Atherosclerosis is a condition characterised by damage to the arteries. During this
condition, the concentration of lipids, specifically cholesterol, in plasma is
increased which may put the patient at an increased risk for ischemic heart
diseases, myocardial infarction, and cerebral vascular accidents. Lipids lack
water solubility and are transported in plasma in the form of lipoproteins.
Hyperlipidaemia, also referred to a s hyperlipoproteinemia, is a condition
characterised by an increase in the lipid concentration in plasma.
Hypocholesterolemic or anti-hyperlipidemic or lipid lowering agents are the
pharmacological agents decreasing the concentration of lipids in plasma.
The anti- hyperlipidemic agents are classified as follows:
1) HMG-CoA Reductase Inhibitors (Statins): Lovastatin, Simvastatin,
Pravastatin, and Atorvastatin.
2) Bile Acid Sequestrants (Resins): Cholestyramine and Colestipol.
3) Fibric Acid Derivatives (Fibrates): Clofibrate, Gemfibrozil, Bezafibrate,
4) Triglyceride Synthesis and Lipolysis Inhibitors: Nicotinic acid.
5) Others: Probucol and Omega-3 fatty acids.
8.1.3. Mechanism of Action
Anti-hyperlipidemic agents act by the following mechanism of action:
1) HMG-CoA Reductase Inhibitors (Statins): HMG-CoA reductase (3 –
hydroxy-3methylglutaryl-coenzyme A reductase) is the enzyme responsible
for the conversion of HMG -CoA to mevalonate. Statins act by inhibiting
HMG-CoA reductase. Biosynthesis of cholesterol requires mevalonate as a
building block. HMG -CoA binds to HMG -CoA reductase. Statins act as a
competitive inhibitor of HMG-CoA resulting in a decrease in the production
of mevalonate. When administered, statins are inactive and is hydrolysed to
the active β-hydroxy acid form within the body.
2) Bile Acid Sequestrants (Resins): These are basically large polymeric
compounds serving as ion exchange resins. They exchange anions like
chloride ions for bile acids. These compounds sequester the bile acids by
binding to them, thus, preventing their enterohepatic circulation. As the bile acid sequestrants are larger in size, they are not absorbed well from the gut
into the bloodstream. And hence, are excreted out from the body in the form
of faeces (once they pass thr ough the GIT), along with any bile acids bound
3) Fibric Acid Derivatives (Fibrates): The mechanism of action of fibrates is
not clear. They act by reducing the synthesis of hepatic triglycerides and
increasing their peripheral clearance. Peroxisome Proliferators Activator
Receptors (PPARs) regulate gene tra nscription and three isotypes of PPAR,
viz., and have been identified. Fibrates act like agonists for the nuclear
transcription factor Peroxisome Proliferators -Activated Receptor -alpha
(PPAR-alpha) at the molecular level.
Thus, fibrates down regulate the apo -lipoprotein C-III (apo C -III) gene and
up regulate the genes for apo -lipoprotein A-I (apo A -I), fatty acid transport
protein, fatty acid oxidation, and LPL by this mechanism. Increase in
catabolism of triglycerides by LPL along with an increase in oxidation of
fatty acids leads to decreased levels of VLDL triglycerides.
Apoprotein I (apo A -I) and apo A -II are the main components of HDL.
Increase in the synthesis of apo A -I and apo A-II increases the concentration
of HDL-C. Fenofibrate increases the concentration of HDL more effectively
Small VLDL particles are formed as the concentration of triglycerides
decreases. These small VLDL particles produce larger LDL particle s, the
buoyancy of which is more and serve as better ligands for the LDL receptors.
In addition, these LDL particles are also cleared easily. Therefore, the
atherogenic potential of LDL is reduced by the use of fibrates.
4) Triglyceride Synthesis and Lipolysi s Inhibitors: The release of free fatty
acids from adipose tissue is partially inhibited by nicotinic acid. It also
increases the lipoprotein activity which may in turn increase the elimination
rate of triglycerides from plasma. As a result, the total LDLs (bad
cholesterol) and triglycerides are reduced, and thus HDLs (good cholesterol)
The therapeutic uses of anti-hyperlipidemic agents include:
1) HMG-CoA Reductase Inhibitors (Statins): These are used in the following
i) In patie nts with symptomatic atherosclerotic disease ( e.g., angina,
transient ischemic attacks, following acute myocardial infarction or
stroke), administration of statins helps in secondary prevention of
myocardial infarction and stroke.
ii) In high risk group patien ts (due to elevated serum cholesterol
concentration), statins help in primary prevention of arterial disease,
particularly when other risk factors for atherosclerosis are also present.
iii) In patients with homozygous familial hypercholesterolemia, serum
cholesterol can be decreased by the use of atorvastatin.
iv) Severe drug -resistant dyslipidemia ( e.g., heterozygous familial
hypercholesterolemia) is treated by supplementing a bile acid binding
resin in addition to treatment using a statin.
2) Bile Acid Sequestrants (Resins): Cholesterol acts as a substrate for the
biosynthesis of bile acids. Therefore, any disturbance in the reabsorption of
bile acids decreases the level of cholesterol, especially that of LDL
(commonly known as “bad cholesterol”). Thus, resins may b e employed in
the treatment of hypercholesterolemia and dyslipidemia. Bile acids may get
deposited on skin in the presence of chronic liver diseases (like cirrhosis),
which in turn may cause pruritus (itching). Thus, pruritus (itching) may be
prevented by using bile acid sequestrants.
When bile salts enter the colon in excess amounts (instead of getting
absorbed in the distal part of the small intestine), it may cause diarrhoea
within a short time period after consumption of food. Removal of gall
bladder m ay possibly cause bile salt diarrhoea. In such patients, bile acid
sequestrants relieve diarrhoea.
3) Fibric Acid Derivatives (Fibrates):These are used in the following conditions:
i) In patients with t ype III hyperlipidaemia or familial
dysbetalipoproteinemia, fibrates are employed as the first-line drugs.
ii) Moderate to severe hypertriglyceridemia and mixed hyperlipidaemia
(where the predominant abnormality is hypertriglyceridemia) are treated
using fibrates in combination with resins.
iii) A fibrate can be employed along with statins for the treatment of patients
with a high risk of CHD and mixed hyperlipidaemia. However, it is required
to carefully monitor the safety of patient as it increases the risk for myopathy.
4) Triglyceride Synthesis and Lipolysis Inhibitors : For treating adults with
very high levels of serum triglyceride and who are at a risk for pancreatitis,
and who do not show adequate response to dietary control, niacin may be
prescribed as an adjunctive to diet.
8.1.5. Structure-Activity Relationship
The SAR of anti-hyperlipidemics has been discussed under the following heads:
1) Structure-activity relationship of HMG CoA-reductase inhibitors, and
2) Structure-activity relationship of fibrates.
184.108.40.206. Structure-Activity Relationship of HMG CoA-Reductase
Mevastatin and lovastatin are the lead compounds in development of additional
HMGRIs. The ethylene bridge present between the lactone and bicyclic rings is
essential for HMGRIs’ activity. It was observed that the replacement of bicyclic
ring with other lipophilic rings is possible. The overall activity of the compounds
is affected by the size and shape of these rings.
Subject:- Medicinal chemistry 2
Semester:- Sem 5
Course:- Bachelor of pharmacy