Lovastatin is a lactone metabolite isolated from the fungus Aspergillus terreus with cholesterol-lowering and potential antineoplastic activities. Lovastatin is hydrolyzed to the active beta-hydroxy acids form, which competitively inhibits 3-hydroxyl-3-methyl glutaryl coenzyme A (HMG-CoA) reductase, an enzyme involved in cholesterol biosynthesis. In addition, this agent may induce tumor cell apoptosis and inhibit tumor cell invasiveness, possibly by inhibiting protein farnesylation and protein geranylgeranylation and may arrest cells in the G1 phase of the cell cycle. The latter effect sensitizes tumor cells to the cytotoxic effects of ionizing radiation.
Lovastatin is a statin drug, used for lowering cholesterol in those with hypercholesterolemia to reduce the risk of cardiovascular disease. Lovastatin is a naturally occurring compound found in low concentrations in food such as oyster mushrooms, red yeast rice. Lovastatin differs structurally from mevastatin by a single methyl group at the 6’ position. Lovastatin is a prodrug that is activated by in vivo hydrolysis of the lactone ring. It, along with mevastatin, has served as one of the lead compounds for the development of the synthetic compounds used today.
Mechanism of Action of Lovastatin
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. 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 cause increased uptake of low-density lipoprotein (LDL) cholesterol and reduce 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.
The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins), atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin, and simvastatin, reduce atherogenesis and cardiovascular morbidity. Besides, there is growing evidence that statins have immunomodulatory activities. Statins downregulate the expression of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1), monocyte chemotactic protein-1 (MAC-1) and lymphocyte function-associated antigen-1 (LFA-1), on leucocytes and endothelial cells and, through binding to LFA-1, interfere with ICAM-1-LFA-1 interaction, which is crucial for activation of lymphocytes by antigen-presenting cells, ingress of leucocytes into the inflammation sites and immunologic cytotoxicity. Statins inhibit the inducible expression of major histocompatibility complex class II in several cell types including macrophages and downregulate the expression of T-helper-1 (Th1) chemokine receptors on T cells, leading further to inhibition of activation of lymphocytes and their infiltration into the inflammation sites. Statins block the induction of inducible nitric oxide synthase and the expression of several proinflammatory cytokines such as tumor necrosis factor-alpha and interferon-gamma in macrophages and possess antioxidant effects. These agents inhibit the proliferation of immunocytes and the activation of natural killer cells.
Indications of Lovastatin
- Hyperlipoproteinemia Type IIa, Elevated LDL
- High cholesterol
- High cholesterol, familial heterozygous
- Hyperlipoproteinemia Type IIb, Elevated LDL VLDL
- Coronary heart disease
- Heterozygous familial hypercholesterolemia
- High blood cholesterol level
- Primary prevention of coronary artery disease
- Primary prevention myocardial infarction
- Primary prevention unstable angina
- For management as an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels in patients with primary hypercholesterolemia and mixed dyslipidemia. For primary prevention of coronary heart disease and to slow progression of coronary atherosclerosis in patients with coronary heart disease.
Contraindications of Lovastatin
- Uncontrolled epilepsy
- Hemorrhage in the brain
- Severely low blood pressure
- Liver problems
- Recent operation
- Loss of memory
- High blood sugar
- Abnormal liver function tests
- A mother who is producing milk and breastfeeding
- Muscle pain or tenderness with increase creatine kinase
- Metabolic syndrome X
- Muscle damage due to auotimmunity
- Pregnancy, breast feeding, and liver disease
Dosage of Lovastatin
Strengths: 10 mg; 20 mg; 40 mg; 60 mg
- Initial dose: 20 mg orally once a day with the evening meal.
- Maintenance dose: 10 to 80 mg orally once a day or in 1 or 2 divided doses.
- Initial dose: 20, 40, or 60 mg orally once a day at bedtime. Patients requiring smaller reductions in cholesterol may start with 10 mg orally at bedtime.
- Maintenance dose: 10 to 60 mg orally given once a day at bedtime.
- 10 to 17 years: 10 mg orally once a day
- 10 to 17 years: 10 to 40 mg orally once a day
Side Effects of Lovastatin
The most common
- Nausea and vomiting
- Severe stomach ache
- epigastric pain,
- cold symptoms such as runny nose, sneezing, and coughing
- joint pain
- Nausea and vomiting
- Severe stomach ache
- Severe diarrhea
- Mouth sores
- Vaginal thrush
- Skin rash
- muscle pain, tenderness, or weakness
- lack of energy
- dark colored urine
- jaundice: yellowing of the skin or eyes
- pain in the upper right part of the stomach
- unusual bleeding or bruising
- loss of appetite
- flu-like symptoms
- difficulty breathing or swallowing
Drug Interactions of Lovastatin
Lovastatin may interact with following drugs, supplements & may change the efficacy of drugs
- antacids (e.g., aluminum hydroxide, calcium carbonate, magnesium hydroxide)
- “azole” antifungal medications (e.g., itraconazole, ketoconazole)
- birth control pills
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- cancer medications (e.g., daunorubicin, doxorubicin, etoposide, methotrexate, mitotane, paclitaxel, temsirolimus, vinblastine, vincristine)
- estrogens (e.g., conjugated estrogen, estradiol, ethinyl estradiol)
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- macrolide antibiotics (e.g., azithromycin, erythromycin, clarithromycin)
- proton pump inhibitors (PPIs; e.g., lansoprazole, omeprazole, pantoprazole)
FDA Pregnancy Category X
This medication should not be used during pregnancy. If you become pregnant while taking this medication, stop taking it immediately and call your doctor.
It is not known if lovastatin passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.