Download Hypolipidemic Drugs

Lipid-Lowering Drugs
What are lipoproteins?
• Lipoproteins are protein-lipid complexes.
The Players – Lipids
Triacylglycerol
Phospholipids
Cholesterol
Cholesteryl esters
The Players - Apolipoproteins
• Apo AI (liver, small intestine)
– Structural; activator of lecithin:cholesterol acyltransferase (LCAT)
• Apo AII (liver)
– Structural; inhibitor of hepatic lipase; component of ligand for HDL
binding
• Apo A-IV (small intestine)
– Activator of LCAT; modulator of lipoprotein lipase (LPL)
• Apo A-V (liver)
– Direct functional role is unknown; regulates TG levels.
Apolipoproteins
• Apo B-100 (liver)
– Structural; synthesis of VLDL; ligand for LDL-receptor
• Apo B-48 (small intestine)
– Structural; synthesis of chylomicrons; derived from apo B100 mRNA following specific mRNA editing
• Apo E (liver, macrophages, brain)
– Ligand for apoE receptor; mobilization of cellular
cholesterol
Apolipoproteins
• Apo C-I (liver)
– Activator of LCAT, inhibitor of hepatic TGRL uptake
• Apo C-II (liver)
– Activator of LPL, inhibitor of hepatic TGRL uptake
• Apo C-III (liver)
– Inhibitor of LPL, inhibitor of hepatic TGRL uptake
Amphipathic Helices
Lipoprotein Surface
Lipoprotein Classes
Chylomicrons,
VLDL, and
their catabolic
remnants
> 30 nm
D<1.006 g/ml
LDL
20–22 nm
D=1.019-1.063g/ml
HDL
9–15 nm
D=1.063-1.21 g/ml
Doi H et al. Circulation 2000;102:670-676; Colome C et al. Atherosclerosis 2000;
149:295-302; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994.
Lipids Online
Lipoprotein Metabolism
• Exogenous/chylomicron pathway (dietary fat)
• Endogenous pathway (lipids synthesized by
the liver)
• HDL metabolism (apolipoprotein transfer,
cholesteryl ester transfer, reverse cholesterol
transport
Lipoprotein Metabolism
• Exogenous/chylomicron pathway (dietary fat)
• Endogenous pathway (lipids synthesized by
the liver)
• HDL metabolism (apolipoprotein transfer,
cholesteryl ester transfer, reverse cholesterol
transport
TG Rich: VLDL
Surface Monolayer
Phospholipids (12%)
Free Cholesterol (14%)
Protein (4%)
Hydrophobic Core
Triglyceride (65%)
Cholesteryl Esters (8%)
Cholesterol and
Atherosclerosis, Grundy)
VLDL
Metabolism
Apo C’s and apoE and
cholesteryl ester are
acquired from HDL in
circulation
Cholesterol and
Atherosclerosis, Grundy)
Fatty Acid Transport
ApoC-II activates
lipoprotein lipase which
catalyses the hydrolysis of
TG
Cholesterol and
Atherosclerosis, Grundy)
VLDL
Conversion to
LDL
Further action on IDL by hepatic
lipase loses additional
apolipoproteins (apoE)
becomes and is converted to
LDL
Cholesterol and
Atherosclerosis, Grundy)
CE Rich: LDL
Surface Monolayer
Phospholipids (25%)
Free Cholesterol (15%)
Protein (22%)
Hydrophobic Core
Triglyceride (5%)
Cholesteryl Esters
(35%)
Cholesterol and
Atherosclerosis, Grundy)
LDL Metabolism
LDL is removed by
apoB100 receptors
which are mainly
expressed in the liver
Hepatic Lipase
Cholesteryl ester
transfer protein
Cholesterol and
Atherosclerosis, Grundy)
LDL Uptake by Tissues
X
X
Defects in the LDL receptor leads to familial hypercholesterolemia
Cholesterol and
Atherosclerosis, Grundy)
CE Rich: HDL
Surface Monolayer
Phospholipids (25%)
Free Cholesterol (7%)
Protein (45%)
Hydrophobic Core
Triglyceride (5%)
Cholesteryl Esters
(18%)
Cholesterol and
Atherosclerosis, Grundy)
HDL Metabolism
Nascent HDL (lipid-poor apoA-I) is produced by the liver and intestine
Hepatic Cholesterol Metabolism
Hepatic Cholesterol Synthesis
Rate Limiting
Only pathway
for cholesterol
degradation
Energetically expensive; prefer to
conserve what is already
made/acquired – LDL receptor
pathway
Cholesterol and
Atherosaclerosis, Grundy)
LDL Cellular Metabolism
LDL are taken up by the LDL Receptor into clathrin-coated pits
Cholesterol and
Atherosaclerosis, Grundy)
Endothelial Dysfunction
•
•
•
•
Increased endothelial permeability
to lipoproteins and plasma
constituents mediated by NO,
PDGF, AG-II, endothelin.
Up-regulation of leukocyte
adhesion molecules (L-selectin,
integrins, etc).
Up-regulation of endothelial
adhesion molecules (E-selectin, Pselectin, ICAM-1, VCAM-1).
Migration of leukocytes into artery
wall mediated by oxLDL, MCP-1,
IL-8, PDGF, M-CSF.
Ross, NEJM; 1999
Formation of Fatty Streak
• SMC migration stimulated by
PDGF, FGF-2, TGF-B
• T-Cell activation mediated by
TNF-a, IL-2, GM-CSF.
• Foam-cell formation mediated
by oxLDL, TNF-a, IL-1,and MCSF.
• Platelet adherence and
aggregation stimulated by
integrins, P-selectin, fibrin,
TXA2, and TF.
Ross, NEJM; 1999
Formation of Advanced, Complicated Lesion
•
•
•
•
Fibrous cap forms in response to
injury to wall off lesion from
lumen.
Fibrous cap covers a mixture of
leukocytes, lipid and debris which
may form a necrotic core.
Lesions expand at shoulders by
means of continued leukocyte
adhesion and entry.
Necrotic core results from
apoptosis and necrosis, increased
proteolytic activity and lipid
accumulation.
Ross, NEJM; 1999
Development of Unstable Fibrous
Plaque
•
•
•
•
Rupture or ulceration of fibrous cap
rapidly leads to thrombosis.
Occurs primarily at sites of
thinning of the fibrous cap.
Thinning is a result of continuing
influx of and activation of
macrophages which release
metalloproteinases and other
proteolytic enzymes.
These enzymes degrade the matrix
which can lead to hemorrhage and
thrombus formation
Ross, NEJM; 1999
Role of LDL in Atherosclerosis
LDL Readily Enter the Artery Wall Where They May be Modified
Vessel Lumen
LDL
Endothelium
Oxidation of Lipids
and ApoB
LDL
Aggregation
Hydrolysis of Phosphatidylcholine
to Lysophosphatidylcholine
Other Chemical Modifications
Modified LDL
Modified LDL are Proinflammatory
Intima
Steinberg D et al. N Engl J Med 1989;320:915-924.
Lipids Online
Role of LDL in Atherosclerosis
Vessel Lumen
Monocyte
Remnant Lipoproteins
Adhesion
Molecules
Cytokines
Macrophage
Endothelium
MCP-1
Remnants
Modified
Remnants
Foam Cell
Intima
Growth Factors
Metalloproteinases
Cell Proliferation
Matrix Degradation
Doi H et al. Circulation 2000;102:670-676.
Lipids Online
HDL Prevent Foam Cell Formation
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
MCP-1
Endothelium
LDL
Modified LDL
Cytokines
Macrophage
Foam
Cell
HDL Promote Cholesterol Efflux
Intima
Miyazaki A et al. Biochim Biophys Acta 1992;1126:73-80.
Lipids Online
Atherosclerosis and lipoprotein metabolism
Atheromatous disease is ubiquitous and underlies the commonest causes
of death (e.g. myocardial infarction) and disability (e.g. stroke) in industrial
countries
Hypertension and dyslipidemia are ones of the most important risk factors,
amenable to drug therapy
ATHEROMA is a focal disease of the intima of large and medium-sized
arteries
A t h e r o g e n e s i s involves several stages:
- endothelial dysfunction with altered PGI2 and NO synthesis
- monocyte attachment
- endothelial cells bind LDL
- oxidatively modified LDL is taken up by macrophages
- having taken up oxidised LDL, these macrophages (now foam cells) migrate
subendothelially
- atheromatous plaque formation
- rupture of the plaque
Atherosclerosis and lipoprotein metabolism
LIPIDS, including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are
transported in the plasma as lipoproteins, of which there are four classes:
- chylomicrons transport TG and CHO from the GIT to the tissues, where
they are split by lipase, releasing free fatty acids.There are taken up in muscle
and adipose tissue. Chylomicron remnants are taken up in the liver
- very low density lipoproteins (VLDL), which transport CHO and newly
synthetised TG to the tissues, where TGs are removed as before, leaving:
- low density lipoproteins (LDL) with a large component of CHO, some of which
is taken up by the tissues and some by the liver, by endocytosis via specific
LDL receptors
- high density lipoproteins (HDL).which absorb CHO derived from cell
breakdown in tissues and transfer it to VLDL and LDL
Atherosclerosis and lipoprotein metabolism
There are two different pathways for exogenous and endogenous
lipids:
THE EXOGENOUS PATHWAY: CHO + TG absorbed from the GIT are
transported in the lymph and than in the plasma as
CHYLOMICRONS to capillaries in muscle and adipose tissues. Here
the core TRIGL are hydrolysed by lipoprotein lipase, and the
tissues take up the resulting FREE FATTY ACIDS
CHO is liberated within the liver cells and may be stored,
oxidised to bile aids or secreted in the bile unaltered
Alternatively it may enter the endogenous pathway of lipid
transpor in VLDL
Atherosclerosis and lipoprotein metabolism
EXOGENOUS
PATHWAY
CHO
may be
stored
oxidised
to
bile acids
ENDOGENOUS
PATHWAY
secreted
in
the bile
unaltered
Atherosclerosis and lipoprotein metabolism
THE ENDOGENOUS PATHWAY
CHO and newly synthetised TG are transported from the liver as VLDL to
muscle and adipose tissue, there TG are hydrolysed and the resulting
FATTY ACIDS enter the tissues
The lipoprotein particles become smaller and ultimetaly become LDL ,
which provides the source of CHO for incorporation into cell membranes, for
synthesis of steroids, and bile acids
Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins
CHO can return to plasma from the tissues in HDL particles and the resulting
cholesteryl esters are subsequently transferred to VLDL or LDL
One species of LDL – lipoprotein - is associated with atherosclerosis
(localised in atherosclerotic lesions). LDL can also activate platelets,
constituting a further thrombogenic effect
Dyslipidemia
The normal range of plasma total CHO concentration < 6.5 mmol/L.
There are smooth gradations of increased risk with
elevated LDL CHO conc, and with reduced HDL CHO conc.
Dyslipidemia can be primary or secondary.
The primary forms are genetically determined
Secondary forms are a consequence of other conditions
such as diabetes mellitus, alcoholism, nephrotic sy,
chronic renal failure, administration of drug…
Lipid-lowering drugs
•
•
•
Several drugs are used to decrease plasma
LDL-CHO
Drug therapy to lower plasma lipids is only
one approach to treatment
and is used in addition to dietary
management
and correction of other modifiable
cardiovascular risk factors
LIPID-LOWERING DRUGS: Statins
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase
inhibitors. The reductase catalyses the conversion of HMG-CoA to
mevalonic acid; blocks the synthesis of CHO in the liver:
Simvastatin + pravastatin + atorvastatin
decrease hepatic CHO synthesis: lowers total and LDL
increase in synthesis of CHO receptors
+ increased clearance of LDL
Stimulates the exprssion of more enzyme  restores CHO synthesis to
normal.
Several studies demonstrated positive effects on morbidity and mortality.
Reltatively few side-effects...
However, adverse effects: myopathy (incr in pts given combined therapy
with nicotinic acid or fibrates. Should not be given during pregnancy.
LIPID-LOWERING DRUGS
Statins
Promising pharmacodynamic actions:
improved endothelial function
 reduced vascular inflammation and platelet aggregability
 antithrombotic action
 stabilisation of atherosclerotic plaques
 increased neovascularisation of ischaemic tissue
 enhanced fibrinolysis
 immune suppression
 osteoclast apoptosis and increased synthetic activity in
osteoblasts

LIPID-LOWERING DRUG
Statins
Pharmacokinetics
- well absorbed when given orally
- extracted by the liver (target tissue), undergo
extensive presystemic biotransformation
Simvastatin is an inactive pro-drug
LIPID-LOWERING DRUG
Statins
Clinical uses
• Secondary prevention of myocardial infarction and
stroke in patients who have symptomatic atherosclerotic disease
(angina, transient ischemic attacks) following acute myocardial
infarction or stroke
• Primary prevention of arterial disease in patients who
are at high risk because of elevated serum CHO concentration,
especially it there are other risk factors for atherosclerosis
• Atorvastatin lowers serum CHO in patients with
homozygous familiar hypercholesterolemia
LIPID-LOWERING DRUG
Statins
A d v e r s e e f f e c t s:
-
mild gastrointestinal disturbances
-
increased plasma activities in liver enzymes
-
severe myositis (rhabdomyolysis)
and angio-oedema (rare)
LIPID-LOWERING DRUGS:
Fibrates
stimulate the β-oxidative degradation of fatty acids
- liberate free fatty acids for storage in fat or for metabolism in
striated muscle
- Are ligands for nuclear txn receptor, peroxisome proliferatoractivated recptor-α (PARP-α)
- increase the activity of lipoprotein lipase,
hence increasing hydrolysis of triglyceride in chylomicrons
and VLDL particles.
-
- reduce hepatic VLDL production and increase hepatic LDL
uptake.
-Produce a modest decrease in LDL (~ 10%) and increase in
HDL (~ 10%).
-But, a marked decrease in TGs (~ 30%).
LIPID-LOWERING DRUGS
Fibrates
Other effects:
improve glucose tolerance
inhibit vascular smooth muscle inflammation
fenofibrate clofibrate
gemfibrozil ciprofibrate
LIPID-LOWERING DRUGS
Fibrates
A d v e r s e e f f e c t s:
in patients with renal impairment myositis (rhabdomyolysis)
myoglobulinuria, acute renal failure
Fibrates should be avoided in such patients and also in alcoholics)
mild GIT symptoms
LIPID-LOWERING DRUGS
Fibrates
1st-line defense for:
*mixed dyslipidemia (i.e. raised serum TG and CHO)
* patients with low HDL and high risk of atheromatous
disease (often type 2 diabetic patients)
* patients with severe treatment- resistant
dyslipidemia (combination with other lipid-lowering
drugs).
* Indicated in patients with VERY HIGH [TG]s who
are at risk for pancreatitis
LIPID-LOWERING DRUGS
Bile acid binding resins (Anion-exchange resins)
sequester bile acids in the GIT
prevent their reabsorption
and enterohepatic recirculation
The r e s u l t is:
decreased absorption of exogenous CHO and increased metabolism of
endogenous CHO into bile acid acids
increased expression of LDL receptors on liver cells
increased removal of LDL from the blood
reduced concentration of LDL CHO in plasma
(while an unwanted increase in TG)
Anion-exchange Resins
• Increase the excretion of bile acids, causing
more CHO to be converted to BAs.
• The decr in hepatocyte [CHO]  compenatory
incr in HMG CoA reductase activity and the
number of LDLRs.
• Because these resins don’t work in patients
with homozygous familial
hypercholesterolemia, increased expression of
hepatic LDLRs is the main mechanism by
which resins lower plasma CHO.
LIPID-LOWERING DRUGS
Bile acid binding resins
Colestyramin colestipol
anion exchange resins
C l i n i c a l u s e s:
heterozygous familiar hypercholesterolemia
an addition to a statin if response has been inadequate
hypercholesterolemia
when a statin is
contraindicated
uses unrelated to atherosclerosis, including:
pruritus in patients with partial biliary obstruction
bile acid diarrhea (diabetic neuropathy)
LIPID-LOWERING DRUGS
Bile acid binding resins
A d v e r s e e f f e c t s:
GIT symptoms - nauzea, abdominal bloating,
constipation or diarrhea, bec resins not absorbed.
resins are unappetizing. This can be minimized by
suspending them in fruit juice
interfere with the absorption of fat-soluble vitamins
and drugs (chlorothiazide, digoxin, warfarin)
These drugs should be given at last 1 hour before or 4-6 hours after a resin
LIPID-LOWERING DRUGS
Others
Nicotinic acid inhibits hepatic TG production and VLDL
Secretion (by ~ 30-50%)
modest reduction in LDL and increase in HDL.
Nicotinic acid was the 1st lipid-lowering drug to decr overall
mortality in patients with CAD.
But its use is limited by the desirable
A d v e r s e e f f e c t s:
flushing, palpitations , GIT disturbances.
Currently, nicotinic acid is rarely used.
LIPID-LOWERING DRUGS
Others
Fish oil (rich in highly unsaturated fatty acids)
the omega-3 marine TG
- reduce plasma TG but increase CHO (CHO is more strongly
associated wih coronary artery disease)
-the effects on cardiac morbidity or mortality is unproven
( although there is epidemiological evidence that eating fish
regularly does reduce ischemic heart disease)
LIPID-LOWERING DRUGS
Others
Inhibitors of Intestinal CHO Absorption: Ezetimibe:
Reduces CHO and phytosterol absorption and decreases LDL
CHP by ~18%, but with little change in HDL CHO.
May be synergistic with statins: so good for combination
therapy.
Drug Combinations
• Severe hyperlipidemia often requires multiple LLDs
to get the job done.
• As usual, combinations should involve drugs with
different mechanisms of action (e.g., statins with
fibrates).
• Even though some combinations (foregoing) may
increase risk of, say, myopathy, the benefits of
lowering LDL CHO outweigh the small incr in
adverse effects.
• Recent trial with gemfibrozil (fibrate) decr
myocardial infarction, stroke, and overall mortality in
men with CAD assoc with low HDL (this drug inc
HDL CHO w/o decr LDL CHO).