Drugs Used in H yperlipidemia - PowerPoint Presentation

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Drugs Used in Hyperlipidemia

By

Dr.

Sasan

Zaeri

PharmD

, PhD

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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 corticosteroidsNeeded for the synthesis of bile salts which are needed for digestion and absorption of fats

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Origin of cholesterolLiver

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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LipoproteinsServe as carriers for transporting lipids (cholesterol and triglycerides) in the blood

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Lipoproteins5

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ApolipoproteinsEmbedded in the lipoprotein shellThree functions

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 9

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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 tissuesMakes the greatest contribution to coronary atherosclerosisOxidized 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 cardioprotectiveTransports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removalAntiatherogenic

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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

T

o prolong life

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Treatment of hyperlipidemiaNon-Pharmacological Therapy – first line treatment

Diet modification

Decrease intake of total fat and especially saturated fat

Increase fiber intakeIncrease Omega-3-fatty acids (found in fish)↑ fruits and vegetables (antioxidants)↓ simple sugars (sucrose)Exercise

(↑

HDL levels)Pharmacological Therapy15

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Sites of Drugs Action

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Treatment of hyperlipidemiaDrug 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 bloodMost Effective for ↓ LDL-CDecrease 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 diseaseUsed in patients with triglycerides levels higher than 250 mg/dL and

with reduced

HDL-C levels

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Statins have high first pass extraction by liver

Prodrugs

– lovastatin and simvastatin

Statins have greatest efficacy when taken at nightAtorvastatin has the longest

half-life

Tolerated best among other hypolipemic drugs

Some Points about Statins

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Statins – Adverse EffectsRashGI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain

)

Hepatotoxicity

Myopathy (myositis and rhabdomyolysis)Risk highest especially in combination with fibratesCyp450 3A4 drug

interactions

Statins are pregnancy category X22

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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- IndicationsUsed 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 toxicityAvailable 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 resins25

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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- IndicationUsed in hypercholesterolemia

As

monotherapy

, ezetimibe reduces LDL-C by about 18%When combined with a statin, it is even more effective

Ezetimibe

is well tolerated27

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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 LDLIncreases clearance of VLDL via lipoprotein lipase pathwayInhibits FFA release from adipose tissues by inhibiting the intracellular lipase system

Decreases

HDL catabolic rate29

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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- IndicationsHypertriglyceridemia

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 effectsFlushingProstaglandin-mediated

Occurs after drug is started or ↑ dose

Lasts for the first several weeks

325mg aspirin 30 minutes before morning dose prevents prostaglandin synthesisNausea and abdominal discomfort

Hyperuricemia

, hepatotoxicity Niacin is NOT well-tolerated

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Fibrates (Gemfibrozil

,

F

enofibrate, Clofibrate)Little or no effect on LDL, ↓VLDL (TG), moderate ↑ of HDL

MOA

: Activation of Peroxisome Proliferator-Activated Receptor-α (PPAR- α)

↑ A

ctivity

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

E

ffects of

F

ibrates

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Fibrates - IndicationsHypertriglyceridemia

Mixed elevation of LDL-C and TG (in combination with statins)

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Fibrates - Adverse EffectsNausea (most prevalent)

Rashes (prevalent)

Cholesterol

gallstones (Gemfibrozil)Use with caution in patients with biliary tract dx, women, obese peopleMyopathy (muscle injury)Will increase risk of statin-induced myopathy when used together

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