Transcript Anti-Histamines

Lipid Lowering Agents
Hamid Boulares, Ph.D.
Department of Pharmacology, LSUHSC,
Email: [email protected]
Tel: 568-2304
LIPID TRANSPORT - Overview
Atherosclerosis
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.
IDL: intermediate Density
VLDL: Very low Density
HDL: High Density
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.
LCAT: Lecithin-Acetyl-CoA
C-acyltransferase
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
Characteristics of Lipoproteins
ApoE
VLDL : endogenous triglycerides; catabolized by lipoprotein lipase (LPL), short halflife
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.
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
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
Plasma Lipoproteins: Classes & Functions
Low Density Lipoprotein (LDL)
– Synthesized from IDL
– Cholesterol transport
– 78% lipid, 58% cholesterol &
CE
– Apo B-100
• Receptor binding
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
Dyslipidemia and atherosclerosis
Many clinical trials demonstrate that increase of LDL levels induce formation of
atherosclerosis plaques.
Risk of CHD
3.0
• For any level of LDL-C,
HDL-C is inversely
related to CHD risk
2.0
1.0
0.0
100
160
220
25
45
65
85
LDL-C
(mg/dL)
Gordon T et al. Am J Med 1977;62:707-714.
Slide source: www.lipidsonline.org
Genetic Causes of Dyslipidemia
Disease
Lipid
Profile
Prevalence
Etiology
Familial Hypercholesterolemia
 LDL
1:500 (+/-)
 LDL Receptor
Familial Defective ApoB100
 LDL
1:100
ApoB100 binding to
LDLR
Polygenic Hypercholesterolemia
 Chol
Common
unknown
TG HDL
VLDL
Common
VLDL breakdown
 VLDL synthesis
LDLTG
 HDL
1:100
Unknown, dominant
inheritance
Polygenic low HDL
 HDL
Common
Obesity, diabetes
high carb diets
Familial hypoalphalipoproteinemia
 HDL
1:100
Unknown, dominant
inheritance
Primary Hypercholesterolemia
Primary Hypertriglyceridemia
Familial Hypertriglyceridemia
Mixed Hyperlipidemia
Familial Combined Hyperlipidemia
Disorders of HDL metabolism
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).
Classification of Lipoprotein Analysis Results (mg/dl)
Total Cholesterol:
<200 desirable
200-239 borderline high
>240 high
HDL Cholesterol:
<40 low
>60 high
LDL Cholesterol:
<100 optimal
100-129 near/above optimal
130-159 borderline high
160-189 high
>190 very high
Triglycerides:
<150 normal
150-199 high
200-499 high
>500 very high
Modes 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.
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
STATINS
HMG CoA reductase
STATINS
Mechanism of Action
Increased LDL
Uptake
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)
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
Pleiotropic effects of statins on the vasculature
Clinical Science
www.clinsci.org
Clin. Sci. (2003) 105, 251-266
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
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 (>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
 Important interactions
 increased risk of myopathy
 in dose requirements (~30%) for
warfarin- fibrates displace warfarin
from albumin
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
Progression of Drug Therapy
in Primary Prevention
Initiate
LDLlowering
drug
therapy
6 wks
If LDL goal
not achieved,
intensify
LDL-lowering
therapy
6 wks
If LDL goal not
achieved,
intensify drug
therapy or
refer to a lipid
specialist
• 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
Q 4-6
mo
Monitor
response
and
adherence
to therapy