What Is Statin Toxicity?

HMG-CoA reductase inhibitor (hydroxymethylglutaryl coenzyme A reductase inhibitor, hydroxy methylglutaryl coenzyme A reductase inhibitor) is a statin drug. HMG-CoA reductase is a rate-limiting enzyme in the process of cholesterol synthesis by liver cells. It catalyzes the formation of mevalonate (MVA), and inhibiting HMG-CoA reductase can hinder cholesterol synthesis.

HMG-CoA reductase inhibitor (hydroxymethylglutaryl coenzyme A reductase inhibitor, hydroxy methylglutaryl coenzyme A reductase inhibitor) is a statin drug. HMG-CoA reductase is a rate-limiting enzyme in the process of cholesterol synthesis by liver cells. It catalyzes the formation of mevalonate (MVA), and inhibiting HMG-CoA reductase can hinder cholesterol synthesis.

Chinese name

HMG-CoA reductase inhibitor

Pharmacological action

Blood lipid regulation and mechanism

Clinical effect

Heterozygous familial and nonfamilial hyperlipidemia

Adverse reactions

Gastrointestinal reactions, myalgias, flushing of the skin

HMG-CoA reductase inhibitors

HMG-CoA (hydroxymethylglutaryl coenzyme A) reductase is a rate-limiting enzyme in the biosynthesis of cholesterol (Ch) in the body. It can catalyze the formation of mevalonate from the substrate HMG-CoA, which is the limit of cholesterol synthesis in the body Speed steps. HMG-CoA reductase is an important target for lipid regulation drugs. HMG-CoA reductase inhibitors have similar structural fragments to the substrate HMG-CoA. The affinity of the inhibitor and HMG-CoA reductase is greater than that of the substrate, which can competitively inhibit the formation of mevalonate from HMG-CoA and reduce the production of cholesterol. And body content, thereby significantly reducing the incidence of fatal and non-fatal cardiovascular disease events ^[1] .

HMG-CoA reductase inhibitors

Commonly used statins are synthesized by mold or artificial. The former includes lovastatin, pravastatin, simvastatin, and cilastatin, while the latter includes fluvastatin and atorvastatin. Simvastatin and mevastatin have structurally similar inner rings in addition to the structurally similar groups to HMG-CoA. Therefore, the two are grouped into one class and are called type I statins. , Cilitatin, Fluvastatin, Atorvastatin have more complex structures than type I, and are called type II statins.

HMG-CoA reductase inhibitor III. Structure-activity relationship

Through the research on statins and related analogs, and the complexes of enzymes and substrates and statins, the structure-activity relationship of statins was initially determined. The structure of statins can be divided into 3 parts: part A, a , -dihydroxyvaleric acid structure similar to the HMG structure in the substrate HMG-CoA of the enzyme; part B, one produced after the enzyme is allosteric Hydrophobic rigid flat structure combined with hydrophobic shallow grooves; part C, the connecting part between the two.

Part A :

, -dihydroxyvaleric acid is an essential group to exert inhibitory activity. Its lactone structure can be converted into , -dihydroxyvaleric acid by enzymatic hydrolysis in vivo to produce activity, but the activity is relatively low. The -methyl , -dihydroxyvaleric acid structure is closer to the HMG structure. If it is replaced by , the -dihydroxyvaleric acid structure results in a significant decrease in activity.

In the , -dihydroxyvaleric acid structure, two hydroxyl groups are located on two chiral carbons, two hydroxyl groups are in cis, and -hydroxyl is in the R configuration is necessary for activity. If the configuration is changed, the activity decreases sharply.

Part B :

Part B is a hydrophobic, rigid planar structure, which can be a benzene ring, a naphthalene ring, a dehydronaphthalene ring, an aromatic heterocycle or a condensed heterocycle. Generally, the activity of a condensed benzene or condensed heterocycle is better than that of the corresponding benzene ring. Or aromatic heterocycle.

A large hydrophobic group is introduced in the ortho position of , -dihydroxy acid chain on the hydrophobic rigid planar structure, which can control the hydrophobic rigid planar structure to produce the best spatial arrangement and enzyme generation. Maximum binding while regulating hydrophobicity is an essential group for optimal activity. It can be substituted phenyl, cyclohexylmethyl, cyclohexyl, etc., among which 4fluorophenyl substituted compounds have the best activity. Type I isoamyl esters act similarly to Type II 4fluorophenyl.

Introducing isopropyl, cyclopropyl, spiropentane, etc. at the other ortho position of the , -dihydroxy acid chain on the hydrophobic rigid planar structure, which can maximize the binding between the compound and the enzyme through stereo adjustment Is an essential group for maximum activity. Isopropyl or cyclopropyl is usually introduced, and compounds introduced into cyclopropyl are relatively more stable in metabolism in vivo than compounds introduced into isopropyl.

Introducing polar substituents such as sulfonyl or ester groups at other positions on the hydrophobic rigid planar structure, the inhibition of HMGR can be enhanced by the hydrogen bonding between these groups and hHMGR.

Part C: The optimal length for connecting A and B is the length of two carbon atoms, with vinyl or ethyl being the best. If substituted with ethynyl or oxymethylene, the activity will be significantly reduced.

When the C part is vinyl, the A and B parts must be in the trans position. If it is cis, the activity will be significantly reduced.

HMG-CoA reductase inhibitor IV. Mechanism

Inhibition of HMG-CoA reductase reduces cholesterol synthesis, which in turn enhances the expression of low-density lipoprotein (LDL) receptors on the cell surface, increases the number and activity of LDL receptors on the cell, and reduces very low-density lipoprotein (VLDL) in the blood, Medium density lipoprotein (IDL) and LDL content. In addition, it can inhibit the synthesis of VLDL in the liver, which can significantly reduce total cholesterol (TC), and also increase high density lipoprotein (HDL) and reduce triacylglycerol (TG).

HMG-CoA reductase inhibitors

1. Inhibit HMG-CoA reductase

HMG-CoA reductase is a key enzyme in the cholesterol synthase system. Statins inhibit liver synthesis of cholesterol through its inhibitory effect. Lovastatin and neovastatin require oral activation in vivo to be biologically active. Atorvastatin and rifavastatin are biologically active after oral absorption ^[2] .

2. Increase the density of LDL receptors

Statins can directly increase the density of LDL receptors in the liver, and can also increase the density of LDL receptors by reducing the serum total cholesterol concentration. LDL particles are cholesterol-rich lipoproteins. After binding to liver LDL receptors, there are Helps the decomposition of LDL and the degradation of cholesterol, thereby increasing the clearance of plasma low-density lipoprotein cholesterol.

3. Inhibition of Very Low Density Protein Cholesterol (VLDL-C) Synthesis

VLDL is a triglyceride-rich lipoprotein, and cholesterol is necessary for the synthesis of VLDL. Statin lipid-lowering drugs reduce plasma cholesterol concentration and reduce the synthesis and secretion of VLDL. VLDL is required to carry and transport triacylglycerols. VLDL-C is the precursor of LDL-C, so this class of drugs can reduce triacylglycerol, VLDL-C and LDL-C.

4. Anti-atherosclerotic effect

This class of drugs can reduce lipid infiltration and foam formation, reduce the volume of atherosclerotic plaques, induce reversal of atherosclerotic plaques, improve vascular endothelial function, and reduce vasoconstriction and spasm induced by acetylcholine, thereby improving myocardial deficiency Blood can also inhibit platelet adhesion, aggregation, and mediate the blood coagulation-anticoagulation system.

5. Inhibition of smooth muscle cell migration and proliferation

When atherosclerotic plaques develop ulcers, the normal repair process requires the proliferation of smooth muscle cells, but excessive proliferation will cause adverse effects. Lovastatin, simvastatin, and fluvastatin all have a strong inhibitory effect on vascular smooth muscle cell proliferation. This effect can delay or inhibit the progression of early atherosclerosis.

6. Anti-lipid oxidation

Statins reduce the oxidation susceptibility of LDL in plasma and plaques by removing oxygen free radicals or metalloid chelates, and this effect is not affected by plasma LDL concentration. In addition, such drugs can also directly inhibit lipid particle oxidation.

7. Anti-inflammatory effect

Statins can inhibit the expression and secretion of macrophage chemokines, prevent monocytes and other inflammatory cells from infiltrating, and significantly reduce the number of arteriosclerotic intima, middle macrophages and new blood vessels.

8. Immunosuppressive effect

Statins can regulate the immune response, inhibit the cytotoxic effects of antibody-dependent cells and natural killer cells, reduce immune damage, and effectively reduce the rejection response after organ transplantation.

9. Regulate endothelial and vasomotor functions

Statins can inhibit nitric oxide and endogenous nitric oxide synthase in macrophages induced by polysaccharides, and the inhibitory effects of the drugs are not affected by cholesterol and coenzyme Q, the final products of mevalonic acid metabolism. Statins can also improve the recovery of coronary vasodilation and vascular endothelial function mediated by active substances.

10. Inhibit platelet aggregation and thrombosis

Statins inhibit the expression of tissue factors by macrophages, reduce plasma fibrinogen, thromboxane A, and thromboxane B levels, inhibit platelet aggregation, and thus inhibit thrombosis.

HMG-CoA reductase inhibitors 6. Adverse reactions

General adverse reaction

Statins are well tolerated. General adverse reactions include digestive system reactions such as nausea, diarrhea, or constipation, neurological symptoms such as dizziness, and skin reactions and rashes. These reactions are generally not serious, and may decrease or disappear with the prolonged use of drugs. Individually, symptomatic treatment or adjustment of drugs is required ^[3] .

2. Myotoxicity

Myotoxicity is the most significant and common adverse reaction caused by statins. It usually includes rhabdomyolysis, myalgia, and myositis. Rhabdomyolysis is the rarest and most severe myopathy, which occurs in about 1.5 of 106 statin users ^[3] .

3. Neurotoxicity

Long-term use of statins can cause a range of neurological symptoms: cognitive impairment, forgetfulness, memory loss, suicidal impulses, hyperactive neurosis, and aggressive behavior. When the above symptoms appear clinically, the drug should be stopped immediately. These symptoms are reversible and will recur if you use statins again, which may be related to the cognitive decline caused by statins.

4. Liver toxicity

The clinical manifestations of statins on liver side effects include asymptomatic elevation of transaminase, cholestasis, hepatitis and even acute liver failure. Among them, asymptomatic transaminase elevation is the most common. In clinical animal studies, simvastatin and lovastatin have been found to cause liver necrosis and liver toxicity.

5. Renal toxicity

Statins inhibit endocytosis, thereby hindering the reabsorption of protein by the proximal tubules, leading to the occurrence of proteinuria. When statins are used in patients with severe renal insufficiency, the plasma concentration of the drug increases, and the risk of myopathy and rhabdomyolysis increases.