ANTIHYPERLIPIDEMI

C DRUGS
Assist. Prof. Dr. Saad Badai
M.B.Ch.B, Ph.D
objectives
• Concept of dyslipidemia
• Types of dyslipidemia
• Treatment of dyslipidemia
• Anti-hyperlipedemic agent groups
Definition
• Hyperlipedemia or dyslipidaemia is a common pathological
disorder including abnormal high serum lipid concentration
- it is either:
• 1-primary : result from single inherited gene or more may be
associated with environmental factors.
• 2- secondary: result from metabolic disorder e.g. DM or excessive
alcohol intake, obesity hypothyroidism..etc.
• Dyslipidemia is a very common disorder especially in older age
groups
• It is directly related to ischemic heart disease as a strong risk factor
• Treatment of dyslipidemia is obligatory to prevent bad
cardiovascular sequlae
• Treatment of dyslipidemia should include the underlying cause (if
any) and other risk factors (e.g. smoking, obesity, endocrine
disorders …etc.)
Lipoprotein metabolism
The genetic Types of hyperlipidemia is summarized as
follows:
• Type I: familial hyperchylomicronemia. (increased
chylomicrons and TG ), rare –genetic defeciency of lipoprotein
lipase.
• Type IIa: (common cause of ischemic heart disease) familial
hypercholesterolemia (increase LDL with normal VLDL)
• Type IIb (familial combined hyperlipidemia): increased both
LDL and VLDL., (common)
• Type III ( familial dyslipoproteinemia) :increased IDL with
triacylglycerol and cholesterol.
• Type IV: (familial hypertriglyceridemia): increased VLDL ,
normal or decreased LDL.
• Type V (familial hypertriglycerdemia): increased VLDL and
chylomicrons levels. So high levels of cholesterol and
triglycerol., LDL is normal or decreased.
Aim of drug therapy
Antihyperlipidemic drugs targets treatment of hyperlipidemia
by:
• decrease production of LP carriers of cholesterol and
triglycerol.
• Increase LP degradation.
• Increase cholesterol removal from the body.
• Increase HDL (good lipid).
• They are used single or in combination .
THE FIBRATES

-Clofibrate
-Fenofibrate
-Gemfibrozil
•derivatives of fibric acid.
•Inhibit liver lipid synthesis leading to decrease in plasma
cholesterol and triglycerides
•and rise of HDL .
Mechanism of action:
• Function by increasing lipprotein lipase enzyme
production (transcriptional up-regulating).
• Thus there will be increased oxidation of fatty acids in
the liver and skeletal muscles.
• leading to lipolysis of TG (in chylomicrons and VLDL)by LP
lipase thus, increase removal of these particles.
• Increase HDL moderately.
• No effect on LDL
• Lower pl. fibrinogen thus, reduce risk of atherosclerosis
Specific agents
• Gemfibrozil used more commonly because Of less side effects
even in renal impaired patients.
• Clofibrate carries high risk of gall stone production so
preserved for use in patients with cholecystectomy.
• all can cause myositis
pharmacokinetics
• Well absorbed by the intestine
• Extensively bound to plasma proteins
• Excreted by the kidneys
Therapeutic uses:

• treatment of primary and secondary

hypertriglyceridemia
• type III. And Type IV Dyslipidemai
Side Effects:

• Cholelithiasis: increase risk of gall stones

(especially clofibrate).
• Malignancy: especially clofibrate.
• Muscle: myositis (inflammation of voluntary
muscles), myopathy.
• GI effects
Drug interaction:

• They displace some drugs from their binding proteins:

• statins (increase risk of myopathy).
• with coumarin anticoagulants.: potentiate their
anticoagulant Effect.
• - increase level of antidiabetics (like sulphonylureas).
Contra indications:

• -pregnancy.
• -hepatic and renal failure.
• - patients with gall bladder stones.
BILE ACID BINDING RESINS
(cholysteramine, colestipol):

• Mechanism of action:
• - cholestyramine and colestipol are anion
exchange resins that bind negatively charged
bile acids and bile salts in small intestine the
resin / bile acid complex is excreted in the feces
• - decrease bile acid conc. Leading to increase
cholesterol conversion to bile a. in hepatocytes
causing reduction of intracellular cholesterol
thus, increase uptake of LDL cholesterol leading
to decrease in LDL level in plasma. And total pl.
cholesterol.
Side effects:

• GIT: constipation, flatulence,nausea.

• Impaired absorption of fat soluble vitaminess (A,D,E,K)
HMG- CoA reductase (statins) :

• Simvastatin
• Atorvastatin
• Rosuvostatin
• Pravastatin

- First -line treatment of dyslipidaemia.

- Reduce cardiac events and prolong life, and are safe and available
and well tolerated by most dyslipidemic patients
Mechanism of action:

• inhibition of HMG-CoA reductase (HMG CoA reductase is the

rate-limiting step in endogenous cholesterol biosynthesis in
the liver).
• these drugs are analogues of HMG-CoA reductase. These
drugs compete effectively to inhibit HMG-CoA reductase, so
decrease cholesterol synthsis so, deplete intracellular supply
of cholesterol (lower cytoplasmic cholesterol).
• Hepatocytes respond by increasing the synthesis of LDL
receptors. This increases hepatic LDL uptake from the plasma,
further reducing the plasma LDL concentration.
• (HMG Co A = hydroxy-methyl-glutaryl coenzyme A)
Therapeutic uses:

• decrease plasma cholesterol levels in all types of

hyperlipidemia.
• Often given in combination with other agents.
Pharmacokinetics:

• well absorbed after oral adminsration.

• - First pass metabolism in the liver.
• - Excreted in bile and faeces.
Side effects:

• Liver: abnormal biochemical liver function : examine serum

transaminase periodically.
• Muscle: myopathy and rhabdomyolysis.
• Drug interaction:
• increase coumarine drugs levels.
Contraindications:

• pregnancy.
• Lactating women.
• Children and teenagers.
EZETIMIBE

Use:
• Ezetimibe is most often used in combination with diet
and
statins for severe hypercholesterolaemia; also in
occasional
patients who cannot tolerate statins or where statins are
contraindicated,
Mechanism of action

- Ezitemib is a selective inhibitor of intestinal absorption of

cholesterol and phytosterols.
- It blocks the NPLC1L sterol transporter in the brush
border of enterocytes, preventing cholesterol and plant
sterols (phytosterols) transport from the intestinal
lumen.
- It is effective even in the absence of dietary cholesterol
because it inhibits reabsorption of cholesterol in the bile
acids.
Pharmacokinetics

• Ezetimibe is administered by mouth and is absorbed into

intestinal epithelial cells, where it localizes to the brush
border.
• It is metabolized, followed by enterohepatic recycling and
slow elimination. It enters breast milk.
Adverse effects and
contraindications
• Diarrhoea, abdominal pain or headaches are occasional
problems.
• rash and angioedema have been reported.
• It is contraindicated in breast-feeding.
NIACIN (nicotinic acid):

• water soluble vitamin (B3).

• Has a broad lipid lowering ability.
• Limited in clinical use due to major SE
Mechanism of action:

Niacin is indirectly converted to nicotinamide and

both are precursors of coenzymes (NAD) and
(NADP) , those are present in the cytosol of
many cells and they are coenzymes for many
dehydrogenases enzymes (eg. Lactate
dehydrogenase and malate dehydrogenase)
which are important in lipid and carbohydrate
metabolism.
EFFECTS
• strongly inhibit lipolysis in adipose tissue ( primary producer
of circulating FFA)
• liver utilizes FFA in production of triglycerol as precursor thus,
decrease liver triglycerol synthesis thus,
• Decrease production of VLDL thus.
• Decrease prod of LDL as a result of this:
• Decrease triglycerol level (in VLDL)
• Decrease cholesterol level (in LDL).
• Also: niacin increase HDL (good lipid)
• Decrease risk of atherosclerosis.
Therapeutic uses:

• type II hyperlipidemia (increase LDL, VLDL).

• Type IV hyperlip. (increase VLDL).
Side Effects:

• intense cutaneous flush and pruritis (PG mediated) which

decreased by pre taking of aspirin.
• Nausea, abdominal pain.
• Decrease tubular secretion of uric acid leading to
hyperuricemia and gout..
• Hepatotoxicity
Summary of anti-lipid drugs
Thank you