemia
• Therapeutic lifestyle change (TLC)
• Lipid-lowing agents
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降血脂藥物 全民健康保險藥品給付規定 (劃線部分為 93/9/1後適用)
血脂異常之
起步治療準則 血脂濃度 ≧ 2個危險因子 (如附註二)
TC/HDL-C>5 或
HDL-C<40mg/dl 治療目標 處方規定
≧ 200mg/dl ˇ × <200mg/dl TC
≧ 240mg/dl × × <240 mg/dl
≧ 130mg/dl ˇ × <130mg/dl LDL-C
≧ 160mg/dl × × <160mg/dl
︵如附註一︶
無心血管疾病患者
三至六個月非藥物治療
有下列情況之一時,應給予
TG ≧ 200mg/dl (需同時合併有TC/HDL-C>5或是HDL-C<40mg/dl)
× ˇ <200mg/dl (87/4/1)
如非藥物治療未達治療目標,得使用降血脂藥物(請附三個月前及本次血脂檢查數據),接受藥物治療後,應每三至六個月抽血檢查一次,同時請注意副作用產生,如肝功能異常或橫紋肌溶解症等,如已達治療目標,請考慮減量,並持續治療之。
TC ≧ 200mg/dl × × < 160mg/dl (87/7/1) LDL-C ≧ 130mg/dl × × ≦ 100mg/dl (87/7/1)
或糖尿病患者
有心血管疾病
非藥物治療
同時予以
TG ≧ 200mg/dl (需同時合併有 TC/HDL-C>5或是HDL-C<40mg/dl)
× ˇ < 150mg/dl (87/7/1)
接受藥物治療後,應每三至六個月抽血檢查一次,同時請注意副作用產生,如肝功能異常或橫紋肌溶解症等。
血中三酸甘油酯高於 500mg/dl,具有罹患急性胰臟炎危險者,得使用降血脂藥物。
附註一:心血管疾病: (ˇ )需符合此項條件 (一)冠狀動脈粥狀硬化患者 (×)不需符合此項條件
? 有心導管檢查證實(附檢查報告、醫院名稱及日期)。 ? 曾患心肌梗塞有心電圖(附心電圖)或住院證實(附檢查醫院名稱及日期)。 ? 心絞痛病患,有缺氧性心電圖變化或運動試驗陽性反應者(附檢查報告)。
(二)腦血管病變患者 ? 腦梗塞。 ? 腦內出血(不含其他顱內出血)。 ? 陣發性腦缺血患者(TIA)其頸動脈超音波證實有粥腫樣變化併有 70%以上阻塞者。
(三)周邊血管粥狀硬化有缺血性症狀且經血管都卜勒超音波或血管攝影證實者。 附註二:危險因子: ? ? ? ≧高血壓 糖尿病 男性 45 ? ? ≧歲 有早發性冠心病家族史 女性 55歲或停經沒有雌激素療法者 ? 吸菸(因吸菸而符合起步治療準則之個案,如要求藥物治療,應以自費治療)。
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Cholesterol-Lowering Drug TherapyCholesterol-Lowering Drug TherapyHMG CoA Reductase HMG CoA Reductase
InhibitorsInhibitors• Amlodipine/Atorvastatin• Aspirin/Pravastatin• Atorvastatin• Cerivastatin (2001/8 withdrawal from
market)• Lovastatin• Niacin/Lovastatin• Pitavastatin• Pravastatin• Rosuvastatin• Simvastatin
FibratesFibrates• Gemfibrozil• Micronized
Fenofibrate• Clofibrate
Bile AcidBile Acid SequestrantsSequestrants
• Cholestyramine• Colestipol• Colesevelam
NiacinNiacin
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B-48
B-100
HMG Reductase
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Effect of Lipid-Modifying Therapies on Lipids
Therapy
Bile acidsequestrants
Nicotinic acid
Fibrates(gemfibrozil)
Probucol
Statins*
* Daily dose of 40 mg of each drug (cerivastatin 0.3 mg)TC–total cholesterolLDL–low density lipoproteinHDL–high density lipoproteinTG–triglyceride.
TC
Down 20%
Down 25%
Down 15%
Down 25%
Down 15–30%
LDL
Down 15–30%
Down 25%
Down 5–15%
Down 10–15%
Down 24–50%
HDL
Up 3–5%
Up 15–30%
Up 20%
Down20–30%
Up 6–12%
TG
Neutral or up
Down 20–50%
Down 20–50%
Neutral
Down 10–29%
Patienttolerability
Poor
Poor toreasonable
Good
Reasonable
Good
(Adapted from Yeshurun 1995, Knopp 1999)
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Primary PreventionPrimary Prevention• Fewer coronary events• Fewer angiographies,
PTCAs, and CABGs
Secondary PreventionSecondary Prevention• Less lesion progression,
fewer new lesions• Increased lesion
regression• Fewer coronary events• Less cardiac-related
mortality• Less overall mortality
Benefits of TherapyBenefits of Therapy
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Pharmacology of Statins
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History
• Isolated from a mold, Penicillium citrinium, and identified as inhibitors of cholesterol biosynthesis in 1976 by Endo et al.
• Brown et al,. (1978) established that statins act by inhibiting HNG-CoA reductase
• Yamamoto et al., first statin studied in human (1984)---compactin (mevastatin)
• Alberts et al., first statin approved (1987) for use in human---lovastain (isolated from Aspergillus terreus)
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Atorvastatin
Simvastatin
PravastatinB M YB M Y
Fluvastatin
LovastatinCerivastatin
Rosuvastatin
19911987 1993
200019961997 2003
2001/8 withdrawal
History of Statins
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Cholesterol Synthesis Pathway
acetyl CoA
HMG-CoA
mevalonic acid
mevalonate pyrophosphate
isopentenyl pyrophosphate
geranyl pyrophosphate
farnesyl pyrophosphate
squalene
cholesterol
dolicholsubiquinones
HMG-CoA synthase
HMG-CoA reductase
Squalene synthase
X Statins
蛋白質合成
信息傳遞
細胞能量代謝
細胞膜穩定維持
細胞能量代謝
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Statin Dose-Response CurveStatin Dose-Response Curve
0
10
20
30
40
50
60
70
Increasing Dose
% L
DL
Red
ucti
on
CURVES Study. Am J Cardiol 1998;81:582-7.
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How do we Choose a Statin?How do we Choose a Statin?Differences among the HMG-CoA Reductase Inhibitors
• Potency (LDL, HDL, TG)
• Clinical efficacy
• Hydrophilic vs Lipophilic
• Pharmacokinetics
• Cost
• Drug Interactions
• Non-lipid effects
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Comparative LDL EffectsComparative LDL Effects
-70
-60
-50
-40
-30
-20
-10
0
10
40
20
80
10
10
20
20
20
20
80
40
40
40
401
5
20
AtorvastatinAtorvastatin SimvastatinSimvastatin PravastatinPravastatin LovastatinLovastatin FluvastatinFluvastatin RosuvastatinRosuvastatin
Am J Cardiol 1998;81:582-7. Am J Cardiol 2001;88:504-8. J Int Med Res 2000;28:47-68. Clin Cardiol 2000;23:39-46.
80
80
80
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-4
-2
0
2
4
6
8
10
12
Atorva Simva Prava Lova Fluva Rosuva
10102020
4040
4040
4040
4040
2020
2020
2020
2020
1010
1010
4040
8080
8080
CURVES Study. Am J Cardiol 1998;81:582-7.
Comparative HDL EffectsComparative HDL Effects
1010
2020 4040
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Comparative TG EffectsComparative TG Effects
-35
-30
-25
-20
-15
-10
-5
0
5
1010
4040
2020
8080
1010
1010
2020
2020
20202020
80804040
40404040
4040
AtorvastatinAtorvastatin SimvastatinSimvastatin PravastatinPravastatin LovastatinLovastatin FluvastatinFluvastatin
CURVES Study. Am J Cardiol 1998;81:582-7.
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Statins – Therapeutic Ratio
Muscle
Liver
Drug interactions
Therapeutic Effects
Adverse Effects
Cardiovascular protection
Benefit
Risk
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Statin – Liver Effects
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70LDL-C reduction (%)
Pers
iste
nt
ALT >
3 ×
ULN
(%
)
Fluvastatin (20–80 mg)
Rosuvastatin (10–40 mg)
Lovastatin (20–80 mg)
Atorvastatin (10–80 mg)
Simvastatin (40–80 mg)
Persistent ALT >3 Persistent ALT >3 ×× ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction
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Statin - Muscle Effects
Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K
Cerivastatin (0.2–0.8 mg)
Rosuvastatin (10–40 mg)
Pravastatin (40–80 mg)
Atorvastatin (10–80 mg)
Simvastatin (40–80 mg)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
20 30 40 50 60 70
LDL-C reduction (%)
CK
>10 ×
ULN
(%
)
CK >10 CK >10 xx ULN: Frequency by LDL-C Reduction ULN: Frequency by LDL-C Reduction
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Drug InteractionsDrug Interactions
• Pharmacodynamic– Risk of hepatotoxicity and/or myalgias or
myopathy when combined with fibrates or niacin
• Pharmacokinetic absorption with bile acid sequestrants– Inhibition or induction of CYP-based
metabolism– Inhibition of CYP activity
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Statin MetabolismStatin Metabolism
CYP3A
CYP2C9
Other enzymes/renal
Lovastatin, Lovastatin, Simvastatin, Simvastatin, AtorvastatinAtorvastatin
FluvastatinFluvastatin
PravastatinPravastatin
Active and inactive
metabolites, which are excreted in
urine and/or bileRosuvastatinRosuvastatin
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Potential Drug Interactions
• Simvastatin
• Atorvastatin
• Lovastatin• Diltiazem
• Clopidogrel
• Amiodarone
• Cimetidine
• Ery/clarithromycin
• Ketoconazole
• Carbamazepine
• Grapefruit juice
• Fluvastatin
• Rosuvastatin• Phenytoin
• Fluconazole
• Warfarin
3A4 2C9
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CYP3A InteractionsCYP3A Interactions• ALL statins (except fluvastatin and rosuvastatin)
are metabolized at least in part by CYP3A
• CYP3A inhibitors may statin concentrations– Verapamil, diltiazem, Azole antifungals, erythromycin,
nefazodone, fluoxetine, Protease inhibitors
• CYP3A inducers may statin concentrations– Rifampin, phenytoin, phenobarbital, troglitazone
• Statins may also interact with other CYP3A substrates (i.e., cyclosporine)
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CYP2C9 InteractionsCYP2C9 Interactions
• Fluvastatin is metabolized by CYP2C9 and inhibits CYP2C9 activity
• CYP2C9 inducers (e.g., rifampin) and inhibitors (e.g., amiodarone) may or fluvastatin concentrations, respectively
• Fluvastatin can inhibit CYP2C9 activity, increasing the concentration and effect(s) of other CYP2C9 substrates (e.g., S-warfarin)
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Pharmacokinetic properties of Statins
Thomas N. Riley, PhD & Jack DeRuiter, PhD (2004); 陳昭姿 , 當代醫學雜誌 (2005)
Parameter Rosuva Atorva Prava Simva Fluva LovaAbsolute
bioavailability,% 20 14 17 < 5 24 <5
Food effect on bioavailability None 13% 30% None
15-25%
50%
Half-life, h19
( 任何時間服用)
14( 任何時間服用 )
2( 晚上服用 )
2( 晚上服用
)
1( 睡前服用)
3( 晚上服用
)
Hepatic extraction,
% dose90 >70 50 78-87 68 >70
Metabolic enzyme2C9
(10%)3A4 Sulfation 3A4
2C9
(75%)3A4
Protein binding, % 88 >90 50 95 98 95Solubility Hydrophilic Lipophilic Hydrophilic Lipophilic Lipophilic Lipophilic
Elimination, %
Feces
Urine
90
10
98
2
70
20
60
13
90
5
83
10
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Pharmacologic properties of Statins
Parameter Rosuva Atorva Prava Simva Fluva Lova
Potency, IC50 5.4 mg 8.2 mg 27.6 mg NA 44.1 mg 11.2 mg
Usual adult dosage (USA)
5-40 mg 10-80 mg 10-80 mg 5-80 mg 20-80 mg 10-80 mg
LDL-C % 45-63 % 39-60 % 22-34 % 26-47 % 22-35 % 21-40 %
HDL-C % 8-14 % 5-9 % 2-12 % 8-16 % 3-7 % 2-9 %
TG % 10-35 % 19-37 % 11-24 % 12-33 % 12-19 % 10-19 %
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Comparative efficacy of Statins
LDL-C % TC % Rosuva Atorva Simva Lova Prava Fluva
27 22 -- -- 10 20 20 40
34 27 -- 10 20 40 40 80
41 32 5 20 40 80 80 --
48 37 10 40 80 -- -- --
55 42 20 80 -- -- -- --
63 47 40 -- -- -- -- --
Am J Cardiol 2004; 93(15): 809-811
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Cost - Effective of Statins
陳昭姿 , 當代醫學雜誌 (2005) Brown WV et al., Am Heart J. 2002; 144:1036-43.
規格 給付價總膽固醇
降值
LDL-C平均降值
降 LDL-C
1% 費年
達目標值病人比例
達目標值每人年費
Rosuva
10 mg 33.6 元 33% 45.9% 267 元 0.8214956元
20 mg 42.1 元 38% 52.3% 294 元 0.8917266元
Atorva10 mg 33.8 元 27% 36.7% 397 元 0.69
17880元
40 mg 57.0 元 36% 47.8% 306 元 0.8524476元
Prava
10 mg 42.3 元 15% 20.1% 768 元 0.3149804元
20 mg 51.0 元 17% 24.3% 365 元 0.4442307元
40 mg 57.0 元 22% 29.7% 701 元 0.5537827元
Simva
10 mg 42.3 元 20% 28.3% 545 元 0.5130273元
20 mg 44.7 元 26% 35.0% 466 元 0.6325898元
40 mg 59.0 元 28% 38.8% 555 元 0.6632369元
Fluva 80 mg 39.9 元 35% 35%
Lova 20 mg 42.0 元 17% 21% 730 元 ?
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Thanks for your attention!
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• Superior LDL-lowering ability
• Combinations with a resin may provide benefit with little risk of additive toxicity
• Some concern about risk of rhabdomyolysis with statin-niacin or statin-fibrate combinations
• Others have found these combinations to be safe
Studied Combinations
Statin + Resin
Statin + Resin + Niacin
Statin + Niacin
Statin + Fibrate
Niacin + Resin
Combination TherapyCombination Therapy
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• Statins and Endothelial Function
• Statins and Plaque Stability
• Statins and Inflammation
• Statins and Lipoprotein Oxidation
• Statins and Coagulation
Possible Non-Lipid-Lowering Possible Non-Lipid-Lowering Effects of the StatinsEffects of the Statins