An overview on the mechanism of action of statins:
HMG CoA reductase inhibitors,or statins are widely prescribed drugs. They are indicated for the treatment of hipercholesterolemia, a condition that increases cardiovascular risk. Currently, the drugs of this group that are available are:
Atorvastatin
Fluvastatin
Lovastatin
Mevastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Mechanism of action. Animation explained
HMG CoA reductase inhibitors competitively inhibit the activity of HMG CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Inhibition of this enzyme results in a transient, modest decrease in cellular cholesterol concentration . The decrease in cholesterol concentration activates a cellular signaling cascade culminating in the activation of sterol regulatory element binding protein (SREBP), a transcription factor that up-regulates expression of the gene encoding the LDL receptor. Increased LDL receptor expression causes increased uptake of plasma LDL, and consequently decreases plasma LDL-cholesterol concentration. Approximately 70% of LDL receptors are expressed by hepatocytes, with the remainder expressed by a variety of cell types in the body.
Clinical uses
- Hypercholesterolemia.
- Familial Hypercholesterolemia (Atorvastatin might be an exception)
- Coronary atherosclerosis
- Prophylaxis for coronary atherosclerosis
Adverse effects and contraindications
- HMG-CoA inhibitors are contraindicated in pregnancy. Limited evidence from animal and human studies indicates that statins should not be taken during pregnancy
- Liver disfunction:Elevations of serum aminotransferase activity (up to three times normal) occur in some patients. This is often intermittent and usually not associated with other evidence of hepatic toxicity. In some patients, who may have underlying liver disease or a history of alcohol abuse, levels may exceed three times normal. This finding portends more severe hepatic toxicity.
- A relatively common side effect of the statins (perhaps 1% of patients) is myositis,that is,infammation of skeletal muscle accompanied by pain,weakness,and high levels of serum creatine kinase. Rhabdomyolysis,i.e.,disintegration of muscle with urinary excretion of myoglobin and
kidney damage, is serious side effect. The risk of muscle damage is said to increase with
simultaneous use of the triglyceride-lowering fibrates.
References
[1] Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, Second Edition
by David E. Golan.
[2] Modern Pharmacology with Clinical Applications, Sixth Edition by Charles Craig.[3] Basic & Clinical Pharmacology, 10th Edition by Bertram G. Katzung.