Hypolipidemic Agents /

Antihyperlipidemic agents / Lipid

Lowering agents
 Lipoprotein Particles

Classification of lipoprotein particles

Composition Density Size

Chylomicrons TG >> C, CE Low Large

VLDL TG > CE
IDL CE > TG
LDL CE >> TG
HDL CE > TG High Small
 Transport of Lipoprotein Particles

Bile Acids LDL

Dietary fat Cholesterol
LDL-R

INTESTINE LIVER EXTRA-HEPATIC

TISSUE

VLDL IDL LDL

Chylomicrons HDL

LCAT
Lipoprotein lipase Lipoprotein lipase

Free fatty acids adipose Free fatty acids adipose

tissue tissue
 Hyperlipidemia

Types of hyperlipidemias
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
 Strategy for Controlling Hyperlipidemia

STATINS
Diet Biosynthesis

HMG CoA reductase

Ezetimibe
LDL-R
Serum Cholesterol Cellular Cholesterol

Conversion to
Bile Acids hormones within
cells or storage
Re-absorption as granules
Intestine
Lipoprotein
BILE ACID catabolism
SEQUESTRANTS FIBRATES
Feces
 Anti-hyperlipidemic Drugs - Statins

HO O HO
R R COONa
R O R OH
O O
R'
O CH2CH2 O CH2CH2
CH3 CH3 CH3 CH3

R'' HO

R' R'' Pravastatin

Mevastatin H H
Lovastatin H CH3
Simvastatin CH3 CH3
 Anti-hyperlipidemic Drugs - Statins

_
HO HO HO
COO Ca + COONa COONa
OH OH OH

F F F
CH3
CH3 CH3
N
H CH3 N
CH3
O N CH3
O H3C

NH H3C CH3

Atorvastatin Cerivastatin Fluvastatin

_ _ +
HO + HO
COO Ca COO Ca
OH OH

F F
CH3

CH3
N N N

N
O S CH3
H3C O

Rosuvastatin Pitavastatin
 Anti-hyperlipidemic Drugs - Statins

Rationale – competitive binding

HO O HO HO
COONa COOH
O OH SCoA

For example, For example, HMG CoA substrate

Mevastatin Fluvastatin
Lovastatin Atorvastatin
Simvastatin Cerivastatin
 Anti-hyperlipidemic Drugs - Statins

Pharmacokinetic properties of statins – case of cerivastatin

Bioavail. Dosage Protein Metabolites

(mg) Binding
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%

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.
 Anti-hyperlipidemic Drugs - Statins

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
 Anti-hyperlipidemic Drugs - 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
{No longer recommended because of an
increase in overall mortality and adverse events}
CH3 CH3 CH3

O CH2CH2CH2 C COOH Cl O C COOCH2CH3

CH3 CH3
H3C
Gemfibrozil Clofibrate

H CH3
N
O O C COOH CH3
O
CH3 O C COOCH(CH3)2

CH3
Cl
Bezafibrate Cl Fenofibrate
CH3

O C COOH {rhabdomyolysis … highest

Cl Cl CH3 PPAR-a affinity  clinical trials
stopped in the US}
Ciprofibrate
 Anti-hyperlipidemic Drugs – Bile Acid Sequestrants

• 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

H H
C C C N CH2CH2 N
H2
CH2
CHOH
Cl
- CH2
+ N CH2CH2 N
CH2CH2 CH2N(CH3)3

n n
Cholestyramine Resin Colestipol hydrochloride

H2 N HN HN HN

(CH2 )6 NMe3+ (CH2 )9 CH3

HO
(CH2 )6 NMe3+ (CH2 )9 CH3

H2 N HN HN HN

Colesevelam
 Anti-hyperlipidemic Drugs – 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

COOH CONH2
N
CH3 N
N N

Anti-hyperlipidemic Drugs – Ezetimibe

OH
• Approved in October 2002 OH

• Reduces serum LDL, TC, and TG and increases HDL

• Prevents the absorption of cholesterol from diet N
F
• Useful in Type IIa, IIb, III, IV and V hyperlipidemias O

F
Classification
(i) HMG CoA / 3-hydroxy-3-methyl glutaryl Co-A reductase inhibitors:
(e.g) Metastatin, Lovastatin, Simvastatin, Pravastatin, Fluvastatin,
Atrovastatin, Cerivastatin, Dalvastatin, Rosuvastatin, Pitavastatin

(ii) Fibrates / Aryloxyisobutyric acid derivatives:

(e.g) Clofibrate, Fenofibrate, Ciprofibrate, Benzafibrate, Etofibrate,
Gemfibrozil

(iii) Bile acid sequestrants / Bile acid–binding resins:

(e.g) Cholestyramine, Colestipol, Colesevelam, Berlex

(iv) Miscellaneous:
(e.g) Probucol, Nicotinic acid (Niacin / Vitamin-B3), β-sitosterol,
Dextrothyroxine, Ezetimibe (Cholesterol absorption inhibitor)
Mechanism of action of HMG CoA reductase inhibitors

 The enzyme that catalyzes the conversion of HMG-CoA to

mevanolate in the cholesterol biosynthesis.
 This reaction is the rate-determining step in the synthetic
pathway of cholesterol.
 Statins are competitive inhibitors of HMG-CoA reductase.
They are “bulky” and “stuck” in the active site. This prevents
the enzyme from binding with its substrate, HMG-CoA and
there by resulting a decrease in serum cholesterol levels.
Adverse Effects
 Mild, transient GI disturbances
 Rashes (change of the skin which affects its color,
appearance or texture)
 Headache
 Myopathy (muscle pain)
 Elevations in liver enzymes or liver disease
Synthesis of Fluvastatin

Villsmeyer reaction is the chemical reaction of a substituted amide / amine with

phosphorus oxychloride and an electron-rich arene to produce an aryl aldehyde or ketone.
Synthesis of Clofibrate

Synthesis of Probucol

Synthesis of Nicotinic acid

/ Niacin / Vitamin-B3
Mechanism of action of Bile acid sequestrants / Bile acid–binding resins

Bile Acid Binding Resins are not absorbed across the gut into the blood – bile
and cholesterol are irreversibly bound in the gut and disposed of in the feces.
Adverse Effects
 Constipation
 Heartburn
 Nausea
 Belching / burping (release of gas from the digestive tract through
the mouth)
 Bloating - abnormal general swelling or increase in diameter of the
abdomen
SAR of Statins

The structure should contains,

a. Lactone ring (sensitive to
stereochemistry of it, ability of ring to hydrolyzed, length of bridge)
a. Bicyclic rings (could be replaced with other lipophilic rings, size and
shape of it are important for activity)
b. Ethylene bridge between them

Mechanism of action of Cholesterol Absorption Inhibitor

 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 in its action (not interfere with TGs, lipid-soluble vitamins
absorption)
Mechanism of action of Fibrates

 Fibrates lower blood triglyceride levels by reducing the liver's production

of VLDL (the triglyceride-carrying particle that circulates in the blood) and
by speeding up the removal of TGs from the blood.

 Fibrates also are modestly effective in increasing blood HDL

cholesterol; however, fibrates are not effective in lowering LDL
cholesterol.

Adverse effects
 Abdominal discomfort, diarrhea, nausea
 Blurred vision, headache
 Increased risk of gallstones
 Prolonged prothrombin time
 Malignancy
SAR of Fibrates
[aromatic ring]-O-[spacer group]-C(CH3)2-CO-OH

Fenofibrate Gemfibrozil
Fenofibrate contain ester (prodrug)
Para-subtitution with Cl or Cl containing isopropyl ring increase half-lives.
n-propyl spacer result in active drugs (Gemfibrozil)
Mechanism of action of Niacin / Nicotinic acid / Vitamin-B3
 Increases the activity of lipase, which breaks down lipids.
 Reduces the metabolism of cholesterol and triglycerides.
Adverse Effects
 Flushing – Red coloration in the face and often other areas of the skin
 Pruritus / Itching
 GI distress