Anti-hyperlipidemic drugs

Anti–hyperlipidemic 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.

CLASSIFICATION:

 

 1. HMG–CoA 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.

 

HMG–CoA REDUCTASE INHIBITORS (Statins)–

 

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

They competitively inhibit conversion of HMG–CoA to mevalonate by the enzyme HMG–CoA
reductase. 

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 long–term induction of HMG–CoA
reductase tends to increase CH synthesis, but a steady–state is finally attained with a dosedependent lowering of LDL–CH levels.

Different statins differ in their potency and maximal efficacy in reducing LDL–CH. 

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

40
mg, simvastatin20 mg, atorvastatin 10 mg, rosuvastatin 5 mg and pitavastatin 2
mg. 

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 30–40%
LDL-CH
reduction. 

All statins produce peak LDL–CH lowering after 1–2 weeks
therapy. 

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

Because HMG–CoA 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
of
this isoenzyme respectively increase and decrease statin blood levels. 

Lovastatin: 

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). 

Simvastatin:
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
pravastatin. 

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

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

Atorvastatin: 

This newer and most popular statin is more potent and appears to have the highest LDL–CH 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 

side
effects not differing from
placebo. 

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

Rashes and sleep disturbances are uncommon. 

Rise  in  serum transaminase can
 occur,
 but  liver  damage  is
 rare. 

Monitoring of liver function is recommended.

Uses: 

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

BILE ACID SEQUESTRANTS (Resins):

Cholestyramine
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 other  g.i. symptoms, interfere with absorption of many drugs and have poor patient acceptability.

LIPOPROTEIN–LIPASE ACTIVATORS(Fibrates):

 

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

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

PPARα  may  also
 mediate  enhanced
 LDL
 recepto r
expression
 in   liver
 seen
 particularly  with
 second   generation
 fibrates  like
bezafibrate,
 fenofibrate.  Fibrates  decrease
 hepatic  TG
 synthesis  as
 well.
 

A
peripheral effect reducing circulating free fatty acids has also been shown. 

Gemfibrozil: 

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 Study’ men without known CAD treated with gemfibrozil had a 34% reduction in fatal and nonfatal MI,  though  overall
 mortality was  not
 affected.
 

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

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

Pharmacokinetics: 

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.

 

LIPOLYSIS AND TRIGLYCERIDE SYNTHESIS INHIBITOR:

 

Nicotinic Acid (Niacin): It is a B group vitamin which in much
higher doses reduces plasma lipids. This action is unrelated to its vitamin activity decrease rapidly, followed by a modest fall in LDL–CH and total CH. A20–50% reduction in plasma TGs and 15–25% 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
 suffices
to  raise  HDL–CH. 

It
 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
has
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
tolerated. 

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

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

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
given.

Peptic
ulcer may be
activated.

 

Dryness and hyperpigmentation of skin can be
troublesome.

 

Other long–term effects are: Liver dysfunction and jaundice. 

Serious liver damage
is
the most important risk. 

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

It is contraindicated during pregnancy and in
children.