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Part 3 Agents Used in Hyperlipidemia

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Part 1Lipid regulating agents

调血脂药

浙江大学医学院药理学系

张世红

shzhang713@zju.edu.cn

Lipid metabolism

(30%)

(70%)

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

Correlation Between Cholesterol Levels and CHD Death

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0

2

4

6

8

10

12

14

16

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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

• 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)

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

7中国营养学会推荐

中国居民平衡膳食宝塔

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）

……

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

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

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

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

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

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

• 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

• 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

• 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

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

• 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)

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

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

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&amp%3bssource=mfr

Part 2

Antianginal drugs

抗心绞痛药物

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浙江大学医学院药理学系

张世红

shzhang713@zju.edu.cn

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

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

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

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

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

Clinical uses

Angina pectoris Acute myocardial infarction Chronic heart failure Acute respiratory failure and pulmonary arterial

hypertension

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Organic nitrates

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

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

Something’s Gotta Give

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Story time

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

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

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

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

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)