This document discusses lipid metabolism and hypolipidemic drugs. It defines different types of lipids including triglycerides, cholesterol, and lipoproteins. It describes the normal metabolism of lipids and how elevated LDL and triglycerides can lead to conditions like atherosclerosis. The document then summarizes several classes of drugs used to treat hyperlipidemia including statins, bile acid sequestrants, cholesterol absorption inhibitors, and fibrates. It provides examples of drugs in each class and their effects on lipid levels as well as common adverse effects.

1. Lipid metabolism and
Hypolipidemic drugs
Dr Urmila M. Aswar,
Sinhgad Institute of Pharmacy,
Narhe, Pune -41

2. LIPIDS
• Esters of fatty acids and alcohols.
• Insoluble in water
• Saturated: lauric acid, palmitic acid, eg
DALDA, increase LDL
• Monounsaturated: oleic acid
• Polyunsaturated fatty acids: arachidonic
acid, abundant in corn oil, hypolipedemic.
• Trans fatty acid: harmful, increase LDL

3. Cont..
• Triglycerides (TG):
• Cholesterol (CH):
• LIPOPROTEINS: They are spherical
particles that transport neutral lipids that is
TG and CH in blood.
• Structure: Core-TG and CE, hydrophilic
surface
-PL,
unestrified
CH
and
Apoprotein

4. TG
• Over 93% of the fat that is consumed in
the diet is in the form of triglycerides (TG).

5. CH
• Dietary intake supplies only about 20 –
25% of the cholesterol needed everyday to
build cell membranes,

6. • synthesize bile acids/salts,

7. • synthesize hormones of the adrenal
glands (aldosterone, cortisol)

8. • and synthesize the sex hormones.

9. • The other 75 – 80%
of our daily need for
cholesterol is
synthesized in the
liver.

10. LIPOPROTEIN
• Apolipoprotein: a protein that
binds to lipids
• cholesteryl
ester:
a
compound of cholesterol and a
fatty acid
• Triglyceride: a compound of
glycerol and three fatty acids,
an ordinary fat molecule
• Phospholipid: a compound of
glycerol, two fatty acids, and
choline
phospate,
an emulsifier like lecithin

11. Types of LP
•
•
•
•
Chylomicrons,
VLDL,
LDL,
HDL

12. Density:HDL>LP(a)>LDL>IDL>VLDL>CM
DM:CM>VLDL>IDL>LDL>LP(a)>HDL
TG:CM>VLDL>IDL>LDL>LP(a)=HDL
CE:LP (a)= LDL>IDL>HDL>VLDL>CM
ATHEROGENOCITY:
LP(a)>LDL>IDL>VLDL=CM
HDL is antiatherosclerotic

13. Apoproteins
•
•
•
•
•
•
•
•
These are surface proteins on LP
Gives structural stability
They help in metabolism/ Fate of LP.
There are 9 types
APO AP-I, AP-II, AP-IV
APO B-48, APO B-100
APO C-I, APO C-II, APO C-III
APO E

14. Normal lipid metabolism:

15. Endogenous Pathway

16. VLDL
• Dietary TGs are packaged by the liver into
a lipoprotein known as very low density
lipoprotein (VLDL).

17. • This lipoprotein delivers the TG to adipose
tissue to be stored.

18. • The primary function of low density
lipoprotein (LDL) is the transport of the
cholesterol synthesized in the liver to the
periphery.

19. • As it travels through the circulation LDL
reacts with LDL receptors on various
nonhepatic cells.

20. • Dietary saturated fat in particular is one of
the primary dietary determinants of
hypercholesterolemia, as demonstrated by
numerous studies.

22. • These studies illustrate the importance of
substituting unsaturated fat for saturated
fat in the diet.

23. • Saturated fats raise LDL cholesterol by
decreasing the synthesis of LDL
receptors,
• Genetic effects involves dysfunction of
LDL receptors or mutation of LDL
receptors or absence of LDL receptors

24. • The overall results is cholesterol is not
removed from the circulation. LDL
cholesterol that does not react with a LDL
receptor continues to circulate.

25. Why LDL is BAD and HDL is
good
• LDL’s are usually not particularly atherogenic
• LDL gets damaged and oxidised by smoking & other
factors producing free radicals
• Damaged LDL is recognised by the scavenger
receptor on macrophages & is engulfed by them
• Because the LDL is damaged & oxidised it causes
the macrophage to become poisoned & die.
• They then transform into a foam cell – which is the start
of the atherosclerosis process
• HDL can do some repair of LDL’s to make them less
damaged
&
less
toxic
to
macrophages

26. • The oxidation of LDL is an important step in
atherogenesis as it activates further immune and
inflammatory responses (i.e. entry of monocytes
across endothelium).

27. • These LDL foam cells accumulate in
significant amounts, forming lesions called
fatty streaks. Once formed, fatty streaks
produce more toxic oxygen radicals and
cause immunologic and inflammatory
changes (production of more cytokines)
resulting in progressive damage to the
vessel wall.

28. HDL – a good cholesterol
• Nascent HDL takes CH from Foam cells
and periphery. CH is converted into CE by
LCAT(lecithin
cholesterol
acyl
transferase). The CE of HDL is
transported to VLDL, LDL, IDL by
CETP(cholesteryl ester transfer protein)
which further goes to liver via LDR
receptor: Reverse cholesterol transfer

30. Hyperlipedaemia
• Primary: genetic
• Secondary: associated with some disease,
diabetes,
myxoedema,
nephrotic
syndrome, chronic alcoholism.

31. • Till 30 yrs possibility of coronary artery
disease is less.
• Later yrs, appearance of angina, coronary
thrombosis and/or sudden death can
happen.

32. Factors causing CAD
• Age
• Obesity
• Menopause

33. •
•
•
•
•
Hyperlipidemia,
hypertension,
Smoking,
Diabetes
Sedentary lifestyle

34. WHY hyperlipedaemia occurs
• The reason for this is that research from
experimental
animals,
laboratory
investigations, epidemiology and genetic
forms of hypercholesterolemia indicate
that elevated LDL cholesterol is a major
cause of CAD and that clinical trials
show that LDL-lowering therapy reduces
the risk for CAD.

35. Pharmacotherapy of
hyperlipidaemias
• Healthy Diet
• HMG-CoA reductase inhibitors: Statins
• Bile acid binding agents: Cholestyramine,
colestipol
• Fibric acid derivatives: Clofibrate,
Gemfibrozil, Benzafiberate
• Inhibitors of absorption of cholesterol:
Stanol esters, Eztimibe

36. 1. HMG-CoA reductase inhibitors
The HMG-CoA reductase inhibitors, or
statins are a class of hypolipidemic agents
that are competitive inhibitors of HMGCoA reductase. They inhibit conversion of
HMG-CoA to mevalonic acid and deplete
intracellular supply of CH.
• Liver compensate this biosynthesis and
take up CH from blood and by increasing
the no of LDR on liver.

38. • They are considered to be the most potent
cholesterol-lowering agents, lowering
LDL-cholesterol between 20–60%.
• They also increase the uptake of VLDL
and IDL remenants.
• Disadvantages: After prolong use only
LDL reduction happens by 6% even after
doubling the dose.
• Ceiling dose effect: induction of HMG-CoA
reductase- More synthsis of CH. This
decreases LDR further.

39. Lovastatin (Mevacor, Altocor) Merck
• Lovastatin was the first statin approved by
the FDA (August 1987).
• The dosage is 20-80 mg and should be
taken in the evening with food.
• Shows 25-40% reduction in LDL.

40. •
•
•
•
•
Simvastatin (Zocor) Merck
Simvastin was approved in the late 1980’s.
The dosage is 20-80 mg and should be
taken in the evening.
Shows 35-50% reduction in LDL.
Simvastatin is highly lipophilic, and there
tends to be more insomnia with the
lipophilic statins (unknown mechanism).

41. Pravastatin (Pravachol) Bristol Meyer
Squibb
• Pravastatin was “discovered” in Japan in
1979, produced by a chemical modification
of lovastatin. In terms of clinical trials,
pravastatin is the most studied statin.The
dosage is 20-80 mg and should be taken
in the evening, with or without food.
Pravastatin is less lipophilic than
simvastatin and is also less likely to cause
insomnia.
• 20-35% reduction in LDL

42. Atorvastatin (Lipitor) Pfizer
• Atorvastatin received FDA approval in
1997 and by 2004 was the best selling
drug in the world with sales of $10.9
billion.
• The dosage is 10-80 mg.

43. • Shows 35-60% reduction in LDL
• One of the advantages of Lipitor is that it
can be taken with or without food at any
time of the day.

44. Adverse effects of statins elevated liver
enzymes
1-2% can have liver disease. Within 6
weeks of the onset of statin therapy the
patient should have a blood test to
determine the concentration of the liver
enzymes aspartate aminotransferase, AST
(normal concentration is 0 – 35 U/L) and
alanine
transaminase,
ALT(normal
concentration is 4 – 36 U/L).

45. • Of these, the AST test is the most
sensitive marker of the impact of statin
therapy. If it is elevated more than 2-3
times the upper limit of normal, therapy
should be terminated.

46. • A fatty liver is the most common cause of
elevated AST and ALT in patients on statin
therapy.

47. Muscle pain
• The most commonly reported adverse
effect with statin use is muscle pain. There
is a serious, but rare complication
associated with the breakdown of muscle
proteins called rhabdomyolysis. These
muscle proteins, especially myoglobin, are
released into the circulation, and result in
the
potentially
life-threatening
complications of myoglobinuric acute renal
failure and cardiac arrest.

48. • The most common
symptoms
of
rhabdomyolysis
include: dark urine,
swollen,
tender
muscles of the thighs
and lower back.

49. • Creatine phosphokinase (CPK) elevation
is one of the most important diagnostic
criteria of rhabdomyolysis. A value above
the upper limit of normal (range of 30 –
200 U/ L), indicates a problem.

50. GI problems
• Common GI problems with statin therapy,
which generally resolve within a couple of
weeks of initiating therapy include:
nausea, diarrhea, constipation, excessive
flatulence.
• Other effects: Headache, dizziness, taste
alterations, insomnia, and photosensitivity
are other reported effects.

51. II. Bile acid binding resins or Bile acid
sequestrants
Bile acid sequestrants are a group of
medications which bind bile in the GI tract.
By binding bile they prevent its
reabsorption, increasing its removal. As
the body loses bile acids, it converts
cholesterol into bile acids, thus lowering
serum cholesterol levels. It reults in
upregulation of LDL receptors and thus
decreases LDL in serum.

53. • Use of these agents has declined since
the introduction of the statins. They require
very large doses and need to be taken
with lots of water. They are most often
used as an adjunct to statins.
• lowering of LDL (generally, no more than
20%) and a very slight elevation of HDL is
seen with in 2-3 weeks.
•

54. Cholestyramine
• This is the major drug in this class.
• The usual dosage of this powder is 4 - 6 g,
mixed with a liquid, twice a day before
meals.
• No more than 24 g/day

55. Colesevelam
• The dosage is three 625 mg tablets, twice
daily, so 6 tablets/day.

56. Colestipol
• Dosage, if granules is 5 g, one or two
times daily
• Tablets, 2 – 4 g/day, tablets are 1 g each.

57. Adverse effects of the bile acid
sequestrants
• These adverse effects are generally GI
related and usually dissipate within a
couple of weeks. They include: nausea,
vomiting, heartburn, bloating, constipation
(most
common),
flatulence,
fecal
impaction, fatty or black stools, and
intestinal obstruction (most severe).
•

58. • Transient increases in AST, ALT and
alkaline phosphatase have been observed
in patients on Colestipol.

59. III. Cholesterol absorption inhibitors
• CH comes from diet and hepatic secretion.
These drugs block dietary absorption of
dietary cholesterol in the small intestine,
this results in uptake of LDL and hence
reduces LDL cholesterol levels. Plant
stanol esters and Ezetimibe are used for
this.

60. Ezetimibe
• A cholesterol inhibitor,
Ezetimibe (Dose: 10 mg)
alone generally reduce
LDL between 10 – 20%.
• Adverse effects include:
fatigue, coughing, nausea,
diarrhea, rash, pancreatitis
and angioedema.

61. Fibrates
• The primary actions of this class of drugs
is to lower triglyceride levels.

62. • This occurs through stimulation of
lipoprotein lipase (which hydrolyzes
triglycerides) and by suppression of
apoprotein C-III production (this is the
protein component of VLDL, the primary
carrier of triglycerides from the liver to
other tissues).

63. • These drugs were first introduced in 1962
and were widely used before the discovery
of the statins.

64. a. gemfibrozil
(Lopid)
• Dosage is 600 mg, bid at least 30 minutes
before eating

65. b. fenofibrate (Antara, Lofibra,
Tricor, Triglide)
•
•
•
•
Antara dosage is 43 – 130 mg/day
Lofibra dosage is 67 – 200 mg/day
Tricor dosage is 48 – 145 mg/day
Triglide dosage is 50 – 160 mg/day

66. adverse effects of fibrates
• These include GI disturbances (nausea,
vomiting, diarrhea, flatulence).

67. • In addition, dizziness, blurred vision,
muscle pain and weakness have been
reported.

68. • Some patients taking gemfibrozil have
reported gallstone formation.

69. • Combination therapy of gemfibrozil and a
statin may be associated with an
increased risk of rhabdomyolisis,
according to the Committee on Safety of
Medicines.

70. • Fenofibrate may be given with a statin, but
only if statin monotherapy is insufficient
(very high LDL AND very high
triglycerides).
• Dosage: 100 – 500 mg/day, increase up to
1 – 2 g tid