Lovastatin – Drug class, mechanism of action, uses, dosage, side effects

What is lovastatin?

Lovastatin belongs to a group of drugs called the statins drugs, also known as HMG-CoA reductase inhibitors. It is a fungal metabolite isolated from Aspergillus terreus cultures. Lovastatin is a potent anticholesteremic agent that works by inhibiting HMG-CoA reductase but also works by stimulating LDL receptors production in the liver.

It is used to lower cholesterol levels in the body. In combination with diet, exercise and weight loss, lovastatin may reduce the risk of heart attack, stroke, and other cardiovascular disorders.

Lovastatin is present in small amounts in foods such as oyster mushrooms and red yeast rice. Lovastatin comes in a tablet and an extended-release tablet.

What are the various trade names under which lovastatin is available?

Lovastatin is the generic name of the drug which is available in the following trade names:

• Altocor
• Altoprev
• Mevacor

Lovastatin IUPAC name, molecular formula, weight, structure and drug class

IUPAC name: (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate

Molecular formula: C₂₄H₃₆O₅

Molecular weight: 54 g/mol

Molecular structure:

Drug class: Lovastatin belongs to the class of organic compounds known as delta valerolactones which are cyclic organic compounds with an oxan-2- one moiety.

Lovastatin history

Lovastatin was the second agent of the statin class discovered. This drug was discovered by Alfred Alberts and his team at Merck in 1978 after screening only 18 compounds over 2 weeks. The agent, also known as mevinolin, was isolated from the fungi Aspergillus terreus.

Research on this compound was suddenly shut down in 1980 and the drug was not approved until 1987. Interesting, Akira Endo at Sankyo Co. (Japan) patented lovastatin isolated from Monascus ruber four months before Merck. Lovastatin was found to be 2 times more potent than its predecessor, mevastatin, the first discovered statin.

What are the functions of lovastatin?

• The primary function of lovastatin is to decrease the amount of low-density lipoprotein (LDL) being formed. LDL is more commonly referred to as the “bad” cholesterol. Lovastatin reduces hepatic cholesterol synthesis by competitively inhibiting HMG-CoA reductase, which is the most important part in the cholesterol biosynthesis pathway via the mevalonic acid pathway. Lowered hepatic cholesterol levels cause increased uptake of LDL cholesterol and reduces cholesterol levels in the blood
• It increases the levels of high-density lipoprotein (HDL), also known as “good” cholesterol in the blood.
• Lovastatin can also lower triglyceride levels
• It lowers the risk of heart attack, stroke, and other heart diseases in people who have the following risk factors: coronary heart disease and diabetes.

By how much lovastatin affects cholesterol levels in the blood?

At therapeutic doses, lovastatin affects lipoprotein levels by:

• Decreasing serum LDL cholesterol by 29-32%
• Increasing HDL cholesterol by 4.6-7.3%
• Decreasing triglyceride levels by 2-12%.

Lovastatin identification

Lovastatin was the first statin to be approved of by the Food and Drug Administration (FDA). It was first derived from the fungus “Aspergillus terreus”. It appears as a white crystalline powder, is insoluble in water and sparingly soluble in ethanol and methanol.

What type of a drug is lovastatin?

Lovastatin is a prodrug. This means that it is an inactive drug when it is administered to a person. After being administered, it undergoes some metabolic and chemical changes to convert to its active form. The effects of lovastatin on cholesterol synthesis can only occur when it converts to its metabolically active form.

What are the various doses in which lovastatin is available?

Lovastatin is available in the following dosages:

• 10 mg
• 20 mg
• 40 mg

What are the inactive ingredients usually present in a tablet of lovastatin?

The various ingredients present in a tablet of lovastatin include (apart from the drug itself):

• Butylated hydroxyanisole (as a preservative)
• Lactose monohydrate
• Magnesium stearate
• Microcrystalline cellulose
• Pregelatinized starch (corn)
• Food colors

What is the mechanism of action of lovastatin?

Lovastatin inhibits the function of the enzyme HMG-CoA reductase. As a result, the conversion of HMG-CoA to mevalonate does not occur. As a prodrug it is activated in vivo via hydrolysis of the lactone ring to form the β-hydroxyacid.

Such product 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.

What are the pharmacokinetics of lovastatin?

After the drug is administered orally, about 10% of this dose is excreted in the urine and about 83% of it is excreted in the feces. The former includes the byproducts of the drug that have been excreted in the bile and includes any component of the drug that was not absorbed by the human body. Plasma concentrations of lovastatin were found to peak at around two hours, after the administration of the first dose.

After twenty-four hours of administration of the first dose, 10% of the peak levels were showed in the blood. In experiments conducted on testing the amount of lovastatin absorbed into the bloodstream, after administration by the oral route, it was showed that about 30% of the total oral dose was absorbed.

It has also been determined that lovastatin has an extremely high affinity for the liver, more so than the non-target organs. The liver is the site in the human body where lovastatin undergoes first-pass extraction. It also happens to be the primary site of action of the drug. As a consequence, a major portion of the degradation products of lovastatin is found in the bile.

Because the drug undergoes extensive first-pass extraction in the liver, the amount of drug available to circulate in the blood is low. In some patients undergoing treatment for hypercholesterolemia, it was observed that less than 5% of the oral dose of the drug reached the blood circulation. The area under the plasma drug concentration-time curve (AUC) for lovastatin was showed to be about 40%.

Both lovastatin and its active metabolic product (β-hydroxyacid) are highly bound (more than 95%) to plasma proteins present in the blood. Lovastatin has also been seen to cross the blood-brain and placental barriers. The major metabolic product formed by the degradation of lovastatin is β-hydroxyacid, as mentioned above.

Peak plasma concentration of this metabolite is achieved two to four hours after the first administration of the drug. In certain experimental settings, it has been seen that if Lovastatin is given under fasting conditions, only two-thirds of the metabolic product formed as a result of the breakdown of lovastatin is seen in the blood.

This is in comparison to a greater amount of degradation products found in the blood if lovastatin is administered in normal conditions or with meals. In patients who are suffering from kidney disease or renal insufficiency, the plasma concentrations of the metabolic products of lovastatin were found to be significantly higher than those of people with normal kidney function, approximately up to two-fold.

The same effects are seen in elderly or geriatric patients. In that age group, the plasma level of the inhibitory products was increased by approximately 45%, as compared to patients in a younger age group.

What are the indications of using lovastatin?

• For patients who have been advised to lower their blood cholesterol levels, lovastatin can be extremely beneficial in case diet and exercise have failed to achieve proper control.
• Lovastatin also reduces the risk of heart attack and unstable angina in patients who are at risk of developing these clinical conditions.
• Lovastatin is also known to slow the progression of atherosclerosis in patients who have preexisting coronary heart disease.
• The use of lovastatin is also indicated in some genetic disorders. These include heterozygous familial hypercholesterolemia. This disorder occurs in adolescents from the ages of ten to seventeen,

How to properly use lovastatin?

• Before embarking on the use of any medicines, the advice of a physician must be sought.
• The directions present on the packaging of the product must be followed correctly.
• Use only the amount of drug prescribed by the doctor. Do not increase or decrease the dose of the drug unless directed by the physician.
• Lovastatin is most commonly taken at bedtime or with an evening meal. If several doses of the drug are required throughout the day, take the medicine with meals unless directed otherwise by the physician.
• Take the tablet whole. Do not break, chew or crush it.
• Lovastatin is used on a long-term basis to control cholesterol levels in the blood. Its use should be stopped prior to a medical or surgical procedure. This includes medical or surgical emergencies. As with any medicines, the use of this medication should not be stopped abruptly unless directed by the physician.
• Periodic blood tests will be required if a patient is taking lovastatin. This is to check liver function.
• Lovastatin is a form of add-on therapy to a complete program that includes dietary modifications, the introduction of an exercise regime and weight control to lower blood cholesterol levels. All the parameters must be carefully controlled and followed in order to achieve optimal blood cholesterol levels.
• This medication is to be stored at room temperature and away from moisture, heat, and light.
• The dosage of lovastatin is incredibly specific and varies from person to person. With the induction of therapy with lovastatin, blood cholesterol levels should be checked two to four weeks after the administration of the first dose, in order to increase or decrease the dose of the drug being given, as needed.
• Peak levels of lovastatin are seen within two hours of it being administered. However, it may take a few weeks of regular dosing in order to achieve the desired effect. In this case, adequate and optimal control of blood cholesterol levels.
• Before starting therapy with lovastatin, other causes of raised cholesterol levels need to be ruled out. These include the following: alcoholism, diabetes mellitus type II, liver diseas, low thyroid hormone levels (also known as hypothyroidism)
• The use of lovastatin has not been studied in pre-pubertal patients or patients below the age of ten years.
• The use of lovastatin should be with extreme caution in the elderly and the geriatric age group.

What to do if a dose of lovastatin is missed?

• The missed dose should be taken as soon as possible (when it is remembered).
• If it is already time for the next dose, the missed dose should be skipped and the current dose should be taken as it is.
• Extra doses should not be taken to compensate for the missed dose.

Lovastatin overdose

• Administration of lovastatin in mice resulted in the observance of a median lethal dose of greater than 15 grams per meter square.
• In human volunteers, a single dose of up to 200 mg of lovastatin did not result in clinically significant adverse effects.
• Some cases of accidental overdosage have been reported. The symptoms described in these patients were non-specific and all patients recovered without the occurrence of any significant consequences. The maximum dose that was taken was reported to be ranging from 5 to 6 grams.
• No specific cure of an overdosage is currently known. This might change in the future with increased experience with the drug and clinical trials.

What are the precautions while using lovastatin?

• Lovastatin is only to be used in children above the age of 10 years and adults.
• Other instances that need special attention before lovastatin is prescribed include:

1. Diabetes (present or past history of). This is because the use of lovastatin may lead to an increase in HbA1c and fasting serum glucose levels.
2. History of kidney disease (lovastatin may cause a clinical condition that results in the breakdown of skeletal muscle leading to kidney failure)
3. History of liver disease
4. The consumption of more than two alcoholic beverages per day
5. Thyroid disorders (particularly hypothyroidism)

What are the contraindications to the administration of lovastatin?

• Lovastatin is contraindicated if a person has active liver disease.
• Lovastatin should not be used if a woman is pregnant. Lovastatin is categorized by the Food and Drug Administration (FDA) as Pregnancy Category X. This means that it can harm the unborn baby and may cause birth defects. Women are advised to discontinue the use of lovastatin as soon as they become aware of their pregnancy. Meanwhile, an effective form of birth control should be used if a woman is being treated with lovastatin.
• The use of lovastatin is also contraindicated if a woman is breastfeeding. Lovastatin is not known to be excreted in breast milk but another statin is known to do so. As a result, Lovastatin is contraindicated in women who are breastfeeding as it may be excreted in the breast milk and can cause harm to a baby that is being weaned.

Pregnancy and the use of lovastatin

• In experiments designed to test the adverse effects of lovastatin on unborn fetuses, the use of this drug was seen to cause skeletal malformations in the offspring of pregnant mice and rats that were given a certain dosage. Other harmful features observed included:

1. Appearance of abnormal behavior
2. Decreased body weight
3. Delays in the ossification of the bones
4. Developmental delays
5. Neonatal mortality
6. The presence of extra ribs

Lovastatin interaction with other drugs

Lovastatin should be avoided completely if someone is taking any one of the following medications:

• Antibiotics for example Clarithromycin, Erythromycin and Telithromycin
• Antifungal medicines for example Itraconazole, Ketoconazole, Posaconazole, Voriconazole
• Hepatitis C medicines for example Boceprevir, Telaprevir
• HIV/AIDS medicines for example Atazanavir, Cobicistat, Darunavir, and Fosamprenavir
• Nefazodone

A physician needs to be notified before the use of lovastatin if someone is taking the following medicines:

• Cyclosporine (can increase the risk of myopathy. Cyclosporine has been found to increase the area under the plasma drug concentration-time curve (AUC), if used concurrently with lovastatin. This signifies that it decreases the clearance of lovastatin)
• Danazol (can also increase the risk of myopathy if used concurrently with lovastatin)
• Gemfibrozil (can cause myopathy)
• Medicines used to treat heart disease for example amiodarone, diltiazem, dronedarone, ranolazine, verapamil

What foods should be avoided while using lovastatin?

• Lovastatin is metabolized by the enzyme pathway known as “CYP3A4”. As a result, the use of grapefruit juice should be avoided if a person is being treated with lovastatin. This is because the side effects of lovastatin are manifested to a greater degree if grapefruit juice is consumed concurrently. Grapefruit juice contains compounds that interact with the enzyme responsible for the metabolism of lovastatin. The usage of grapefruit juice increases the risk of myopathy by decreasing the elimination of lovastatin. In one experimental study, a group of people was given grapefruit juice to drink before taking lovastatin. It resulted in increased plasma levels of the drug being present in the blood.
• Avoid eating foods that contain a high amount of fat or cholesterol. If this guideline is not followed, the efficacy of lovastatin will decrease significantly.
• The use of alcoholic beverages should be stopped completely. This is because the consumption of alcoholic beverages can cause an increase in the triglyceride levels in the blood. This, in turn, might result in liver damage.

What are the side effects of lovastatin?

As with any drug, side effects are a common problem. A wide variety of commonly experienced side effects have been reported with the use of lovastatin. Broadly, the side effects of using lovastatin include (but are not limited to):

• Since Lovastatin is primarily metabolized by the liver, it can take a toll on a person’s liver functions. This can cause liver function tests (LFTs) reports to be deranged or in severe cases, can lead to liver necrosis and failure.
• In rare cases, the use of lovastatin has been linked to severe, life-threatening conditions like rhabdomyolysis.
• The use of lovastatin has been linked to neurological symptoms like memory loss and impairment which can interfere with a person’s daily life activities.

These have been expounded on further in the paragraphs below.

Immediate medical attention is required if any of the following signs of an allergic reaction are noticed:

• Difficulty in breathing (dyspnea)
• Hives (swollen, red bumps)
• Swelling of the following regions: face, lips, tongue or throat

In rare instances, the use of Lovastatin can result in the breakdown of skeletal muscle. The following signs and symptoms should necessitate immediate medical attention if any one of them is experienced:

• Being unusually tired
• Fever
• Muscle pain that is not attributed to exercise or any other similar cause
• Tenderness
• Urine that is dark in color
• Weakness

Lovastatin interactions with laboratory tests?

Slightly deranged laboratory reports while testing the blood might be expected. The parameters likely to be impaired include:

• Creatine phosphokinase
• Serum transaminases

Can I take lovastatin with amiodarone?

Concomitant use of amiodarone with higher dosages of lovastatin may be associated with an increased risk of myopathy since amiodarone can increase lovastatin levels in blood. The suggested mechanism is inhibition of lovastatin metabolism by amiodarone of intestinal and hepatic CYP450 3A4 inhibition, which can result in enhanced bioavailability as well as reduced clearance of this statin.

In general, the risk of myopathy associated with the statin use is considered to be dose-related and increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Myopathy demonstrated as muscle pain with or without weakness related with grossly elevated creatine kinase exceeding 10 times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

Can I take lovastatin with diltiazem?

Concomitant use of diltiazem and lovasatin has been shown to significantly increase the blood concentrations of lovastatin acid, which is the active metabolite of lovastatin. The mechanism of interaction is however not fully understood but may involve diltiazem inhibition of the CYP450 3A4 isoenzyme and/or P-glycoprotein efflux transporter, of which both lovastatin and lovastatin acid are substrates.

Myopathy exhibited as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding 10 times the upper limit of normal has been reported rarely. Rhabdomyolysis has been also repoted, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death.

Can I take lovastatin with antifungal agents (fluconazole, miconazole, itraconazole)?

Concomitant use of lovastatin and annitfungals drugs such as fluconazole, miconazole, itaconazle etc that are potent inhibitors of CYP450 3A4 may significantly increase the plasma levels of lovastatin that are substrates of the isoenzyme. High levels of HMG-CoA reductase inhibitory activity in plasma is linked with an increased risk of musculoskeletal toxicity.

Myopathy manifested as muscle pain and/or weakness associated with grossly elevated creatine kinase exceeding ten times the upper limit of normal has been reported occasionally. Rhabdomyolysis has also occurred rarely, which may be accompanied by acute renal failure secondary to myoglobinuria and may result in death. Within the azole class, ketoconazole and itraconazole are considered the most potent inhibitors, while fluconazole is comparatively weak and generally causes clinically significant interactions with CYP450 3A4 substrates only at dosages of 200 mg/day or more.

Can I take lovastatin with niacin?

There are reported cases of severe myopathy and rhabdomyolysis after concomitant use of lovastatin and niacin. The exact mechanism is unknown; but, the development of myopathy has been linked with both the uses of lovastatin alone and lipid-modifying dosages of niacin with 1 g/day or more alone. Certain races may be more susceptible to the interaction.

The incidence of myopathy was found to be higher in patients of Chinese descent (0.43%) compared to patients not of Chinese descent (0.03%) taking 40 mg simvastatin and lipid-modifying dosages of a niacin-containing product. The exact cause of the increased incidence is unknown, and it is also unknown if the increased risk applies to other Asian populations or to other statins when given to Chinese patients.

Can I take lovastatin with hydralazine?

The risk of peripheral neuropathy may be increased during concurrent use lovastatin and hydralazine. A patient who are at higher risk and diabetics and patients older than 60 years. In some cases, the neuropathy may progress or become irreversible despite discontinuation of the medications.

Can I take lovastatin with warfarin?

Concomitant use of warfarin together with lovastatin may provoke the increased risk of bleeding. Patents may need a dose adjustment based on your prothrombin time or International Normalized Ratio (INR). Call your doctor promptly if you have any unusual bleeding or bruising, vomiting, blood in your urine or stools, headache, dizziness, or weakness.

It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Can I take lovastatin with levothyroxine?

Rarely, lovastatin has been reported to reduce the pharmacologic effects of thyroid hormone. The exact mechanism of interaction is unknown but in isolated cases, those who were stabilized on levothyroxine developed symptoms of hypothyroidism and/or elevated thyroid-stimulating hormone (TSH) levels after lovastatin use.

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