1. Lipid-regulators (Agents Used in Hyperlipidemia)
Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology, School of Medicine, Zhejiang University

2. Lipids include: Triglyceride (TG) Cholesterol (TC) Free cholesterol
Cholesterol ester
Others, e.g. phospholipids
Lipids + apolipoprotein (apoprotein, apo) = lipoprotein

3. LIPOPROTEINS Density (g/ml) Diameter (nm) VLDL VLDL Remnants IDL
0.95
VLDL
VLDL
Remnants
Chylomicron
Remnants
IDL
1.006
Density (g/ml)
1.02
LDL
1.06
HDL2
1.10
HDL3
1.20 5 10 20 40 60 80
1000
Diameter (nm)

4. Age-adjusted 6-year CHD death rate per 1000 men
Correlation Between Cholesterol Levels and Coronary Heart Disease Events 2 4 6 8 10 12 14 16 18
RULE:
For every 1% increase
in LDL-C, there is a 1%
increase in CHD events
Age-adjusted 6-year CHD death rate per 1000 men
140
160
180
200
220
240
260
280
300
n=325,000 men
Serum total cholesterol (mg/dL)
Martin MJ et al. Lancet. 1986;II:

5. TC
TG and TC
LPL TG

6. Low-Density Lipoprotein (LDL)
apo B-100
Diameter Å
Phospholipid
Unesterified
cholesterol
Cholesterol
ester
Triglyceride

7. 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)

8. Hypertriglyceridemia
Simple Classification of Hyperlipidemias 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

9. LDL (low density lipoprotein)
LDL is associated with increased heart disease “lousy cholesterol” “bad cholesterol”
The major carrier of cholesterol in the blood
Role: transport cholesterol to peripheral tissues
Half-life: ~ 24 hrs (every day about half of the circulating LDL is removed via receptor mediated endocytosis)

10. LDL receptor
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

11. Pharmacotherapy: Effect on Serum Lipids

12. 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)

13. Cholesterol Synthesis Pathway
9.01

14. NATURAL PRODUCT HMG CoA REDUCTASE INHIBITORS
6,000 microbial extracts screened
R = H, mevastatin
R = CH3, lovastatin
Penicillium citrinum (mevastatin)
Aspergillus terreus (Lovastatin, Merck)
Required 600 L of culture to be solvent extracted
IC50 = ~ 2 nM

15. NATURAL PRODUCT INHIBITORS
Pravastatin
First isolated as metabolite in dog urine
Currently produced by microbial
transformation of mevastatin
Hydrophilic in nature
Administered in active form

16. Summary of Pharmacological Properties of Statins
9.19
Hepatic
metabolism by CYP3A4
Potency on
enzyme IC50 (nM)
Elimination
half life (h)
Bioavailability
Rosuvastatin
5.4
~20% 20 No
Atorvastatin
8.2
~14% 14
Yes
Cerivastatin
2–3
10.0
60%
Yes
Simvastatin
11.2
 5%
1–2
Yes
Fluvastatin
24%
1–2
27.6 No
Pravastatin
44.1
17%
1–2 No
McTaggart F et al. Am J Cardiol 2001;87(suppl):28B-32B; Knopp RH. N Engl J Med 1999;341:

17. Pharmacologic Therapy: Statins—Dose Response
Response to Minimum/Maximum Statin Dose
Fluvastatin
20/80 mg
Pravastatin
20/80 mg
Lovastatin
20/80 mg
Simvastatin
20/80 mg
Atorvastatin 10/80 mg
% Reduction in LDL-C 31
37* 40 47 55
Adapted from Illingworth. Med Clin North Am. 2000;84:23. *Pravachol® (pravastatin) PI.

18. 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.

19. Statins - Clinical Use 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)

20. Statins – Benefits Demonstrated therapeutic benefits
8.11
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:

21. Statins – Adverse Effects
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

22. Hepatotoxicity ?
Hepatic transaminase elevations; occur in % and are dose dependant
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:

23. 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;2:269-86
Davidson MH. Am J Cardiol 2002;90 (suppl):50K-60K

24. CHOLESTEROL ABSORPTION INHIBITORS
Ezetimibe

25. Net Cholesterol Balance in Humans

26. 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)

27. Ezetimibe+ Statin vs. Statin Titration
5%-6%
5%-6%
5%-6%
Statin – starting dose
1st
2nd
3rd
3-STEP TITRATION
Doubling
15%-18%
+ Zetia
10 mg
1-STEP COADMINISTRATION
Statin – starting dose
% Reduction in LDL-C

28. Hydrophobic Side Chain Quaternary Amine Side Chains
Bile Acid-Binding Resins (Resins)
Colesevelam
Cholestyramine
Polymer Backbone
Hydrophobic Side Chain
Primary Amines
Quaternary Amine Side Chains
Bound Bile Acid

29. Resins - Colestipol, cholestyramine, and colesevelam
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

30. Resins 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.

31. Nicotinic Acid (NIACIN)
apo B-100
apo E
Decreased VLDL
Production
¯ VLDL
apo C
¯ VLDL
Remnant
Liver
CONVERSION
Increased VLDL
Clearance through LPL
Other sites
¯ LDL

32. Nicotinic Acid (Niacin, Vitamin B3)
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.

33. 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

34. Fibrates (贝特类) 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

35. Fibrates 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

36. Summary of Clinical Effects

37. Summary of Side Effects
8.05
Drug Class Side Effects
Resins Unpalatability, bloating,
constipation, heartburn
Nicotinic acid Flushing, nausea, glucose
intolerance, abnormal liver
function tests
Fibrates Nausea, skin rash
Statins Myositis, myalgia, elevated
hepatic transaminases

38. Thanks!