pharmacology of hypoglycemic agents for undergraduate students

1. HYPOLIPIDEMIC
AGENTS
BY
DR. HARSHIKA PATEL
KeMU
PHRM 300
PHARMACOLOGY

2. 29-2
CHOLESTEROL
Critical substrate for the body:
 Fundamental building block of steroid hormones
 Essential for building cell membranes, the myelin sheath,
and the brain
 Core component of bile salts, which helps in digest dietary
fats

3. 29-3
LIPOPROTEINS
There are several different lipoproteins:
Low-density lipoprotein (LDL)
Very-low-density lipoprotein (VLDL)
High-density lipoprotein (HDL)

4. CONTD’…
1.Chylomicrons (TGs): → fat globule formed in GIT from
dietary TG.
2. VLDL (TGs and cholesterol) → endogenously
synthesized in liver.
Degraded by LPL into free fatty acids (FFA) for storage in adipose tissue
and for oxidation in tissues such as cardiac and skeletal muscle.
 Chylomicrons are found in the blood and lymphatic fluid where they
serve to transport fat from its port of entry in the intestine to the liver
and to adipose (fat) tissue.
 After a fatty meal, the blood is so full of chylomicrons that it looks

5. CONTD’…
3. IDL (TGs, cholesterol); and LDL
(cholesterol) → derived from VLDL hydrolysis by
lipoprotein lipase. Normally, about 70% of LDL is
removed from plasma by hepatocytes.
4. HDL (protective) →exert several anti
atherogenic effects. They participate in retrieval of
cholesterol from the artery wall and inhibit the
oxidation of atherogenic lipoproteins & removes

6. 1-6

7. ATHEROSCLEROSIS
Plaque buildup can block arteries, causing:
Angina
TIA
Stroke
Intermittent claudication
29-7

8. CAUSATIVE AGENTS
Diet
Hypothyroidism
Nephrotic syndrome
Anorexia nervosa
Obstructive liver disease
Obesity
Diabetes mellitus
Pregnancy
Obstructive liver disease
Acute hepatitis
Systemic lupus
erythematous
AIDS (protease inhibitors)

9. MANAGEMENT OF
HYPERLIPIDEMIA
1.Diet: Avoid saturated fatty acids (animal fats)
and give unsaturated fatty acids (plant fats).
Regular consumption of fish oil which contains
omega 3 fatty acids and vitamins E and C
(antioxidants).
2.Exercise: ↑ HDL levels and insulin sensitivity.
3.Drug therapy: the primary goal of therapy is
to decrease levels of LDL .

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MONITORING THE DISEASE
The goals of treatment are:
Lowering LDL cholesterol
Reducing total serum cholesterol and triglycerides
Increasing HDL cholesterol

11. HMG-CO-A REDUCTASE
INHIBITORS
Atorvasatatin
Simvastatin
Lovastatin
Pravastatin
Fluavastatin
Rosuvastatin

12. BILE ACID BINDING
RESINS
Cholestyramine
Colestipol
Colesevelam

13. INTESTINAL CHOLESTEROL
ABSORPTION INHIBITORS
Stanol esters
Ezetimibe

14. ACTIVATORS OF LIPOPROTEIN
LIPASE (FIBRATES)
Gemfibrozil
Benafibrate
Fenofibrate
Ciprofibrate

15. INHIBITOR OF VLDL SECRETION
AND LIPOLYSIS
Niacin (Nicotinic acid)
Miscellaneous: Gugulipid and fish oil
derivatives

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HMG-COA REDUCTASE
INHIBITORS
Also referred to as statins
MOA—inhibit enzyme that causes cholesterol
synthesis
IND—adjunct to dietary treatment to decrease total
serum and LDL cholesterol:
Reduce LDL level up to 30%
Raise HDL level up to 20%

17. 1-17
HMG-COA REDUCTASE INHIBITORS
An early, very important
step in this process is the
conversion of acetyl-CoA
molecules into HMG-CoA,
which is then converted to
mevalonic acid by HMG-
CoA reductase.
Mevalonic acid is a rate-
limiting pivotal step in
steroid and cholesterol
biosynthesis.
The liver makes two-
thirds of the daily

18. HMG-COA REDUCTASE INHIBITOR
All of the statins reduce LDL up to 30 percent.
When a greater reduction of LDL is required, simvastatin
(Zocor), atorvastatin (Lipitor), and rosuvastatin (Crestor)
reduce more than 45 percent; in fact, rosuvastatin and
atorvastatin have been demonstrated to reduce up to 60
percent.
All of the statins raise the HDL level up to 20
percent.
Again, simvastatin (Zocor), atorvastatin (Lipitor), and

19. HMG-COA REDUCTASE INHIBITORS
Adverse effects:
Headache, dizziness, alteration of taste,
insomnia, abdominal cramping and
photosensitivity
May cause myalgias, leg ache, and
muscle weakness
Contraindicated during pregancy

20. CHOLESTEROL ABSORPTION
INHIBITORS
Ezetimibe:
Inhibits intestinal cholesterol absorption → ↓
concentration of intrahepatic cholesterol→
compensatory ↑ in LDL receptors →↑ uptake of
circulating LDL →↓ serum LDL cholesterol levels
(17%).
Used in hypercholesterolemia together with statins
& diet regulation.
Adverse effects: diarrhea and abdominal pain,
coughing, back pain, and arthralgia

21. BILE ACID SEQUESTRANTS
Cholestyramine, colestipol and
colesevelam.
MOA: anion exchange resins; bind bile
acids in the intestine forming complex
→so, bile acids loss in the stools →↑
conversion of cholesterol into bile acids in
the liver  in results, dec’ed concentration
of intrahepatic cholesterol → compensatory

22. NICOTINIC ACID
MOA: It strongly inhibits lipolysis in adipose tissues  which is the
primary producer of circulating free fatty acids
The liver normally utilizes these circulating fatty acids as a major
precursor for triacylglycerol synthesis.
Thus  Dec’ in liver triacylglycerol synthesis  required for VLDL
production  dec’ VLDL  which dec’ plasma LDL conc.
Thus  both plasma triacylglycerol and cholesterol are lowered.
Increases HDL cholesterol levels
Boosting secretion of tissue plasminogen activator and lowering the
level of plasma fibrinogen  red’ thrombosis
IND—hyperlipidemia
Adverse effects—cutaneous flushing, nausea, vomiting, and diarrhea

23. THERAPEUTIC USES
&PHARMACOKINETICS:
Treatment of type IIA and IIB hyperlipidemias (along with statins
when response to statins is inadequate or alternative when they are
contraindicated).
Useful for Pruritus in biliary obstruction (↑ bile acids).
Treatment of diarrhea resulting from bile acid mal-absorption or
secondary to Crohn's disease or the postcholecystectomy syndrome.
Pharmacokinetics:
Orally given but neither absorbed nor metabolically altered by
intestine, totally excreted in feces.

24. ADVERSE EFFECTS:
CONSTIPATION IS MAJOR
↓ absorption of fat soluble vitamins (A, D, K, E)
, ↓ Vit K → hypoprothrombinemia.
↓ absorption of many drugs as digitoxin,
warfarin, aspirin, phenobarbitone.

25. FIBRIC ACID DERIVATIVES
(FIBRATES)
Fenofibrate and gemfibrozil
MOA: Agonists at PPAR (peroxisome
proliferator-activated receptor) → expression of
genes responsible for increased activity of
plasma lipoprotein lipase enzyme → hydrolysis
of VLDL and chylomicrons→ ↓ serum TGs
Increase clearance of LDL by liver & ↑ HDL.
IND—Hypertriglyceridemia (the most effective in reduction
TGs, combined hyperlipidemia (type III) if statins are
contraindicated.
Adverse effects—nausea, vomiting, diarrhea, and

26. GUGULIPID
Consists of Z and E gugulsterone
Inhibit cholesterol biosynthesis and also
enhance rate of cholesterol excretion
Dose 25 mg 3 times a day
Reduced total CH, LDL-C with an elevation of
HDL-C
It is well tolerated, no side effect, except
loose stool

27. FISH OIL DERIVATIVE
Omega-3-fatty acids
Eicosa-pentanoic and docosa-
hexanoic acid
Prophylaxis use in high risk patient
of CAD
Usually formulated with vit.E

28. COMBINATION DRUG THERAPY
Bile acid binding resins+Fibrates
Bile acid binding resins+Niacin
Bile acid binding resins+Statins
Bile acid binding resins+Niacin+ Statins
Niacin +Statin (Atorva 10+ Nia 500)
Statins+Ezetimibe
Statins+Fibrate

29. 29-29
HYPOLIPIDEMIC DRUGS

30. PREFERRED THERAPY
All hypolipidemic drugs are indicated as adjunctive
therapy to reduce elevated cholesterol levels.
HMG-CoA reductase inhibitors are the most
prescribed.
Cholestyramine can also be used in the treatment
of partial biliary obstruction.

31. CONTRAINDICATIONS
Systemic hypolipidemic drugs should not be used in
patients with liver dysfunction.
Bile acid sequestrants should not be used in patients with
biliary obstruction.
Statins should not be used in pregnant women.

32. DRUG INTERACTIONS

33. NEW DRUGS
Cholesteryl ester transfer protein
(CETP)
Torcetrapib
Anacetrapib

34. REFERENCES
Katzung’s pharmacology
Lipincott’s illustrated pharmacology
K.d. tripathi textbook
Internet sources