Anti-Histamines

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Lipid Lowering Agents
Hamid Boulares, Ph.D. Department of
Pharmacology, LSUHSC, Email hboulr_at_lsuhsc.edu T
el 568-2304
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LIPID TRANSPORT - Overview
IDL intermediate Density VLDL Very low
Density HDL High Density LCAT
Lecithin-Acetyl-CoA C-acyltransferase
Chylomicrons large lipoprotein particles that
transport dietary lipids from the intestines to
other locations in the body. They are one of the
5 major groups of lipoproteins (chylomicrons,
VLDL, IDL, LDL, HDL) which enable fats and
cholesterol to move within the water based
solution of the blood stream. Chylomicron
remnant Once triglyceride stores are
distributed, the chylomicron returns APOC2 (but
keeps APOE) back to the HDL and thus becomes a
chylomicron remnant. APOB48 and APOE are
important to identify the chylomicron remnant in
the liver for endocytosis and breakdown.
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Lipoproteins and Their Structure
Surface monolayer of polar lipids, unesterified
cholesterol and apolipoproteins Apolipoproteins
Add stability to structure act as ligands for
cell surface receptors or co-factors for
enzymatic reactions Core Cholesteryl esters
(cholesterol esterified to fatty acid), TG
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Characteristics of Lipoproteins
ApoE
VLDL endogenous triglycerides catabolized by
lipoprotein lipase (LPL), short half-life IDL
cholesteryl esters, converted to LDL by hepatic
lipase LDL apoB-mediated uptake by LDL receptor,
long half-life HDL phospholipids cholesteryl
esters, removed by hepatic scavenger receptor
B secreted to bile, steroid synthesis, VLDL
synthesis.
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Plasma Lipoproteins Classes Functions

• Very Low Density Lipoprotein (VLDL)
• Synthesized in liver
• Transport endogenous triglycerides to peripheral
  tissue
• 90 lipid, 10 protein
• Metabolized by LPL
• Apo B-100
• Receptor binding
• Apo C-II
• LPL activator
• Apo E
• Remnant receptor binding

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Plasma Lipoproteins Classes Functions

• Intermediate Density Lipoprotein (IDL)
• Synthesized from VLDL during VLDL degradation
• Triglyceride transport and precursor to LDL
• Apo B-100
• Receptor binding
• Apo C-II
• LPL activator
• Apo E
• Receptor binding

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Plasma Lipoproteins Classes Functions

• Low Density Lipoprotein (LDL)
• Synthesized from IDL
• Cholesterol transport
• 78 lipid, 58 cholesterol CE
• Apo B-100
• Receptor binding

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FYI
LDL receptor

• Characterized by Michael Brown and Joseph
  Goldstein (Nobel prize winners in 1985)
• Receptor also called B/E receptor because of its
  ability to recognize particles containing both
  Apo B and E
• Activity occurs mainly in the liver
• Receptor recognizes apo E more readily than apo
  B-100

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Dyslipidemia and atherosclerosis Many clinical
trials demonstrate that increase of LDL levels
induce formation of atherosclerosis plaques.
3.0

• For any level of LDL-C, HDL-C is inversely
  related to CHD risk

2.0
Risk of CHD
1.0
25
45
65
HDL-C (mg/dL)
0.0
85
100
160
220
LDL-C (mg/dL)
Gordon T et al. Am J Med 197762707-714.
Slide source www.lipidsonline.org
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Genetic Causes of Dyslipidemia
Disease Lipid Profile Prevalence Etiology
Primary Hypercholesterolemia
Familial Hypercholesterolemia ?? LDL 1500 (/-) ? LDL Receptor
Familial Defective ApoB100 ?? LDL 1100 ?ApoB100 binding to LDLR
Polygenic Hypercholesterolemia ? Chol Common unknown
Primary Hypertriglyceridemia
Familial Hypertriglyceridemia ?TG ?HDL ?VLDL Common VLDL breakdown ? VLDL synthesis
Mixed Hyperlipidemia
Familial Combined Hyperlipidemia ?LDL?TG ? HDL 1100 Unknown, dominant inheritance
Disorders of HDL metabolism
Polygenic low HDL ? HDL Common Obesity, diabetes high carb diets
Familial hypoalphalipoproteinemia ? HDL 1100 Unknown, dominant inheritance
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Secondary Hyperlipidemia
Hypertriglyceridemia (VLDL) Diabetes, oral
contraceptives (estrogen), hypothyroidism,
hypopituitarism, high sugar diet and high alcohol
intake (increased production and decreased
clearance of VLDL). Hypercholesterolemia
(LDL) High cholesterol (fat) diet,
hypopitutarism and hypothyroidism (decreased LDL
receptors).
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Classification of Lipoprotein Analysis Results
(mg/dl)
Total Cholesterol lt200 desirable 200-239
borderline high gt240 high
HDL Cholesterol lt40 low gt60 high
LDL Cholesterol lt100 optimal 100-129 near/above
optimal 130-159 borderline high 160-189 high gt190
very high
Triglycerides lt150 normal 150-199 high 200-499
high gt500 very high
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Modes to reduce lipid levels 1. Therapeutic
lifestyle changes. - improved diet reduce the
intake of saturated fat to lt 7 of calories. -
reduce the cholesterol intake to lt 200 mg/day. -
weight reduction - increased physical
activity 2. Medication.
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Lipid Lowering Drugs Anion-Exchange Resins
Cholestyramine and Colestipol and Colesevelam
Sequester bile acids (BA) in the gut hence
blocking enterohepatic cycling of BA
Usually used in combination with a statin
Major side effects bitter taste, nausea
constipation Important interactions bind polar
drugs such as warfarin, digoxin, thyroxine and
statins give 1 hr before resin
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STATINS
Increased LDL Uptake
HMG CoA reductase
STATINS Mechanism of Action
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Lipid Lowering Drugs STATINS

1. Fungal metabolites Lovostatin (MEVACOR),
   Simvastatin (ZOCOR), Provastatin (PRAVACHOL)
2. Synthetic derivatives Fluvastatin (LESCOL),
   Atorvastatin (LIPITOR) and Rosuvastatin (CRESTOR)
   
3. They have short half-lives (2 hours except
   atorvastatin at 14h) but effective with once
   daily administration
4. All have slightly higher efficacy if given at
   night
5. All except pravastatin are metabolised through
   CYP enzymes in the liver which is the source of
   important drug-drug interactions (e.g. with
   warfarin)
6. Major side effects Hepatitis and myositis
   (inflammation of the muscles)

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Fatal Rhabdomyolysis with Statins

• The major adverse effect of clinical significance
  associated with statin use is myopathy
• Rhabdomyolysis Breakdown of muscle proteins
  (myoglobin, creatine kinase) that leads to renal
  toxicity. Symptoms include muscle pain and
  weakness and dark urine due to muscle catabolism
• Reason for Cerivastatin (Baycol) withdrawal from
  the market (20-fold greater risk compared to
  other statins)
• Risk increased by combination with
• Fibrates especially for gemfibrozil/cerivastatin
• Nicotinic acid
• Protease Inhibitors (HAART therapy)-Highly Active
  AntiRetroviral Therapy

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Pleiotropic effects of statins on the vasculature
Clinical Science www.clinsci.org
Clin. Sci. (2003) 105, 251-266
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Lipid Lowering Agents Nicotinic Acid (Niacin)

• ? hepatic VLDL synthesis by inhibiting adipose
  tissue lipolysis
• ? VLDL clearance by ? LPL activity

• Is the licensed agent with largest impact on HDL
  (30-50 ?)
• Lowers lipoproteins VLDL, IDL, LDL (by 30)
• Usually employed in combination with fibrate,
  resin or statin
• Major side effects
• Flushing prostaglandin mediated
• Skin drying GI intolerance
• Exacerbates gout (? uric acid secretion),
  diabetes (promotes insulin resistance) and peptic
  ulcers

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Lipid Lowering Drugs Fibrates
Gemfibrozil and Fenofibrate

• Act as PPAR? ligands- multiple changes
• ? ApoA? ? HDL
• ? LPL
• ? FA uptake and oxidation in muscle cells
• ? FA oxidation in hepatocytes and ? TG synthesis
• Net Effects ?? VLDL (TG), ? LDL and ? HDL
• Absorbed efficiently (gt90) when given with a
  meal but not on an empty stomach
• Main side effects
• GI intolerance
• 1-2 ? in the incidence of gallstones due to ?
  cholesterol synthesis

• Important interactions
• ? increased risk of myopathy
• ? in dose requirements (30) for warfarin-
  fibrates displace warfarin from albumin

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Lipid Lowering Drugs EZETIMIBE

• Novel inhibitor of intestinal cholesterol
  transporter - inhibits intestinal cholesterol
  uptake and transport by 50
• Metabolite has 400x the potency of parent
  compound and prolongs action by enterohepatic
  cycling
• No important adverse effects OR significant drug
  interactions
• Unlike resins does not raise TG -
• synergism with statins
• (e.g. ezetimibe/simvastatin, marketed as Vytorin
  and Inegy)

NPCIL1 Niemann-Pick Cl-like channel 1 protein
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Progression of Drug Therapy in Primary Prevention
If LDL goal not achieved, intensify drug therapy
or refer to a lipid specialist
If LDL goal not achieved, intensifyLDL-lowering
therapy
Monitor response and adherence to therapy
Initiate LDL-lowering drug therapy
6 wks
6 wks
Q 4-6 mo

• Start statin or bile acid resin or nicotinic acid

• Consider higher dose of statin or add a bile
  acid sequestrant or nicotinic acid

• If LDL goal achieved, treat other lipid risk
  factors

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