This document provides information on hyperlipidemic drugs. It begins with an introduction to hyperlipidemia and its causes. It then discusses various drug classes for treating hyperlipidemia, including their mechanisms of action, effects on lipid levels, pharmacokinetics, therapeutic uses, adverse effects and interactions. The major drug classes discussed are HMG-CoA reductase inhibitors (statins), bile acid sequestrants, fibrates, and niacin. For each class, specific drugs are highlighted and their properties compared.

1. Moderator:
Dr. Ali Ahmad
Presentor:
Dr.Roohana Hasan
JR-1
HYPOLIPIDEMIC
DRUGS

2. Introduction
 Hyperlipidemia is a condition excess
of fatty substances called lipids,
largely cholesterol and triglycerides,
in the blood.
 It results from abnormalities in lipid
metabolism or plasma lipid transport
or a disorder in the synthesis and
degradation of plasma lipoproteins.

3. Serum Lipid Level (mg/dL) and Risk of
CAD and IHD based on NCEP Guidelines
2001

4.  Lifestyle
 Diabetes Mellitus
 Kidney disease
 Pregnancy
 Hypothyroidism
 Genetic
 Alcohol
 Drugs- Thiazides, Cyclosporin,
Glucocorticoids, Beta Blockers.
Causes of Hyperlipidemia

5. Current cigarette smoking Defined
as smoking within the preceding 30
days
Age Male >45 years of age or
female >55 years of age
Family history of premature CHD A first-
degree relative (male <55 years of age or
female <65 years of age when the first CHD
clinical event occurs)

6.  Hypertension Blood pressure
140/90 or use of
antihypertensive medication,
irrespective of blood pressure
 Low HDL-C <40 mg/dL
(consider <50 mg/dL as "low" for
women)
 Obesity
Body mass index >25 kg/m2
and waist circumference >40
inches (men) or >35 inches
(women)
 Type 2 diabetes mellitus

7. Hyperlipoproteinaemias
 Primary: due to:
(a) A single gene defect: is familial and
called ‘monogenic’ or genetic
(b) Multiple genetic, dietary and
physical activity related causes:
‘polygenic’ or multifactorial.

8. Types of primary
hyperlipoproteinaemias

9.  Secondary: associated with
Diabetes,
Myxoedema,
Nephrotic syndrome,
Chronic alcoholism,
Drugs (corticosteroids, oral
contraceptives, β blockers) etc.

10.  Lipids- Hterogenous group of compounds
related to fatty acids, which are insoluble in
fatty acids and are source of energy.
 Lipoproteins- Spherical particles of water
soluble proteins, that transport neutral lipids
through body fluids.

12. Lipid metabolism

13. • Life style modification.
Regular exercise.
• Obesity reduction.
• Stop smoking &
alcoholism.
• Diet.
• Restrict intake of saturated
fat.
Fish intake-oily sea fish.
Eg-Tuna & Mackarel.
• Plenty of fruits &
vegetebles.
• TREAT THE UNDERLYING
Treatment strategies

14. Clinical guidelines
recommend the drug
therapy to be started along
with lifestyle changes in
patients with IHD or in
patients with having LDL
greater than 130mg/dl.

15. Lowering LDL cholesterol
Reducing total serum cholesterol
and triglycerides
Increasing HDL cholesterol
The goals of treatment are:

18. Primary prevention involves
management of risk factors to prevent a
first-ever CHD event.
 Secondary prevention patients are
those who have had a prior CHD event
and whose risk factors are treated most
aggressively.
Recently, the concept of primordial
prevention has been applied to CHD

19. The primordial prevention guidelines include

150 minutes/week of moderate-intensity exercise (walking
20-30 minutes/day.
 Dietary recommendations include
reducing total calories from fat to <30% and saturated fat to
<7% to avoid trans fat;
 consuming <300 mg of cholesterol/day,
a variety of oily fish twice a week or more often, and
oils/foods rich in -linolenic acid (canola, flaxseed, and
soybean oils; flaxseed; and walnuts);
restricting sugary beverages to <36 oz/week for a person
consuming 2000 Kcal daily

20. HYP0LIPIDEMIC
DRUGS
Several different classes of drugs are
used to treat hyperlipidemia. These
classes differ not only in their
mechanism of action but also in the
type of lipid reduction and the
magnitude of the reduction.

21. Classification of Hypolipidemic
Drugs
First Line Therapy
1. HMG-CoA reductase inhibitors (Statins): Lovastatin,
Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin,
Pitavastatin
2. Bile acid sequestrants (Resins):
Cholestyramine, Colestipol
3. Inhibitors of Intestinal Absorption of
Cholesterol: Stanol Esters, Ezetimibe.
4. CETP Inhibitors: Torcetrapib,
Anacetrapib

22. Second Line Therapy
Lipoprotein lipase activators (PPARα
activators, Fibrates): Clofibrate,
Gemfibrozil, Bezafibrate, Fenofibrate
Lipolysis and triglyceride synthesis
inhibitor: Nicotinic acid (Niacin)
Miscellaneous Agents: Gugulipid and
Fish oil Derivatives.

23. HMG-CoA REDUCTASE
INHIBITORS (Statins)
The statins are the most effective and
best-tolerated agents for treating
dyslipidemia.
These drugs are competitive inhibitors of
HMG-CoA reductase, which catalyzes an
early, rate-limiting step in cholesterol
biosynthesis.

24. History
 Statins were isolated from a mold,
Penicillium citrinum, and identified
as inhibitors of cholesterol
biosynthesis in 1976 by Endo and
colleagues.
 The first statin studied in humans
was compactin, renamed
mevastatin, which demonstrated
the therapeutic potential of this

25. Alberts and colleagues at Merck
developed the first statin approved for
use in humans, lovastatin (formerly
known as mevinolin), which was
isolated from Aspergillus terreus.
Pravastatin and simvastatin are
chemically modified derivatives of
lovastatin.
Atorvastatin, fluvastatin,
rosuvastatin, and pitavastatin are
structurally distinct synthetic

26. They competitively inhibit
conversion of 3-Hydroxy-3-
methyl glutaryl coenzyme A
(HMG-CoA) to mevalonate
(rate limiting step in CH
synthesis) by the enzyme
HMG-CoA reductase.

27. Cholesterol Synthesis

28.  LDL is also reduced by
enhancing the removal of
precursors of of LDL. Eg;
VLDL and IDL.
 Reducing hepatic VLDL
production also leads to
reduction in the level of
LDL. This also reduced the
level of TG.

29.  Therapeutic doses reduce CH synthesis by
20–50%. This results in compensatory
increase in LDL receptor expression on liver
cells → increased receptor mediated uptake
and catabolism of IDL and LDL.
 Over long-term, feedback induction of HMG-
CoA reductase tends to increase CH
synthesis, but a steady-state is finally attained
with a dose-dependent lowering of LDL-CH
levels.

30. Actions
Effect on Lipid Levels
 Effect of TG:
• Significant reduction in TG Level (35-45%)
if the TG > 250mg/dl.
• If TG <250 mg/dl – maximum reduction is
<25%
• LDL is also reduced.

31.  Effect on LDL-C
• Depending upon the statin its dose the degree
of reduction in the level of LDL ranges from
20-55%Statins Dose Range
Fluvastatin 20-80mg 20 35
Pravastatin 10-40mg 20 35
Lovastatin 10-80mg 20 40
Cervistatin 0.2-0.8mg 20 40
Simvastatin 10-80mg 26 50
Atorvastatin 10-80mg 31 55
Rosuvastatin 5-40mg 36 55
Percentage Reduction in LDL-C in
Min Dose Max Dose

32.  Effect on HDL-C
• Increased irrespective of the dose and statins
used but if the HDL-C <35mg/dl- the effect
may be variable.
• Simvastatin produces greater increase in HDL-
C and apoA-1 level than Atorvastatin and
Rosuvastatin.
 Level of Lp(a) is not affected by the Statins.

33. Direct Cardioprotective Effects
Statins have
direct
cardioprotecti
ve effects
independant
of lipid
lowering
effects

34. Effect on Endothelium
 Hypercholestroleamia depresses the
acetylcholine induced vasodilatation in coronary arteries.
 Statins increase the synthesis of endothelial NO by stabilization of
endothelial synthase mRNA.
 Endothelial dysfunction is also reversed by statins.

35. Effect on Plaque Stability
 Inhibits the infilteration of monocytes in
arterial wall.
 Inhibits the secretion of metalloproteinases secreted
by macrophages.
 The metalloproteinases degrade matrix and weaken
the fibrous cap of atherosclerotic plaque.
 Statins also appear to modulate the cellularity of the
artery wall by inhibiting proliferation of smooth muscle
cells and enhancing apoptosis.
 Reduced proliferation of smooth muscle cells and
enhanced apoptosis- retard initial hyperplasia and
restenosis.

36. Effect on Inflammation
 C- Reactive Protein – marker for high risk
CAD.
 Statins Reduces the baseline CRP.

37. Effect on Lipoprotein Oxidation
 Oxidative changes in LDL
occurs and important in
the uptake of lipoprotein
cholesterol by
macrophages,
cytotoxicity with lesions.
 Statins inhibits the
oxidative changes and
thus subsequent effect.

38. Effect on Coagulation
Statins decrease platelet
aggregation and also reduce the
level of fibrinogen.
Increased level of fibrinogen may
be involved in increased incidence
of CAD

39. Atorvastatin
 This newer and most popular statin is more
potent and appears to have the highest LDL-CH
lowering efficacy at maximal daily dose of 80 mg.
 At this dose a greater reduction in TGs is noted if
the same was raised at baseline.
 Atorvastatin has a much longer plasma t½ of 18–
24 hr than other statins, and has additional
antioxidant property.

40. Rosuvastatin
 This is another newer, commonly used and
potent statin (10 mg rosuvastatin ~ 20 mg
atorvastatin), with a plasma t½ of 18–24 hours.
 Greater LDL-CH reduction can be obtained in
severe hypercholesterolaemia; partly due to its
longer persistence in the plasma.
 In patients with raised TG levels, rosuvastatin
raises HDL-CH by 15–20% (greater rise than
other statins).

41. Potency of Statins
 Potency Order for reduction in LDL-C:
Rosuva > Atorva > Simva > Lova > Prava >
Fluva
 Potency Order for reduction in TG:
Atorva >Prava > Rosuva > Simva > Lova
>Fluva
 Potency Order for increase in HDL-C:
Prava >Simva > Rosuva = Fluva = Lova >
Atorva

42. HMG-CoA reductase activity is
maximum at midnight, so all statins are
administered at bed time to obtain
maximum effectiveness.
However, this is not necessary for
atorvastatin and rosuvastatin, which
have long plasma t½.
All statins, except rosuvastatin are
metabolized primarily by CYP3A4.

43. Adverse effects
Gastrointestinal
complaints
Headache
Rashes
Sleep disturbances
Hepatotoxicity- Rise in
serum transaminase
Myopathy- Rise in CPK
levels
Peripheral Neuropathy
Cataract
Lupus Like Syndrome

44. Interactions
 Enzyme inducers (Phenytoin, Rifampicin,
Greisofulvin, Phenobarbitone)
 Reduces the plasma concentration of statins
metabolized by CYP3A4 (Lovastatin,
Simvastatin, Atorvastatin)
 Simulataneous consumption of grape or its juice
 Increases the plasma levels of statins.

45. Contraindications
Liver Disease-Inc
serum Tranaminase
Pregnant Women
Lactating Women
Trauma
Major surgeries

46. Therapeutic Uses
 Primary hyperlipidaemias with raised LDL and
total CH levels, with or without raised TG
levels (Type IIa, IIb, V),
 Secondary hypercholesterolaemia- (diabetes,
nephrotic syndrome)

47. Bile Acid Sequestrants
Mechanism of Action
 Bile acid sequestrants are polymeric compounds
that serve as ion-exchange resins.
 Bile acid sequestrants exchange anions such
as chloride ions for bile acids.
 By doing so, they bind bile acids and sequester
them from the enterohepatic circulation.
 The liver then produces more bile acids to
replace those that have been lost.
 Because the body uses cholesterol to make bile
acids, this reduces the amount of LDL
cholesterol circulating in the blood.

48. Pharmacokinetics
 Bile acid sequestrants are large polymeric
structures, and they are not significantly
absorbed from the gut into the bloodstream.
 Thus, bile acid sequestrants, along with any
bile acids bound to the drug, are excreted
via the feces after passage through the
gastrointestinal tract.

49. Therapeutic Uses
Heterozygous familial
hypercholestrolemia/
Type 3
Hyperlipoprotenemia
Pruritis
Digitalis Toxicity
Coronary Artery
Disease

50. Adverse Effects
 Gastrointestinal side effects-
• Dyspepsia
• Bloating
• Constipation
• Gritty sensation
 Hypoprothrombenemia –
reduced absorption of Vitamin
K- Patients taking
Anticoagulant.
 Malabsorption of Folic Acid
 Hyperchloreamic Acidosis
 Hypertriglyceridemia
 Dry flaking Skin

51. Interactions
 Cholestyramine and
colestipol bind and interfere
with the absorption of many
drugs
 They reduce the absorption
of vitamins
Thiazides
Furosemide
Propranolol
L-thyroxine
Digoxin
Warfarin,
Statins(Pravastatin
and Fluvastatin).
Vitamin K
Folic Acid
Ascorbic Acid
Severe
Hypertriglyceridemi
a- Increase TG
levels
Contraindications

52. Lipoprotein Lipase Activators
(Fibrates)Halogenated Fibrates
First Generation: Clofibrate
Second Generation: Fenofibrate, Bezafibrate,
Ciprofibrate
Non Halogenated Fibrates
 Gemfibrozil

53. Mechanism of Action
 Fibrates reduce TG- activate a nuclear receptor-
PPAR alpha
 Stimulates beta oxidation of Fatty Acids
 Increase LPL synthesis
 Reduce production of Apo C3
 Inhibits Lipolysis and receptor mediated clearance.
 VLDL clearance is enhanced

54.  Fibrate-mediated increases in HDL-C are due to
PPAR stimulation of apoA-I and apoA-II
expression, which increases HDL levels.
 PPARα may also mediate enhanced LDL
receptor expression in liver seen particularly with
second generation fibrates like bezafibrate,
fenofibrate.
 Fibrates decrease hepatic TG synthesis as well.

55. Pharmacokinetics
 All of the fibrate drugs are absorbed rapidly and
efficiently (>90%) when given with a meal but
less efficiently when taken on an empty
stomach.
 The ester bond is hydrolyzed rapidly.
 Peak plasma concentrations -within 1-4 hours.
 The t1/2 ranges from 1.1 hours (gemfibrozil) to
20 hours (fenofibrate).
 The fibrate drugs are excreted predominantly
as glucuronide conjugates; 60-90% of an oral
dose is excreted in the urine.

56. Adverse Effects
Gastrointestinal side
effects
Myopathy
Rash
Urticaria
Hair loss
 Fatigue
 Headache
 Impotence
Anemia
Increse in serum
transaminases and ALP

57. Therapeutic Uses
 Type 3
Hypercholestrolemia
 Severe
Hypertriglyceridemia
 Familial combined
hyperlipidemia

58. Interactions
 Coagulants
 Gemfibrozil+ Cervistatin- Rhabdomyolysis,
Acute Renal Failure
Contraindications
Pregnancy
Renal Dysfunction
Hepatic Dysfunction

59. Niacin –Pyridoxine-3-
carboxylic acid
Water soluble vitamin B
complex group
One of the oldest drug used in
the treatment of dyslipidemia
LIPOLYSIS AND TRIGLYCERIDE
SYNTHESIS INHIBITOR (Niacin)

60. Mechanism of Action
 In adipose tissue, niacin inhibits the lipolysis of
triglycerides by hormone-sensitive lipase- reduces
transport of free fatty acids to the liver and
decreases hepatic triglyceride synthesis.
 Acting on GPR109A, niacin stimulates the Gi–
adenylyl cyclase pathway in adipocytes, inhibiting
cyclic AMP production and decreasing hormone-
sensitive lipase activity, triglyceride lipolysis, and
release of free fatty acids.
 Niacin also may inhibit a rate-limiting enzyme of
triglyceride synthesis, diacylglycerol
acyltransferase-2.

61.  In the liver, niacin reduces triglyceride synthesis
by inhibiting both the synthesis and
esterification of fatty acids, effects that increase
apoB degradation.
 Reduction of triglyceride synthesis reduces
hepatic VLDL production-reduced LDL levels.
 Niacin also enhances LPL activity-promotes
clearance of chylomicrons and VLDL
triglycerides.

62.  Niacin raises HDL-C levels by decreasing the
fractional clearance of apoA-I in HDL rather than
by enhancing HDL synthesis.
 This effect is due to a reduction in the hepatic
clearance of HDL-apoA-I, but not of cholesteryl
esters, thereby increasing the apoA-I content of
plasma and augmenting reverse cholesterol
transport.

63. Adverse Effects
 Flushing
 Acanthosis Nigricans
 Gastrointestinal-
Dyspepsia,Vomiting, Diarrhoea
 Hepatotoxicity- elevated
transaminases and alkaline
phosphatase
 Hyperglycemia
 Ocular -Toxic amblyopia and
maculopathy
 Cardiovascular-Atrial
tachyarrhythmias and Atrial
fibrillation

64. Interactions
 Postural hypotension may occur in patients on
antihypertensives when they take nicotinic acid.
Risk of myopathy due to statins is increased.
Contraindication
s
Diabetes Mellitus
Peptic Ulcer
Pregnancy
Gout

65.  It is a novel drug that acts by inhibiting
intestinal absorption of cholesterol and
phytosterols.
Ezetimibe
( Cholesterol Absorption Inhibitor)
N
OH
O
F
OH
F
EZETIMIBE

66. Mechanism of action
 Lowers plasma cholesterol levels by inhibiting the
absorption from intestine
 This cause a decrease in the cholesterol delivery to
the liver which in turn clears more cholesterol from
the blood.
 Selective action (( not interfere with TGs, lipid-
soluble vitamins absorption))

67. • Monotherapy or in combination with HMGRI for
reduction of elevated total cholesterol.
Therapeutic uses
Important Points
Should not be given
with Resins
Should not be given in
pregnancy

68. Adverse effects
 Abdominal pain,
 Fatigue,
 Coughing,
 Diarrhea,
 Back pain
 Arthralgia

69. LDL oxidation inhibitor:
Probucol
 Acts by inhibiting the synthesis of sterols.
 Inhibits atherogenesis- Antioxidant action
 Reduces LDL as well as HDL.
 Used in patients of severe atherosclerosis with
hypercholestrolemia.
 Cardiotoxicity
 HDL-C is decresed.

70. Gugulipid
 Guggul is made from the sap (gum resin) of the
Commiphora mukul tree, which is native to India.
 Reduces the sectretion and enhances the
excretion of cholesterol.
 VLDL,LDL,TG are reduced.
 HDL is incresed
 Used is type 2b and Type 4 hyperlipidemia.

71. Adverse Effects
Hepatic
damage
Diarrhoea
Dysentry

73. CETP-INHIBITORS
 The cholesteryl ester transfer protein (CETP)
facilitates exchange of CHEs with TGs
between HDL particles and chylomicrons,
VLDL, LDL, etc.
 It plays an important role in the disposal of
HDL-associated CH.
 Inhibitors of this protein, torcetrapib,
anacetrapib, etc. markedly raise HDLCH and
lower LDL.

74.  They were presumed to have
antiatherosclerotic action.
 However, during a large randomized clinical
trial, torcetrapib was found to increase
cardiovascular events like angina, MI, heart
failure and death.
 The trial and further development of the drug
was stopped in 2007.
 Whether other CETP inhibitors will have
therapeutic value is being investigated, but

76.  Statin + Niacin- Type 2a and 2b
 Can be used for incresed LDL and decreased
HDL levels.
 Statins + Ezetimibe- Synergistic combination for
Primary Hypercholestrolemia and Type2a
 Statins + Fibrates- High risk patients on Statin
therapy having increased TG levels as their main
lipid abnormality.
 Patient treted with this combination must be
observed for Myopathy.

77.  Bile Acid Binding Resin + Fibrates- Type 2b.
 Increased risk of Cholelithiasis.
 Bile Acid Binding Resin + Niacin- Type 2a and
2b.
 Resin has neutralizing action which
reduces gastric irritation caused by niacin.
 Resin + Statins- Reduces LDl-C in Type 2a
 Statins should be given one hour before or
four hours after the resin to ensure proper
absorption.
 Resin+ Statin +Niacin- Used in severe disorders
due to increased levels of LDL- Type 2a and
2b.

78. Summary