This document discusses hyperlipidemia and its treatment. It begins by describing how lipids are transported through the body by chylomicrons and lipoproteins like LDL and HDL. High LDL and oxidized LDL can lead to atherosclerosis. Causes of high lipids include diet, diseases, and medications. Treatment involves lifestyle changes and lipid-lowering drugs like statins, fibrates, bile acid sequestrants, nicotinic acid, and ezetimibe. These drugs work to lower LDL and triglycerides and raise HDL to reduce cardiovascular risk. Side effects of the drugs are also outlined.

1. Hyperlipidemia
Assistant Professor of Pharmacology and Toxicology
Head of Department of Pharmacology and Medical
Sciences, Faculty of Pharmacy- Al azhar University

2. The story of lipids
 Chylomicrons transport fats from the intestinal
mucosa to the liver
 In the liver, the chylomicrons release triglycerides
and some cholesterol and become low-density
lipoproteins (LDL).
 LDL then carries fat and cholesterol to the body’s
cells.
 High-density lipoproteins (HDL) carry fat and
cholesterol back to the liver for excretion.

3. The story of lipids (cont.)
 When oxidized LDL cholesterol gets high,
atheroma formation in the walls of arteries
occurs, which causes atherosclerosis.
 HDL cholesterol is able to go and remove
cholesterol from the atheroma.
 Atherogenic cholesterol → LDL, VLDL, IDL

4. Atherosclerosis

5. Atherosclerosis and lipoprotein metabolism
Atheromatous disease is 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

6. Causes of Hyperlipidemia
 Diet
 Hypothyroidism
 Nephrotic syndrome
 Anorexia nervosa
 Obstructive liver
disease
 Obesity
 Diabetes mellitus
 Pregnancy
 Obstructive liver
disease
 Acute heaptitis
 Systemic lupus
erythematousus
 AIDS (protease
inhibitors)

7. Dietary sources of Cholesterol
Type of Fat Main Source Effect on
Cholesterol levels
Monounsaturated Olives, olive oil, canola oil, peanut oil,
cashews, almonds, peanuts and most
other nuts; avocados
Lowers LDL, Raises
HDL
Polyunsaturated Corn, soybean, safflower and cottonseed
oil; fish
Lowers LDL, Raises
HDL
Saturated Whole milk, butter, cheese, and ice cream;
red meat; chocolate; coconuts, coconut
milk, coconut oil , egg yolks, chicken skin
Raises both LDL and
HDL
Trans Most margarines; vegetable shortening;
partially hydrogenated vegetable oil; deep-
fried chips; many fast foods; most
commercial baked goods
Raises LDL

8. Goals for Lipids
 LDL
 < 100 →Optimal
 100-129 → Near optimal
 130-159 → Borderline
 160-189→ High
 ≥ 190 → Very High
 Total Cholesterol
 < 200 → Desirable
 200-239 → Borderline
 ≥240 → High
 HDL
 < 40 → Low
 ≥ 60 → High
 Serum Triglycerides
 < 150 → normal
 150-199 → Borderline
 200-499 → High
 ≥ 500 → Very High

9. Treatment of Hyperlipidemia
 Lifestyle modification
 Low-cholesterol diet
 Exercise

10. 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

11. Fibrates
Others
Resins
Statins

12. Medications for Hyperlipidemia
Drug Class Agents Effects (% change) Side Effects
HMG CoA reductase
inhibitors
Lovastatin
Pravastatin
↓LDL (18-55),↑ HDL (5-15)
↓ Triglycerides (7-30)
Myopathy, increased liver
enzymes
Cholesterol
absorption inhibitor
Ezetimibe ↓ LDL( 14-18), ↑ HDL (1-3)
↓Triglyceride (2)
Headache, GI distress
Nicotinic Acid ↓LDL (15-30), ↑ HDL (15-35)
↓ Triglyceride (20-50)
Flushing, Hyperglycemia,
Hyperuricemia, GI distress,
hepatotoxicity
Fibric Acids Gemfibrozil
Fenofibrate
↓LDL (5-20), ↑HDL (10-20)
↓Triglyceride (20-50)
Dyspepsia, gallstones,
myopathy
Bile Acid
sequestrants
Cholestyramine ↓ LDL
↑ HDL
No change in triglycerides
GI distress, constipation,
decreased absorption of
other drugs

14. LIPID-LOWERING DRUGS
1- StatinsStatins
HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A)
reductase inhibitors. The reductase catalyses the conversion
of HMG-CoA to mevalonic acid
Simvastatin + pravastatin + atorvastatin ,
Rusevustatin
decrease hepatic CHO synthesis
increase in synthesis of CHO receptorsincrease in synthesis of CHO receptors
+ increased clearance of LDL+ increased clearance of LDL
Several studies demonstrated positive effects on morbidity and
mortality

15. LIPID-LOWERING DRUGS
StatinsStatins
Promising pharmacodynamic actionsPromising pharmacodynamic actions::
 improved endothelial functionimproved endothelial function
 reduced vascular inflammation and platelet aggregabilityreduced vascular inflammation and platelet aggregability
 antithrombotic actionantithrombotic action
 stabilisation of atherosclerotic plaquesstabilisation of atherosclerotic plaques
 enhanced fibrinolysisenhanced fibrinolysis
 immune suppressionimmune suppression


16. LIPID-LOWERING DRUG
StatinsStatins
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)

17. 2- FibratesFibrates
 fenofibrate , clofibrate , gemfibrozil
- 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
- improve glucose tolerance
- inhibit vascular smooth muscle inflammation

18. A d v e r s e e f f e c t s:A d v e r s e e f f e c t s:
in patients with renal impairment myositisin patients with renal impairment myositis
(rhabdomyolysis)(rhabdomyolysis)
myoglobulinuria, acute renal failuremyoglobulinuria, acute renal failure
Fibrates should be avoided in such patients and also inFibrates should be avoided in such patients and also in
alcoholics)alcoholics)

19. 3- Bile acid bindingBile acid binding resinsresins
Colestyramin colestipol
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)

20. A d v e r s e e f f e c t sA d v e r s e e f f e c t s::
GITGIT symptomssymptoms -- nauzea, abdominal bloating,nauzea, abdominal bloating,
constipation or diarrheaconstipation or diarrhea
resins areresins are unappetisingunappetising. This can be. This can be
minimized byminimized by
suspending them in fruit juicesuspending them in fruit juice
interfere with the absorption of fat-solubleinterfere with the absorption of fat-soluble
vitaminsvitamins
andand drugs (chlorothiazide, digoxin, warfarin)drugs (chlorothiazide, digoxin, warfarin)
These drugs should be given at last 1 hour before or 4-6 hours after aThese drugs should be given at last 1 hour before or 4-6 hours after a
resinresin

21. 4- Nicotinic acid
inhibits hepatic TG production and VLDL
secretion
modest reduction in LDL and increase in HDL

22. Adverse effects:
 1-The most common side effects of niacin therapy
are an intense cutaneous flush (accompanied
 uncomfortable feeling of warmth) and pruritus.
Administration of aspirin prior to taking niacin decreases
 the flush, which is prostaglandin mediated. The
sustained-release formulation of niacin, which is taken
once daily at bedtime,.
 2- Some patients also experience nausea and
abdominal pain.
 3- Niacin predisposes to hyperuricemia and gout.
 4- Impaired glucose tolerance and hepatotoxicity have
also been reported

23. 5- Cholesterol absorption inhibitors
Ezetimibe ( Ezetrol)
 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. Ezetimibe lowers LDL
 Ezetimibe is primarily metabolized in the small
intestine and liver via glucuronide conjugation
(a Phase II reaction),
 Ezetimibe has no clinically effect on the plasma
concentrations of the fat-soluble vitamins A, D, and E.