Download Hyperlipidemias

Hyperlipidemias
Cholesterol is absorbed from the intestine and transported to the liver by
chylomicron remnants. Hepatic cholesterol enters the circulation as very low
density lipoprotein VLDL which is metabolized by lipoprotein lipase
enzyme to intermediate lipoprotein LDL and low density lipoprotein LDL
which are then removed by liver liver or peripheral tissues. In the peripheral
tissues cholesterol is converted to steroid hormones or used to form cell
walls and membranes. The quantity of cholesterol transported from the liver
to peripheral tissues greatly exceeds its catabolism, so the excess amount of
cholesterol is returned back to the liver by high density lipoprotein HDL.
Atherosclerosis and coronary heart disease are associated with elevated
levels of low density lipoprotein (LDL cholesterol) and triacyglycerol with
low levels of HDL cholesterol. Other risk factors include smoking,
hypertension, obesity, diabetes, lack of exercise and consumption of a diet
containing saturated fat. Hyperlipidemia can also result from a single
inherited
gen
defect
in
1
lipoprotein
metaboli
2
Treatment strategies
A.
Diet: by reducing the total intake of cholesterol and saturated
B.
Drugs
aft. Alcohol raises triglyceride TG and VLDL so should be avoided.
3
1- HMG CoA reductase inhibitors: Statins.
Mechanism of action
 Inhibition of HMG CoA reductase: they inhibit 3-hydroxy-3methyl glutaryl (HMG)coenzyme A(CoA) which is the rate
limiting step in cholesterol synthesis, so depleting the
intracellular supply of cholesterol.
Ac-CoA
HMG-CoA
cholesterol
bile acid
inhibited by resin
gut
 Increase in LDL receptors: as a compensatory mechanism for
the depletion of intracellular cholesterol synthesis, liver
increases the number of LDL receptors as a method to recapture
cholesterol. Thus the end result is a reduction in plasma
cholesterol both by lowered synthesis and increase catabolism
of LDL.
Clinical uses: lowering plasma cholesterol in all types of hyperlipidemia
and reduce the risk of coronary events and ischemic heart disease.
4
Pharmacokinetics: well absorbed after oral administration undergo first
pass metabolism, excreted through bile and feces and some urinary
elimination also occurs.
Adverse effects: Biochemical abnormalities in liver function have occurred,
therefore it important to evaluate liver function and measure serum
transaminase levels periodically. Myopathy and rhabdomyolysis
(disintegration or dissolution of muscle) rarely reported.
Drug interactions: these drugs increase warfarin levels; on the other hand
enzyme inhibitors increase the risk of hepatotoxicity because they increase
statins level.
Statins are contraindicated during pregnancy, nursing mothers and in
children.
Some adverse effects and precautions
5
2- resin or called bile binding resins
They are anion-exchange resins that bind negatively charged bile acids and
bile salts in the small intestine. The resin/bile acid complex is excreted in the
feces, thus preventing the bile acids from returning to the liver by the
enterohepatic circulation. This causes hepatocytes to increase conversion of
cholesterol to bile acids, resulting in decreasing the intracellular cholesterol
concentration which activates an increased hepatic uptake of cholesterolcontaining LDL particles ( by increasing surface LDL receptors),
leading to a fall in plasma LDL.
Clinical uses: treatment of hypercholesterolemia and relieve pruritus caused
by accumulation of bile acids in patients with biliary obstruction.
Pharmacokinetics: they are taken orally. Because they are insoluble in
water and are very large , they are neither absorbed nor metabolically altered
by the intestine. Instead, they are totally excreted in the feces.
Adverse effects:
1- constipation, nausea, and flatulence.
2- impair the absorption of the fat-soluble vitamins (A, D, E, and K).
3- interfere with the intestinal absorption of many drugs for example,
tetracycline, phenobarbital, digoxin, warfarin, pravastatin, fluvastatin,
aspirin, and thiazide diuretics. Therefore, drugs should be taken at
least 1 to 2 hours before, or 4 to 6 hours after, the bile acid binding
resins.
6
7
3- Cholesterol absorption inhibitors
Ezetimibe selectively inhibits intestinal absorption of dietary and biliary
cholesterol in the small intestine, leading to a decrease in the delivery of
intestinal cholesterol to the liver. This causes a reduction of hepatic
cholesterol stores with a compensatory increase in the synthesis of high
affinity LDL receptors lead to increase the removal of LDL from the
blood.
Ezetimibe metabolized in the small intestine and liver with subsequent
biliary and renal excretion. It is used to treat hypercholesterolemia but
should be avoided in patients with moderate to sever hepatic
insufficiency.
4- Niacin (nicotinic acid)
Mechanism of action: niacin strongly inhibits lipolysis in adipose tissuethe primary producer of circulating free fatty acids. The liver normally
utilizes these circulating fatty acids in triacylglycerol synthesis. Thus, niacin
causes a decrease in liver triacylglycerol synthesis, which is required for
VLDL production. LDL (the cholesterol-rich lipoprotein) is derived from
VLDL in the plasma. Therefore, a reduction in the VLDL concentration also
results in a decreased plasma LDL concentration. Thus, both plasma
triacylglycerol (in VLDL) and cholesterol (in VLDL and LDL) are lowered.
Niacin treatment increases HDL cholesterol levels.
Therapeutic uses: treatment of severe hypercholesterolemias.
Pharmacokinetics: Niacin is administered orally. It is converted in the body
to nicotinamide, and excreted in the urine.
Adverse effects: flushing, feeling of warmth and pruritus. Administration of
aspirin prior to taking niacin decreases flushing. Other side effects include
nausea, abdominal pain and hyperuricemia.
8
4- The fibrates: Fenofibrate and gemfibrozil
Mechanism of action: they interact with peroxisome proliferator activated
receptor-alpha (PPAR-ά) protein, a receptor that regulates transcription of
genes involved in lipid metabolism. This interaction results in increased
activity of lipoprotein lipase and enhanced clearance of VLDL (triglyceride
rich lipoprotein) they decrease cholesterol synthesis and increase HDL level.
Therapeutic uses: The fibrates are used in the treatment of
hypertriacylglycerolemias, and incombination with other cholesterol
lowering agents for treatment of patients with elevated concentration of both
LDL and VLDL.
Pharmacokinetics: well absorbed orally, widely distributed, undergo
extensive biotransformation and excreted in urine.
Adverse effects:
Nausea, Lithiasis: Because these drugs increase biliary cholesterol excretion,
lead to the formation of gallstones. Others is Myositis (inflammation of a
voluntary muscle)
9
They should not be used in patients with severe hepatic and renal
dysfunction or in patients with preexisting gallbladder disease.
Drug interactions: Both fibrates compete with the coumarin anticoagulants
for binding sites on plasma proteins, thus transiently potentiating
anticoagulant activity. these drugs may transiently elevate the levels of
sulfonylureas.
10
Combination drug therapy
It is often necessary to employ two antihyperlipidemic drugs to achieve
treatment goals in plasma lipid levels. The most commonly combined
agents:
Niacin + bile acid-binding agent.
HMG-CoA reductase inhibitor + bile acid- binding agent.
Low dose statin + ezetimibe.
11