Statins bile acid sequestrants

Four main classes of lipid-lowering medications are available HMG CoA reductase inhibitors (otherwise known as statins), bile acid sequestrants, nicotinic acid, and fibric acids. 

Dosingof selected agents by class fibrate (gemfibrozil 600 mg twice a day) niacin (1.5-3 g/day of immediate-release product) statin (simvastatin 10-40 mg/day if glomerular filtration rate [GFR] <30 mL/min, 20-80 mg/day if GFR >30 mL/min) bile acid sequestrant (cholestyramine 4-16 g/day). 

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

It is well established that HMG-CoA reductase inhibitors and bile acid sequestrants can be used together safely, with a greater reduction in LDL cholesterol than is obtainable when either drug is used alone. Unfortunately, bile acid sequestrants are often poorly tolerated, which limits the usefulness of this combination. Relatively low doses of niacin, when used in combination with statins, produce a very attractive effect on the lipoprotein profile (Gardner et al., 1996 Stein et al., 1996) the ability of niacin to substantially increase HDL cholesterol is additive, with the profound reduction in LDL cholesterol produced by the statin, and there is also a moderate reduction in triglycerides. However,... 

The primary goal of therapy is the control of the hypercholesterolemia and prevention of atherosclerotic cardiovascular disease. Patients with heterozygous FH can usually be successfully treated with medications to lower the LDL cholesterol to acceptable levels (Table 14-2). They are generally responsive to treatment with statins, alone or in combination with other drugs, such as bile acid sequestrants (such as cholestyramine) or cholesterol absorption inhibitors (such as ezetimibe) that act additively to upregulate the expression of the functioning LDL receptor as described in the Biochemical Perspectives section. In a few cases, a more aggressive treatment with LDL apheresis (discussed in this section) may have to be considered in order to reach acceptable LDL cholesterol levels. 

In addition to the statin drugs which inhibit HMG-CoA reductase a number of other drugs are used to lower cholesterol levels. The first are resins which are also referred to as bile acid sequestrants such as cholestyramine. The resins work by binding to the bile acids followed by excretion of the resin-bile complex. To make up for the loss of the bile acids the body converts cholesterol into bile acids thus reducing the cholesterol levels. 

Statins Ezitimibe Omega-3 triglycerides Bile acid sequestrants Fibrates Nicotinic acid derivatives Inhibit HMG-CoA reductase Inhibits absorption of cholesterol from the intestine Inhibit VLDL synthesis in the liver Bind bile acids in the intestine Lower levels of circulating VLDLs and LDLs by unknown mechanism Reduce the release of VLDLs from the liver... 

The two established bUe-acid sequestrants or resins (cholestyramine and colestipol) are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently. When used with a statin, cholestyramine and colestipol usually are prescribed at submaximal doses. Maximal doses can reduce LDL-C by up to 25% but are associated with unacceptable gastrointestinal (GI) side effects (bloating and constipation) that limit compliance. Colesevelam is a newer bile-acid sequestrant that is prepared as an anhydrous gel and taken as a tablet. It lowers LDL-C by 18% at its maximum dose. The safety and efficacy of colesevelam have not been studied in children or pregnant women. 

Ann Jeina was treated with a statin (pravastatin) and cholestyramine, a bile acid sequestrant. With the introduction of the cholesterol absorption blocker ezetimibe, the use of cholestyramine with its high level of gastrointestinal side effects may decline. Ezetimibe reduces the percentage of absorption of free cholesterol present in the lumen of the gut and hence the amount of cholesterol available to the enteroc5de to package into chylomicrons. This, in turn, reduces the amount of cholesterol returning to the liver in chylomicron remnants. The net result is a reduction in the cholesterol pool in hepatocytes. The latter induces the synthesis of an increased number of LDL receptors by the hver cells. As a consequence, the capacity of the liver to increase hepatic uptake of LDL from the circulation leads to a decrease in serum LDL levels. 

Key randomized clinical trials employing niacin with cardiovascular and clinical endpoints are summarized in Table 39.2. Most of the trials used niacin in combination with other agents—bile acid sequestrants, fibrates or statins. 

Drug interactions The extent to which vitamin D supplementation alters drug effectiveness and toxicity in humans has been systematically reviewed. Bile acid sequestrants and lipase inhibitors were found to inhibit the absorption of vitamin D from the gut. Statins, rifampicin, isoniazid, hydroxychloroquine, antiepileptics, corticosteroids, immimo-suppressive and chemotherapeutic agents, antiretroviral drugs and H2 receptor antagonists interfered with vitamin D metabolism. The interaction between vitamin D and thiazide diuretics could result in hypercalcaetnia. Vitamin D supplementation decreases concentrations of atorvastatin, and could cause hypercalcaetnia in elderly individuals or tixose with compromised renal function or hyperparathyroidism [84 ]. 

Bile acid sequestrants are charged resins that are ingested in a liquid suspension. They bind to bile acids in the intestine and prevent their reabsorption. Since bile acids normally feed back on their own synthesis from cholesterol, these agents evoke a compensatory increase in bile acid synthesis. The diversion of liver cholesterol for bile acid production leads to an upregulation of the LDL receptor and thus a reduction in LDL levels. Because bile acid sequestrants increase cholesterol catabolism and statins decrease cholesterol synthesis, the two agents together act synergistically. 

Bile acid-binding resin therapy Oral administration of a bile acid-binding resin, or sequestrant (D), increases the loss of bile acids from the body by preventing their absorption by intestinal epithelial cells through the IBAT transport protein and reduces bile acids delivered to the blood (0) and then to the liver (0) by the transporter NTCR Step The lower levels of cytoplasmic bile acids reduce the amount of bile acid bound to the nuclear hormone receptor EXP (0) and its suppression (0) of the expression of cholesterol 7a-hydroxylase. The consequent increased levels of expression and activity of cholesterol 7a-hydroxylase (B) reduce the levels of intracellular cholesterol (0). As with the statin treatment, the reduced cellular cholesterol levels (EHB) increase LDLR activity, lower plasma LDL levels, and protect against atherosclerosis. [Part (a) adapted from M. S. Brown and J. L. Goldstein, 1986, Sdence 232 34.]... 

MECHANISM OF ACTION The bUe-acid sequestrants are highly positively charged and bind negatively charged bile acids. The resins are not absorbed, and the bound bile acids are excreted in the stool. Since >95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids and increases hepatic bile-acid synthesis. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors. The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase. Inhibition of reductase activity by a statin substantially increases the effectiveness of the resins. 

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