ANTI-HYPERLIPIDEMIC DRUGS

1.6.1. Introduction

Lipids or fats, which are usually transported in various combinations with

proteins (lipoproteins), play a key role in cardiovascular disorders. Lipids,
including cholesterol and trigl ycerides, are essential elements in the body. They
are synthesised in the liver; therefore, they can never be eliminated from the
body. Dietary or drug therapy of elevated plasma cholesterol levels can reduce
the risk of atherosclerosis, and subsequent cardiovascular disease.

A patient with high serum cholesterol and increased Low -Density Lipoprotein

(LDL) is at risk of atherosclerotic coron ary disease and myocardial infar ction.
Atherosclerosis is a disorder in which lipid sub -groups [total cholesterol,
triglycerides, Low -Density Lipoproteins (LDL), and High -Density Lipoproteins
(HDL)] in various proportions indicate risk factors for the individual.

Antihyperlipidemics are the group of drugs prescribed in adjuvant therapy to

reduce elevated cholesterol lev els in patients with high cholesterol and LDL
levels in the blood. These medications are used to decrease the risk of
arteriosclerosis.

The major drugs for reduction of LDL cholesterol levels are bile acid

sequestrants and nicotinic acid. The fibric acid derivatives and clofibrate
(Atromid-S) are less effective in reducing LDL cholesterol. The most effective
agents for reducing plasma LDL levels are the statins.

1.6.2. Classification

The anti- hyperlipidemic drugs are classified into:
1) HMG-CoA Reductase Inhibit ors (Statins): Lovastatin, Simvastatin,
Pravastatin, and Atorvastatin.
2) Bile Acid Sequestrants (Resins): Cholestyramine and Colestipol.
3) Fibric Acid Derivatives (Fibrates): Clofibrate, Gemfibrozil, Bezafibrate,
and Fenofibrate.
4) Triglyceride Synthesis and Lipolysis Inhibitors: Nicotinic acid.
5) Others: Probucol and Omega-3 fatty acids.

1.6.3. HMG-CoA Reductase Inhibitors (Statins)

Statins are the most effective and best tolerated agents used to treat

hyperlipidemia. Statins are competitive inhibitors of 3 -hydroxy-3-methylglutaryl

coenzyme reductase and also the most effective and best tolerated agents for

treating hyperlipidemia.

They catalyse an early, rate limiting step in cholesterol biosynthesis. Hi gher

doses are more potent and can even reduce the triglyceride levels caused by high

VLDL levels.

1.6.3.1. Mechanism of Action

Statins inhibit the enzyme 3 -hydroxy-3-methylglutaryl-coenzyme A reductase
(HMG-CoA reductase) which catalyses the conversion of HMG -CoA to
mevalonate. Mevalonate is required to initiate cholesterol biosynthesis and its
production is inhibited by statins. Statins act as a competitive inhibitor for HMG -
CoA which binds to the HMG -CoA reductase. Statins are inactive in its native
form, so the form in which they are administered is hydrolysed to the β-hydroxy
acid form and becomes active.

1.6.3.2. Therapeutic Uses

The therapeutic uses of statins are:

1) They are used for secondary prevention of myocardial infarction and stroke
in patients having symptomatic atherosclerotic disease (e.g., angina, transient
ischemic attacks, following acute myocardial infarction or stroke).
2) They are used for primary prevention of arterial disease in patients having
high risk due to increased serum cholesterol concentration, specifically when
there are other risk factors for atherosclerosis.
3) Serum cholesterol level can be lowered by atorvastatin in patients with
homozygous familial hypercholesterolemia.
4) A bile acid binding resin is added to treatment with a statin in cases of severe
drug-resistant dyslipidaemia (e.g., heterozygous familial hypercholesterolemia ).

1.6.3.3. Adverse Effects

Statins are generally well -tolerated and adverse effects are very rare. However,
some patients may experience some mild and transient reactions like h eadache,
rashes, and GI disturbances (dyspepsia, cramps, flatulence, constipation, and
abdominal pain).

Some serious side effects that may occur rarely are hepatotoxicity and myopathy.

However, some statins give more hazardous reactions than others:

1) Myopathy/Rhabdomyolysis: Sometimes statins can cause muscle injury.
Mild injury characterised by muscles ache, tenderness or weakness localised
to certain muscle group occurs in 5-10% patients.
2) Hepatotoxicity: It may develop in 0.5-2% of patients treated for one or more
year with statins. But jaundice and other clinical signs are very rare. Use of
statin in patients with active liver disease depends on the disease;
for example, statins should not be given to patients suffering from viral or
alcoholic hepatitis, while statins use is acceptable in patients of non-alcoholic
fatty liver disease.

1.6.3.4. Individual Drugs

Some commonly used statins are discussed below:

1) Atorvastatin: It is an aromatic heterocyclic compound belonging to the class
diphenylpyrroles, having a structure based on a pyrrole ring linked to two
phenyl groups.

Atorvastatin acts by decreasing hepatic cholesterol levels. It is a selective and
competitive inhibitor of HMG -CoA reductase enzyme which catalyses
conversion of HMG -CoA to mevalonate in t he cholesterol biosynthesis
pathway.

Atorvastatin has the following therapeutic uses:

i) It may be used as a primary prevention in patients of multiple risk factors
for Coronary Heart Disease (CHD) and as secondary prevention in
individuals with CHD to redu ce the risk of myocardial infarction (MI),
stroke, angina, and revascularisation procedures.
ii) It reduces the risk of cardiovascular events in patients with Acute
Coronary Syndrome (ACS).
iii) It may be used in the treatment of primary hypercholesterolemia and
mixed dyslipidaemia, homozygous familial hypercholesterolemia,
primary dysbetalipoproteinemia, and/or hypertrigly ceridemia as an
adjunct to dietary therapy to decrease serum total and Low-Density
Lipoprotein-Cholesterol (LDL-C), apolipoprotein B (apoB), an d
triglyceride concentrations, while increasing High-Density Lipoprotein
Cholesterol (HDL-C) levels.

The common adverse effects occurring with the use of atorvastatin include

muscle pain, confusion, memory problems, fever, unusual tiredness, dark
coloured urine, weight gain, and urinating less than usual or not at all.
2) Lovastatin: It is used as a cholesterol-lowering agent. It is a prodrug,

showing structural similarity with HMG, a substituent of the endogenous
substrate of HMG -CoA reductase. It gets activated in vivo by the hydr olysis
of lactone ring to form β-hydroxy acid. The hydrolysed lactone ring mimics
the tetrahedral intermediate produced by the reductase. The resultant
hydrolysed lactone ring binds to HMG -CoA reductase with 20,000 times
greater affinity than its natural s ubstrate. Thus , the bicyclic portion of
lovastatin binds to the coenzyme A portion of the active site.

Lovastatin is used as an adjunct to diet to reduce elevated total -C, LDL-C,

apo B, and TG levels in patients with primary hypercholesterolemia and
mixed dyslipidaemia. It is also used for primary prevention of CHD and for
slow progression of coronary atherosclerosis in patients with CHD.
The more common adverse effects of lovastatin include gastric disturbance s
like (pain in abdominal area, nausea, heart burn, and constipation), headache,
weakness, muscle pain, memory loss, confusion, and inability to fall asleep.

1.6.4. Bile Acid Sequestrants (Resins)

Bile acid sequestrants bind with certain components of bile in the gastrointestinal
tract. They prevent the re -absorption of bile acids from the gut by disrupting the
enterohepatic circulation of bile acids by sequestering them. They may be used
for purposes other than lowering cholesterol, but they are cla ssified as
hypolipidemic agents.

1.6.4.1. Mechanism of Action

Bile acid sequestrants are polymeric compounds which act as ion exchange
resins. They exchange anions (like Cl− ions) for bile acids by binding with
bile acid and sequestering them from enterohepatic circulation. They are not
well-absorbed from the gut into the bloodstream because they have large
polymeric structures. Therefore, the bile acid sequestrants along with the bile
acid bound to the drug , are excreted via faeces after passing through the
gastrointestinal tract.

1.6.4.2. Therapeutic Uses

Bile acid sequestrants are used for the treatment of hypercholesterolemia and

dyslipidemia as they help in decreasing the cholesterol levels, mainly low density
lipoprotein (commonly known as “bad cholesterol”). They act by inhibiting the
re-absorption of bile acid, which is biosynthesised from cholesterol.

They may cause pruritus during chronic liver diseases (such as cirrhosis )

because the bile acids may deposit in the skin. Therefore, in patients with
chronic live r diseases, bile acid sequestrants may be used for the prevention
of pruritus.

They are also used in the treatment of diarrhoea caused by excess bile salts

entering the colon rather than being absorbed at the end of the small intestine.
Diarrhoea caused by excessive bile is a possible side effect occurring after
surgical removal of gallbladder.

1.6.4.3. Adverse Effects

Bile acid sequestrants do not have any systemic side effects because they are
designed to stay in the gut. However, they may cause problems like constipation,
diarrhoea, and flatulence in the gastrointestinal tract

1.6.4.4. Individual Drug - Cholestyramine

Cholestyramine is a bile acid sequestrant which serves as ion exchange resins. It

is a quite hydrophilic compound, but insoluble in water.

Cholestyramine acts by preventing the reabsorption of bile in the gastrointestinal

tract. It binds to bile as it is a strong anion exchange resin which can exchange
its chloride anions with anionic bile acids in the GIT and bind them in the resin
matrix strongly.

It is used as an adjunctive therapy to diet for reducing the increased serum

cholesterol in the patients who have primary hypercholesterolemia (elevated
LDL cholesterol) and do not respond adequately to diet. It can also be used for
pruritus associated with partial biliary obstruction.

Cholestyramine gives rise to many adverse effects which include mild

constipation, diarrhoea, stomach pain, nausea, loss of appetite, weight changes,
bloating, hiccups, a sour taste in mouth, skin rashes, itching, irritation of tongue
and around the rectal area, and muscle or joint pain.

1.6.5. Fibric Acid Derivatives (Fibrates)

Fibrates are the drugs reducing the triglyceride levels more than LDL cholesterol
levels. The m ost common examples of fibrates are gemfibrozil, bezafibrate,
ciprofibrate, and fenofibrate. They are the most heterogeneous lipid modifying
drugs.

1.6.5.1. Mechanism of Action

The mechanism of action of fibrates is not completely understood but it is

believed tha t they increase peripheral clearance and reduce hepatic
triglyceride synthesis. The effects given by fibrates on blood lipids depend on
their binding to Peroxisome Proliferators Activator Receptors (PPARs) ,
which regulate gene transcription. , , and  are the three PPAR isotopes
that have been identified.

Fibrates act as agonists for the nuclear transcription factor Peroxisome

Proliferators-Activated Receptor-alpha (PPAR-alpha), at the molecular level.
This mechanism is used by fibrates for the down reg ulation of the apolipoprotein
C-III (apo C-III) gene and up regulation of the genes for apolipoprotein A -I (apo
A-I), fatty acid transport protein, fatty acid oxidation, and LPL. Thus, VLDL
triglycerides get reduced due to the enhanced catabolism of trigly cerides by LPL
along with enhanced fatty acid oxidation.

1.6.5.2. Therapeutic Uses

The fibrates are used in the following cases:
1) Fibrates (gemfibrozil) are the first -line of drugs f or patients with type III
hyperlipidaemia or familial dysbetalipoproteinemia.
2) They are used to treat mixed hyperlipidaemia, where in the predominant
abnormality is hypertriglyceridemia (in combination with resins) and to treat
moderate to severe hypertriglyceridemia.
3) They are used with statins in patients with high risk of CHD and mixed
hyperlipidaemia. But because of the increased risk of myopathy, careful
safety monitoring is required.

1.6.5.3. Adverse Effects

Generally, fibrates do not give an y adverse reaction and are well -tolerated in

most of the patients. But in some patients minor side -effects like GI disturbance
symptoms like abdominal pain, diarrhoea, and nausea may be seen that are
corrected by the discontinuation of the treatment.

An important but rare adverse effect of fibrates is myositis with muscle pain and

tenderness and elevated creatinine kinase levels.

fibrates Are contraindicated in patients of renal dysfunction , as they get

accumulated in the kidney leading to enhanced frequency of adverse effects
specially myositis.

1.6.5.4. Individual Drug - Clofibrate

Clofibrate is an anti -lipidemic drug that lowers the elevated serum lipids by

reducing the very low -density lipoprotein fraction (S f 20-400) rich in
triglycerides. Serum cholesterol may be decreased in those patients whose
cholesterol elevation is due to the presence of IDL as a result of Type III
hyperlipoproteinemia.

Clofibrate enhances lipoprotein triglyceride lipolysis by increasing the activity

of extrahepatic Lipoprotein Lipase (LL). Degradation of chylomicrons converts
VLDLs to LDLs , which are further converted into HD Ls. These changes occur
by a minor increase in the secretion of lipids into bile and finally in the
intestine.

Clofibrate also helps to inhibit the synthesis , and thus increases the clearance of

apolipoprotein B (a carrier molecule for VLDL).

Clofibrate is used to treat primary dysbetalipoproteinemia (Type III

hyperlipidaemia) which does not respond adequately to diet. Thus , it helps to
control high cholesterol and high triglyceride levels.

Clofibrate may cause diarrhoea, nausea, headache, dec reased sexual ability,

increased appetite, slight weight gain, muscle aches or cramps, sores in mouth
and on lips, stomach pain, gas, heartburn, unusual tiredness or weakness, and
vomiting.

1.6.6. Triglyceride Synthesis and Lipolysis Inhibitors

Triglyceride synthesis and lipolysis inhibitors act either by inhibiting the
synthesis of triglyceride or by inhibiting the process of lipolysis. These agents
reduce the level of LDLs and VLDLs in blood, and thus prevent the deposition of
lipid in blood vessels. Nicotinic acid is the most common example of this class.
Higher doses of nicotinic acid help in the reduction of plasma lipid concentration.

Individual Drug

1) Nicotinic Acid (Niacin): Nicotinic acid is an organic compound that belongs
to the pyridine carboxylic acids group of compounds. At high concentrations,
this drug gives cholesterol and triglyceride lowering effects, resulting in a
decrease of LDLs and VLDLs and an increase in HDLs.
Mechanism of Action
Nicotinic acid helps in the inhibition of release of free fatty acids from
adipose tissue and enhances the lipoprotein activity. It results in increased
rate of triglyceride removal from plasma. These actions decrease the total
LDL (bad cholesterol) and triglyceride levels, causing increased HDLs (good
cholesterol).

Therapeutic Uses

Nicotinic acid is not used therapeutically due to its side effects but
sometimes can be prescribed as an adjunct to diet for treatment of high serum
triglyceride levels in adult patients who have a risk of pancreatitis, and who
do not respond properly to dietary control.

Adverse Effects

The major adverse effects of nicotinic acid are headache, anxiety,

hypotension, dry skin, flushing or burning of skin, peptic ulcer, and abnormal
liver function tests.

Other mild ad verse effects are hyperuricemia, glucose intolerance, nausea,

vomiting, diarrhoea, hyperglycaemia, and elevated plasma uric acid.

2) Probucol: It helps in the reduction of LDL and HDL levels, but shows
minute effects on serum-triglyceride or VLDL cholesterol levels.
Mechanism of Action

Probucol acts by increasing the fractional rate of LDL catabolism in the

final metabolic pathway for cholesterol elimination from the body. This
results in t he reduction of serum cholesterol level s. It can also inhibit
early stages of cholesterol biosynthesis and slightly inhibit dietary
cholesterol absorpti on. According to recent studies, probucol can also
control atherogenesis as it may inhibit the oxidation and tissue deposition
of LDL cholesterol.

Therapeutic Uses

Probucol is used to lower LDL and HDL cholesterol levels.

Adverse Effects

The common adverse effects of probucol are d izziness or fainting and fast or
irregular heartbeat.
Some rarely occurrin g adver se effects are s wellings on face, hands, or
feet, or in mouth, unusual bleeding or bruising, and unusual tiredness or
weakness

1.6.7. Other Drugs

Some rarely used anti-hyperlipidemic drugs are omega-3 fatty ac ids (fish oils).
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the omega-3
fatty acids richly found in fish oil ; while linoleic acid is the omega -3 fatty acid
obtained from p lant sources , such as mustard oil, canola oil, linseed oil, black
gram dal, fenugreek seeds, walnuts, and green leafy vegetables. EPA and DHA
are formed by linoleic acid conversion in the body. Clinical studies have shown
that they reduce serious coronary events.

Mechanism of Action

Hepatic VLDL triglyceride synthesis is reduced by omega -3 fatty acids , thus,
reducing the plasma triglyceride levels. Secretion of VLDL apo B is reduced at
high doses of omega -3 fatty acids . The triglyceride levels ar e reduced at low
doses of omega -3 fatty acids, but LDL cholesterol levels may rise due to
conversion of VLDL to LDL -HDL cholesterol. Because of the decrease in
thromboxane synthesis, fish oils also have antiplatelet aggregatory activity.
Plasma fibrinogen levels are also reduced.

Therapeutic Uses

1) Fish oils, available as gela tin capsules are used in severe
hypertriglyceridemia along with fibrates.
2) Fish oils along with statins (LDL-C may increase during monotherapy, thus
they should not be used alone) are helpful in patients having mixed
hyperlipidaemia with slight increase in triglycerides.

Adverse Effects

The most common side effect of fish oils is nausea. However, their long-term use
has no obvious side effect.

1.7. SUMMARY

The details given in the chapter can be summarised as follows:
1) Cardiovascular system comprises of the heart and an extensive ly branched
structure of blood vessels that transports oxygen, nutrients, heat, and other
substances throughout the body.
2) The myocardial tissue is made up of contracting cells and conducting cells.
3) The study of the dynamic behaviour of blood is termed hemodynamics.
4) There are five phases of the action potential of cardiac cells.
5) When a heart fails to pump blood in a quantity sufficient to fulfil the body
requirements, a condition of Congestive Heart Failure (CHF) occurs,
which is also known as a Heart Failure (HF).
6) Cardiac glycosides are derived from plant derivatives and are steroidal in
nature.
7) Digoxin, digitoxin, and ouabain are the commonly used cardiac glycosides.
8) Route of administration of digitalis is either oral or intravenous.
9) When administered in co mparatively small therapeutic doses, digitalis
improves the ability of excitation of the myocardium and the conduction
velocity.
10) Digitalis improves circulation and decreases sympathetic activity, thereby
increasing the blood flow to kidneys.
11) Digitalis is highly toxic . It has a low margin of safety with a therapeutic
index ranging from 1.5-3.
12) Bipyridine derivatives (e.g., amrinone and milrinone) show
phosphodiesterase (PDE) inhibiting activity.
13) Bipyridines increase the production of cAMP in the heart and blo od vessels,
and thus exert a positive inotropic action along with vasodilator activities.
14) The β-adrenergic agonists increase the cardiac output, and decrease the
ventricular filling pressure and pre-load.
15) The β-adrenergic agonists may cause tachyphylaxis.
16) Diuretics increase the excretion of salt and water.
17) The production of angiotensin II from angiotensin I is inhibited by ACE
inhibitors.
18) A condition in which the blood pressure of systemic artery increases beyond
the normal pressure is known as hypertension.
19) Drugs promoting urine output are known as diuretics.
20) Losartan is a competitive antagonist of angiotensin II.
21) Trimethaphan is the only ganglionic blocker used nowadays.
22) Reserpine is an alkaloid obtained from the roots of the plant Rauwolfia
serpentina.
23) Propranolol is used in mild to moderate hypertension.
24) Calcium channel blocker sare commonly used in the treatment of hypertensio n.
25) Vasodilators cause vasodilation by directly relaxing the vascular smooth
muscles.
26) Angina pectoris (or chest pain) is a symptom experienced due to myocardial
ischemia, wherein the blood supply to the heart decreases.
27) Organic nitrates and nitrates are used in angina pectoris.
28) Ranolazine reduces the number of angina episodes per week and increases
exercise tolerance.
29) Arrhythmia is a common disorder of cardiac excitation, which may be
benign but may also be fatal ( e.g., ventricular fibrillation following a heart
attack).
30) Sodium channel blockers are the most widely used antiarrhythmic agents.
31) Antihyperlipidemics are the group of drugs p rescribed in adjuvant therapy
to reduce elevated cholesterol levels in patients with high cholesterol and
LDL levels in the blood.
32) Statins are the most effective and best tolerated agents used to treat
hyperlipidemia.
33) Cholestyramine is a bile acid sequestrant which serves as ion exchange resins.
34) Fibrates are the drugs reducing the triglyceride levels more than LDL
cholesterol levels.
35) Fibrates act as agonists for the nuclear transcription factor Peroxisome
Proliferators-Activated Receptor -alpha (PPAR-alpha), at the molecular
level.
36) Triglyceride synthesis and lipolysis inhibitors act either by inhibiting the
synthesis of triglyceride or by inhibiting the process of lipolysis.