Hyperlipidemia refers to elevated levels of lipids or lipoproteins in the blood. It is caused by disorders involving elevations of lipoproteins such as low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and triglycerides. This puts one at risk for complications like atherosclerosis and pancreatitis. Treatment involves medications that lower LDL and triglyceride levels such as statins, resins, fibrates, and nicotinic acid. Each work by different mechanisms but commonly decrease lipid synthesis or increase lipid clearance to normalize lipid profiles and reduce cardiovascular risk. Side effects depend on the specific drug but may include gastrointestinal issues or myopathy.

1. Hyperlipidemia
• Lipids of human plasma are transported as
complexes with proteins, such macromolecular
complexes are termed lipoproteins; except fatty
acids which are bound to albumin.
• Any metabolic disorders involving the elevations
in plasma concentrations of any lipoprotein
species known as hyperlipoproteinemias or
hyperlipidemias.
• Hyperlipidemia is generally restricted to
conditions that involve increased level of
triglycerides in plasma.

2. • The major complications are acute
pancreatitis and atherosclerosis
• Those which contain apolipoprotein (apo)
B100 act as vehicles by which cholesterol are
transported into artery wall.
• Those are low-density (LDL), intermediate
density (IDL), very low density (VLDL) and
Lp(a) lipoproteins.

3. • Cellular components in atherosclerotic plaque
are foam cells, derived form macrophages and
smooth muscle cells filled with cholesteryl
esters.
• The atheromatous plaque grows over time
with the accumulation of increased no. of
foam cells and of collagen and fibrin.
• High-density lipoproteins (HDL) exert antiatherogenic effects.

4. RISK FACTORS
1) Cigarette is a major risk factor for coronary disease
– Associated with reduced HDL levels
– Impaired cholesterol level
– Cytotoxic effects on endothelium
– Increased oxidation of atherogenic lipoproteins
– Stimulates thrombogenesis
2) Hypertension
3) Diabetes
4) LDL levels

5. • Normally EDRF, nitric oxide are responsible for
vessels regulation but it is impaired in
hyperlipidemia.
• So natural antioxidants such as tocopherol and
ascorbic acid can reduce such impairment.

6. Pathophysiology of
hyperlipoproteinemia
•
1.
2.
•
Major lipoproteins are:
Cholesteryl esters and
Triglycerides
A monolayer of unesterified cholesterol and phospholipids
surrounds the hydrophobic core of above lipoproteins.
• Specific proteins (apolipoproteins) are located on the
surface.
• Also certain lipoproteins contain large mol. wt
apolipoproteins(B lipoproteins) which don’t migrate like
smaller ones.
• Subtypes of B apolipoproteins:
–
–
B-48 formed in intestine with chylomicrons
B100 synthesized in liver and found in VLDL, VLDL
remnants,LDL and the Lp(a) lipoproteins.

7. • Chylomicrons:
– Lagest type;formed in intestine and carry dietary lipids
–triglycerides
– Responsible for transport of lipids
• Very low density lipoproteins (VLDL) :
– Secreted by liver; means for transporting triglycerides
to peripheral tissues
– Hydrolyzed by lipoprotein lipase yielding free fatty
acids for oxidation and storage.
– Intermediate particles called IDL are formed after the
VLDL is depleted of triglycerides.

8. • Low density lipoproteins:
– Further removal of triglycerides by hepatic
lipaseresults in its formation.
– Hepatocytes play a major role for its catabolic
activity.
• Lp(a) lipoprotein:
– Formed form an LDL-like moiety
– The Lp(a) lipoprotein complex can be found in
atherosclerotic plaques and contribute to
coronary disease by inhibiting thrombolysis.

9. • High density lipoproteins:
– Secreted by the liver and intestine
– Comes from surface of chylomicrons and VLDL
during lipolysis.

10. • Atherosclerosis: It is a disease which affects large and
medium size arteries, and a leading cause of death.
• consists of localized plaque in the intima, and is
composed of cholesterol esters, proliferation of
smooth muscle, deposition of fibrous proteins and
calcifications.
• Effects:
– Narrowing of the arterial lumen
– Ulceration of arterial lumen and thrombosis of artery and
embolization.
– Weakens arterial wall and formation of aneurysms.

12. Classification of anti-hyperlipidemics:
• HMG-CoA reductase inhibitors ( statins)
– Lovastatin
– Atorvastatin
– Simvastatin
– Pravastatin
– Rosuvastatin

13. • Bile acid sequestrants (resins):
– Cholestyramine
– Colestipol
• lipoprotein lipase inducers (fibric acid derivative)
– Clofibrate
– Gemfibrozil
– Benzafibrate
• Inhibit lipolysis and triglycerides synthesis
– Nicotinic acid ( niacin)
• Inhibit intestinal cholesterol absorption
– Ezetimibe
• Others
– Probucol
– gugulipid

14. HMG-CoA reductase inhibitors
• Mechanism of action
The de novo synthesis of cholesterol involves a
pathway in which mevalonic acid is formed and by the
enzyme hydroxymethylglutaryl co-enzyme reductase
(HMG-Co A reductase); the statins inhibits this step
resulting in decrease hepatic cholesterol synthesis.
Resultantly synthesis of high affinity LDL receptors on
the liver occurs and increased clearance of plasma LDL.
• Decrease liver cholesterol
• Increase LDL gene expression
• Decrease plasma LDL
• Decrease VLDL synthesis
• Decrease TGLs

15. • Pharmacokinetics:
– Given orally except fluvastatin
– Upto 90% available
– Undergoes first pass metabolism and secreted in
bile
– 5-10% excreted in urine

16. • Adverse effects:
–
–
–
–
–
–
Headache, nausea, bowel upsets, rashes
Sleep disturbances
Rhabdomyolysis
Myalgia , myopathy
Rise in LFTs particularly serum transaminases
Muscle weakness
• Indications:
– Hyperlipidemia with raised LDL and Cholesterol level
– Progression of atherosclerotic lesion
– Ischemic heart disease of elderly

17. • Drug interactions :
– Gemfibrogil
– Cyt P450 enzymes

18. Cholestyramine
• Also known as bile acid binding resin.
• Bile acid binding resins are cholesterol lowering
drugs that are man made resins. They are gritty,
insoluble granules which are available in the form
of a bar that has to be chewed thoroughly or
comes in the form of a powder and needs to be
mixed with a liquid.
• These prevent re-absorption of cholesterol into
the body when they bind with the cholesterolrich bile acids secreted by the liver.

19. • Resulting in decreased enterohepatic
circulation of causing the liver to increase
production of bile acids utilizing cholesterol
• Decrease LDL levels
• Increase LDL receptor gene expression.
• It significant effect on LDL levels by utilizing
the LDL receptors but no effect on the HDL
levels.

20. • Pharmacokinetics:
– Orally (chewed)
– No systemic effects as it is retained in the GI tract
– Usual dose of 12-36g of resin per day in divided
doses with meals.

21. • Side-effects:
– Increased VLDL and triglycerides
– Usually causes GI symptoms like constipation and
flatulence.
– May interfere with the absorption of fat-soluble
vitamins and may bind with other drugs if taken
concurrently.
Drug interactions
– Orally administered drugs
Contraindication:
– Hypertriglyceridemia

22. Nicotinic acid
• Inhibition of VLDL synthesis( inhibiting
ApoB100 gene expression and resulting in:
– Decreased plasma VLDL
– Decreased plasma LDL
– Increased plasma HDL
Side effects :
– Flushing , pruritus , rashes
– hepatotoxicity

24. Fibric acid derivatives
• Prototype: Gemfibrozil
• Others : clofibrate , benzafibrate
• Mechanism of action:
– Induction of lipoprotein lipase
– Activation of the nuclear transcription receptor
“peroxisome proliferator - activated receptor alpha” (PPARα). –mediate effects of insulin
– class of intracellular receptors that modulate carbohydrate
and fat metabolism and adipose tissue differentiation.
– PPAR-α activation by fibrates results in numerous changes
in lipid metabolism that act together to decrease plasma
triglyceride levels & increase plasma HDL.
– Decrease VLDL and IDL

26. • Indications:
– Hypertriglyceridemias in which VLDL predominate
& in dysbetalipoproteinemia.
– Treatment of hypertriglyceridemia resulting from
treatment with viral protease inhibitors.
Contraindication:
Hypercholesteremia

27. • Pharmacokinetics:
– absorbed from the GI tract & undergoes
enterohepatic circulation
– most (70%) is eliminated unchanged through the
kidneys
– half life : 1.5 hrs.

28. • Side Effects:
–
–
–
–
–
–
–
–
rare cases of rash
GI symptoms
Gall stones
Myositis
Myopathy
Arrhythmias
Hypokalemia &
High aminotransferase or alkaline phosphatase levels,
risk of cholesterol gallstones.

29. Lab findings
Drugs
Hypercholesteremia
Cholestyramine ,
colestipol, ezetimibe
Hypertriglyceridemia
Gemfibrozil
Combined hyperlipidemia
(Statins and niacin) +
ezetimibe