Cholesterol Zocor

The cholesterol-lowering agents called statins, such as simvastatin (Zocor) and pravastatin (Pravachol), are among the most widely prescribed drugs in the world. Identify the functional groups in both, and tell how the two substances differ. 

Baycol (cerivastatin, sold as Lipobay in Europe, Bayer) is a statin, a class of cholesterol-lower drugs. Statins are the most prescribed drugs in the United States, with more than 12 million people taking them, and more than 700,000 people in the United States taking cerivastatin. It received marketing approval on June 26, 1997 and was voluntarily removed from the market on August 8, 2001 because of its link to 100 deaths and several injuries from potentially the muscle disease rhabdomyolysis. The other statins — lovas-tatin (Mevacor Merck) pravastatin (Pravachol Bristol-Myers Squibb) simvastatin (Zocor Merck) fluvastatin (Lescol Novartis) atorvastatin (Lipitor Parke-Davis) rosuvastatin... 

Most of us are familiar with the effects of cholesterol. Exhibit 1.3 provides an explanation of how cholesterol is formed and the mechanism of action for Lipitor and Zocor in lowering the sterol. 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

Atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck) HMG-coenzyme A inhibitors for the reduction of cholesterol level in blood (refer to Exhibit 1.3). 

A 42-year-old man presents with a chief complaint of intermittent claudication during exercise. His fomHy history is significant for the presence of cardiovascular disease on his fether s side, but not on his mother s side. Physical exam reveals xanthelasmas and bilateral tendon xanthomas. A plasma lipid profile reveals a cholesterol level of 340 mg/dL, with a high LDL/HDL ratio. He is given instructions for dietary modifications and a prescription for Zocor (simvastatin). 

A number of cholesterol-lowering drugs (Pravachol, zocor, and mevacor) are prepared by enzymatic processes. Penicillin antibiotics that have been on the market for decades are produced in large quantities by the enzymatic process. 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

It makes Cozaar and Hyzaar for hypertension Vytorin, Zetia, and Zocor to lower cholesterol Pro-pecia for male-pattern baldness Singulair for asthma Fosamax for osteoporosis and Gardasil, a vaccine for cervical cancer but it is also well known for making Vioxx, a pain relief drug taken off the market for causing heart problems. 

Simvastatin (Zocor) [Anrilipemic/HMG-CoA Reductase Inhibitor] Uses X Cholesterol Action HMG-CoA reductase inhibitor Dose Adults. 5-80 mg PO w/ meals X in renal insuff Peds. 10-17 y 10 mg, 40 mg/daily max Caution [X, —] Avoid concurrent use of gemfibrozil Contra PRG, liver Dz Disp Tabs 5,10, 20, 40, 80 mg SE HA, GI upset, myalgia, myopathy (muscle pain, tenderness or weakness w/ creatine kinase 10 x ULN), Hep Interactions T Effects OF digoxin, warfarin T risk of myopathy/iiiabdomyolysis W/ amiodarone, cyclosporine, CYP3A4 inhibitors, fibrates, HIV protease inhibitors, macrolides, niacin, verapamil, grapefruit juice X effects W/ cholestyramine, colestipol, fluvas-tatin, isradipine, propranolol EMS T Effects of warfarin use amiodarone and... 

This category includes atorvastatin (Lipitor), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava-chol), and simvastatin (Zocor) (Table 25-2). These drugs, known commonly as statins, are characterized by their ability to inhibit an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.96 This enzyme catalyzes one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol produc-... 

One class of antihyperlipidemic drugs is the statins. Statins interfere with the biosynthesis of cholesterol (A.103) and specifically inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Scheme A.l). The statins that have been approved by the FDA include lovastatin (Mevacor, A.104), simvastatin (Zocor, A.105), pravastatin (Prava-chol, A.106), atorvastatin (Lipitor, A.107), rosuvastatin (Crestor, A.108), and fluvastatin (Lescol, A.109) (Figure A.29). All six compounds are drawn here to highlight the similarities between HMG-CoA (A.99) and mevalonic acid (A.100), and the top portion of the various statins. As a class, the statins have been extremely successful in terms of sales and effective in decreasing LDL cholesterol levels in the blood. 

The high-value HMG-CoA reductase inhibitor Simvastatin (8) is marketed by Merck under the name Zocor. The active ingredient is obtained from a fermentation approach. It is very similar in structure to lovastatin, which has fallen from the top-sellers list. Lovastatin (9) is also a cholesterol-reducing drug that is isolated from Aspergillus terreus.51-60 It is still obtained by fermentation,61 and with the current advances in molecular biology,62 64 chemical approaches are not able to compete in a cost-effective manner.65-67 The usage of lipases allows for the manipulation of the butyric acid sidechain to access other HMG-CoA reductase inhibitors such as simvastatin.68 A number of routes to various portions of lovastatin have been reported.69... 

The current therapy leaders are the anti-ulcerants such as Omeprazole (Prilosec ) or Lansoprazole (Prevacid ), which accounted for US 19.5 billion in 2001, thus claiming a market share of 6%. The anti-ulcerants are closely followed by the cholesterol reducers, e.g., Atorvastatin (lipitor ) and Simvastatin (Zocor ), totaling US 18.9 billion, the antidepressants (US 15.9 billion), and the NSAIDs (nonsteroidal anti-inflammatory drugs US 10.9 billion). Calcium antagonists, antipsychotics, oral antidiabetics, ACE inhibitors, cephalosporins, and antihistamines complete the list of the best-selling therapy classes, with sales between US 9.9 and 6.7 billion. It is interesting to note that four classes grew more than 20% in 2001, namely the cholesterol reducers (22%), the antipsychotics (30%), the oral antidiabetics (30%), and the antihistamines (22%) [4],... 

One after another, the company s scientists spit out more than 10 m or new drugs in the 1980s and 1990s and launched research on a dozen others. Most of the blockbusters that would put Merck on the map began under Vagelos s leadership, when he was either head of research or CEO Mevacor and Zocor for cholesterol, Vasotec and Prinivil for hypertension. 

For the cholesterol market, Merck was counting on Zetia and Zocor. Arthritis, though, was a more depressing story. Targeting a market of anywhere from 21 million to 90 million Americans, Vioxx and its successor, Arcoxia, were supposed to be the blockbusters that would save Merck as patents on... 

But David W. Anstice, Merck s head of human health for the Americas, probably was closer to his company s true feelings when he described the potential market for Zocor and Zetia at the company s annual meeting for Wall Street analysts in December 2001. As he put it, If you look at patients not yet treated with statins [the cholesterol drugs like Zocor]—they may be in dietary or exercise regiments— there are 24 million in the United States alone. In other words, diet and exercise is all well and good, but sooner or later those 24 million will be ripe for a prescription. 

Again, Merck spent 91.2 million on DTC ads for Zocor in 2000, versus just 58.2 million that Pfizer spent on Lipitor, yet Lipitor led in sales—and this time, Merck had no excuses. It was Merck that had created the whole anticholesterol category in 1987 with Mevacor. But it lost cholesterol. Lipitor blew it away with a lower price and a more potent initial dose. While the higher dose might cause worse side effects, it sure made the drug look more effective in the marketing. 

Statins. Statins, such as atorvastatin (Lipotor), simvastatin (Zocor) and lovastatin (Mevacor), are fungal-derived HMG-CoA reductase inhibitors. Treatment results in an increased cellular uptake of LDLs, since the intracellular synthesis of cholesterol is inhibited and cells are therefore dependent on extracellular sources of cholesterol. However, since mevalonate (the product of the HMG-CoA reductase reaction) is also required for the synthesis of other important isoprenoid compounds besides cholesterol, long-term treatments carry some risk of toxicity. 

Cholesterol and cholesterol-lowering drugs atorvastatin (Lipitor) and simvastatin (Zocor) (Section 29.8B)... 

Trade name Zocor (cholesterol-lowering drug)... 

Several drugs are now available to reduce the level of cholesterol in the bloodstream. These compounds act by blocking the biosynthesis of cholesterol at its very early stages. Two examples include atorvastatin (Lipitor) and simvastatin (Zocor), whose structures appear in Figure 29.12. 

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