Transcript DRUGS for DYSLIPIDEMIAS MED PHARM

DRUGS for DYSLIPIDEMIAS
MED PHARM
2/22/2010
DYSLIPIDEMIAS
A MODIFIABLE RISK FACTOR for CV
DISEASE
• LIFESTYLE MODIFICATION WORKS BETTER
THAN DRUGS AND IS CHEAPER
• 1 MG/ML INCREASE LDL-C INCREASES RISK OF
CV DISEASE 2-3%
• 1 MG/ML HDL DECREASE INCREASES CHD
RISK BY 3-4%
An Unstable Arterial Plaque and the Mechanisms of
Plaque Rupture
Heistad D. N Engl J Med 2003;349:2285-2287
FATES OF CHOLESTEROL
Membrane structure
Precursor of steroid hormones and vitamin D
Esterification for storage
Esterification for elimination
Precursor to bile salts
The Basic Components of Cholesterol Synthesis and
Excretion
Nabel E. N Engl J Med 2003;349:60-72
Figure 1. General structure of a lipoprotein.
General Features of Lipoproteins

Apolipoproteins:
specific lipid-binding proteins that attach to the surface
intracellular recognition for exocytosis of nascent particle after synthesis
activation of lipid-processing enzymes in the bloodstream,
binding to cell surface receptors for endocytosis and clearance.

Main lipid components
triacylglycerols
cholesterol esters
phospholipids

Major lipoproteins of the endogenous system:
very low density lipoproteins (VLDL)
intermediate density lipoproteins (IDL)
low density lipoproteins (LDL)
high density lipoproteins (HDL)

Electrophoretic mobility (charge):
HDLs =  lipoproteins
LDLs = - lipoproteins
VLDLs = pre- lipoproteins (intermediate between  and  mobility).
P
100%
C
P
P
Composition
80%
C
P
60%
C
T
40%
C
T
20%
T
T
0%
ChyloVLDL
LDL
microns Lipoprotein Type
HDL
Figure 2. The major classes of lipoproteins and their relative
content of triacylglycerol (T), cholesterol (C) and protein (P).
Summary of Lipoprotein classes:
Lipoprotein
Source
Apo
Protein:Lipid/
Proteins in Major (minor) Lipid
Mature
Transported
Function
VLDL
liver
B100,
CII, E
1:9
triacylglycerol (CE)
Synthesized:
FFA adipose/muscle
CE  LDL
IDL
Blood
B100, E
1:3
cholesterol ester
CE  liver via apo E
receptor
LDL
blood
B100
1:3
cholesterol ester
CE to liver (70%) and
peripheral cells (30%)
Causal agent in CHD
H
DL
liver
A1, CII, E
("ACE")
1:1
cholesterol ester
supplies apo CII, E to
chylomicrons and VLDL;
mediates reverse
cholesterol transport
OAAmalatepyruvate+NADPH
malic enzyme
Fatty acids oxaloacetate
-oxidation
Citrate
Acetyl CoA
Citrate
Lyase (requires ATP)
(2) Acetyl CoA
+Acetyl CoA
Thiolase
cytoplasm
Acetoacetyl CoA
HMG-CoA
synthase
MITOCHONDRION
HMG CoA
HMG CoA
Statins
reductase
Figure 2. Formation of mevalonate from
HMG-CoA is the rate limiting and
regulated step in the biosynthesis of
cholesterol
Mevalonate
CHOLESTEROL
smooth
endoplasmic
reticulum
Stage 1
Acetyl CoA (C2)
HMG-CoA
NADPH
HMG-CoA
Reductase
NADP+
rate-determining step
cholesterol activates proteolytic degradation
amount controlled by induction/repression
hormonally controlled via phosphorylation
Mevalonate (C6)
Stage 2
Mevalonate
CO2
Active Isoprenoids (C5)
NADPH
Several
Condensation Steps
NADP+
Squalene (C30)
Lanosterol (C30)
Squalene (C30)
3ATP
3ADP
Stage 4
Stage 3
O2
NADPH
NADP+
Cyclization
Squalene
epoxidase/
cyclase
O2
(19 steps)
NADPH
NADP+
Lanosterol (C30)
(4-ring structure)
Figure 3. The four stages of cholesterol biosynthesis
3 CH3
Cholesterol (C27)
THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA
STATINS
Competitive inhibitors of HMG-CoA reductase
Act at low concentration (10-9)
Block HMG-CoA binding site limiting substrate access to catalytic site
Decreased cholesterol synthesis:
in liver = decreased VLDL output and hence LDL production
in all tissues = LDL receptor induction  increased LDL uptake
Increase HDL by boosting apo A1 production
Side effects:
liver damage (monitor plasma AST/ALT)
myopathy that can lead to fatal rhabdomyolysis (monitor plasma CK)
negative interactions with other lipid-lowering drugs (fibrates inhibit
statin metabolism)
THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA
BILE ACID SEQUESTERING RESINS
(cholestyramine/colestipol)
Cholesterol is excreted by conversion to bile acids in liver cells
Bile acids are recycled from ileum via enterohepatic circulation to feedback repress 7hydroxylase
Sequestering resins bind bile salts (made from bile acids) to reduce recycling
Chain of events:
reduced recycling lowers liver bile salt concentration 
lowers feedback repression 
increases hydroxylase activity 
increases cholesterol conversion to bile acids 
lowers cholesterol concentration 
more LDL receptors 
increased hepatic uptake of LDL 
lowers plasma cholesterol
Side effects:
increases blood triglycerides
abdominal fullness  lowers food intake

THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA
NICOTINIC ACID
Water soluble vitamin (niacin; B3)
Increases circulating HDL
May lower circulating LDL
Combined with statin may slow progression of heart disease
Proposed mechanism – decreased release by adipsoe tissue of fatty acids to
lower availability for making TAGs and cholesterol for VLDL
Side effects:
headache, dizziness
long term use linked to liver damage (monitor ALT/AST)
flushing (most common)
THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA
FIBRATES
Improve HDL
Little effect on LDL
Lower circulating triglyceride concentrations
Prescribed in combination with statins
Mechanism unknown
Inhibit the metabolism of statins – Increases
risk of statin myopathy
THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA
EZETIMIBE (ZETIA)
Lowers intestinal absorption of dietary cholesterol
Binds to the Niemann-Pick C1-Like1 (NPC1L1) protein
on epithelial cells
NPC1L1 mediates cholesterol uptake from intestinal
lumen
Side effects: diarrhea, headache, and less commonly
myalgia and liver effects that should be monitored.
STATINS
Actions independent of lipid lowering
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Endothelial function
Coagulation
Vascular inflammation
Smooth muscle
Plaque stability