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Part 3 Agents Used in Hyperlipidemia
1
Part 1Lipid regulating agents
调血脂药
浙江大学医学院药理学系
张世红
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Lipid metabolism
(30%)
(70%)
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Classification of Dyslipidemia
TypeElevated lipo-protein
Ch TG Risk of CHD
I CM + +++ /IIa LDL ++ / High IIb LDL+VLDL ++ ++ High III βVLDL ++ ++ ModerateIV VLDL + ++ ModerateV CM+VLDL + ++ /
3Ch: cholesterol; TG: triglyceride; /: no change
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Correlation Between Cholesterol Levels and CHD Death
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140 160 180 200 220 240 260 280 300Serum total cholesterol (mg/dL)
Age-adjusted 6-yearCHD death rateper 1000 men
Martin MJ et al. Lancet. 1986;II:933-936.
n=325,000 men
Role:For every 1% increasein LDL-C, there is a 1% increase in CHD events
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• Lipids of HDL come from CM and VLDL during lipolysis, or acquires cholesterol from peripheral tissues.
• HDL brings cholesterol back to liver or transfers to IDL
• The role of HDL is keeping the cholesterol homeostasis of cells
• Low HDL is an independent risk factor for CHD.
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HDL (high density lipoprotein)
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Strategies to regulate serum lipid
1. Identify patients at risk
- Routine screening of serum cholesterol
- Assessment of contributing risk factors
2. Non-pharmacologic therapy
- Diet modification
- Lifestyle modification
3. Pharmacological therapy6
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7中国营养学会推荐
中国居民平衡膳食宝塔
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Drugs used for dyslipidemia HMG CoA reductase inhibitors (他汀类): lovastatin洛伐他汀, etc.
羟甲基戊二酸单酰辅酶A还原酶抑制剂
Cholesterol absorption inhibitors: ezetimide依折麦布,
Bile acid binding resins (树脂类, colestryramine, colestipol)
Fibrates (贝特类): gimfibrozil吉非贝齐, feinofibrate非诺贝特
Nicotinic acids (烟酸类): nicotinic acid烟酸, acipimox阿昔莫司
Antioxidants (抗氧化剂): probucol普罗布考
Others: EPA (廿碳戊烯酸), DHA(廿二碳六烯酸), linoleic acid (亚
油酸) , policosanol多廿烷醇,
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Action sites of drugs for hypercholesterolemia
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HMG-CoA Reductase Inhibitors (Statins)
Lovastatin(洛伐他汀)
Simvastatin(辛伐他汀)
Pravastatin (普伐他汀)
Atorvastatin(阿伐他汀,立普妥)
Fluvastatin(氟伐他汀)
Rosuvastatin(瑞舒伐他汀)
……
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StatinsMechanisms:
• Structural analogs of the HMG-CoA, inhibit synthesis of Ch.
• Increase in high-affinity LDL receptors
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(异戊二烯焦磷酸)
鲨烯
甲羟戊酸
类异戊二烯
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StatinsPharmacological effects:• Lipid regulating effects: reduce LDL, VLDL, TC,
TG, increase HDL.
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StatinsPharmacological effects:• Lipid regulating effects: reduce LDL, VLDL, TC, TG,
increase HDL.
• Pleiotropic effects多效性作用: ameliorate the functions of vascular endothelial cells, inhibit the proliferation and migration of VSMCs, inhibit the function of inflammatory cells and platelet aggregation, antioxidant effect, bone metabolism (formation↑, absorption↓), renal protection
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Indications:– Hypercholesterolemia and associated diseases
– Renal syndrome
– Reduce restenosis after PTCA, reduce rejection rate after organ transplantation, treatment of osteoporosis.
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Statins
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Statins– Due to the first pass hepatic extraction, the major
effect is in the liver
– Enhanced if taken with food (except for pravastatin –
taken without food)
– Taken in the evening (Why?)
– May need to increase the dosage during the
treatment period (Why?)
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Summary of Pharmacokinetics of Statins
McTaggart F et al. Am J Cardiol 2001;87(suppl):28B-32B; Knopp RH. N Engl J Med 1999;341:498-511.
Drugs
Pravastatin 44.1 1-2 No17%
Atorvastatin 8.2 Yes14~14%
Fluvastatin 27.6 No1-224%
Simvastatin 11.2 Yes1-2< 5%
Rosuvastatin 5.4 19 No~20%
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Adverse effects– Statins are pregnancy category X– Rash, GI disturbances (dyspepsia, cramps,
flatulence, constipation, abdominal pain) – Myopathy (0.5% of pts)
»Risk highest with lovastatin and especially in combination with fibrates (贝特类降脂药)
– CYP3A4 or CYP2C9 drug interactions– Hepatotoxicity– Increase the risk of diabetes (slightly)
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Statins
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Risk factors for myopathy• Advanced age
– > 80 yo– Women > men
• Multisystem disease– diabetes, thyroid,
liver• Perioperative period• Major trauma• Electrolyte imbalance
• Metabolic acidosis• Hypoxia• Infection• Large quantities of
grapefruit juice (>1 L/day)• Alcohol abuse• Drug interactions
18Jacobson TA. Expert Opin Drug Saf 2003;2:269-86Davidson MH. Am J Cardiol 2002;90 (suppl):50K-60K
Statins
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Cholesterol absorption inhibitors
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• Ezetimibe (依折麦布): inhibits intestinal cholesterol absorption
• Resins (cholestyramine, 考来烯胺; colestipol, 考来替泊) : bind bile acids
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Ezetimibe• Mechanisms and effects:
– Blocks cholesterol absorption at the intestinal brush border (Niemann-Pick C1-like 1 protein, NPC1L1)
– Reduces LDL (upregulates LDL receptors)
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Ezetimibe ↓ 18 ↑ 1 ↓ 8
Resins ↓ 15-30 ↑ 3-5 ↑ /Neutral
Statins ↓ 18-60 ↑ 5-15 ↓ 7-30
Fibrates ↓ 5-20 ↑ 10-35 ↓ 20-50
Niacin ↓ 5-25 ↑ 15-35 ↓ 20-50
Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.JAMA. 2001;285:2486-2497.
LDL-C HDL-C TGDrug class (% ∆) (% ∆) (% ∆)
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Ezetimibe
• Mechanisms and effects:
– No effect on absorption of lipid-soluble vitamins– Minimal systemic exposure and very well tolerated– Additive in combination with statins with monitoring ALT
1-STEP COADMINISTRATION
3-STEP TITRATION
% Reduction in LDL-C
5%-6% 5%-6%
Statin – starting dose 1st 2nd 3rd
5%-6%
Statin – starting dose + Zetia10 mg
15%-18%
Doubling
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• Mechanisms:- Bind to bile acid in the intestines, interrupting enterohepatic circulation (肠肝循环) and increasing bile acid production and fecal excretion with cholesterol.
- LDL receptors
• Efficacy:LDL 15-30%
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Resins
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Indications:
- High LDL- Pruritis due to cholestasis胆汁淤积症 and bile salt accumulation;- Diarrhea after post-cholecystectomy胆囊切除术
- May be useful in digitalis洋地黄 toxication
Resins
Adverse effects:
- Constipation, bloating, indigestion, nausea, large doses may impair absorption of fats (脂肪痢) or fat soluble vitamins (A, D, E, and K)
- Affect absorption of other drugs, should be given 1 hour before the resin or 4 hours after.
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Gemfibrozil(吉非贝齐)
Fenofibrate(非诺贝特,力平之)
Benzafibrates(苯扎贝特)
Fibrates
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• Mechanisms• Act as PPARα ligands (peroxisome proliferator-activated
receptor-α, 过氧化物酶体增殖物激活受体α) PPARα, a nuclear receptor that regulates lipid metabolism
and glucose homeostasis
VLDL catabolism by lipoprotein lipase
Apo CIII, VLDL production
apoA I and II, HDL
Antioxidant, antiproliferation and antiinflammation effects
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Fibrates
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• Efficacy:TG 40-55%, HDL 10-25%, LDL + 10%
• Indications:High TG and/or low HDL
• Adverse effects:Rashes, GI upset, gallstones (increase biliary cholesterol saturation)Use with caution in pts with biliary tract disease, hepatic or renal dysfunctionIncrease risk of statin-induced myopathyDisplaces warfarin from plasma albumin due to highly protein bound property.
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Fibrates
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Nicotinic acid and Acipimox
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• Nicotinic acid (烟酸, Vitamin B3)
• Acipimox (阿昔莫司)
Increased apo-B 100 clearance apo B-100
apo C
apo E↓ VLDL
↓ VLDLRemnant
↓ LDL
Liver
Decreased VLDLProduction
Other sites Increased VLDLclearance through LPL
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• Mechanisms and effects- Suppress synthesis of VLDL, IDL, & LDL in the liver.- Increase clearance of VLDL via the LPL pathway, TG catabolism
- May HDL catabolism
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Nicotinic acid and Acipimox
• Efficacy:TC 25%, LDL 10-25%, HDL 10-40%, TG 20-50%
• Indications:• High LDL (and/or VLDL) • Combined hyperlipidemia (including low levels of HDL--Niaspan® , approved for elevating HDL levels)
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Adverse effects:– Flushing (very uncomfortable, aspirin may helpful)– Pruritis, rashes, dry skin– Nausea and abdominal discomfort
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– Rare hepatotoxicity
– Hyperuricemia (occurs in about 1/5 of pts, occasionally
precipitates gout)
– Carbohydrate tolerance may be moderately impaired
(reversible hyperglycemia)
Nicotinic acid and Acipimox
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Probucol (普罗布考)• Action: Taken up by LDL particles and endothelial cells,
inhibits oxidation of LDL, decreases atherosclerotic plaque formation; small reduction in LDL; greater reduction in HDL.
• Clinical uses: may be used in combination therapy with other drugs that lower serum LDL.
• Disadvantages: not effective in single drug therapy; no long term clinical data.
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Antioxidants
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Polyunsaturated fatty acids: EPA, DHA (ω-3 PUFAs)• Reduce TG
• Only highly purified preparation (>96%) approved.
• Risk in increase of LDL (more strongly associated wih coronary artery diseases)
• The effects on cardiac morbidity or mortality is unproven(although there is epidemiological evidence that eating fish regularly does reduce ischemic heart disease)
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Others
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http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.short?rss=1&%3bssource=mfr
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Outline
1 Overview of angina pectoris
2 Antianginal drugs
- Nitrate esters
- β-blockers
- Calcium channel blockers
3 Combination of antiganginal drugs
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Leading Sources of Disease Burden*
• Ischemic Heart Disease
• Unipolar Major Depression
• Cardiovascular Disease
• Alcohol Use
• Traffic Accidents
• Lung and other cancers
• Dementia and Neurodegenerative Disorders
*based on DALY’s (Disability Adjusted Life Years, WHO) which measure lost years of healthy life due to premature death or disability
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http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf
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Sudden, uncomfortable pressure, fullness, squeezing or severe substernal pain, radiating to the left arm, shoulders, neck, etc.
Symptoms:
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• Stable angina pectoris• Unstable angina pectoris
initial onset typeaccelerated typespontaneous type
angina at restVariant/Prinzmetal’s angina pectoris
• Mixed angina pectoris
Caused by atherosclerosis plaque and/orthrombus formation
Caused by spontaneous spasm of coronary arteries
Classification of angina pectoris:
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Effort angina
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Extreme weather
Excessive food intake Excessive smoking
ExerciseStrong emotion
Variant/Prinzmetal’s angina: usually occur when a person is at rest between midnight and 8am
Occurrence of stable and unstable angina pectoris
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Demand of the myocardium for oxygen
Oxygen delivery to the myocardium by the coronary circulation
Normal Ischemia
How does angina pectoris happen?
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动脉粥样硬化斑块
和血栓形成
冠脉痉挛
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Decrease the oxygen demand and/or increase the delivery
BY
Strategies for angina treatment
- Dilating arteries, especially coronary arteries, including relieving spasm and opening collateral circulation
- Dilating veins
- Antiatherosclerosis and prevention of thrombosis
- Cardiac inhibition: decrease HR, contractility, tensility of myocardium
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Quiz time
Which one of the following drugs does not show potential to treat stable angina pectoris?
A AtropineB NifedipineC PropranololD EnalaprilE Aspirin
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Antianginal drugs
Nitrate esters (organic nitrates) β-receptor blockers Calcium channel blockers Other drugs (ACEIs, potacium
channel openers, molsidomine吗多明)
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Nitroglycerin(硝酸甘油)
Isosorbide dinitrate(硝酸异山梨酯,消心痛)
Isosorbide mononitrates(单硝酸异山梨酯)
Actions• Dilate vessels:
- Dilate veins (small doses) and arteries, decrease pre/after-load and cardiac oxygen demand- Dilate coronary arteries, epicardial vessels and open collateral circulation, redistribute blood to ischemic area- Decrease LVFP, increase blood to subendocardial area
• Protect myocardial cells against ischemic injury• Anticoagulation of platelets
Nitrate esters(硝酸酯类)
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Organic nitrates
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Nitroglycerin
Isosorbide dinitrate
Time to peak effect
Duration of action
Pharmacokinetics
2 min
25 minSublingual
15 min
1 hourSublingual
Organic nitrates
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硝酸异山梨酯
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Clinical uses
Angina pectoris Acute myocardial infarction Chronic heart failure Acute respiratory failure and pulmonary arterial
hypertension
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Organic nitrates
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Adverse effects
Symptoms due to vasodilation: headache, increase of intraocular pressure, postural hypotension, facial flushing and tachycardia
Allergy Methaemoglobinaemia (高铁血红蛋白血症,at
very high doses)
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Organic nitrates
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Tolerance Provision of daily “nitrate-free interval” To supplement –SH (food, drugs), Vc To inhibit RAAS and sympathetic system
Drug interactions (aware of severe hypotension) Antihypertensive drugs Alcohol and Viagra
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Organic nitrates
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Something’s Gotta Give
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Story time
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Propranolol, metoprolol, atenololActions
- Inhibit cardiac contractility, decrease O2 demand
- Increase blood supply to ischemic area: perfusion time ↑ (heart rate↓), vascular tone in normal tissues ↑
- Improve myocardial metabolism (FFA ↓)
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β-blockers
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Clinical uses:- stable and unstable angina pectoris,
especially associated with hypertension or arrhythmias, even with myocardial infarction.
- NOT used for variant angina.
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β-blockers
Notices:AsthmaStart from small dosesWithdraw gradually (rebound phenomenon)Combined with nitroglycerin when neededCardiac depression
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Calcium channel blockers, CCBs
Actions contributing to antianginal effect :
- Decrease peripheral resistance and myocardial oxygen consumption- Increase myocardial blood supply: dilate coronary vessels, open collateral circulation- Protect ischemic myocardial cells by inhibiting Ca2+ overload- Inhibit coagulation of platelets
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Clinic uses:• Angina pectoris
- Variant angina: ver, dil, nif- Stable angina: ver, dil, nif- Unstable angina: ver, dil, nif + β blockers
• Arrhythmias• Hypertension• Cerebrovascular diseases• Other diseases: peripheral vascular spasmodic
disease, arteriosclerosis, migraine
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Calcium channel blockers, CCBs
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Adverse effects:- peripheral edema- sympathetic
excitation (nif)- cardiac inhibition
(ver, dil)- hypotension (nif)
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CCBs
Contraindications:- hypotension- severe heart failure- sinus bradycardia- atrioventricular
block
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心肌耗氧因素 硝酸酯类β受体阻断药
CCBs硝苯地平 维拉帕米
硝酸酯类+ β受体阻断药
动脉压
心率
心肌收缩力 不变或降低
射血时间 不变
左室舒张末压 - 不变或降低
Combination of antianginal drugs
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Rationality: O2 demand, adverse reactions
Caution:Hypotension, low cardiac perfusion
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(ACEIs, β blocker, CCBs, Diuretics)