Statins available in Bangladesh for the treatment of Hypercholesterolemia

Contents:01.Description
02.Classification
03.Mechanism of Action(Mode of Action)
04. Beneficial effects of Statins
05. Adverse effects of Statins
06. Clinical Studies
07. Available Brands 
08. References

Description:
Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase.The most efficient agents for reducing plasma cholesterol with good tolerance. Angiographic studies have demonstrated that these compounds- 

• Reduce the progression of atherosclerosis
• Induce the regression of atherosclerosis     

Statins reduce the endogenous cholesterol synthesis by competingly inhibiting the principal enzyme involved.In addition, statins show some benefits towards patients-

• Can Inhibit tumor cells growth;
• Enhance intracellular calcium mobilization;
• A reduction in the number of bone fractures;
• The reductiion of the number of major coronary events as well as general mortality in coronary patients.

Classification of Statins:

There are a few number of classification criteria for statins,they are-

1. How they are obtained
2. Liver metabolism
3. Physico-chemical properties
4. Specific activity

How they are obtained

Some of the statins ae obtained from fungal fermentation-

1. Lovastatin
2. Pravastatin
3. Simvastatin

Some statins are obtained by lab synthesis-

1. Fluvastatin
2. Atorvastatin
3. Cerivastatin (Withdrawn on August 8,2001 due to 31 patients died by acute renal failure caused by Rhabdomyolysis)

Liver Metabolism

• Follow the Citocrom P450 (CYP 3A4) Pathway-

1. Lovastatin
2. Simvastatin
3. Atorvastatin
4. Cerivastatin

• Follow  CYP 2C9 Pathway-Fluvastatin

• Different Pathway- Pravastatin

Physico-Chemical Properties

• Hydrophobic in nature-

1. Lovastatin
2. Simvastatin
3. Atorvastatin
4. Cerivastatin

• Intermediate Characteristics- Fluvastatin
• Hydrophilic in nature - Pravastatin

Specific Activity

Active Compound (Acid Form)-

1. Atorvastatin
2. Cerivastatin
3. Fluvastatin
4. Pravastatin

Inactive forms (Lactone), which have to be enzymatically hydrolyzed to generate active forms-

1. Lovastatin
2. Simvastatin

Mechanism of Action:

Mechanism of action involves with categories:

• Mechanism Involving Lipids
• Mechanism Involving Intracellular Signaling Pathways

Mechanism Involving Lipids

• Inhibition of HMG CoA reductase
• Direct effects of HMG CoA reductase inhibition
• Reduction of LDL Susceptibility towards oxidation
• Inhibition of the expression of type A Scavenger receptor

Inhibition of HMG-CoA reductase

• Statins compete with the normal substrate in the enzymes active site
• Statins alter the  conformation of the enzyme (HMG CoA reductase) when they bind to its active site.
• The inhibition of HMG CoA reductase determines the reduction of intracellular cholesterol.

Direct effects of HMG CoA reductase inhibition

• Statins inhibit hepatic synthesis of apolipoprotein B-100.(Which determine a reduction of synthesis and secretion of Triglyceride rich lipoproteins and an reduction of receptors production for apolipoproteins B/E.)
•  This is the answer of the question- why Atorvastatin and Simvastatin are capable of reducing  LDL in patients with homozigous family hypercholesterolemia?
• Statins have a modest effect on HDL increase.

Reduction of LDL Susceptibility towards oxidation

Four mechanisms were proposed to explain statins' antioxidant properties-

One: Hypochlesterolemic effect .......>Reduced lipoprotein CHOLESTEROL......>the reduced level of oxidation substrate.

Two:  The decrease of cell oxygen production by inhibiting the generation of superoxide by macrophages.

Statins can also prevent LDL oxidation by preserving the activity of the endogenous antioxidant system, superoxide dimutase

Three:  The binding of statins to phospholipids on the surface of lipoproteins (Fluvastatin and Lovastatin bind to LDL phospholipids) preventing the diffusion towards the lipoprotein core of free radicals generated during oxidative stress.

Four:     The potent antioxidative potential of the metabolites (i.e. Atorvastatin and Fluvastatin metabolites) also results in lipoproteins protection from oxidation.

Inhibition of the expression of type A Scavenger receptor

·         Inhibition of expression of type A scavenger receptor in THP-1 cells and in human monocytes.

·         This decreases the receptor-mediated degradation of oxidised LDL.

·         Statins reduce mRNA level and CD36 expression on the cell surface as well as LDL binding to human U937 monocytes.

Mechanism Involving Intracellular Signaling Pathways

Prenylated proteins and their role in cellular signaling

Prenylated proteins:

A variety of proteins have covalently attached isoprenoid groups, mainly the C15 farnesyl and C20  geranygeranyl residues, that proteins are termed as Pronylated proteins.

Many pronylated proteins are associated with intracellular membranes and mutating their Cys prenylation sites blocks their membranes localization.

The hydrophobic prenyl group can act to anchor its attached protein to amembrane.

Prenylated protein may interact with specific membrane -bound receptor proteins and hence prenylation mediates protein-protein interaction.

Their role in cellular signaling:

The complex process of  cell signaling is very important for intracellular communication.Many intracellular signaling molecules are prenylated proteins.

The specific surface on the cell surface are associated with trimeric G protein.The trimeric G protein has gamma sub unit allowing this signaling protein to be inserted in the cell membrane near specific memmbrane receptors and to receive extracellular signals,which are then transfered  to the secondary signaling molecules in the cells.

The important role of the prenylated signaling molecules for the living cell is presented below-

Beneficial Effects of Statins:

1.  Effects on cholesterol esterification and its accumulation in macrophages

2.  Effects on endothelial cell function

3.  Effects on inflammatory process

4.  Effects on proliferation ,miration and apoptosis of arterial SMC(Smooth Muscle Cells)

5.  Effects on the stability of atherosclerotic plaque

6.  Effects on platelet activation

7.  Effects on coagulation process.

Adverse effects of Statin Therapy:

• Liver toxicity
• Muscle toxicity
• Hepatic dysfunction
• Renal insufficiency
• Hypothyroidism
• Serious infections.

Available Brands:

1. Lipitor(Atorvastatin)-Pfizer
2. Anzitor (Atorvastatin)- Square Pharmaceuticals Ltd.
3. Lipicon (Atorvastatin)-Sk+f Bangladesh Limited.
4. Tiginor (Atorvastatin)- Incepta Pharmaceuticals Ltd.
5. Avas (Atorvastatin)-Opsonin Pharma Ltd.
6. Ropitor (Rosuvastatin)-Opsonin Pharma Ltd.
7. Rocovas (Rosuvastatin)- Incepta Pharmaceuticals Ltd.
8. Rosuva (Rosuvastatin)-Square Pharmaceuticals Ltd.

References

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