Saturday, February 17, 2018

Lovastatin-hypolipidiaemic drug


The primary cause of cardiovascular disease is atherosclerotic plaque formation. Sustained elevations of cholesterol in the blood increase the risk of cardiovascular disease. Lovastatin lowers hepatic cholesterol synthesis by competitively inhibiting HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step in the cholesterol biosynthesis pathway via the mevalonic acid pathway. Decreased hepatic cholesterol levels causes increased uptake of low density lipoprotein (LDL) cholesterol and reduces cholesterol levels in the circulation. At therapeutic doses, lovastatin decreases serum LDL cholesterol by 29-32%, increases high density lipoprotein (HDL) cholesterol by 4.6-7.3%, and decrease triglyceride levels by 2-12%. HDL cholesterol is thought to confer protective effects against CV disease, whereas high LDL and triglyceride levels are associated with higher risk of disease.

Mechanism of action
Lovastatin is structurally similar to the HMG, a substituent of the endogenous substrate of HMG-CoA reductase. Lovastatin is a prodrug that is activated in vivo via hydrolysis of the lactone ring to form the β-hydroxyacid. The hydrolyzed lactone ring mimics the tetrahedral intermediate produced by the reductase allowing the agent to bind to HMG-CoA reductase with 20,000 times greater affinity than its natural substrate. The bicyclic portion of lovastatin binds to the coenzyme A portion of the active site.

Studies suggest that <5% of the oral dose reaches the general circulation as active inhibitors. Time to peak serum concentration is 2-4 hours. Lovastatin undergoes extensive first-pass metabolism so the availability of the drug in the system is low and variable.

Volume of distribution 
Lovastatin is able to cross the blood-brain-barrier and placenta.

Protein binding
Lovastatin and its β-hydroxyacid metabolites are highly protein bound (>95%).

Lovastatin is hepatically metabolized in which the major active metabolites are the β-hydroxyacid of lovastatin, the 6’-hydroxy derivative, and two additional metabolites.

Route of administration
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. 83% of the orally administered dose is excreted in bile and 10% is excreted in urine.

Half life
5.3 hours

Drug drug interaction 
Acipimox + lovastatin = Acipimox may increase the myopathic rhabdomyolysis activities of Lovastatin.

Aluminum hydroxide + lovastatin = The serum concentration of Lovastatin can be decreased when it is combined with Aluminum hydroxide.

Amiodarone + lovastatin = The metabolism of Lovastatin can be decreased when combined with Amiodarone.

Aprepitant + lovastatin = The serum concentration of Lovastatin can be increased when it is combined with Aprepitant.

Food interaction 
Avoid alcohol.
Avoid drastic changes in dietary habit.
Avoid taking with grapefruit juice.
Take with food, 50% increase in bioavailability when taken with food.

Therapeutic uses
Lovastatin is used to lower the risk of stroke, heart attack, and other heart complications in people with diabetes, coronary heart disease, or other risk factors.

Reference- Tripathi KD "Essential of medical pharmacology" 7th edition, page no- 636,637

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