Antiatherosclerotic drugs
Learning Objectives:
■
Describe the four main classes of drugs used
to treat hyperlipidemia
■
Explain their mechanisms of action, effects
upon serum lipid concentrations and ADR
Introduction
Atherosclerosis is a disease which
characterized by intimal thickening and
lipid deposition.
Hyperlipidemia
Endothelial injury
Thrombosis
Atherosclerosis
Smooth muscle
cell proliferation
Macrophage
Inflammatory mechanism
Introduction

Antiatherosclerotic drugs
– Used to prevent or slow progression of
atherosclerosis to reduce the risk of coronary
artery disease and prolong life
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Lipid-regulating drugs
Antioxidant
Endothelium protective drugs
Polyunsaturated fatty acids
Goals for Lipids & diagnosis of
hyperlipidemia
• LDL(mg/dL)
–
–
–
–
–
• HDL
< 100 →Optimal
100-129 → Near optimal
130-159 → Borderline
160-189→ High
≥ 190 → Very High
– < 40 → Low
– ≥ 60 → High
• Serum Triglycerides
–
–
–
–
• Total Cholesterol
– < 200 → Desirable
– 200-239 → Borderline
– ≥240 → High
•
< 150 → normal
150-199 → Borderline
200-499 → High
≥ 500 → Very High
Cholesterol (TC, LDL-C, HDL-C)
1 mg/dL = 0.02586 mmol/L
•
TG
1 mg/dL = 0.01129 mmol/L
Treatment of hyperlipidemia
– Non-Pharmacological Therapy – 1st line tx
• 1. Diet modification
–
–
–
–
–
–
–
Decrease intake of total fat and especially saturated fat
Increase fiber intake
Increase Omega-3-fatty acids (found in fish)
↓ homocysteine
↑ fruits and vegetables (antioxidants)
↓ simple sugars (sucrose)
Moderate alcohol consumption (EtOH can ↑ TG)
2. Exercise
Treatment of hyperlipidemia
• Niacin (Nicotinic acid, niaspan®, slo-niacin, Vitamin B3, V-pp)
– Decreases VLDL and LDL and significantly ↑ HDL
– Mechanism of action (MOA)
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1. Inhibits free fatty acid (FFA) release from
adipose tissues by inhibiting the intracellular
lipase system
2. Increases clearance of VLDL via lipoprotein lipase
pathway
3. Inhibits VLDL secretion into the blood thereby
preventing production of LDL
4. Reduces circulating fibrinogen (contributes to clot
formation) and ↑ tissue plasminogen activator (clot
dissolver)
5. HDL catabolic rate is decreased
• Niacin
–Indications
»↓ levels of TG (VLDL)
» Mixed elevation of LDL and VLDL
(alone or in combination with
reductase inhibitors)
» Elevation of TG (VLDL) and low
levels of HDL (Niaspan® approved for elevating HDL levels)
• Niacin - Adverse effects
–Flushing
»Harmless cutaneous vasodilation
»Uncomfortable sensation of warmth
»Occurs after drug is started or ↑ dose
»Lasts for the first several weeks
»Can give 325 mg aspirin 30 minutes
before each dose (prevents
prostaglandin synthesis). Can also
take ibuprofen in place of
ASA(acetylsalicylic acid)
• Niacin - Adverse effects
– Pruritis, rashes, dry skin
– acanthosis nigricans (黑棘皮症 , eruption of
velvet warty benign growths and
hyperpigmentation)
» Associated with insulin resistance
– Nausea and abdominal discomfort
– Hepatotoxicity
– Hyperuricemia
– Hypotension
Antilipemic agents
•Fibrates (gemfibrozil [Lopid®], fenofibrate
[Tricor®], clofibrate [Atromid-S®], bezafibrate)
–
–
–
–
Little or no effect on LDL
↓ VLDL (TG)
moderate ↑ of HDL
MOA
» Ligand for the nuclear transcription regulator,
peroxisome proliferator-activated receptor-α
(PPAR- α)
» MOA mostly unknown
• Fibrates
–MOA
»↑ activity of lipoprotein lipase for
lipolysis of triglyceride (↑ clearance)
»↓ lipolysis in adipose tissue, ↓ FFA
release
»↓ secretion of VLDL by liver
»↓ uptake of FFA by liver
»↑ HDL levels moderately
• Fibrates
– Indication: Hypertriglyceridemia
» Gemfibrozil – 600mg QD-BID (half life
1.5hrs)
» Fenofibrate – 1-3 67mg tablets QD (half life
20hrs)
» Taken with food - ↑ absorption
» Max reduction of VLDL is achieved within 34 weeks of treatment
– Adverse Effects
» Rashes
» GI disturbances (nausea, abdominal pain,
diarrhea)
• Fibrates - Adverse Effects
– Gallstones (upper abdominal discomfort)
» Gemfibrozil ↑ biliary cholesterol saturation
» Use with caution in pts with biliary tract ds,
women, obese pts, and Native Americans
– Myopathy (muscle injury)
» Tenderness, weakness, or unusual muscle
pain
» Will increase risk of statin-induced myopathy
when used together (rhabdomyolysis has
occurred rarely)
• Fibrates - Adverse Effects
–Hepatoxicity
–Arrythmias
–Hypokalemia
–Displaces warfarin from plasma albumin
since drug is highly protein bound.
Need to ↓ warfarin dose
• Bile Acid-Binding Resins
(colestipol [Colestid®] and cholestyramine
[Questran®])
– Will ↓ LDL, may ↑ VLDL (would require niacin if ↑ TG
prior to tx)
– MOA
» Bile acids, the metabolites of cholesterol, are
normally reabsorbed in the jejunum and ileum.
When resins are given, they bind to bile acids in the
intestinal lumen, prevent their reabsorption and
increase their excretion.
• Bile Acid-Binding Resins
– MOA
» ↑ excretion creates a demand for ↑
synthesis of bile acid. Liver cells must have
an ↑ cholesterol supply (provided by LDL) to
synthesize bile acid. Liver cells will ↑ their
LDL receptors, ↑ing uptake of LDL from
plasma.
– Indication
» Used alone to ↓ LDL (by 15-20%)
» Normally used as adjuncts to the statins to ↓
LDL (by 50%)
• Bile Acid-Binding Resins
– Indication
» Can be used to relieve pruritis in pts who
have cholestasis
» Dispensed in powder form (must be mixed
with fluid).
– Adverse Effects
» Must be taken with meals
» Constipation, bloating, indigestion, nausea
» Large doses may impair absorption of fats
or fat soluble vitamins (A, D, E, and K)
• HMG CoA Reductase Inhibitors
(“statins”) (lovastatin [Mevacor®], fluvastatin
[Lescol®], pravastatin [Pravachol®], simvastatin
[Zocor®], atorvastatin [Lipitor ®], cerivastatin
[Baycol ®])
–Most Effective for ↓ LDL
–moderately ↑ HDL and ↓ VLDL
–Fewest adverse effects and tolerated
best
Acetyl-CoA, 乙酰辅酶A
Acetoacetyl-CoA 乙酰乙酰辅酶A
Statins，他汀类
HMG-CoA Reductase
HMG-CoA
MVA, 甲羟戊酸
Squalene, 鲨烯
Cholesterol, 胆固醇
de novo synthesis pathway of Cholesterol , 胆固醇从头合成
• “Statins”
– MOA
» Inhibits hepatic HMG CoA reductase
» Inhibition of cholesterol synthesis causes
hepatocytes to synthesize more LDL
receptors
» Hepatocytes are able to remove more LDLs
from the blood
» Decrease production of apolipoprotein B100, thereby ↓ production of VLDL
» ↓ plaque cholesterol content
• “Statins”
– MOA
» ↓ inflammation at the plaque site
» Improve abnormal endothelial function
» Enhance the ability of blood vessels to dilate
» ↓ risk of thrombosis (inhibits platelet
aggregation and blocks thrombin synthesis)
» Statins have high first pass extraction by liver
(only a small fraction of each dose reaches
the general circulation)
• (“Statins”) – Indications
alone to ↓ LDL
 Used with bile acid – binding resins to ↓ LDL
 Used with niacin to ↓ LDL, ↓ VLDL, and ↑ HDL
 Enhanced if taken with food (except for
pravastatin – taken without food)
 Used
• “Statins” – Indications
– Atorvastatin is most efficacious agent for use in
severe hypercholesterolemia
– High potency (>40-50% LDL lowering) –
atorvastatin, simvastatin, cerivastatin
– Low potency (20-40% LDL lowering) –
lovastatin, fluvastatin, pravastatin
– ↓ LDL within 2 weeks; max reduction in 4-6
weeks
• “statins” – Adverse Effects
–Since LDL cholesterol levels will return to
pretreatment values if drugs are
withdrawn, treatment must continue
lifelong
–Statins are pregnancy category X
–Headache, rash, GI disturbances
(dyspepsia, cramps, flatulence,
constipation, abdominal pain)
• “Statins” – Adverse Effects
– Hepatotoxicity
» Discontinue medication(D/C med) if
aminotransferase activity is elevated more
than 3X the upper normal limit
» Check LFTs at baseline, 6 wks, 12 wks,
then every 6 months
– Myopathy (0.5% of pts)
» Risk highest with lovastatin and especially
in combination with Fibrates
Antioxidant ---probucol
• Pharmacological effects:
 to lower TC, LDL-C and HDL
• MECHANISM:
 to inhibit the oxidative modification of LDL
via the combination with lipoprotein for its
hyper-lipophilic property
Vit E, C - antioxidant
Endothelium protective drugs
• Drugs: polysaccharide sulfate
• Mechanisms of action:
 to prevent the conglutination of white cell
and platelet
 to inhibit the proliferation of vascular
smooth muscle
Polyunsaturated fatty acids---fish oil
• EPA and DHA


to decrease TG, VLDL,LDL-C
to increase HDL-C
• Potentially important effects:
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Inhibition of platelet function
Prolongation of bleeding time
Decrease of blood mucosity
Prevention of atherosclerosis
Summary
Medications for Hyperlipidemia
Drug Class
Agents
Effects (% change)
Side Effects
HMG CoA reductase
inhibitors
Lovastatin
Pravastatin
LDL (18-55), HDL (5-15)
 Triglycerides (7-30)
Myopathy, increased liver
enzymes
Cholesterol
absorption inhibitor
Ezetimibe
 LDL( 14-18),  HDL (1-3)
Triglyceride (2)
Headache, GI distress
LDL (15-30),  HDL (15-35)
 Triglyceride (20-50)
Nicotinic Acid
Flushing, Hyperglycemia,
Hyperuricemia, GI distress,
hepatotoxicity
Fibric Acids
Gemfibrozil
Fenofibrate
LDL (5-20), HDL (10-20)
Triglyceride (20-50)
Dyspepsia, gallstones,
myopathy
Bile Acid
sequestrants
Cholestyramine
 LDL
 HDL
No change in triglycerides
GI distress, constipation,
decreased absorption of
other drugs
TCM Tx for AS
• Folium Ginkgo 银杏叶
• Radix Salviae Miltiorrhizae 丹参
• Gynostemma pentaphyllum 绞股兰/七叶胆