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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