The summarized Pathophysiology of Hyperlipidemia, Mechanism of actions for hyperlipidemic drugs.

1. Drug Therapy for
Hypercholesteromia &
Dyslipidemia
URVI KOLHATKAR

2. What is Hyperlipidemia?
• Characterized by abnormally high concentration
of Fats and lipids in the blood.
• Increased level of Low Density Lipoproteins as
well as Triacylglycerols and decreased levels of
High Density Lipoproteins.
• Hyperlipidemia is a major cause of
Atherosclerosis and Atherosclerosis induced
conditions such as Coronary Heart Disease(CHD)
, Unstable Angina (Unexpected Chest pain),
Myocardial Infarction (Heart attack).

3. Causes of Hyperlipidemia
• Diet or change in Lifestyle.
• Obesity
• Pregnancy
• Acute Hepatitis
• Diabetes Mellitus
• Nephrotic Syndrome
• Obstructive Liver Disease
• Single Inherited Gene defect in Lipoproteins metabolism.

4. ATHEROGENIC AND ANTIATHEROGENIC LIPOPROTEINS
THE ATHEROGENIC LIPOPROTEIN
PHENOTYPE:
1.Low Density Lipoprotein- Derived
from VLDL in the capillary beds.
Measured by friedewald formula.
2.Plasma Lipoprotein A : Complex of
LDL and large glycoprotein apoA.
Interaction with proteoglycans-oxidative
modification-Key event for CHD.
3.Very Low Density Lipoprotein: High
VLDL conc indicates, high triglyceride
concentration.
ANTIATHEROGENIC
High Density Lipoprotein: Protective
factor against coronary heart disease.
Reverse cholesterol transport.
Lack apoB

5. LIPID METABOLISM

6. DRUG THERAPY OF DYSLIPIDEMIA
1.STATINS :
Competitive Inhibitors of (3-Hydroxy-3-
methylglutaryl) HMG-CoA reductase, which lowers
LDL by inhibiting an early rate-limiting step in
cholesterol synthesis.
• Drugs under this class are:
Lovastatin,pravastatin,simvastatin,Atorvastatin,fluvasta
tin,rosuvastatin and pitavastatin.

7. Mechanism of Action:

8. By reducing the conversion of HMG CoA reductase to Mevalonate, Statins inhibit an
early rate-limiting step in cholesterol biosynthesis.
By reducing the hepatic cholesterol synthesis, they also lead to an increased
expression of LDL receptor gene.
Statin therapy leads to enhanced production of vasodilator Nitric oxide,
contributing to an improved endothelial function.
• Statins lead to plaque stabilization and modulate cellularity of the artery wall.
• Statins decreased the levels of CRP, thus they lower the risk of CHD and inhibit
the inflammatory processes.
• Statins prevent susceptibility of Lipoprotein to oxidation.
• Statins repurposed for increasing the bone cell volume and to bolster the bones,
this could be a new therapeutic breakthrough for treatment of Osteoporosis.
Ref:http://www.ncbi.nlm.nih.gov/pubmed/10583956

9. Therapeutic Uses:
• Effective in all types of hyperlipidemias
• Patients with homozygous familial hypercholesteromia benefit less
with this drug class.

10. Adverse Effects:
a.Liver:
• Hepatotoxicity.
• Hepatic Insufficiency can cause drug
accumulation.
b.Muscle:
• Muscle myopathy and rhabdomyolysis has
also been reported rarely.

11. Drug Interactions:
• The HMG CoA reductase inhibitors could
increase warfarin levels.
Contraindications:
Statins are contraindicated during pregnancy
and for nursing mothers.

12. Why are statins administered before
bedtime or evening?

13. Hepatic cholesterol synthesis is maximal between
midnight and 2:00 AM, thus statins with a t1/2 of
4 hours should be administered in the evening
with a recommended dose of 20 mg.

14. 2.The Fibrates:
• This drug class includes Fenofibrate and gemfibrozil.
• These drugs are derivative of fibric acid and they execute the lipid
lowering action by decreasing the serum triacylglycerols and by
increasing the serum HDL levels.
Mechanism of Action: Lipid lowering action by interaction with
peroxisome proliferator-activated receptors (PPARs). This receptor
supergene family regulates the Lipid Metabolism.
Fibrate mediated PPAR gene expression leads to decreased triglycerol
concentration by increasing the expression of lipoprotein lipase and
decreasing apolipoprotein C II concentration.

15. THERAPEUTIC USES:
Gemfibrozil and fenofibrate are particulary useful in treating Type III
Hyperlipidemia. (high IDL)

16. Adverse Effects:
• Gastrointestinal Disturbances
• Increased lithogenecity of bile
• Myopathy syndrome
• Myositis
Contraindications: Their safety has not been established for
pregnant or lactating women. Patients with renal or hepatic
insufficiency or pre-existing gall bladder disease should not be
administered with this class of hyperlipidemic drugs.
Drug Interactions: Compete with coumarin anti-coagulants for
binding sites on plasma proteins, hence INR should be
monitored.

17. 3.Niacin (Nicotinic acid)
MECHANISM OF ACTION:
They exert their effect on lipolysis by
inhibiting adipocyte adenyl cyclase.
GPCR109A has been identified and
established for niacin, its mRNA is highly
expressed in adipose tissue and spleen,
high affinity nicotinic acid binding sites.

18. Pharmacokinetics :
• Niacin is biotransformed to nicotinamide, which is incorporated
in its cofactor NAD+. These metabolites excreted in the urine.
Adverse Effects: Cutaneous Flush, Pruritus,
hyperuricemia, and Gout. Impaired Glucose tolerance and
hepatotoxicity are also rarely observed.

19. 4.Bile acid-Sequestrants
Mechanism of Action : Colestipol and cholestyramine are
anion exchange resins.
Lowered Bile acid concentration= Hepatocyte conversion of
cholesterol to bile acid increased.

20. 5.EZETIMIBE (Cholesterol Absorption Inhibitor)
• Selectively inhibits absorption of Dietary and
biliary cholesterol in the small intestine.
• Blockade of sterol transporter on the brush border
membrane of Intestinal epithelial cells.
• Thus decreases delivery of cholesterol to the liver
& increases expression of LDL receptors.
• Cholesterol content of atherogenic particles also
decreases.
• Niemann-Pick C1 Like 1 Protein transporter has been
discovered that appears to be critical for intestinal
cholesterol absorption.

21. Summary :
TYPE OF DRUG MECHANISM OF ACTION
STATINS Inhibits a rate limiting step in Cholesterol
Biosynthesis
FIBRATES Modulates Lipid metabolism through
PPAR supergene family
NIACIN Inhibits Lipolysis in adipose tissue
BILE ACID SEQUESTRANTS Anion exchange resins that lower bile
acid concentration
EZETIMIBE Inhibits absorption of cholesterol from
the small intestine

22. Study Questions:
1. Which of the following drug decreases de-novo cholesterol synthesis
by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A
reductase?
a)Fenofibrate
b)Niacin
c)Lovastatin
d)Gemfibrozil

23. 2.Which one of the following drug causes decrease in liver triacylglycerol
synthesis by limiting available free fatty acids needed as building blocks for this
pathway?
a)Niacin
b)Fenofibrate
c)Cholestyramine
d)Gemfibrozil
3.Which of the following drugs binds bile acids in the intestine, thus preventing
their return to the liver via the enterohepatic circulation?
a)Niacin
b)Fluvastatin
c)Cholestyramine
d)Lovastatin

24. REFERENCES:
• The NEW ENGLAND JOURNAL OF MEDICINE:
http://www.nejm.org/doi/full/10.1056/nejm199506013322207
• http://science.sciencemag.org/content/193/4258/1094.short
• NCBI : Ref:http://www.ncbi.nlm.nih.gov/pubmed/10583956
• Lippincott’s illustrated Reviews
• Prevalence and treatment of hyperlipidemia in patients with chronic hepatitis C infection:
http://www.ncbi.nlm.nih.gov/pubmed/19398918
• Goodman & Gilman’s The Pharmacological Basics of Therapeutics

25. Thank You.