HMG CoA Reductase Inhibitors

Source

Lovastatin and Mevastatin are obtained from natural source, from micro-organisms, penicillin and micromonosporas.

Pravastatin and Simvastatin are semi-synthetic drugs.

Rosuvastatin, Atorvastatin and Fluvastatin are fluorine containing compounds.

Site of action

Main site of action is liver. In liver, they decrease the synthesis of TGs that in turn lead to decrease in VLDL as well as LDL.

Chemistry

Active forms of these drugs are structural analogs of enzyme hydroxyl methyl glutaryl CoA reductase. This enzyme is involved in the synthesis of sterols, and is responsible for the 1^st step in that synthesis.

Mechanism of Action

1. Competitive Inhibition

These drugs by competitive inhibition interfere with the synthesis of sterols.

2. Up regulation of LDL receptors

They can cause compensatory upregulation of LDL receptors in liver, which can cause increase extraction of LDL from plasma, so LDL levels are again decreased. Thus affect mainly LDL levels.

3. Catabolism

Can also enhance catabolism of LDL. Thus cause:

Reduction in LDL about 20-80%
Reduction in TGs about 25%
However, raised HDL 10-30%

Statins decrease the availability of isoprenyl groups from HMG CoA pathway, leading to:

I. decreased prenylation of Rho proteins, decreasing the activity of Rhokinase, decreasing the incidence of new coronary events.

II. decreased prenylation of Rab proteins, leading to decreased accumulation of Aβ in neurons, decreasing the manifestations of Alzheimer’s disease.

Statins decrease the oxidative stress by LDL and decrease atherosclerosis.

Statins stabilize the plaque, decreasing the chances of embolism.

Statins increase the NO.

Pharmacokinetics

Administration

Administered at bed time. Since activity of HMG CoA reductase is maximum at night.

Absorption

Incompletely absorbed after oral administration.

Extensive first pass metabolism

Bioavailability is increased when given with meals, so given with food.

PPC

Peak plasma concentration is achieved in 2-4 hours.

PPB

These drugs have extensive plasma protein binding.

Excretion

Mainly excreted in bile. About 10% eliminated in urine.

T1/2

Most statins have half life of 2 hours, except atorvastatin (14 hours) and Rosuvastatin (19 hours).

Uses

1. Familial hypercholesterolemia (due to increased LDL) not used in children

2. Acute coronary syndrome

Adverse effects

Remarkably well tolerated except for a few adverse effects.

1. GIT –abdominal discomfort, gastric irritation, diarrhea

2. Skin rashes, urticaria, allergic manifestations, and lupus like syndrome

3. May cause myopathies, where there is muscle tenderness, muscle cramps, fatigue. This myopathy is seen when given with Verapamil and Amiodarone.

4. Rabdomyolysis can lead to myoglobinurea and renal damage. This muscular injury is manifested by a rise in serum creatinine kinase levels.

5. These drugs cause polyneuropathies.

6. They can produce liver damage and increased serum transaminase levels, due to high 1^st pass metabolism.

7. In experimental animals, are found to be teratogenic.

Contraindications

Pregnancy

Liver diseases

Dose

Started from 20 mg and may be increased up to 80 mg, given twice or thrice daily, depending upon the severity of hyperlipidemias.

Drug Interactions

Simvastatin, Atorvastatin and Lovastatin are metabolized through CYP3A4. Drugs that inhibit CYP3A4 like Ketoconazole, Macrolides and Cyclosporins, can increase levels of statins, when given together.

Drugs like Phenytoin and Rifampicin act as enzyme inducers.

Rosuvastatin and Fluvastatin are metabolized through CYP2C9. Drugs that inhibit the cytochrome CYP2C9 like Metamindazole, Cimetidine and Ketoconazole increase the levels. Pravastatin is metabolized through sulphation.