Transcript STATINS
By
Dr. Sasan Zaeri
PharmD, PhD
Introduction
Cholesterol
Serves as a component of cell membranes and
intracellular organelle membranes
Is involved in the synthesis of certain hormones
including estrogen, progesterone, testosterone,
adrenal corticosteroids
Needed for the synthesis of bile salts which are
needed for digestion and absorption of fats
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Origin of cholesterol
Liver
Acetyl CoA is converted to mevalonic acid and
ultimately to cholesterol by HydroxyMethyl
Glutaryl Coenzyme A (HMG-CoA) reductase
Endogenous synthesis of cholesterol increases
at night
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Lipoproteins
Serve as carriers for transporting lipids (cholesterol
and triglycerides) in the blood
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Lipoproteins
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Apolipoproteins
Embedded in the lipoprotein shell
Three functions
1.
2.
3.
Serve as recognition sites for cell-surface
receptors; allowing cells to bind and ingest the
lipoprotein
Activate enzymes that will metabolize the
lipoprotein
↑ structural stability of the lipoprotein
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Types of
lipoproteins
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Types of
lipoproteins
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VLDL (very low density lipoprotein)
Contain triglycerides (TGs) and some
cholesterol
Account for nearly all TGs in the blood
Contain Apo B-100
Deliver triglycerides from the liver to adipose
tissues and muscles
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LDL (low density lipoprotein)
“Bad cholesterol”
Contains cholesterol
Accounts for 60-70% of cholesterol in the blood
Contains Apo B-100
Delivers cholesterol to peripheral tissues
Makes the greatest contribution to coronary
atherosclerosis
Oxidized LDL contributes to atherosclerotic plaque
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HDL (high-density lipoprotein)
“Good cholesterol”
Contain cholesterol
Account for 20-30% of cholesterol in the blood
Some contain Apo A-I and Apo A-II
Apo A-I is cardioprotective
Transports cholesterol from the peripheral tissues back
to the liver – promotes cholesterol removal
Antiatherogenic
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Metabolism of Lipoproteins of Hepatic Origin
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Classification of Plasma Lipid Levels
Total cholesterol
<200 mg/dl
Desirable
HDL-C
<40 mg/dl
Low (consider <50 mg/dl as low for women)
LDL-C
<70 mg/dl
Optimal for very high risk (minimal goal for CHD
equivalent patients)
<100 mg/dl
Optimal
Triglycerides
<150 mg/dl
Normal
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Why to Treat Hyperlipidemia
To prevent or slow progression of
atherosclerosis
To reduce the risk of coronary artery disease
To prolong life
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Treatment of hyperlipidemia
Non-Pharmacological Therapy – first line treatment
Diet modification
Decrease intake of total fat and especially saturated fat
Increase fiber intake
Increase Omega-3-fatty acids (found in fish)
↑ fruits and vegetables (antioxidants)
↓ simple sugars (sucrose)
Exercise (↑ HDL levels)
Pharmacological Therapy
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Sites of Drugs Action
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Treatment of hyperlipidemia
Drug therapy
HMG-CoA Reductase Inhibitors (Statins)
Bile Acid-binding Resins (e.g. Cholestyramine,
Cholestipol)
Inhibitors of cholesterol absorption (Ezetimibe)
Niacin (Nicotinic Acid)
Fibric Acid Derivatives (e.g. Gemfibrozil)
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Statins (Atorvastatin, Lovastatin, Fluvastatin,
Simvastatin etc.)
MOA
Inhibits hepatic HMG CoA reductase >>> Inhibition of
cholesterol synthesis causes hepatocytes to synthesize more
LDL receptors >>> Hepatocytes will remove more LDLs from
the blood
Most Effective for ↓ LDL-C
Decrease production of apolipoprotein B-100, thereby ↓
production of VLDL
↓ Plaque cholesterol content and ↓ inflammation at the plaque
site (Anti-atherosclorotic properties)
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STATINS: effects on lipoproteins
LDL-C: 20-55%
TG: 7-45% (for TG>250 mg/dL, the percent is
same as that of LDL; for TG<250 mg/dL
maximum 25% reduction)
HDL-C: 5-15%
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Statins-Indication:
Used in hypercholesterolemia
Atorvastatin is most efficacious agent for use in severe
hypercholesterolemia (>40-50% LDL-C lowering)
↓ LDL within 2 weeks; max reduction in 4-6 weeks
Used in Coronary Artery Disease (CAD)
Clinical trials have shown that they reduce mortality in
patients with ischemic heart disease
Used in patients with triglycerides levels higher than 250
mg/dL and with reduced HDL-C levels
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Some Points about Statins
Statins have high first pass extraction by liver
Prodrugs – lovastatin and simvastatin
Statins have greatest efficacy when taken at night
Atorvastatin has the longest half-life
Tolerated best among other hypolipemic drugs
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Statins – Adverse Effects
Rash
GI disturbances (dyspepsia, cramps, flatulence,
constipation, abdominal pain)
Hepatotoxicity
Myopathy (myositis and rhabdomyolysis)
Risk highest especially in combination with fibrates
Cyp450 3A4 drug interactions
Statins are pregnancy category X
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Bile Acid-Binding Resins (Cholestyramine and
Colestipol)
MOA
Binding to bile acids (the metabolites of cholesterol) in
the intestinal lumen and inhibition from their
reabsorption >>> ↑ LDL receptors by liver cells to
capture more cholesterol and synthesize bile acids
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Bile-acid binding resins- Indications
Used in hypercholesterolemia (↓ LDL-C 15-20%)
Normally used as adjuncts to the statins to ↓ LDL-C (by 50%)
Can be used to relieve pruritis in patients with cholestasis
Can be used for severe digitalis toxicity
Available in powder form (must be mixed with fluid)
Must be taken with meals
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Bile Acid-Binding Resins- Adverse Effects and Drug
Interactions
GI discomfort: (bloating, dyspepsia, nausea, constipation)
Large doses may impair absorption of fats or fat soluble
vitamins (A, D, E, and K)
Resins bind many drugs e.g. digoxin, warfarin,
tetracycline, thyroxine etc.
These agents should be given either 1 hour before or 4 hours
after the resins
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Inhibitors of cholesterol absorption (Ezetimibe)
MOA:
Prevention of absorption of
dietary cholesterol and
cholesterol that is excreted
in bile >>> ↑ LDL receptors
in liver and ↑removal of
LDL-C from
the blood
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Ezetimibe- Indication
Used in hypercholesterolemia
As monotherapy, ezetimibe reduces LDL-C by about 18%
When combined with a statin, it is even more effective
Ezetimibe is well tolerated
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Niacin (Nicotinic acid)
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MOA of Niacin (Nicotinic acid)
Inhibits VLDL secretion into the blood thereby preventing
production of LDL
Increases clearance of VLDL via lipoprotein lipase pathway
Inhibits FFA release from adipose tissues by inhibiting
the intracellular lipase system
Decreases HDL catabolic rate
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NICOTINIC ACID: effects on lipoproteins
LDL-C: 5-25 %;
TG: 20-50 %
HDL-C: 15-35 %
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Niacin- Indications
Hypertriglyceridemia
Mixed elevation of LDL-C and TG (in combination with
statins)
Elevation of TG (VLDL) and low levels of HDL
Start with low dose and gradually increase
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Niacin - Adverse effects
Flushing
Prostaglandin-mediated
Occurs after drug is started or ↑ dose
Lasts for the first several weeks
325mg aspirin 30 minutes before morning dose prevents
prostaglandin synthesis
Nausea and abdominal discomfort
Hyperuricemia, hepatotoxicity
Niacin is NOT well-tolerated
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Fibrates (Gemfibrozil, Fenofibrate, Clofibrate)
Little or no effect on LDL, ↓VLDL (TG), moderate ↑ of
HDL
MOA: Activation of Peroxisome Proliferator-Activated
Receptor-α (PPAR- α)
↑ Activity of endothelial lipoprotein lipase
↑ FFA oxidation in hepatocytes
↓ Secretion of VLDL by liver
↑ HDL levels moderately by ↑ Apo AI and Apo AII
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Hepatic & Peripheral
Effects of Fibrates
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Fibrates - Indications
Hypertriglyceridemia
Mixed elevation of LDL-C and TG (in combination with
statins)
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Fibrates - Adverse Effects
Nausea (most prevalent)
Rashes (prevalent)
Cholesterol gallstones (Gemfibrozil)
Use with caution in patients with biliary tract dx, women,
obese people
Myopathy (muscle injury)
Will increase risk of statin-induced myopathy when used
together
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