Atorvastatin action

A 6.5-year-old male post-Ml with an elevated LDL level is treated with atorvastatin. What is the mechanism of action of atorvastatin ... 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

In another development, the statin side chain en route to Atorvastatin (Lipitor , Pfizer) is synthesized via the key intermediate alkyl 3-hydroxy-4-cyanobutyrate (Figure 13.17). Instead of the currently practiced six-step route, a much more concise three-step route starts from epichlorohydrin via Cl chain length enhancement by both nucleophilic substitution of chloride and nucleophilic ring opening of the epoxide with cyanide to yield symmetric dicyanoisopropanol. Nitrilase action desymmetrizes the dinitrile intermediate with the creation of a chiral center in C3 to yield (R)-3-hydroxy-4-cyanobutyrate, which is esterified to the key intermediate ethyl (R)-3-hydroxy-4-cyanobutyrate. 

Serebruany VL, Midei MG, Malinin Al, etal. Absence ofinter-action between atorvastatin or other statins and clopidogrel results from the interaction study. Arch Intern Med 2004 164 2051-2057. 

Other statins include simvastatin (also a lactone prodrug), pravastatin, atorvastatin, and cerivastatin (active form with open ring). The statins are the most important therapeutics for lowering cholesterol levels. Their notable cardiovascular protective effect, however, appears to involve additional actions. 

All of these drugs have the same mode of action. They are HMG co-A reductase inhibitors. Simply stated, they inhibit the liver s production of an enzyme that s essential to the manufacture of cholesterol. These are very powerful drugs, the most potent of which are atorvastatin and rosuvastatin, and are capable of reducing cholesterol, especially LDL, by as much as 50 percent or even more. 

In patients taking fenofibrate and atorvastatin, increased concentrations of plasma homocysteine were attributed to an action of the fibrates themselves and not indirectly via their lipid-lowering effect (8). Concomitant administration of folic acid, at least in part, offset this adverse effect... 

Describe the mechanism of action of HMG-CoA reductase inhibitors (e.g., simvastatin, atorvastatin). 

Six months after beginning atorvastatin, the patient s total and LDL cholesterol concentrations remained above normal and he continued to have anginal attacks despite good adherence to his antianginal medications. His physician decided to add niacin. The major recognized mechanism of action of niacin is... 

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