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