Antihyperlipidemic drug

Dr. Josim Uddin

Department of Pharmacy
Independent University, Bangladesh
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Outline
1. Introduction and classification of Antihyperlipidemic drug

2. Mechanism of action of Antihyperlipidemic drug

3. SAR of Antihyperlipidemic drug

4. Therapeutic Uses

5. Chemical syntheses of Antihyperlipidemic drug

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Introduction
The major lipids found in the bloodstream are cholesterol, cholesterol esters, triglycerides,
and phospholipids. An excess plasma concentration of one or more of these compounds is
known as hyperlipidemia. This disease is usually chronic and requires continuous
medication to control blood lipid levels. Hyperlipidemias are classified according to which
types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in
combined hyperlipidemia. Hyperlipoproteinemia has been strongly associated with
atherosclerotic lesions and coronary heart disease (CHD).
Atherosclerosis (ATCS) is a disorder in which lipid deposits on the lining of the blood
vessels, eventually producing degenerative changes and obstruction of blood flow. ATCS is a
major contributor in the development of heart disease.
Triglycerides (TG) and cholesterides are insoluble in water and must be bound to a lipid-
containing protein (lipoprotein) for transportation throughout the body.

Although several lipoproteins are found in the blood, we will focus on the low density
lipoproteins (LDL), very low-density lipoproteins (VLDL) and high density lipoproteins
(HDL). 3
Introduction
What are triglycerides?
Triglycerides are a type of fat (lipid) found in blood.
Body converts any calories it doesn't need to use right
away into triglycerides. The triglycerides are stored in
fat cells. Later, hormones release triglycerides for energy
between meals.
If one regularly eat more calories than one burn,
particularly from high-carbohydrate foods, one
have high triglycerides (hypertriglyceridemia).
may
What's considered normal?
A simple blood test can reveal whether your triglycerides fall into a healthy range:
Normal — Less than 150 milligrams per deciliter (mg/dL), or less than 1.7 millimoles per liter
(mmol/L)
Borderline high — 150 to 199 mg/dL (1.8 to 2.2 mmol/L)
High — 200 to 499 mg/dL (2.3 to 5.6 mmol/L)
Very high — 500 mg/dL or above (5.7 mmol/L or above) 4
Introduction
What's the difference between triglycerides and cholesterol?
Triglycerides and cholesterol are different types of lipids that circulate in your blood:
Triglycerides store unused calories and provide your body with energy.
Cholesterol is used to build cells and certain hormones.
Why do high triglycerides matter?
• High triglycerides may contribute to hardening of the arteries or thickening of the artery walls
(arteriosclerosis) — which increases the risk of stroke, heart attack and heart disease. Extremely high
triglycerides can also cause acute inflammation of the pancreas (pancreatitis).
• High triglycerides are often a sign of other conditions that increase the risk of heart disease and
stroke, including obesity and metabolic syndrome-a cluster of conditions that includes too much fat
around the waist, high blood pressure, high triglycerides, high blood sugar and abnormal cholesterol
levels.
High triglycerides can also be a sign of:
Type 2 diabetes or prediabetes
Metabolic syndrome — a condition when high blood pressure, obesity and high blood sugar occur
together, increasing risk of heart disease
Low levels of thyroid hormones (hypothyroidism) 5
Certain rare genetic conditions that affect how your body converts fat to energy
Introduction
What's the best way to lower triglycerides?
Healthy lifestyle choices are key:
• Exercise regularly. Aim for at least 30 minutes of physical activity on most or all days of the
week. Regular exercise can lower triglycerides and boost "good" cholesterol. Try to
incorporate more physical activity into your daily tasks — for example, climb the stairs at
work or take a walk during breaks.
• Avoid sugar and refined carbohydrates. Simple carbohydrates, such as sugar and foods
made with white flour or fructose, can increase triglycerides.
• Lose weight. If you have mild to moderate hypertriglyceridemia, focus on cutting
calories. Extra calories are converted to triglycerides and stored as fat. Reducing your
calories will reduce triglycerides.
• Choose healthier fats. Trade saturated fat found in meats for healthier fat found in plants,
such as olive and canola oils. Instead of red meat, try fish high in omega-3 fatty acids-such
as mackerel or salmon. Avoid trans fats or foods with hydrogenated oils or fats.
• Limit how much alcohol you drink. Alcohol is high in calories and sugar and has a
particularly potent effect on triglycerides. If you have severe hypertriglyceridemia, 6
drinking any alcohol.
avoid
Introduction

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 Antihyperlipidemic agents
Antihyperlipidemic agents
Antihyperlipidemic agents promote reduction of lipid levels in the blood.
Some antihyperlipidemic agents aim to lower the levels of low-density lipoprotein (LDL)
cholesterol, some reduce triglyceride levels, and some help raisethe high-
density lipoprotein (HDL) cholesterol.

Classification of antihyperlipidemic agents

• Hydroxymethylglutaryl-CoA (HMGCoA) reductase inhibitors Ex. Statins (Atorvastatin,

• lovastatin, Metastatin, Pravastatin, Fluvastatin)

• Phenoxyisobutyric acid derivatives Ex. Fibrates (Clofibrates, Gemfibrozil)

• Pyridine derivatives Ex. Nicotinic acid, Nicotinamide

• Bile acid sequestrans Ex. Cholestyramine, Colestipol

• Cholesterol absorption inhibitors Ex. Ezetimibe

• LDL oxidation inhibitors Ex. Probucol

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Ex. Alirocumab

• Miscellaneous Antihyperlipidemic Agents Ex. β-Sitosterol, Dextrothyroxine

Classification of antihyperlipidemic agents
HMG CoA—Reductase Inhibitors
Classification of antihyperlipidemic agents
Fibric acid derivative Bile Acid Sequestrants
Classification of antihyperlipidemic agents

Pyridine derivatives LDL oxidation inhibitors Miscellaneous

Mechanism of antihyperlipidemic agents
HMG-CoA reductase inhibitors (statins)
Statins, also known as HMG-CoA
reductase inhibitors, inhibit HMG-CoA
reductase (3-hydroxy-3-methylglutaryl
coenzyme A reductase) an enzyme
involved in the synthesis of cholesterol
especially in the liver. Decreased
cholesterol production leads to an
increase in the number of LDL (low
density lipoprotein) membrane
receptors, which increases clearance of
LDL cholesterol from circulation.
Statins are used to treat hyperlipidemia
and are the most effective drugs in
lowering LDL cholesterol.
Atorvastatin
This drug possesses the heptanoic acid side chain, which
is critical for inhibition of HMG-CoA reductase. Although
the side chain is less lipophilic than the lactone form, the
high amount of lipophilic substitution causes this agent to
have a slightly higher level of CNS penetration than
pravastatin, resulting in a slight increase in CNS side
effects. Even so, its CNS profile is much
lower than that of lovastatin.
• Atorvastatin reduces levels of LDL and triglycerides in
the blood, while increasing levels of HDL.
• Atorvastatin is used to treat high cholesterol and to
lower the heart complications in people with type 2
diabetes, coronary heart disease, or other risk factors.
• Atorvastatin is used in adults and children who are at
least 10 years old. 14
Lovastatin
Lovastatin is a fungal polyketide derived synthetically from a fermentation product of Aspergillus terreus.
It is a prodrug. The inactive gamma-lactone closed ring-form is hydrolysed in vivo to the active β-hydroxy
acid open ring form. Lovastatin was the first specific inhibitor of HMG CoA reductase to receive approval for
the treatment of hypercholesterolemia.
Mechanism of action
• Lovastatin is a potent competitive reversible inhibitors of HMG-CoA reductase.
• HMG-CoA reductase enzyme is required for mevalonate synthesis which an important building blocks in
cholesterol biosynthesis.
• Lovastatin acts primarily in the liver, where decreased hepatic cholesterol concentrations stimulate the
upregulation of hepatic low density lipoprotein (LDL) receptors which increase hepatic uptake of LDL.
• Lovastatin also inhibits hepatic synthesis of very low density lipoprotein (VLDL).
• The overall effect is a decrease in plasma LDL and VLDL and a significant reduction in the risk of
development of CVD and all-cause mortality.
Uses
• Lovastatin is used to reduce the risk of myocardial infarction, unstable angina, and the need for coronary
revascularization procedures in individuals without symptomatic cardiovascular disease
• Lovastatin is also used to slow the progression of coronary atherosclerosis in patients with coronary heart
disease.
Fluvastatin
Fluvastatin possesses a heptanoic acid side chain that is superimposable
over the lactone ring found in lovastatin and simvastatin. This side
chain is recognized by HMG-CoA reductase. Also, much like
pravastatin, the CNS side effects of this lipid-lowering agent are much
lower than those of the agents that possess a lactone ring.

•Lowering high cholesterol and triglycerides in certain patients. It also

increases high-density lipoprotein (HDL) cholesterol levels. It is used
along with an appropriate diet.
Mechanism of Action
Fluvastatin selectively and competitively inhibits the hepatic enzyme hydroxymethylglutaryl-
coenzyme A (HMG-CoA) reductase. HMG-CoA reductase is responsible for converting HMG-
CoA to mevalonate, the rate-limiting step in cholesterol biosynthesis. Inhibition results in a
decrease in hepatic cholesterol levels which stimulates the synthesis of LDL receptors and
increases hepatic uptake of LDL cholesterol. The end result is decreased levels of plasma total
and LDL cholesterol.
Fluvastatin
Synthesis n-Butyllithium (C4H9Li)
Fluvastatin
Structure activity relationship

The dihydroxyheptan(en)oic acid segment

is essential.
•Hydroxyls at chiral C3 and C5 have
important interactions at HMGR and must
have the proper absolute configuration.
• C3 requires the R configuration.
•Statins with polar functional groups
positioned to bind to Arg568 and Ser565
(rosuvastatin, atorvastatin) show significant
increases in affinity and potency.
Fibric acid derivatives: Clofibrate
• Clofibrate is an ester of phenoxyisobutyric acid (fibric acid).
• It is regarded as a broad spectrum lipid lowering drug.
• It is a prodrug, metabolized to chlorophenoxyisobutyric acid (CPIB) which is the active form of the drug.
Mechanism of action
• Clofibrate increases the activity of extrahepatic lipoprotein lipase (LL), thereby increasing lipoprotein
triglyceride lipolysis.
• Chylomicrons are degraded, VLDLs (Very low density lipoprotein) are converted to LDLs, and LDLs are
converted to HDL.
• This is accompanied by a slight increase in secretion of lipids into the bile and ultimately the intestine.
• Clofibrate also inhibits the synthesis and increases the clearance of apolipoprotein B, a carrier molecule for
VLDL.
• Also, as a fibrate, clofibrate is an agonist of the PPAR-α receptor (peroxisome proliferator-activated
receptor alpha) in muscle, liver, and other tissues.
• This agonism ultimately leads to modification in gene expression resulting in increased beta-oxidation,
decreased triglyceride secretion, increased HDL, and increased lipoprotein lipase activity.
Uses
• It is used as an anticholesteremic agents or antilipemic agents.
• It is used to treat xanthoma tuberosum and type III hyperlipidemia that doesn’t respond adequately to
diet.
• Clofibrate was discontinued in 2002 due to adverse effects.
LDL Oxidation Inhibitors: Probucol
Synthesis
Pyridine derivatives: Nicotinic acid
Synthesis