Hamid Boulares, Ph.D. Department of Pharmacology, LSUHSC, Email: hboulr@lsuhsc Tel: 568-2304
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Transcript of Hamid Boulares, Ph.D. Department of Pharmacology, LSUHSC, Email: hboulr@lsuhsc Tel: 568-2304
Hamid Boulares, Ph.D.Hamid Boulares, Ph.D.
Department of Pharmacology, LSUHSC,
Email: [email protected]
Tel: 568-2304
Lipid Lowering AgentsLipid Lowering Agents
LIPID TRANSPORT - OverviewLIPID TRANSPORT - Overview
Chylomicrons: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: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.
IDLIDL: intermediate DensityVLDLVLDL: Very low DensityHDLHDL: High Density
LCATLCAT: Lecithin-Acetyl-CoAC-acyltransferase
AtherosclerosisAtherosclerosis
Lipoproteins and Their Structure
SurfaceSurface: monolayer of polar lipids, unesterified cholesterol and apolipoproteins
ApolipoproteinsApolipoproteins: Add stability to structure; act as ligands for cell surface receptors or co-factors for enzymatic reactions
CoreCore: Cholesteryl esters (cholesterol esterified to fatty acid), TG
Characteristics of Lipoproteins
ApoE
VLDL VLDL : endogenous triglycerides; catabolized by lipoprotein lipase (LPL), short half-lifeIDLIDL: cholesteryl esters, converted to LDL by hepatic lipaseLDLLDL: apoB-mediated uptake by LDL receptor, long half-lifeHDLHDL: phospholipids cholesteryl esters, removed by hepatic scavenger receptor Bsecreted to bile, steroid synthesis, VLDL synthesis.
Plasma Lipoproteins: Plasma Lipoproteins: Classes & FunctionsClasses & 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 bindingApo C-II
•LPL activatorApo E
•Remnant receptor binding
Plasma Lipoproteins: Plasma Lipoproteins: Classes & FunctionsClasses & Functions
• Intermediate Density Lipoprotein (IDL)Synthesized from VLDL during VLDL degradationTriglyceride transport and precursor to LDL– Apo B-100
• Receptor binding– Apo C-II
• LPL activator– Apo E
• Receptor binding
Plasma Lipoproteins: Plasma Lipoproteins: Classes & FunctionsClasses & Functions
Low Density Lipoprotein (LDL)– Synthesized from IDL– Cholesterol transport– 78% lipid, 58% cholesterol &
CE– Apo B-100
• Receptor binding
LDL receptorLDL 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
FYI
Dyslipidemia and atherosclerosis
Many clinical trials demonstrate that increase of LDL levels induce formation of atherosclerosis plaques.
Gordon T et al. Am J Med 1977;62:707-714.
Ris
k o
f C
HD
LDL-C(mg/dL)
0.0
1.0
2.0
3.0
100 160 220 8565
4525
HDL-C
(mg/d
L)
• For any level of LDL-C, HDL-C is inversely related to CHD risk
Slide source: www.lipidsonline.org
Disease Lipid Profile
Prevalence Etiology
Primary Hypercholesterolemia
Familial Hypercholesterolemia LDL 1:500 (+/-) LDL Receptor
Familial Defective ApoB100 LDL 1:100 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 LDLTG
HDL
1:100 Unknown, dominant inheritance
Disorders of HDL metabolism
Polygenic low HDL HDL Common Obesity, diabetes high carb diets
Familial hypoalphalipoproteinemia HDL 1:100 Unknown, dominant inheritance
Genetic Causes of Dyslipidemia
HypertriglyceridemiaHypertriglyceridemia (VLDL)
Diabetes, oral contraceptives (estrogen), hypothyroidism, hypopituitarism, high sugar diet and high alcohol intake (increased production and decreased clearance of VLDL).
HypercholesterolemiaHypercholesterolemia (LDL)
High cholesterol (fat) diet, hypopitutarism and hypothyroidism (decreased LDL receptors).
Secondary HyperlipidemiaSecondary Hyperlipidemia
Classification of Lipoprotein Analysis Results (mg/dl)Classification of Lipoprotein Analysis Results (mg/dl)
Total Cholesterol:<200 desirable
200-239 borderline high>240 high
LDL Cholesterol:<100 optimal
100-129 near/above optimal130-159 borderline high
160-189 high>190 very high
HDL Cholesterol:<40 low>60 high
Triglycerides:<150 normal150-199 high200-499 high
>500 very high
Modes to reduce lipid levelsModes to reduce lipid levels:
1. Therapeutic lifestyle changes.
- improved diet: reduce the intake of saturated fat to < 7% of calories.
- reduce the cholesterol intake to < 200 mg/day.
- weight reduction
- increased physical activity
2. Medication.
Cholestyramine and Colestipol and Colesevelam
Lipid Lowering Drugs:Lipid Lowering Drugs: Anion-Exchange ResinsAnion-Exchange Resins
Sequester bile acids (BA) in the gut hence blocking enterohepatic cycling of BA
Usually used in combination Usually used in combination with a statinwith 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
STATINSSTATINS
Increased LDLIncreased LDLUptakeUptake
STATINSSTATINS Mechanism of ActionMechanism of Action
HMG CoA reductaseHMG CoA reductase
Lipid Lowering Drugs: Lipid Lowering Drugs: STATINSSTATINS
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 but effective with once daily administrationeffective with once daily administration
4. All have slightly higher efficacy if given at nightslightly 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)
6.6. Major side effects:Major side effects: Hepatitis and myositis (inflammation of the muscles)
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:Risk increased by combination with: – Fibrates especially for gemfibrozil/cerivastatin– Nicotinic acid– Protease Inhibitors (HAART therapy)-Highly Active AntiRetroviral
Therapy
Pleiotropic effects of statins on the vasculature Pleiotropic effects of statins on the vasculature
Clinical Science www.clinsci.org Clin. Sci. (2003) 105, 251-266 Clinical Science www.clinsci.org Clin. Sci. (2003) 105, 251-266
Lipid Lowering Agents: Lipid Lowering Agents: Nicotinic Acid (Niacin)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 effectsFlushing – prostaglandin mediatedSkin drying & GI intoleranceExacerbates gout ( uric acid secretion), diabetes (promotes insulin resistance) and peptic ulcers
Lipid Lowering Drugs: Lipid Lowering Drugs: FibratesFibrates
Important interactions
increased risk of myopathy
in dose requirements (~30%) for warfarin- fibrates displace warfarin from albumin
• 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 (>90%) 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
Gemfibrozil and Fenofibrate
• 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
Lipid Lowering Drugs: Lipid Lowering Drugs: EZETIMIBEEZETIMIBE
Progression of Drug Therapy Progression of Drug Therapy in Primary Preventionin Primary Prevention
If LDL goal not achieved, intensifyLDL-lowering therapy
If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist
Monitor response and adherence to therapy
• Start statin or bile acid resin or nicotinic acid
• Consider higher dose of statin or add a bile acid sequestrant or nicotinic acid
6 wks 6 wks Q 4-6 mo
• If LDL goal achieved, treat other lipid risk factors
Initiate LDL-lowering drug therapy