Transcript drugs for hyperlipidemia

Lipid-lowering drugs
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
ENDOGENOUS
PATHWAY
may be
stored
oxidised
to
bile acids
secreted
in
the bile
unaltered
EXOGENOUS
PATHWAY for lipids
ENDOGENOUS
PATHWAY for lipids
HEPATOCYTE
CHO
Fig.1a
GIT
bile acids
Bile duct
CHO
bile acids
v.portae
Fat
+ CHO
+ fatty acids
ENDOGENOUS
PARTHWAY
chylomicr
remn
CHO TG
chylomicr
TG CHO
Peripheral tissues
Fatty acids
(According to Rang, Dale 1999)
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
ENDOGENOUS
PATHWAY for lipids
Fig.1b
EXOGENOUS
PATHWAY for lipids
GIT
HEPATOCYTE
ACoA
MVA
Bile duct
CHO
bile acids
bile acids
CHO
v.portae
CHO
LDL
receptors
VLDL
CHO
HDL
CHO
CHO
TG CHO
LDL
CHO
lipase
CHO
from cells
Uptake
of CHO
Fatty
acids
Peripheral tissues
(According to Rang, Dale 1999)
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
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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
Statins
Fibrates
LIPID-LOWERING
DRUGS
Others
Resins
ENDOGENOUS
PATHWAY for lipids
EXOGENOUS
PATHWAY for lipids
Fig.1c
GIT
GIT
HEPATOCYTE
STATINS
ACoA
Bile duct
MVA
STATINS
FIBRATES
CHO
bile acids
bile acids
CHO
v.portae
RESINS
fat
+ CHO
+ fatty
acids
LDL
receptors
FIBRATES
VLDL
CHO
Chylomikr remn
TG CHO
FIBRATES CHO TG
Chylomikr
HDL
CHO
CHO
LDL
CHO
TG CHO
lipase
CHO
from cells
Uptake
of CHO
Fatty
acids
Fatty
acids
Peripheral tissues
(According to Rang, Dale 1999)
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
Simvastatin + pravastatin + atorvastatin
decrease hepatic CHO synthesis
increase in synthesis of CHO receptors
+ increased clearance of LDL
Several studies demonstrated positive effects on morbidity and mortality
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
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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 beta-oxidative degradation of fatty acids
- liberate free fatty acids for storage in fat or for metabolism in
striated muscle
-
- 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
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
Clinical uses
mixed dyslipidemia (i.e. raised serum TG and CHO)
patients with low HDL and high
disease (often type 2 diabetic patients)
risk of atheromatous
patients with severe treatment- resistant
dyslipidemia (combination with other lipid-lowering
drugs)
LIPID-LOWERING DRUGS
Bile acid binding 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)
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
resins are unappetising. 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
modest reduction in LDL and increase in HDL
A d v e r s e e f f e c t s:
flushing, palpitations , GIT disturbances
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