Lipid-regulatorsLipid-regulators(Agents Used in Hyperlipidemia)(Agents Used in Hyperlipidemia)

Yun-Bi Lu, PhDYun-Bi Lu, PhD卢韵碧卢韵碧

Dept. of Pharmacology, Dept. of Pharmacology, School of Medicine, Zhejiang UniversitySchool of Medicine, Zhejiang University

yunbi@zju.edu.cnyunbi@zju.edu.cn

Lipids include:• Triglyceride (TG)

• Cholesterol (TC)

Free cholesterol

Cholesterol ester

• Others, e.g. phospholipids

Lipids + apolipoprotein (apoprotein, apo) = lipoprotein

1.20

1.10

1.06

1.02

1.006

0.95

5 10 20 40 60 80 1000

ChylomicronRemnants

VLDL

IDL

LDL

HDL2

HDL3

Diameter (nm)

Den

sity

(g/

ml)

VLDLRemnants

LIPOPROTEINS

0

2

4

6

8

10

12

14

16

18

140 160 180 200 220 240 260 280 300

Serum total cholesterol (mg/dL)

Age-adjusted6-year

CHD death rateper 1000 men

Correlation Between Cholesterol Levels and Correlation Between Cholesterol Levels and Coronary Heart Disease EventsCoronary Heart Disease Events

Martin MJ et al. Lancet. 1986;II:933-936.

n=325,000 men

RULE:For every 1% increasein LDL-C, there is a 1% increase in CHD events

LPL

TG and TC

TG

TC

Low-Density Lipoprotein (LDL)

apo B-100

Diameter 225-275 Å

Phospholipid

Unesterified cholesterol

Cholesterolester

Triglyceride

• Physiologic Role of Cholesterol– Component of all cell membranes– Precursor of other steroids

• Cortisol(糖皮质激素 )• Progesterone(孕酮 )• Estrogen(雌激素 )• Testosterone(睾酮 )• Bile acids(胆酸 )

• Excess cholesterol and/or triglyceride– Hyperlipmia (高脂血症 ) or

hyperlipoproteinemia (高脂蛋白血症 )– Atherosclerosis (动脉粥样硬化 )– Coronary heart disease (CHD)– Xanthomas (黄瘤 )

TC TG

Hypercholestrolemia高胆固醇血症

↑

Hypertriglyceridemia高甘油三酯血症

↑

Mix Hyperlipidemia混合型高脂血症

↑ ↑

Simple Classification of Hyperlipidemias

• LDL is associated with increased heart disease “lousy cholesterol” “bad cholesterol”

• The major carrier of cholesterol in the blood

LDL (low density lipoprotein)

•Role: transport cholesterol to peripheral tissues

•Half-life: ~ 24 hrs (every day about half of the circulating LDL is removed via receptor mediated endocytosis)

•The LDL receptor is central to cholesterol homeostasis

(1970’s Brown and Goldstein)

• When LDL binds to its receptor (via recognition of the apoprotein B100) the entire LDL molecule is taken up (engulfed) by the cell in clatherin coated pits endosomes lysosomes

LDL receptor

Pharmacotherapy: Effect on Serum Lipids

Pharmacotherapy

• 他汀类 (Statins)：羟甲基戊二酸单酰辅酶 A还原酶抑制剂 (HMG-CoA Reductase Inhibitors) – 洛伐他汀 (lovastatin)、辛伐他汀(simvastatin)、普伐他汀 (pravastatin) 、氟伐他汀 (fluvastatin) 、阿伐他汀 (atovastatin)

• 胆固醇吸收抑制药 (Cholesterol absorption inhibitors) –依泽替米贝 (ezetimibe)

• 胆酸结合树脂 (Bile Acid-Binding Resins, RESINS) – 考来替泊 (Colestipol), 考来烯胺 (cholestyramine)

• 烟酸 (NICOTINIC ACID, NIACIN)

• 苯氧酸类 (贝特类 ) FIBRIC ACID DERIVATIVES (FIBRATES) – 氯贝特 (clofibrate)、吉非贝齐 (gemfibrozil)、苯扎贝特(benzafibrate)、非诺贝特 (fenofibrate)、环丙贝特 (ciprofibrate)

Cholesterol Synthesis Pathway

NATURAL PRODUCT HMG CoA NATURAL PRODUCT HMG CoA REDUCTASE INHIBITORSREDUCTASE INHIBITORS

6,000 microbial extracts screened

CH3

O

OOH

O

CH3

CH3 H

RIC50 = ~ 2 nM

R = H, mevastatinR = CH3, lovastatin

Penicillium citrinum (mevastatin)

Aspergillus terreus (Lovastatin, Merck)

Required 600 L of culture to be solvent extracted

NATURAL PRODUCT NATURAL PRODUCT INHIBITORS INHIBITORS

Pravastatin

CH3

COONaOH

O

CH3

CH3 H

HO

OH

First isolated as metabolite in dog urine

Currently produced by microbialtransformation of mevastatin

Hydrophilic in nature

Administered in active form

Summary of Pharmacological Properties of Statins

McTaggart F et al. Am J Cardiol 2001;87(suppl):28B-32B; Knopp RH. N Engl J Med 1999;341:498-511.

Potency on

enzyme IC 50 (n

M)

Hepatic

metabolism

by CYP3A4

Eliminatio

n

half life

(h)

Rosuvastatin

Pravastatin

5.4

44.1 1–2

Cerivastatin 10.0 Yes2–3

Atorvastatin 8.2 Yes14

Fluvastatin 27.6 No1–2

Simvastatin 11.2 Yes1–2

20 No

No

Bioavailabilit

y

17%

60%

~14%

24%

5%

~20%

Pharmacologic Therapy: Pharmacologic Therapy: StatinsStatins——Dose ResponseDose Response

% R

edu

ctio

n in

LD

L-C

1927 28

35 37

12

10 12

1218

0

10

20

30

40

50

60

Lovastatin20/80 mg

Fluvastatin20/80 mg

Simvastatin20/80 mg

Pravastatin20/80 mg

Atorvastatin10/80 mg

Response to Minimum/Maximum Statin Dose

3137*

40

47

55

Adapted from Illingworth. Med Clin North Am. 2000;84:23.*Pravachol® (pravastatin) PI.

Statins - Mechanism of Action

• Structural analogs of the HMG-CoA intermediate

• Increase in high-affinity LDL receptors

• Increase catabolic rate of LDL and the liver's

extraction of LDL precursors (VLDL remnants),

thus reducing plasma LDL.

• Due to the first pass hepatic extraction, the major

effect is on liver.

– Most Effective for ↓ LDL

– Some ↑ HDL and good ↓ VLDL

– Used alone to ↓ LDL

– Used with resins, CAIs to ↓ LDL

– Used with niacin to ↓ LDL, ↓ VLDL, and ↑ HDL

– Enhanced if taken with food (except for pravastatin – taken without food)

– Give in the evening(Cholesterol synthesis

highest at night)

Statins - Clinical UseStatins - Clinical Use

Statins – Benefits

• Demonstrated therapeutic benefits

– Reduce major coronary events– Reduce CHD mortality– Reduce coronary procedures

(PTCA/CABG)– Reduce stroke– Reduce total mortality

NCEP ATP III. JAMA 2001;285:2486-2497.

– Rash, GI disturbances (dyspepsia(消化不良 ),

cramps, flatulence(肠胀气 ), constipation(便秘 ),

abdominal pain)

– Hepatotoxicity

– Myopathy (肌病 )(0.5% of pts)

» Risk highest with lovastatin and especially in

combination with Fibrates

– Cyp3A4 or CYP2C9 drug interactions with many

statins

Statins – Adverse EffectsStatins – Adverse Effects

Hepatotoxicity ?

• Whether transaminase elevation with statin therapy constitutes true hepatotoxicity has not been established

• Progression to liver failure specifically due to statins is exceedingly rare, if it ever occurs

• No evidence exists showing exacerbation of liver disease when statins are given to patients with cholestasis and active liver disease

• Statins may actually improve transaminase elevations in individuals with fatty liver

Pasternak RC et al. Circulation. 2002;106:1024-1028.

Hepatic transaminase elevations; occur in 0.5-2% and are dose dependant

Risk Factors for Myopathy• Advanced age

– > 80 yo

– Women > men

• Multisystem disease

– thyroid, liver

• Perioperative period

• Major trauma

• Electrolyte imbalance

• Metabolic acidosis

• Hypoxia

• Infection

• Large quantities of grapefruit juice

– > 1 qt./day

• Alcohol abuse

• Drug interactions

Jacobson TA. Expert Opin Drug Saf 2003;2:269-86Davidson MH. Am J Cardiol 2002;90 (suppl):50K-60K

CHOLESTEROL ABSORPTION INHIBITORS

Ezetimibe

Net Cholesterol Balance in Humans

Cholesterol Absorption Inhibitor (ezetimibe)

• Mechanisms:– Blocks cholesterol absorption at the intestinal

brush border – No effect on absorption of lipid-soluble vitamins

• Indications:High LDL (Additive in combination with statin )

• Pharmacology– Intestinal wall localization– Enterohepatic circulation– Minimal systemic exposure (Very well tolerated)

Ezetimibe+ Statin Ezetimibe+ Statin vs. Statin Titrationvs. Statin Titration

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+ Zetia

10 mg

15%-18%

Doubling

Polymer Backbone

Bound Bile Acid

CholestyramineCholestyramine ColesevelamColesevelam

Hydrophobic Side Chain

Primary Amines

Quaternary Amine Side

Chains

Bile Acid-Binding Resins (Resins)

• Mechanisms:

─ Binds to bile acid in the intestines, interrupting enterohepatic circulation and increasing fecal excretion of the acid

─ LDL receptors(外源性的吸收减少，内源性代谢进入胆酸，导致肝内受体代偿性表达 )

• Efficacy: LDL 20-30%

• Indications: High LDL

• Uses: be used to relieve pruritis(瘙痒症 ) in patients who have

cholestasis and bile salt accumulation; and/or to relieve

diarrhea in post-cholecystectomy(胆囊切除术后 ) patients

Resins - Colestipol, cholestyramine, and colesevelam

Adverse effects

– Constipation(便秘 )

– Bloating(腹胀 ), indigestion, nausea

– Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K)

– Drug Interactions

• Resins bind digoxin, warfarin, thiazide diuretics, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone(保泰松 ), aspirin, ascorbic acid (these agents should be given 1 hour before the resin or 4 hours after)

• may be useful in digitalis toxicity.

ResinsResins

Nicotinic Acid (NIACIN)

apo B-100

apo C

apo E

VLDL

VLDLRemnant

LDL

Liver

Decreased VLDLProduction

CONVERSION

Other sitesIncreased VLDL

Clearance through LPL

• Mechanism─ Increase clearance of VLDL via the LPL pathway, TG

catabolism

─ Suppress synthesis of TG,VLDL, IDL, & LDL in the liver.

─ May HDL catabolism (via apoA-I catabolism )

• Efficacy:– TC 25% LDL 10-25%

– HDL 10-40% TG 20-50%

• Indications:– High LDL-C and/or high TG

– Combined hyperlipidemia

Start with low dose and gradually increase

Give at night with food.

Nicotinic Acid (Niacin, Vitamin B3)

Adverse effects– Flushing(潮红 )

» Harmless cutaneous vasodilation» VERY Uncomfortable» Occurs after drug is started or ↑ dose» Lasts for the first several weeks» Can give aspirin 30 minutes before dose

– Pruritis, rashes, dry skin– Nausea and abdominal discomfort

» Peptic disease– Hepatotoxicity

» Rare true hepatotoxicity occur» Monitor liver functions regularly» Liver injury is less likely with Niaspan

– Hyperuricemia» Occurs in about 1/5 of pts» Occasionally precipitates gout

– Carbohydrate tolerance may be moderately impaired (hyperglycemia)» Reversible» Can be given to diabetics receiving insulin

– contraindicates use» Pregnancy

Nicotinic Acid (Niacin, Vitamin B3)

• Mechanisms

• Act as PPAR ligands (peroxisome proliferator-activated receptor-alpha)

• a nuclear receptor that regulates lipid metabolism and glucose homeostasis

FA oxidation in muscle and liver

• Reduced expression of Apo CII is key to VLDL catabolism

clearance of VLDL by action of lipoprotein lipase. VLDL production

• ↓ Intracellular lipolysis in adipose tissue

• Efficacy:

LDL + 10%

HDL 10-25%

TG 40-55%

• Indications:

TG and/or HDL

Fibrates (贝特类 )

• Adverse effects– Rashes

– GI upset

– Gallstones (upper abdominal discomfort, intolerance

of fried food, bloating)

» ↑ biliary cholesterol saturation

» Use with caution in pts with biliary tract disease

– Highly protein binding.

– Will increase risk of statin-induced myopathy when

used together (rhabdomyolysis has occurred rarely)

– Avoid in patients with hepatic or renal dysfunction

FibratesFibrates

Summary of Clinical Effects

Summary of Side Effects

Resins Unpalatability, bloating,constipation, heartburn

Nicotinic acid Flushing, nausea, glucoseintolerance, abnormal liverfunction tests

Fibrates Nausea, skin rash

Statins Myositis, myalgia, elevatedhepatic transaminases

Drug Class Side Effects

Thanks!