Anti-hyperlipidemic drugs

Antihyperlipidemic drugs


These are drugs which lower the levels of lipids and lipoproteins in blood.


The hypolipidaemic drugs have attracted considerable attention because of their potential to prevent cardiovascular disease by retarding the accelerated atherosclerosis in hyperlipidaemic individuals.



 1. HMGCoA reductase inhibitors (Statins): Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin, Pitavastatin

2. Bile acid sequestrants (Resins): Cholestyramine, Colestipol


3. Lipoprotein lipase activators (PPARα activators, Fibrates): Clofibrate, Gemfibrozil, Bezafibrate, Fenofibrate.

4. Lipolysis and triglyceride synthesis inhibitor: Nicotinic acid.


5. Sterol absorption inhibitor: Ezetimibe.




Introduced in the 1980s, these classes of compounds are the most efficacious and best tolerated hypolipidaemic drugs. 

They competitively inhibit conversion of HMGCoto mevalonate by the enzyme HMGCoA

Therapeutic doses
reduce CH synthesis by 20–50%. 

This results in compensatory increase in LDL
receptor expression on
 liver  cells
 increased receptor  mediated
 uptake  and
catabolism of IDL and LDL. 

Over longterinduction of HMGCoA
reductase tends to increase CH synthesis, but a steadystate is finally attained with a dosedependent lowering of LDLCH levels.


Different statins differ in their potency and maximal efficacy in reducing LDLCH

The daily dose for lowering LDLCH by 30–35% is lovastatin 40 mg, pravastatin

mg, simvastatin20 mg, atorvastatin 10 mg, rosuvastatin 5 mg and pitavastatin 2

Moreover, at their maximum recommended doses simvastatin (80 mg) causes

45–50% reduction, while atorvastatin (80 mg) and rosuvastatin (40 mg)
can reduce LDL-CH by upto 55%. The ceiling effect of lovastatin and pravastatin is 3040%

All statins produce peak LDLCH lowering after 1–2 weeks

Hepatic synthesis of VLDL is concurrently reduced and its removal from plasma is enhanced.

Because HMGCoA reductase activity is maximum at midnight, all statins are
administered at bed time to obtain maximum effectiveness. 

However, this is not
necessary for atorvastatin and rosuvastatin, which have long plasma t½. 

All statins, except rosuvastatin are metabolized primarily by CYP3A4. 

Inhibitors and inducers
this isoenzyme respectively increase and decrease statin blood levels


It is the first clinically used statin; is lipophilic and given orally in the precursor lactone form. 

Absorption is incomplete and first pass metabolism is extensive. 

Metabolites are
excreted mainly in bile. The t½ is short (1–4 hours)

It is twice as potent as lovastatin; also more efficacious. 

A greater
rise in HDLCH (when low) has been noted with simvastatin than lovastatin or

Like lovastatin, it is lipophilic and given in the lactone precursor form

Oral absorption is better and first pass metabolism extensive; t½
2–3 hr


This newer and most popular statin is more potent and appears to have the highest LDLCH lowering efficacy at maximal daily dose of 80 mg. 

At this dose a greater reduction in TGs is noted if the same was raised at baseline

Atorvastatin has a much longer plasma t½ of 18– 24 hr than other statins, and has additional antioxidant property.

Side Effect 

effects not differing from

Notable side effects are: Gastrointestinal
complaints and
 headache are
 usually  mild.  

Rashes and sleep disturbances are uncommon. 

Rise  in  serum transaminase can
 but  liver  damage  is

Monitoring of liver function is recommended.


Statins are the first choice drugs for primary
hyperlipidaemias with raised
 CH  levels,  with
 or  without
 raised  TG
 as  well  as  for
secondary (diabetes, nephrotic syndrome) hypercholesterolaemia.


and Colestipol:

These are basic ion exchange resins supplied in the
chloride form. 

They are neither digested nor absorbed in the gut: bind bile acids in the intestine interrupting their enterohepatic circulation. 

Faecal excretion of bile salts and CH (which is absorbed
with the help of bile salts) is increased. 

This indirectly leads to enhanced hepatic metabolism
of CH to bile acids. 

More LDL
receptors are
expressed on liver cells: clearance of plasma IDL, LDL and indirectly
that of VLDL is increased. 

Resins have been shown to retard atherosclerosis, but are not popular clinically because they are unpalatable, inconvenient, have to be taken in
large doses, cause flatulence and otheg.i. symptoms, interfere with absorption of many drugs and have poor patient acceptability.



The  fibrates  (isobutyric  acid
 derivatives)  primarily
 lipase which is a key enzyme in the degradation of VLDL resulting in lowering of circulating TGs. 

This effect is exerted through
peroxisome proliferatoractivated receptor α (PPARα) that is a gene transcription regulating receptor expressed in 
and  fatty
 acid  oxidation.

PPARα  may  also
 mediate  enhanced
 recepto r
 in   liver
 particularly  with
 secon generation
 fibrates  like
 fenofibrate.  Fibrates  decrease
 hepatic  TG
 synthesis  as

peripheral effect reducing circulating free fatty acids has also been shown


This fibric acid derivative effectively lowers plasma TG level by enhancing breakdown and suppressing hepatic synthesis of TGs. Besides high
efficacy in type III hyperlipoproteinemia, gemfibrozil has shown action in subjects with raised blood CH in addition. 

In the Helsinki Heart Studymen without known CAD treated with gemfibrozil had a 34% reduction in fatal and nonfatal MI,  though  overall
 mortality was  not

That  these  benefits
 extend  to
secondary prevention of coronary events in men with existing CAD and low HDLCH, has
demonstrated in another trial. 

Additional actions to decrease the level
of clotting factor VIIphospholipid complex and promotion of fibrinolysis have been observed, which may contribute to the antiatherosclerotic effect. 


Gemfibrozil is completely absorbed orally, metabolized by
glucuronidation and undergoes some enterohepatic circulation. It is excreted in
urine; elimination t½ is 1–2 hr.

Adverse effects: Common side effects are epigastric distress, loose motions. Skin
rashes, body ache, eosinophilia, impotence, headache and blurred vision
have been
reported.  Myopathy
 is   uncommon.
 Gemfibrozil  +
statin   increases
 risk  of
myopathy. Incidence of gallstone is not increased as was seen with clofibrate.

It is contraindicated during pregnancy.




Nicotinic Acid (Niacin): It is a B group vitamin which in much
higher doses reduces plasma lipids. This action is unrelated to its vitamin activit
decrease rapidly, followed by a modest fall in LDLCH and total CH. A2050% reduction in plasma TGs and 1525% reduction in CH levels has been recorded.

Nicotinic acid is the most effective drug to raise HDL-CH, probably by decreasing
rate of HDL destruction; a 20–35% increase is generally obtained. 

Relatively lower dose
to  raise  HDLCH. 

 also  reduces  lipoprotein Lp
 (a),  which
 is considered more atherogenic. 

Nicotinic acid reduces production of VLDL in liver by inhibiting TG synthesis. 

Indirectly the VLDL degradation
products IDL and
LDL are also reduced.

No direct effect on CH and bile acid metabolism
been found. 

It inhibits intracellular lipolysis in adipose tissue and increases the activity of lipoprotein lipase that clears TGs.

Adverse effects: 

The large doses needed for hypolipidaemic action are poorly

Only about half of the patients
are able to take the full doses. 

acid is a cutaneous vasodilator: marked flushing, heat and itching (especially in the
area) occur after every

This is associated with release of PGD2 in the
skin, and can be minimized
by starting with a low dose taken with meals and gradually increasing as tolerance develops.

Dyspepsia is very common; vomiting and diarrhoea occur when full doses are

ulcer may be


Dryness and hyperpigmentation of skin can be


Other longterm effects are: Liver dysfunction and jaundice. 

Serious liver damage
the most important risk. 

Hyperglycemia, precipitation of diabetes (should not be used in diabetics).

It is contraindicated during pregnancy and in





It  is
 novel drug  that  acts  by  inhibiting intestinal absorption of
cholesterol and phytosterols. 

interferes with a specific CH transport protein
NPC1L1 in the  intestinal mucosa  and reduces absorption of both dietary and biliary CH. 

There is compensatory increase in hepatic CH synthesis, but LDLCH
level is lowered by 15–20%. 

The enhanced CH synthesis can be blocked by statins,
and the two drugs have synergistic LDLCH lowering
effect. Due to very poor aqueous solubility, ezetimibe is not absorbed
as such. 

A fraction is absorbed after getting conjugated with glucuronic acid in the intestinal mucosa. 

This is secreted in bile and undergoes enterohepatic circulation to be mainly excreted in faeces. A
plasma t½ of 22 hours has been calculated.

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