The role of statin drugs in combating cardiovascular diseases

Statins act by competitively inhibiting HMG-CoA reductase,the
first committed enzyme of the HMG-CoA reductase pathway
(Fig.1). HMG-CoA reductase inhibitors are a group of prescription
drugs used to lower cholesterol, a white waxy substance that can
stick to the inside of blood vessels, resulting in clogged arteries,
heart disease, and strokes. These medicines work by slowing down
the body's ability to make cholesterol. Because statins are similar
to HMG-CoA on a molecular level they take the place of HMG-CoA in
the enzyme and reduce the rate by which it is able to produce
mevalonate,the next molecule in the cascade that eventually
produces cholesterol, as well as a number of other compounds.
This ultimately reduces cholesterol via several mechanisms[6].

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<       (HMGXoA)

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Mevalonate -6 -phosphate

▼ ^

MevaJonate-S-pyrophosphate

DImethiyfaIIyI-PP →— Iaopontofiyl-S-Pyrophosphate (PP)

BisPHOSPIKMATtS

Goranyl PP

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Г 4    T

GeranylQeranyf-PP ------ FarnesyI-PP

Squalene

2.3 Oxldoiqualone

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PREtWLATEO DOLICHOL    L∙noιt∙r_t>l

PROTEINS      LieiQUINON        j IS Ikaclicns

CHOLESTEROL

Fig.1.The HMG-CoA reductase pathway, which is blocked by
statins via inhibiting the rate-limiting enzyme HMG-CoA
reductase[6].

Inhibiting cholesterol synthesis

By inhibiting HMG-CoA reductase, statins block the pathway for
synthesizing cholesterol in the liver(Fig.2). This is significant
because most circulating cholesterol comes from internal
manufacture rather than the diet. When the liver can no longer
produce cholesterol, levels of cholesterol in the blood will fall.
Cholesterol synthesis appears to occur mostly at night,so statins
with short half-lives are usually taken at night to maximize their
effect. Studies have shown greater LDL and total cholesterol
reductions in the short-acting simvastatin taken at night rather
than the morning,but have shown no difference in the long-acting
atorvastatin[6].

Fig.2. Statins block the pathway for synthesizing cholesterol
in the liver [6].

A ^~'~^'"^*^-~"^,~⅛⅛           Statin

.        Liver            /

___√¹⅜¾P7         Cholesterol Production
у             ⁱ       ~ ~--.^F∣⅜ocl(cd by Statin

∖c^2^°∣

Zfi      Reductase

f                   ∖

HMG-CoA ÷ ^      Statin             1

V

∖ ^χ4                     I

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