Review of Pharmacology - 9E (2015)

Cardiovascular System
Contd...
• Major adverse effect of these drugs is myopathy and hepatotoxicity. Chances of
myopathy increases if these are co-administered with fibrates (maximum with
gemfibrozil) or niacin. Myopathy can proceed to rhabdomyolysis with resultant
renal shutdown. Pravastatin remains confined to the liver and is safer in this regard.
These agents should be avoided in pregnancy and lactation.
• Statins are the first line drugs for type IIa, type IIb and secondary hyperlipoproteinemia
(in these conditions, cholesterol level is raised more than TG).
• In children with heterozygous familial hypercholesterolemia, pravastatin is
approved for children ≥ 8 years whereas other statins are approved for children
≥ 10 years. Pitavastatin has not been studied for this indication.
INTESTINAL CHOLESTEROL ABSORPTION INHIBITOR
Ezetimibe inhibits a transporter involved in intestinal absorption of cholesterol called NPC1L1.
Due to decreased absorption, cholesterol content of the liver decreases and it responds by
increasing LDL receptor synthesis. It can be used alone or combined with statins for type IIa
and IIb hyperlipoproteinemia.
BILE ACID BINDING RESINS
These drugs bind to bile acids in the intestinal lumen and decrease its reabsorption (resulting in
more excretion through faeces). Cholesterol pool of liver is depleted because it is utilized for
the formation of bile acids. Liver acquires cholesterol from the plasma by increasing LDL
receptors. Bile acids inhibit TG production in the liver and their deficiency results in elevation
of TGs. Bile acid binding resins are used only for type IIa disorder (TGs are normal in this
condition). Drugs in this group include cholestyramine, colestipol and colesevelam.
Cholestyramine and colestipol are available as sachets. These are mixed with water, kept for
some time (to increase the palatability) and then taken with meals. Colesevelam is available as
a tablet and has better patient compliance. Major adverse effect of these drugs is constipation.
FIBRIC ACID DERIVATIVES
This group of drugs acts by activating LPL by activating a nuclear receptor, PPARα (peroxisome
proliferator activated receptor alpha). Major effect of the fibrates is to reduce TG (contained
in VLDL) and to increase HDL. Clofibrate is not used now because it resulted in increased
mortality (due to malignancies and post cholecystectomy complications) and did not prevent
fatal MI. Gemfibrozil, fenofibrate and bezafibrate are currently available. Fenofibrate is a prodrug
with longest half life. It has maximum LDL cholesterol lowering action. Fibrates also reduce
plasma fibrinogen level. Fibrates are the drugs of choice in hypertriglyceridemia (type III
and IV) and can be used with other drugs in type IIb (fenofibrate, as it has maximum LDL
reducing action). Fenofibrate is uricosuric and can be used in the setting of hyperuricemia.
GI distress and elevation of aminotransferases are important adverse effects of fibric acid
derivatives. Risk of myopathy is increased if these are used with statins except bezafibrate.
NICOTINIC ACID
Niacin (not nicotinamide) is an inexpensive drug (vitamin B 3
) that produces decrease in
LDL cholesterol and VLDL triglycerides along with increase in HDL cholesterol. It acts
by inhibiting lipolysis in the adipose tissue. Among all hypolipidemic drugs, niacin has
maximum HDL increasing property; therefore it is useful in patients having increased risk
of CAD. Further, it can also decrease lipoprotein (a) and fibrinogen. It is useful for type IIb,
III and IV disorders. Main compliance limiting feature is cutaneous flushing and pruritis.
These symptoms are due to vasodilatory action of niacin through release of PGs and can
be prevented by pretreatment with aspirin. To minimize the side effects, niacin should be
started at low doses. Other important adverse effects are GI toxicity and hyperuricemia.
Niacin can also lead to hepatotoxicity which is manifested by fall in both LDL as well HDL
cholesterol.
Pleotropic Effects of Statins
• Antioxidant
• Anti-inflammatory
• Anti-proliferative
All statins can be absorbed orally
(maximum fluvastatin).
Bile acids inhibit TG production
in the liver and their deficiency
results in elevation of TGs.
N
Mipomersen is an antisense oligonucleotide
inhibitor of mRNA
of apo B-100 synthesis. It is
indicated as once weekly injection
for treatment of homozygous
familial hypercholestrolemia
Fibrates are drugs of choice in
hypertriglyceridemia (type III
and IV)
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