drugs for dyslipidemias med pharm 2/22/2010 dyslipidemias a modifiable risk factor for cv disease...
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DRUGS for DYSLIPIDEMIASMED PHARM
2/22/2010
DYSLIPIDEMIASA 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%
Heistad D. N Engl J Med 2003;349:2285-2287
An Unstable Arterial Plaque and the Mechanisms of Plaque Rupture
FATES OF CHOLESTEROL
Membrane structure
Precursor of steroid hormones and vitamin D
Esterification for storage
Esterification for elimination
Precursor to bile salts
Nabel E. N Engl J Med 2003;349:60-72
The Basic Components of Cholesterol Synthesis and Excretion
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
synthesisactivation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance.
Main lipid componentstriacylglycerolscholesterol estersphospholipids
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 = lipoproteinsLDLs = -lipoproteins VLDLs = pre- lipoproteins (intermediate between and mobility).
0%
20%
40%
60%
80%
100%
Chylo-microns
VLDL LDL HDL
Lipoprotein Type
Co
mp
osi
tio
n
C
P
T
C
P
T
T
P
C
C P
T
Figure 2. The major classes of lipoproteins and their relative content of triacylglycerol (T), cholesterol (C) and protein (P).
Summary of Lipoprotein classes:
Lipo-protein
Source Apo Proteins in
Mature
Protein:Lipid/Major (minor) Lipid
Transported
Function
VLDL liver B100, CII, E
1:9triacylglycerol (CE)
Synthesized:FFA adipose/muscleCE LDL
IDL Blood B100, E 1:3cholesterol ester
CE liver via apo E receptor
LDL blood B100 1:3cholesterol ester
CE to liver (70%) and peripheral cells (30%)Causal agent in CHD
HDL
liver A1, CII, E("ACE")
1:1cholesterol ester
supplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport
MITOCHONDRION
Fatty acids
Acetyl CoA-oxidation
oxaloacetateCitrate Citrate
Mevalonate
CHOLESTEROL
smoothendoplasmicreticulum
HMG CoA reductase
Acetoacetyl CoA
HMG CoA
cytoplasm
HMG-CoAsynthase
Thiolase
Figure 2. Formation of mevalonate from HMG-CoA is the rate limiting and regulated step in the biosynthesis of cholesterol
Lyase (requires ATP)
OAAmalatepyruvate+NADPH malic enzyme
(2) Acetyl CoA
Statins
+Acetyl CoA
Mevalonate
Active Isoprenoids (C5)
Squalene (C30)
3ATPCO2
SeveralCondensation Steps
3ADP
NADPH
NADP+
Stage 2
Squalene (C30)
Cyclization
Squaleneepoxidase/cyclase
Lanosterol (C30)
(4-ring structure)
O2
NADPH
NADP+
Stage 3Stage 4
Lanosterol (C30)
(19 steps)O2
NADPH
NADP+ 3 CH3
Cholesterol (C27)
Acetyl CoA (C2)
HMG-CoA
HMG-CoAReductase
Mevalonate (C6)
NADPH
NADP+
Stage 1
Figure 3. The four stages of cholesterol biosynthesis
rate-determining step cholesterol activates proteolytic degradation amount controlled by induction/repression hormonally controlled via phosphorylation
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 productionin 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, dizzinesslong 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.
STATINSActions independent of lipid lowering
• Endothelial function• Coagulation • Vascular inflammation• Smooth muscle• Plaque stability