Statins inhibitors

Cholesterol lowering drugs are indicated for the prevention and treatment of atherosclerosis. There are three families of these dmgs inhibitors of HMG-CoA reductase (statins), inhibitors of cholesterol transport protein, and inhibitors of cholesteryl ester transfer protein (CETP). They are important drugs from an economical point of view. Among them, several are fluorinated. 

Cooper JB, Foundling SI, Blundell TL, Boger J, Jupp R, Kay J. X-ray studies of aspartic proteinase-statine inhibitor complexes. Biochemistry 1989 28 8596-8603. 

The reaction in which HMG-CoA reductase reduces HMG to form mevolonate is a rate-limiting step in cholesterol synthesis. Statins, inhibitors of this enzyme, act to lower blood levels of cholesterol in patients. 

Fig. 3. Chemical structures of HMG-CoA and several statin inhibitors of HMG-CoA reductase. Atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol) are widely prescribed cholesterol-lowering drugs.

Weakness can result from medications that have a direct myotoxic effect, such as blockade of myocyte glycoprotein synthesis and eleetron transport eaused by statins (inhibitors of the hydroxy-methylglutaryl-coenzyme A reduetase) used in patients with hyperlipidemia or nucleoside analogues used in patients with human immunodefieieney virus (40). Weakness can also result from neuromuscular blocking agents and aminoglyeosides, which interfere with neuromuscular transmission. 

For ISIS 301012, a second-generation antisense inhibitor of apoB-100 in November 2006. Isis announced results from two Phase 2 clinical trials of ISIS 301012. In the first study repotted, patients with high cholesterol on stable doses of statins were treated with ISIS 301012 for 5 weeks. Patients who received 300 mg/week of ISIS 301012 in this study achieved a 51% reduction in LDL-cholesterol (LDL), a 42% reduction in total cholesterol (TC), and a 4l% reduction in triglycerides (TG) beyond the levels achieved with statins alone. 

Statins (3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors)... 

HMG-CoA reductase inhibitors (statins). This effect has been suggested to account for some of the side effects of statins like myositis or rhabdomyolysis. 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

Once has been determined in the absence of inhibitor, can be calculated from equation (47). K, values are used to compare different inhibitors of the same enzyme. The lower the value for K, the more effective the inhibitor. For example, the statin drugs that act as competitive inhibitors of HMG-CoA reductase (Chapter 26) have values several orders of magnimde lower than the AT for the substrate HMG-CoA. 

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to improve vascular outcomes due to their cholesterol-lowering effects as well as multiple pleiotropic effects. In high-risk populations, statin therapy is known to reduce the risk of vascular events such as myocardial infarction and stroke. A meta-analysis of 10 trials involving 79,494 subjects showed that statin therapy reduced the incidence of stroke by 18%, major coronary events by 27%, and all-cause mortality by 15%. The SPARCL trial recently showed that high-dose HMG-CoA reductase inhibitors prevent recurrent stroke and transient ischemic attacks. ... 

To control risk factors and prevent major adverse cardiac events, statin therapy should be considered in all patients with ischemic heart disease, particularly in those with elevated low-density lipoprotein cholesterol. In the absence of contraindications, angiotensin-converting enzyme inhibitors should be considered in ischemic heart disease patients who also have diabetes melli-tus, left ventricular dysfunction, history of myocardial infarction, or any combination of these. Angiotensin receptor blockers... 

Formulate a monitoring plan for a patient with ST-segment elevation acute coronary syndrome receiving fibrinolytics, aspirin, unfractionated heparin, intravenous nitroglycerin, intravenous (3-blockers followed by oral P-blockers, an angiotensin-converting enzyme inhibitor, and a statin. 

Because the costs for chronic preventative pharmacotherapy are the same for primary and secondary prevention, while the risk of events is higher with secondary prevention, secondary prevention is more cost effective than primary prevention of CHD. Pharmacotherapy demonstrating cost effectiveness to prevent death in the ACS and post-MI patient includes fibrinolytics ( 2,000 to 33,000 cost per year of life saved), aspirin, glycoprotein Ilb/IIIa receptor blockers ( 13,700 to 16,500 per year of life added), (3-blockers (less than 5,000 to 15,000 cost per year of life saved), ACE inhibitors ( 3,000 to 5,000 cost per year of life saved), eplerenone ( 15,300 to 32,400 per year of life gained), statins ( 4,500 to 9,500 per year of life saved) and gemfibrozil ( 17,000 per year of life saved).49-58 Because cost-effectiveness ratios of less than 50,000 per added life-year are considered economically attractive from a societal perspective,49 pharmacotherapy described above for ACS and secondary prevention are standards of care because of their efficacy and cost attractiveness to payors. 

Specific concomitant medications or consumptions (check specific statin package insert for warnings) fibrates (especially gemfibrozil, but other fibrates too), nicotinic acid (rarely), cyclosporine, azole antifungals such as itraconazole and ketoconazole, macrolide antibiotics such as erythromycin and clarithromycin, protease inhibitors used to treat Acquired Immune Deficiency Syndrome, nefazodone (antidepressant), verapamil, amiodarone, large quantities of grapefruit juice (usually more than 1 quart per day), and alcohol abuse (independently predisposes to myopathy)... 

The NKF suggests that CKD should be classified as a coronary heart disease (CHD) risk equivalent and the goal LDL-C level should be below 100 mg/dL in all patients with CKD.22 The most frequently used agents for the treatment of dyslipidemias in patients with CKD are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ( statins ) and the fibric acid derivatives. However, other treatments have been studied in patients with CKD and should be considered if first-line therapies are contraindicated. 

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