Hyperlipidemia, or high lipid levels, is a common disorder that increases the risk of heart disease. It results from abnormalities in lipid metabolism or transport. The main causes are lifestyle factors like obesity and lack of exercise, as well as medical conditions like diabetes. Drugs used to treat hyperlipidemia work by inhibiting cholesterol biosynthesis, sequestering bile acids to reduce cholesterol absorption, altering cholesterol metabolism, or inhibiting absorption of dietary cholesterol. Statins are the most commonly used class that lower LDL cholesterol by inhibiting HMG-CoA reductase. Other drug classes include bile acid sequestrants, fibrates, and niacin. Combination therapies may be used for more severe or treatment-resistant cases of

1. Seminar on
Hyperlipidemia and drugs for its treatment
M. V. P. Samaj’s College of Pharmacy, Nashik-02
Presented by : Komal A. Rajgire
Roll No :59
Pharmaceutical Chemistry
Guided by : Dr. A. P. Pingle
Asso. Professor
Pharmaceutical Chemistry
1

2. What is Hyperlipidemia?
Hyperlipidemia a broad term, also called hyperlipo-
proteinemia, is a common disorder in developed countries
and is the major cause of coronary heart disease.
It results from abnormalities in lipid metabolism or plasma
lipid transport or a disorder in the synthesis and degradation
of plasma lipoproteins
2

3. Causes of Hyperlipidemia
• Mostly hyperlipidemia is caused by lifestyle
habits or treatable medical conditions.
• Obesity, not exercising, and smoking
• Diabetes, kidney disease, pregnancy, and an under
active thyroid gland, Inherit hyperlipidemia
3

4. Lipoproteins are macromolecules consisting of
lipoid substances (cholesterol, triglycerides) non-
covalently bound with protein and carbohydrate.
These combinations solublize the lipids and
prevent them from forming insoluble aggregates in the
plasma.
4

5. Normal Level Of Lipid in Normal Human
Body
• Total plasma cholesterol level < 200 mg/dL are
considered desirable.
• Levels between 200 and 239 mg/dL are considered
border line
• Levels > 240 mg/dL are considered high
5

6. Cholesterol Sources, Biosynthesis and
Degradation
• Diet
Only found in animal fat
• Biosynthesis
Primarily synthesized in the liver from acetyl
CoA
• Degradation
Only occurs in the liver
Cholesterol is converted to bile acids
6

7. Biosynthesis of Cholesterol
CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA
O O
OH
CH3
acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA
CH3
CH3
CH3
CH3
CH3
OH
cholesterol
-OOC-CH2-C-CH2-CH2-OH
OH
CH3
mevalonate
HMG CoA
Reductase
7

8. Metabolism
8

9. 9

10. CH3
CH3
CH3
OH
CH3
CH3
CH3
CH3
CH3
OH R7
H
R12 R
O
CH3
CH3
CH3
OH
O
CH3
CH3
CH3
O
O
cholesterol
cholic acids; R7 and R12 = H or OH; R = OH
glycocholic acid R7 = R12 = OH; R = NHCH2COOH
taurocholic acid R7 = R12 = OH; R = NHCH2CH2SO3H
pregnenolone
Liver
Liver, tissues
progesterone
Metabolism of Cholesterol
10

11. Types of Hyperlipidemias
Types I IIa IIb III IV V
Lipids
Cholesterol N- N- N- N-
Triglycerides N N-
Lipoproteins
Chylomicrons N N N N
VLDL N- N- N-
LDL N-
HDL N N N N-
N = Normal, = Increase; = Decrease; = Slight increase; = Slight decrease
11

12. Hyperlipoprot
einemia
Synonyms Increased
lipoprotein
Treatment
Type I (rare) ''Buerger-Gruetz syndrome'', ''Primary
hyperlipoproteinaemia'', or ''Familial
hyperchylomicronemia''
Chylomicrons Diet control
Type IIa ''Polygenic hypercholesterolaemia'' or
''Familial hypercholesterolemia
LDL Bile acid
sequestrants,
statins, niacin
Type IIb ''Combined hyperlipidemia'' LDL and VLDL Statins,
niacin, fibrate
Type III (rare) ''Familial dysbetalipoproteinemia'' IDL Fibrates,
statins
Type IV ''Familial hyperlipidemia'' VLDL Fibrate,
niacin],
statins
Type V (rare) ''Endogenous hypertriglyceridemia VLDL and
Chylomicrons
Niacin, fibrate
Types , Synonyms & their treatment
12

13. Strategy for Controlling Hyperlipidemia
13

14. 14

15. Classification
A) Inhibitor of de novo cholesterol biosynthesis HMG
CoA Reductase inhibitors (Statins)
B) Sequestering agents (Bile acids sequestrants)
C) Alteration of cholesterol metabolism
D) Inhibition of cholesterol absorption
15

16. A) Inhibitor of de novo cholesterol biosynthesis
HMG CoA Reductase inhibitors - Statins
• Statins are the drugs that competitively inhibit HMG-
CoA reductase, resulting a decrease in serum
cholesterol levels .
• Till now there are seven statins available in
pharmaceutical form. (lovastatin, simvastatin,
pravastatin, fluvastatin, atorvastatin, rosuvastatin,
and pitavastatin).
• Statins can be classified into naturally derived and
chemically synthesized .
• The first statin identified was Mevastatin, which is
not in use now 16

17. Drugs
CH3
CH2CH2O
O
CH3
R'
R''
O
OOH
R' R''
Mevastatin H H
Lovastatin H CH3
Simvastatin CH3 CH3
CH3
CH2CH2O
O
OH
CH3
OH
OH
COONa
Pravastatin
17

18. NH
N
H
F
OH
OH
COO Ca
CH3
CH3
O
_
+
N
OH
OH
COONa
CH3
CH3
CH3
CH3
O
CH3
F
N
OH
OH
COONa
CH3
CH3
F
Atorvastatin Cerivastatin Fluvastatin
N N
OH
OH
CH3
CH3
N
S CH3
F
O
O
CH3
COO Ca
_
+
N
OH
OH
COO Ca
F
_ +
Rosuvastatin Pitavastatin
18

19. • Th 3,4-dihydroxycarboxylate is essential for
inhibitory action
• Compound containing a lacton are prodrugs required
in-vivo hydrolysis.
• Stereochemistry of 3- & 5- hydroxyl group same
• Alteration the 2 –C distance between C5 & the ring
diminish activity
• Double bond between C6 & C7 or activity.
• Ethyl group provides optimal activity
SAR of HMG-CoA Reductase inhibitors
19

20. The structure should contains
a. lactone ring (sensitive to stereochemistry of
it, ability of ring to hydrolyzed, length of
bridge)
b. Bicyclic rings ( could be replaced with other
lipophlic rings, size and shape of it are
important for activity)
c. Ethylene bridge between them is
essntial
20

21. Drugs Bioavailability Dosage (mg) Protein
Binding
Metabolites
Atorvastatin ~14% 10 – 80 >98% Active
Cerivastatin ~60% 0.2 – 0.3 >99% Active
Fluvastatin ~24% 10 – 80 98% Active
Lovastatin ~5% 10 – 80 >95%
Pravastatin ~17% 10 – 40 ~50%
Simvastatin ~5% 10 - 80 ~95%
Pharmacokinetic properties of statins – case of cerivastatin
Typically all statins possess side effects. The most dominant
side effect, cited in the withdrawal of cerivastatin, is
rhabdomyolysis (lysis of rhabdomyose) or weakening of
skeletal muscles. 21

22. Metabolic properties of statins
• Rapid first pass metabolism significantly reduces bioavailability
• Metabolism is complex
• Extensive conversion between the lactone and open-chain forms
• Glucuronidated forms as well
• Other than these three, many other lesser metabolites
• Inhibitors of cytochrome P450 increase bioavailability of statins
….. Greater incidences of myopathy ….. E.g., cyclosporin,
gemfibrozil, erythromycin, itraconazole, etc.
• Rhabdomyolysis A rare complication of statin treatment.
Characterized by breakdown of muscles
Release of myoglobin into blood, which travels to kidneys
and stops working of its tubules
Also muscle breakdown increase K+, which induces cardiac
arrythmias and death
22

23. • Adverse Effects of HMGRIs
Constipation, abdominal pain, diarrhea, nausea,
vomiting, headache, elevated hepatic enzymes,
myalgia, myopathy, muscle cramps,
rhabdomyolysis, and chest pain
• Uses
For primary hypercholesterolemia and familial
combines hyperlipidemia ( type II a, II b )
In combination with bile acid sequestrants, ezetimibe,
or niacin
23

24. Combination Products That Include an HMGRI
• HMGRI and antithrombotic
Pravastatin/aspirin (Pravigard PAC)
• HMGRI and calcium channel blocker
Atrovastatin/amlodipine (Caduet)
• HMGRI and additional antihypercholesterolemic
agent
Lovastatin/niacin (Advicor)
Simvastatin/ezetimibe (Vytorin)
24

25. • Anion exchange resins
• Water insoluble and inert to digestive enzymes
• Not absorbed through the GI tract
• Positively charged nitrogens sequester bile acid
re-absorption
• Lower serum LDL levels
• Most useful in type IIa and IIb hyperlipidemias
B) Bile Acid Sequestrants
25

26. Sequestering agents (Bile acids sequestrants)
N CH2CH2 N
CH2
CHOH
CH2
N CH2CH2
N
C
H
C
H2
C
H
CH2N(CH3)3
nn
CH2CH2
Cl
-
+
Cholestyramine Resin Colestipol hydrochloride
NH
(CH2
)9
CH3
NH
(CH2)6NMe3+
NHNH2
NH
(CH2)9CH3
NH
(CH2)6NMe3+
NH
OH
NH2
Colesevelam
26

27. Cholestyramine (Questran)
• Non-absorbed bile acid sequestrant that is used a
therapy of hyperlipidemia
• It is Large & Highly positively charged anion
exchange resin binds to bile acid
• The binding of bile acids to cholestyramine creates an
insoluble compound that cannot be reabsorbed
27

28. • Cholestyramine and colestipol are basic anion
exchange resins, which sequester bile acids in the
intestine and prevent their re-absorption and their
enterohepatic re-circulation.
• The result is a decreased in the absorption of
exogenous cholesterol and increase in the metabolism
of endogenous cholesterol into bile acids in the liver.
28

29. Adverse effects
•Beceause they are not orally absorbed, they produce
minimal systemic side effects
•Constipation, Heartburn, nausea, bloating
– These adverse effects tend to disappear over
time
29

30. C) Alteration of cholesterol metabolism
Fibrates
• Older generation drugs; introduced in 1981
• Second most useful anti-hyperlipidemic drugs
• Primarily decrease serum triglycerides
• Increase lipoprotein catabolism; increase TG usage by the
body
• activate PPAR-a (peroxisome proliferator-activated
receptor a)
• Most used in Type III, IV and V hyperlipidemias
30

31. Drugs - Fibrates
O
CH3
CH3
CH2
CH2
CH2 COOH
CH3
CH3
OCl COOCH2
CH3
CH3
CH3
O
N
H
O
Cl
COOH
CH3
CH3
O
O
Cl
COOCH(CH3
)2
CH3
CH3
O
Cl Cl
COOH
CH3
CH3
Gemfibrozil Clofibrate
C C
C
Bezafibrate
C
Fenofibrate
C
Ciprofibrate
{No longer recommended because of an increase
in overall mortality and adverse efects}
{rhabdomyolysis … highest PPAR-a affinity
 clinical trials stopped in the US} 31

32. SAR of Fabric acid derivatives
[aromatic ring]-O-[spacer group]-C(CH3)2-CO-OH
1) They are classified as analogues of isobutyric
acid derivatives (essential for activity)
Fabric acid
32

33. gemfibrozil
Fenofibrate
2) Fenofibrate contain ester (prodrug) and requires for in vivo
hydrolysis.
3) Para-subtitution with Cl or Cl containing isopropyl ring
increase half-lives.
4) A phenoxy isobutyric acid, the addition of an n-propyl spacer,
as seen in gemfibrozil , results in an active drug.
33

34. Adverse Effects
Abdominal pain, nausea, vomiting, diarrhea,
constipation, cholestasis, jaundice, cholelithiasis,
pancreatitis,
headache, dizziness, drowsiness, blurred vision,
mental depression, impotence, myopathy, myositis,
anemia, leukopenia, eosinophilia, pruritus, and
rash
34

35. Nicotinic Acid
• Administered in large doses (0.5 to 6 grams daily)
• Reduces triglycerides and total cholesterol
• Increases biliary secretion of cholesterol, but not bile acids
• Useful in Type IIa, IIb, III, IV and V hyperlipidemias
N
N
CH3
N
CONH2
N
COOH
NICOTINIC ACID (NIACIN)NICOTINE NICOTINAMIDE
35

36. • Mechanism of action
Increases activity of lipase, which breaks down lipids
Reduces the metabolism of cholesterol and
triglycerides
• Adverse Effects of Niacin
Flushing, headache, nausea, vomiting, diarrhea, hepatic
dysfunction, jaundice, hyperglycemia,
hyperuricemia, blurred vision, and tachycardia
36

37. D) A Cholesterol Absorption Inhibitor– Ezetimibe
• Approved in October 2002
• Reduces serum LDL, TC, and TG and increases HDL
• Prevents the absorption of cholesterol from diet
• Useful in Type IIa, IIb, III, IV and V hyperlipidemias
N
O
F
F
OH
OH
Ezetimibe 37

38. • Mechanism of action
Is a drug that lowers plasma cholesterol levels. It
acts by decreasing cholesterol absorption in the intestine
• Adverse Effects of Ezetimibe
Abdominal pain, diarrhea, arthralgia, back pain,
cough, pharyngitis, sinusitis, fatigue, and viral infection
38

39. Generic Brand
Atorvastatin Lipitor
Fluvastatin Lescol
Lovastatin Mevacor
Pravastatin Pravachol
Simvastatin Zocor / vytorin
Rosvastatin Crestor
Fenofibrate Tricor
Gemfibrat Lopid
Colstipol Colestid
Chlolstyramine Qstron
Ztimibe zetia
39

40. Condition Brand Name Generic Drug
Angina Coduet Amolodipin + Atorvastatin
Diabetic (Type II ) Juvisync Simvastatin + Sitagliptin
High B.P. Caduet Amolodipine + Atrovastatin
High cholestrol Vytorin Ztimib + Simvastatin
Simcor Niacin + Simvastatin
Advicor Lovastatin + Niacin
Javisyne Simvastatin + Sitagliptin
Liptruzet Atrovatatin + Eztimib
LDL Simcor Niacin + Simvastatin
Advicor Lovastatin + Niacin
Type IIa &IIb &
LDL &VLDL
Simcor Niacin + simvastatin
40

41. 41