Pharmacology Lecture Slides on Hypolipidemic drugs by Sanjaya Mani Dixit Assistant Professor of Pharmacology at Kathmandu Medical College

1. Hypolipidemic Drugs
Sanjaya Mani Dixit
Assistant Prof of Pharmacology

2. Why Hypolipidemic Drugs?
• They can decrease the cases of atherosclerosis which in
turn will decrease the cardiovascular disease.
• Atherosclerosis is associated with elevated levels of certain plasma LPs,
especially the LP involved in cholesterol transport.
• For example: LDL; IDL; VLDL; TG & decreased HDL

3. What are lipoproteins?
• Lipoproteins are protein-lipid complexes, that help transport the
water insoluble lipids.
•Inner droplet of neutral (water-insoluble
core lipids); primarily triglycerides and
cholesteryl esters
•A solubilizing surface layer of
phospholipids and un-esterified
cholesterol
•Specific proteins (apo-lipoproteins)
attached to the outer lipid layer through
their specific lipophilic domains

4. Lipoprotein Particles
Classification of lipoprotein particles

6. Hyperlipidemias
• Hyperlipidemias are grouped according to their
lipid levels in
• hypercholesterolemia,
• hypertriglyceridemias, and
• mixed hyperlipidemias.
• Among these, hypercholesterolemia has the
strongest correlation to the risk for coronary heart
disease.

8. FREDERICKSON classification of
hyperlipoproteinemias

9. Treatment strategies
Diet: dietary measures
Drugs:
1.Reduce fat absorption from the intestine
[Resins]
2. Modify hepatic cholesterol synthesis
[Statins--HMG-CoA-Reductase Inhibitors]
3. Increase secretion of LP [Niacin]
4. Increase peripheral clearance of LP
[Fibrates]

10. Lipid
Lowering
Drugs
Statins
Resins
Others
Fibrates
Treatment strategies

11. CLASSIFICATION
1. Inhibitors of HMG Co-A Reductase (STATINS):
– Lovastatin, Simvastatin, Pravastatin, Atrovastatin
2. Bile Acid Sequestrants (RESINS):
– Cholestyramine, Colestipol, Colsevalam
3. Activators of Lipoprotein Lipase (FIBRATES):
– Clofibrate, Gemofibrizil, Bezafibrate, Fenofibrate
4. Inhibitors of TG Synthesis & Lipolysis:
– Nicotinic Acid
5. Inhibitors of Cholesterol Absorption:
– Ezetimibe
6. Others:
– Probucol

12. Hepatic Cholesterol Metabolism

13. Statins
• HMG- CoA- Reductase Inhibitors
(Competitive)
• The most effective and best-tolerated agents for
treating dyslipidemia.
• Atrovastatin
• Lovastatin
• Rosuvastatin
• Pravastatin

14. Statins-MOA

15. Statins-MOA
• Inhibit mevalonate synthesis by HMG-CoA-reductase
[RLS in cholesterol synthesis in liver]
• The number of high-affinity LDL receptors are
increased in liver.
• Thereby, increased clearance of VLDL remnants
[IDL] and LDL from blood.
• Higher dose of potent statins (Atorva..,Simva..) also
reduce TG levels due to elevated VLDL levels.
• Increases HDL levels in blood

16. Statins-- Therapeutic uses
• Treatment of primary hyperlipidemia (IIa, IIb
and V).
• Treatment of secondary hypercholesteronemia
(diabetes, nephrotic syndrome).
• Atorvastatin/Simvastatin: Efficacy > others:
reduces TG > others
• With Ca-channel blocker, used in hypertension
as well.
• Since it increases endothelium production and
NO production, beneficial role in CAD.

17. Statins-- Side effects
• Mild rise in aminotransferase
• Increase in CPK (creatine phosphokinase)
levels[10%] and myopathy.
• Myalgia [rhabdomyolysis]
• Risk of hepatotoxicity & myopathy following
drug interactions
• Headache, Nausea, bowel upsets, rashes
• Sleep disturbances

18. Resins
• Bile acids are needed for absorption of fats and
lipids from GIT.
• Resins bind to bile acids and similar steroids in
the intestine, bound complex excreted in feces.
• Reduce the availability of cholesterol for production
of plasma protein
• A compensatory increase in high-affinity LDL
receptors: elimination of LDL-cholesterol from blood
• To compensate the excreted bile acids, more
cholesterol is utilized in the synthesis of bile acids.

20. Therapeutic uses and S/Es
Uses:
Hyperlipidemia
• Pruritus due to cholestasis & bile salt accumulation
Also in some diarrheas caused by bile acids.
• Suitable only when LDL-CH levels are raised (IIa, IIb,
and V). Can reduce risk of angina and MI in them.
ADR:
Bloating, constipation, & unpleasant taste (nausea)
• Impaired absorption of fat soluble vitamins & drugs
[digitalis, thiazides, warfarin, lovastatin]

21. Fibrates
• Bind the peroxime proliferator-activated-alpha [PPAR-
alpha] protein and regulate transcription of the genes
involved in lipid metabolism.
• Increases / activates the synthesis of the enzyme
LP lipase and induce the metabolism of VLDL.
• Decreases the release of free F A from adipose tissue 
thus their levels in peripheral circulation are decreased.
• Also reduces hepatic TG levels.
• Reduce cholesterol production in liver.
• Reduce in LDL-cholesterol and increase in HDL levels.

23. Fibrates—Clinical uses
Uses:
Hyperlipidemias with elevated of both LDL and
VLDL level
In treating severe hypertriglyceridemia (TG
>1000mg/dl), patients at risk for pancreatitis.
• Contraindicated in renal and/or hepatic
failure; should be avoided in pregnant women
and in children.

24. Fibrates—S/Es
• Nausea & GI upsets[common]
• Skin rash with Gemfibrozil
• Alopecia, myalgias, headache, impotence
• Decrease WBC or hematocrit (anemia)
• Potentiate the action of anticoagulants
• Risk of cholesterol gallstones esp. with
Clofibrate.

25. Niacin /Nicotinic acid
• A water soluble vitamin (B3); reduces plasma lipid
levels at high doses; the dose is usually not tolerated
thus use is not frequent.
• Directly reduces the secretion of VLDL from liver.
• Inhibits hepatic synthesis of TGs & cholesterol
• Reduced LDL: LDL-cholesterol
• HDL level is elevated (Best agent)
Uses:
1. Hypertriglyceridemia with high LDL-cholesterol.
2. HTG with low HDL levels.

27. Niacin /Nicotinic acid—S/Es
• Cutaneous flushing [mediated by PGE] give NSAID
30 mins before therapy
• Dose dependent gut distress
• Pruritis and rashes in skins
• Serious hepatotoxicity (fulminant hepatic failure/ acute
liver failure) --dose dependant
• Hyperuricemia [20%]
• Moderate Carbohydrate intolerance
• Insulin resistance  hyperglycemia in DM.
• Atrial tachyarrhythmias and atrial fibrillation
esp. in elderly patients.

29. EZETIMIBE
• First compound approved for lowering total and LDL-C
levels that inhibits cholesterol absorption by
enterocytes in the small intestine.
• Lowers LDL-C levels by about 18% and is used
primarily as adjunctive therapy with statins.
• Rare allergic reactions are reported; no other
significant A/E.
• Available usually combined with statins (co-
formulation).

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