ANTI-HYPERLIPIDEMIC AGENTS Dr.

Gajanan Kalyankar
ANTI-HYPERLIPIDEMIC AGENTS
Anti-hyperlipidemic agents: Clofibrate, Lovastatin,
Cholesteramine and Cholestipol
 WHAT IS HYPERLIPIDEMIA?

Hyperlipidemia is a condition characterized by elevated levels of lipids (fats)

in the blood, primarily cholesterol and triglycerides. It is a major risk factor for
cardiovascular diseases, including atherosclerosis, heart attack, and stroke.
Hyperlipidemia can be classified into primary (genetic causes) and
secondary (due to lifestyle, diet, or underlying conditions such as diabetes,
obesity, or hypothyroidism).
 LIPID PROFILE AND NORMAL RANGES
Lipid Type Normal Range (mg/dL) High Levels Indicate
Risk for heart disease if >
Total Cholesterol < 200
240
LDL (Low-Density Lipoprotein)
< 100 (Optimal) Increased risk if > 160
- "Bad Cholesterol"
HDL (High-Density
Low HDL increases heart
Lipoprotein) - "Good > 40 (Men), > 50 (Women)
disease risk
Cholesterol"
Triglycerides < 150 High risk if > 200
VLDL (Very Low-Density Associated with high
30
Lipoprotein) triglycerides
 DIFFERENCE BETWEEN BAD CHOLESTEROL (LDL) AND GOOD CHOLESTEROL (HDL)
LDL (Low-Density Lipoprotein) – "Bad HDL (High-Density Lipoprotein) – "Good
Feature
Cholesterol" Cholesterol"

Transports cholesterol from the liver to

Carries excess cholesterol from the
Function the bloodstream, where it can deposit
bloodstream back to the liver for excretion.
in artery walls.

Increases the risk of plaque

Health Helps remove cholesterol from arteries,
formation, leading to atherosclerosis,
Impact reducing the risk of cardiovascular diseases.
heart attack, and stroke.
Optimal: > 40 mg/dL (Men), > 50 mg/dL
Optimal: < 100 mg/dL
(Women)
Normal
Higher levels (> 60 mg/dL) are considered
Levels Borderline high: 130–159 mg/dL
protective.
High: > 160 mg/dL
 DIFFERENCE BETWEEN BAD CHOLESTEROL (LDL) AND GOOD CHOLESTEROL (HDL)

Saturated and trans fats in fried

Healthy fats from nuts, seeds,
Sources foods, processed foods, red meat,
olive oil, fish, and avocados.
and full-fat dairy.

Leads to fat deposits in arteries,

Effect of High Protects against heart disease by
increasing the risk of
Levels clearing cholesterol from arteries.
cardiovascular diseases.

Reduce intake of saturated fats,

Increase physical activity, eat
trans fats, and processed foods.
How to Improve? healthy fats, and consume more
Use cholesterol-lowering
fiber-rich foods.
medications if needed.
 SATURATED FATS
What are they?
Saturated fats are solid at room temperature and primarily found in animal-
based and some plant-based foods.
Sources of Saturated Fats:
•Animal Products: Red meat (beef, pork, lamb), processed meats (sausages,
bacon), full-fat dairy (cheese, butter, whole milk, cream).
•Fried & Processed Foods: Fast food, deep-fried snacks, packaged baked
goods.
•Tropical Oils: Coconut oil, palm oil (often used in processed foods).
 TRANS FATS
What are they?
Trans fats are artificially created through hydrogenation, a process that
turns liquid oils into solid fats to increase shelf life.
Sources of Trans Fats:
•Fried Fast Foods: French fries, fried chicken, onion rings.
•Processed Snacks: Packaged chips, frozen pizzas, microwave popcorn.
•Baked Goods: Cakes, pastries, cookies, doughnuts, margarine.
•Hydrogenated Oils: Found in some peanut butter, coffee creamers, and
processed spreads.
CAUSES OF HYPERLIPIDEMIA

•Genetic factors (Familial hypercholesterolemia)

•Unhealthy diet (high saturated fat intake)
•Obesity and sedentary lifestyle
•Diabetes mellitus
•Hypothyroidism
•Chronic kidney disease
•Certain medications (e.g., steroids, diuretics, beta-blockers)
 CLASSIFICATION OF ANTI-HYPERLIPIDEMIC AGENTS
A. Statins (HMG-CoA Reductase Inhibitors)-
o Fungal-derived: Lovastatin, Simvastatin, Pravastatin
o Synthetic: Atorvastatin, Rosuvastatin

B. Bile Acid Sequestrants (Resins)- Cholestyramine, Colestipol, Colesevelam

C. Fibric Acid Derivatives (Fibrates) - Clofibrate, Fenofibrate, Gemfibrozil
D. Azetidinone Derivatives- : Ezetimibe
E. Monoclonal Antibodies (PCSK9 Inhibitors)-Alirocumab, Evolocumab
F. Omega-3 Fatty Acid Esters-EPA, DHA
G. Niacin Derivatives-Niacin
STATINS (HMG-COA REDUCTASE INHIBITORS)-
LOVASTATIN
STATINS (HMG-COA REDUCTASE INHIBITORS)-
ATORVASTATIN
STATINS (HMG-COA REDUCTASE INHIBITORS)-
ROSUVASTATIN
MECHANISM OF ACTION

Statins, as structural analogs of HMG-CoA, competitively inhibit

HMG-CoA reductase, blocking the conversion of HMG-CoA to
mevalonate, thereby reducing hepatic cholesterol synthesis. The
resulting drop in intracellular cholesterol triggers the
upregulation of LDL receptors in the liver, enhancing LDL-C uptake
from the bloodstream. This leads to a significant reduction in
plasma LDL-C and total cholesterol levels, with a mild increase in
HDL and decrease in triglycerides.
 SAR

A. Lactone or Open Acid Form (HMG-like Moiety)

•Statins contain a structural analog of HMG-CoA, either in the form of a lactone ring
(prodrug) or its open acid form (active form).
•This moiety is crucial for binding to HMG-CoA reductase by mimicking the natural substrate.
•Example:
• Prodrugs: Lovastatin, Simvastatin, Mevastatin (contain lactone ring, requiring hydrolysis
for activation).
• Active Drugs: Atorvastatin, Rosuvastatin, Pravastatin (exist in the active open-acid form)
 SAR
Hydrophobic Ring System (Core Structure)
•Statins possess a hydrophobic, rigid ring system (either a decalin ring or
synthetic aromatic heterocycle).
•This core structure anchors the molecule in the enzyme's active site and affects
binding affinity and potency.
•Types of Ring Systems:
• Decalin (Hydronaphthalene) Ring – Found in natural statins (e.g.,
Lovastatin, Simvastatin, Pravastatin).
• Heteroaromatic Ring – Present in synthetic statins (e.g., Atorvastatin,
Rosuvastatin, Fluvastatin).
 SAR
Side Chain Modifications (Enhancing Potency & Solubility)

•The ethyl or hydroxyl substitutions on the hydrophobic ring influence

binding affinity and selectivity.

•Hydroxyl (-OH) groups improve hydrophilicity (e.g., Pravastatin,

Rosuvastatin), leading to lower muscle toxicity.

•Lipophilic groups (e.g., methyl, fluorophenyl in Atorvastatin) enhance

hepatic uptake and potency.
 COMPARISON OF NATURAL VS. SYNTHETIC STATINS (IMPACT ON SAR)

Natural Statins (Lovastatin, Synthetic Statins (Atorvastatin,

Feature
Simvastatin, Pravastatin) Rosuvastatin, Fluvastatin)
Core Structure Decalin ring Aromatic/Heterocyclic ring
Higher in Rosuvastatin, lower in
Hydrophilicity Moderate to high
Atorvastatin
Requires activation (Prodrug
Metabolism Directly active
in Lovastatin, Simvastatin)
Higher (due to additional fluorine
Potency Moderate
and heterocyclic rings)
Less selective (Lipophilic
Tissue More selective (Hydrophilic statins
statins enter non-hepatic
Selectivity are liver-specific)
tissues)
FIBRIC ACID DERIVATIVES (FIBRATES)

Clofibrate
FIBRIC ACID DERIVATIVES (FIBRATES

Fenofibrate
MECHANISM OF ACTIONS- PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR
ALPHA
1. Activation of PPAR-α (Nuclear Receptor)
•Fibrates bind to and activate PPAR-α, a nuclear receptor predominantly
expressed in the liver, skeletal muscles, and heart.
•PPAR-α regulates genes involved in lipid metabolism, leading to multiple
lipid-lowering effects.
2. Increased Lipoprotein Lipase (LPL) Activity → Lower Triglycerides
•PPAR-α activation upregulates Lipoprotein Lipase (LPL), an enzyme that breaks
down triglyceride-rich lipoproteins (VLDL & chylomicrons) into free fatty acids
(FFAs), which are then utilized for energy.
•This process reduces circulating triglycerides significantly.
 MECHANISM OF ACTIONS
3. Increased Fatty Acid Oxidation
•PPAR-α enhances β-oxidation of fatty acids in the liver and muscles,
reducing triglyceride synthesis.
4. Increased HDL Levels via ApoA-I & ApoA-II Synthesis
•PPAR-α stimulates the production of ApoA-I and ApoA-II, key components
of HDL (high-density lipoproteins).
•This leads to an increase in plasma HDL levels, promoting reverse
cholesterol transport.
5. Decreased VLDL and LDL Levels
•By reducing hepatic VLDL production, fibrates indirectly lower LDL (bad
cholesterol) levels, though the effect on LDL is modest.
AZETIDINONE -CHOLESTEROL ABSORPTION
INHIBITORS

Ezetimibe
 MECHANISM OF ACTION
1. Inhibition of NPC1L1 Transporter in the Small Intestine
•Ezetimibe selectively inhibits the Niemann-Pick C1-Like 1 (NPC1L1)
transporter, a protein found in enterocytes of the small intestine.
•NPC1L1 is responsible for the absorption of dietary and biliary cholesterol into
the bloodstream.
•By blocking NPC1L1, Ezetimibe prevents cholesterol uptake into enterocytes,
reducing the amount of cholesterol entering the liver.
2. Reduced Cholesterol Delivery to the Liver
•Since less cholesterol is absorbed from the intestine, the liver receives less
cholesterol from dietary and biliary sources.
•The liver compensates by increasing cholesterol uptake from the bloodstream.
MECHANISM OF ACTION
3. Upregulation of LDL Receptors & Increased LDL Clearance
•The liver responds to reduced cholesterol availability by upregulating LDL
receptors (LDL-R) on hepatocyte membranes.
•This leads to increased uptake of LDL-C from the bloodstream.
4. Minimal Effect on HDL & Triglycerides
•Ezetimibe has little effect on HDL (good cholesterol) and triglycerides.
•It is often used in combination with statins to enhance LDL reduction.
MONOCLONAL ANTIBODIES (PCSK9 INHIBITORS)

o Alirocumab
o Evolocumab
MECHANISM OF ACTIONS
PCSK9 is a protein that binds to LDL receptors on liver cells, promoting their
degradation and preventing recycling. This reduces the number of LDL
receptors available to clear LDL-cholesterol (LDL-C) from the bloodstream,
leading to higher LDL-C levels. PCSK9 inhibitors (e.g., Alirocumab,
Evolocumab) block PCSK9, allowing more LDL receptors to recycle to the
liver surface, increasing LDL-C clearance and significantly lowering blood
LDL-C levels by 50-70%.
BILE ACID SEQUESTRANTS (RESINS)- CHOLESTYRAMINE
BILE ACID SEQUESTRANTS (RESINS)-
COLESTIPOL
 MECHANISM OF ACTIONS
Bile Acid Sequestrants (Resins) such as Cholestyramine, Colestipol, and
Colesevelam are non-absorbable, positively charged polymers that lower
cholesterol levels by binding bile acids in the intestine, preventing their
reabsorption. This leads to increased bile acid excretion and compensatory
cholesterol metabolism changes.
As bile acid levels decrease, the liver senses a deficiency and compensates by increasing the
conversion of cholesterol to bile acids.
This process is regulated by cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid
synthesis.
OMEGA-3 FATTY ACID ESTERS

• Polyunsaturated fatty acids (PUFAs)

• Examples: EPA, DHA

MECHANISM OF ACTION
Omega-3 fatty acid esters, primarily Eicosapentaenoic
Acid (EPA) and Docosahexaenoic Acid (DHA), are used
to reduce triglyceride (TG) levels and improve
cardiovascular health. Their lipid-lowering effects are
achieved through multiple mechanisms, primarily by
reducing hepatic triglyceride synthesis and increasing lipid
clearance.
NIACIN DERIVATIVES

Niacin
MECHANISM OF ACTION
Niacin (Vitamin B3) is a water-soluble vitamin that acts
as an effective lipid-lowering agent by reducing
triglycerides, increasing HDL-C (good cholesterol), and
lowering LDL-C.