Lipid Modifying Agents PDF

Lipid modifying agents Lipid transport As complexes termed lipoproteins Elevations termed hyperlipidemias Number of metabolic disorders Atherosclerosis and pancreatitis Atherosclerosis Leading cause of US death LDL, IDL and VLDL can deposit lipids into artery wall Me...

Lipid modifying agents Lipid transport As complexes termed lipoproteins Elevations termed hyperlipidemias Number of metabolic disorders Atherosclerosis and pancreatitis Atherosclerosis Leading cause of US death LDL, IDL and VLDL can deposit lipids into artery wall Mechanism of plaque formation Involves foam cells ( macrophages filled with cholesterol) Plaque grows and accumulates foam cells, collagen, fibrin, and calcium, proinflammatory factors from macrophages are involved Although the plaque can occlude a vessel, rupture of unstable plaques is responsible for most symptoms Rupture can cause clot formation HDL is protective Retrieve cholesterol from artery wall Inhibit oxidation of lipoproteins Risk factors Smoking Directly damaging to endothelium Reduces HDL Increases oxidation of LDL Obesity Diabetes Glycosylated LDL is better able to invade endothelium Sedentary lifestyle Western diet Types of lipoproteins Chylomicron Delivers TG from intestines , carries cholesterol and cholesterol esters ( CE) TG cleaved off by LPL Remnants taken up by liver and repackaged as VLDL VLDL Exports TGs to peripheral tissues Cleaved off by LPL Results in IDL Some taken up by liver Some converted to LDL by removal of TGs by a hepatic lipase LDL Taken up by liver and other tissues by receptor mediated endocytosis ( LDL receptors) Cholesterol used for membranes and bile acid production Cells can synthesize cholesterol via HMG COA reductase Receptor number is dictated by cellular cholesterol content Liver responsible for removal of most cholesterol HDL Secreted by liver and intestines Scavenges cholesterol from tissues and delivers to the liver for use or removal Lp(a) lipoprotein: formed from an LDL-like moiety and the Lp(a) protein linked by a disulfide bridge (LDL variant). found in atherosclerotic plaques may also contribute to coronary disease by inhibiting thrombolysis ( competes with plasminogen). It is also associated with aortic stenosis. Pro-inflammatory Statins (HMG CoA reductase inhibitors)  Competitive inhibitors ( Structural analogs of HMG CoA) Most effective agents for LDL reduction Decrease inflammation and oxidative stress Plaque stabilization Given post MI even in presence of normal lipids Also to reduce stroke risk Lovastatin and simvastatin are pro-drugs All have high first pass extraction Cause partial inhibition of HMG CoA reductase Cause liver to upregulate LDL receptors Reduces plasma LDL Not very effective in patients that lack functional LDL receptors ( type IIa) Also decreases triglycerides and increased HDL Effective as monotherapy but often combined with bile acid resins Absolutely contraindicated in pregnancy or breastfeeding women, liver disease (pravastatin is excreted renally may be less of a problem) Lovastatin-prodrug (Mevacor), Atorvastatin (Lipitor), Fluvastatin (Lescol), Pravastatin (Pravachol), and Simvastatin-prodrug (Zocor), Rosuvastatin (Crestor). Fluvastatin, pravastatin and Rosuvastatin are less lipophilic and may have less side effects Extended dosing intervals may be helpful as well ( ie every other day etc)  Adverse Effects Elevation of liver enzymes Often intermittent Does not usually require discontinuation Exception: Patients with liver disease or Hx of alcohol abuse Monitoring of enzyme levels periodically If enzymes elevated > 3X normal this suggests severe hepatotoxicity ( discontinue ) Muscle pain and weakness Can indicate rhabdomyolysis Serious can cause kidney failure Can occur with monotherapy Risk increases in presence of other drugs Creatine kinase activity monitored in this case Patients should report muscle pain or weakness immediately Simvastatin 80 mg not as initial therapy due to high incidence of rhabdo. Grapefruit juice can raise levels Hypersensitivity – lupus like syndrome and peripheral neuropathy (rare) Progression of cataracts Can increase action of coumadin Interacts with many drugs  Niacin ( Nicotinic Acid) Decreases LDL and VLDL ,large increases in HDL Inhibits VLDL secretion which decreases LDL production Increases in VLDL clearance decreases Triglycerides Stimulates lipoprotein lipase increasing hydrolysis of VLDL Often used in combination with other agents Large doses required for efficacy Uses: lower Triglycerides and hyperlipoproteinemia Adverse effects Flushing and warmth due to cutaneous vasodilation ASA 30 min prior will reduce Diminishes with time but alcohol ingestion worsens Nausea, abdominal pain Elevations in blood glucose Avoid in PUD Liver enzyme elevations Toxicity rare but warrants discontinuation Rhabdomyolysis in combination with statins Hyperuricemia, arrhythmias Severe hyperglycemia in diabetics Potentiates action of antihypertensives Contraindicated in gout, rhabdomyolysis, PUD, bleeding , liver disease Questions Two large studies called its usefulness into question even when used to raise HDL is no longer recommended as an add-on to statin therapy Outcomes no better and perhaps worse Fibrates Gemfibrazole (Lopid) , fenofibrate (Tricor) Peroxisome Proliferator-Activated Receptor, PPAR ligands. Increases lipoprotein lipase synthesis and fatty acid oxidation Decreases VLDL and triglycerides Only small reductions in LDL Small increases in HDL LDL can increase in some patients Very useful for elevated TG and VLDL Adverse effects Rhabdomyolysis in combo with statins GI Disturbances Gallstones due to increased cholesterol in bile ( decrease bile acid production, leaving more cholesterol in bile) Contraindicated in liver disease, pregnancy and breastfeeding , renal failure, and gall stones May increase mortality in those with pre existing coronary atherosclerotic disease  Bile acid sequestrants (Resins) Colestipol(Colestid), cholestyramine (questran), Colesevelam( Whelcol) Nonabsorbable, bind bile acids in the intestine , prevent recycling and promote excretion of bile acids Liver upregulates LDL receptors , increases LDL and IDL uptake to make bile acids , reducing plasma cholesterol Not useful in disorders where patients lack functional LDL receptors ( homozygous familial disorder IIa) Adverse effects May elevate VLDL GI , gas cramping, discomfort, diarrhea Can interfere with vitamin K absorption contraindicated in coagulation disorders Interferes with absorption of drugs and fat soluble vitamins, including warfarin digoxin and thiazides Dose one hour prior or 4-6 hours after Colesevelam affects drug absorption less Use can be used in pregnancy as they are not absorbed Lower LDL , large reductions second only to statins Monotherapy or in combination with statins Not useful for elevated triglycerides Contraindicated in GI obstruction (drug causes constipation and fecal impaction), serum TGs >500 mg/dL coagulopathy and phenylketonuria (it contains aspartame which contains phenyl alanine). Administered orally Dry gritty powders with less than amazing taste Often mixed with juice Cholesterol absorption inhibitors Ezetimibe (Zetia) Inhibits absorption of ingested cholesterol and recycling of bile acids Weak as monotherapy Often combined with other agents (statins) Hypersensitivity Adverse effects : less hepatotoxicity than other drugs, less incidence of myositis Infection and respiratory disorders, coughing, sinusitis Administered orally as a pro-drug Fibrates can increase levels, bile acid resins will decrease Can potentiate statin myositis, and liver enzyme elevations from statins PCSK9 inhibitors  Decrease degradation of LDL Receptors in hepatocytes Results in an increase in recycled receptor inserted into the cell surface Increases LDL uptake from blood Injectable Large reductions in LDL Approved for familial hypercholesterolemia (hetero and homozygous forms) Evolocumab ( Repatha) Approved for CV disease (heart attack or stroke) if additional cholesterol lowering is required Alirocumab ( Praluent) approved for CV disease if additional cholesterol reductions are needed Very very costly Over 10.000/year Summary Statins Most effective at reducing LDL, Decrease TGs , and increase HDL moderately Fibrates Major effect is reduction of VLDL and therefore TGs, low reduction of LDL and may raise in some, moderate increases in HDL Bile acid resins Second most effective at reducing LDL, small increases in HDL Niacin Large elevations in HDL , lowers LDL, large reductions in VLDL and TGs Eztimibe , low reductions in LDL and VLDL , often combined with statins Mechanism summary of BABRs, Statins and cholesterol absorption inhibitor