Hyperlipidemic Drugs.pdf

Hyperlipidemias Condition in which elevated levels of lipids (fats) in the blood, including cholesterol and triglycerides Causes ○ Genetic factors Familial refers to a group of genetic disorders that result in significantly elevat...

Hyperlipidemias Condition in which elevated levels of lipids (fats) in the blood, including cholesterol and triglycerides Causes ○ Genetic factors Familial refers to a group of genetic disorders that result in significantly elevated levels of lipids in the blood Genetic mutations: gene mututations that affect lipid metabolism, altered processing and storing of fats ○ Environmental factors High consumption in saturated fats, trans fats excessive high glycemic diet leading to high triglycerides Sedentary lifestyle can lead to obesity and higher levels of lipids despite a relatively healthy diet Excess body weight can disrupt the body’s normal lipid metabolism - increased levels of LDL cholesterol and triglycerides Smoking can lower HDL (good cholesterol), while excessive alcohol intake can raise triglyceride levels Familial Hyperlipidemia (4 types) ○ Type I: familial hyperchylomicronemia ○ Type IIA: familial hypercholesterolemia ○ Type IIB: familial combined (mixed) hyperlipidemia ○ Type III: familial dysbetalipoproteinemia ○ Type IV: familial hypertriglyceridemia ○ Type V: familial mixed hypertriglyceridemia Goals of Tx ○ Decrease production of lipoproteins ○ Increase catabolism of lipoproteins ○ Increase removal of cholesterol ○ Tx leads into a decline in progression of plaques and regression of preexisting lesions ○ Target levels Cholesterol levels: below 200 mg/dl LDL levels: below 130 mg/dl HDL levels: higher than 60 mg/dl Lipoproteins: endogenous molecules that contains both Apo- proteins and lipids in their structures Apo-proteins ○ Crucial parts of the structure of lipoproteins ○ Essential roles in lipid metabolism and transport ○ Functions Structural stability Facilitate the transport of lipids in the bloodstream  Act as cofactors for enzymes involved in lipid metabolism Interact w/ specific receptors on cell surfaces, facilitating the uptake of lipoproteins by cells Involved in the metabolism of various lipoproteins ○ They transport lipid around the body in the blood ○ 5 types: differ in the amount of cholesterol, triglycerides and types of Apo-proteins they contain Chylomicrons (CM) We get this when we consume fat Very low-density lipoprotein (VLDL) Intermediate- density lipoproteins (IDL) Low density lipoprotein (LDL) High density lipoprotein (HDL) ○ Atherogenic particles Low density lipoprotein (LDL) Very low-density lipoprotein (VLDL) Intermediate- density lipoproteins (IDL) Chylomicrons (CM) ○ High-density lipoprotein considered as a good cholesterol carrier 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors AKA statins Most effective Tx First-line drugs when LDL-lowering drugs are indicated MOA ○ Inhibits of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase  ○ Compensation by increasing # of LDL receptors on the surface of hepatocytes (upregulation) ○ Results in increased removal of LDL from the blood ○ VLDL (LDL precursor) production is decreased ○ Reduction of LDL and VLDL results in modest decrease TGs and HDL Rosuvastatin (Crestor) Atorvastatin (Lipitor) Simvastatin (Zocor) Pravastatin (Pravachol) Lovastatin (Mevacor) Kinetics ○ High first-pass clearance by the liver ○ Highly protein bound, short ½ life (except atorvastatin) ○ Most metabolized CYP3A4 ○ Influenced by the cytochrome P450 (CYP) enzyme system SE ○ HA, myalgia Take them at night, help minimize symptoms ○ Hepatotoxicity, raised concentrations of liver enzymes (serum aminotransferases) If a patient is taking CYP450 inhibitor (PACMAN), statin ingredient stays longer in system and can cause liver toxicity Overtime, monitor liver enzymes (order CNP) ○ Myopathy (increased creatine kinase [CK] released from muscles) — nephrotoxicity ○ Teratogenicity, statins should be avoided during pregnancy Bile Acid Sequestrants Colestipol, Cholestyramine, Colesevelam MOA ○ Binds to the bile acids, forming insoluble complex and preventing fat emulsification and reabsorption via enterohepatic circulation Upregulation: cellular level increase in trans expression of what is happening in the cell ○ LDL receptors upregulation to obtain more cholesterol from blood  SE ○ Resins are clinically safe as they are not systemically absorbed ○ Abdominal discomfort, bloating, constipation ○ Decreased absorption of fat-soluble vitamins (Vitamin A, D, K) ○ *The concentration of HDL is unchanged Drug interaction ○ Interfere w/ the absorption of statins, ezetimibe except Colesevelam Colesevelam is the only one that still works in conjunction Contraindications ○ Complete biliary obstruction - b/c bile is not secreted into the intestine Cholelithiasis ○ Chronic constipation Already having constipation so not a good idea to make it worse ○ Severe hypertriglyceridemia (TG >400 mg/dL) - bile acid binding resins can raise triglycerides somewhat Cholesterol Absorption Inhibitors Ezetimibe Pharmacology action ○ Decrease LDL 20%, TG 8%, Increases HDL 1-4% MOA ○ Reduces cholesterol reabsorption (EHC) ○ LDL receptors upregulation to obtain more cholesterol from blood ○ Decreases LDL and VLDL  Kinetics ○ Reaches peak blood level in 12-14 hours ○ Undergoes enterohepatic circulation ○ It’s ½ life is 22 hrs ○ Most of the drug is excreted in feces Indications ○ As monotherapy: primary prevention of low risk of coronary heart disease which needs modest low LDL normally we use statins for those at high risk ○ As combo.therapy: safe ○ W/ stains: synergistic* in moderate/severe increase LDL ○ Or if must decrease statin dose because of SE ○ Or with other lipid lowering drugs; as fibrates (to lower triglycerides) SE: not common Niacin (Nicotinic Acid) (Vitamin B3) MOA ○ Binds to adipose nicotinic acid receptors ○ Leads to decrease in free fatty acids mobilization from adipocytes to the liver resulting in lower TG and thus VLDL synthesis ○ In the liver inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis - it decreases VLDL production ○ Decreased LDL Monotherapy or in combo.w/ fibrate, resin, or statin SE ○ MC - cutaneous flushing (which is excessive production of prostaglandin - mediated can be avoided by low dose aspirin ½ h before Niacin) ○ GIT - dyspepsia, nausea, vomiting, reactivation of peptic ulcer (can be decreased if taken after meal) ○ In high doses ○ Reversible increased liver enzymes -> hepatotoxicity ○ Impairment of glucose tolerance -> overt diabetes ○ Increases uric acid Contraindication (can exacerbate the symptoms of GI disease) ○ Gout ○ Peptic ulcer ○ Hepatotoxicity ○ Uncontrolled diabetes mellitus  Fibrates (Fibric Acid Derivatives) Agonists of peroxisome proliferator activated receptors (PPARα) ○ @ surface at the nuclear membrane PPARα: a group of nuclear receptor proteins that function as transcription factors to regulate the expression of lipoprotein lipase (LPL) leading to increased catabolism of TG in VLDL and chylomicrons- most bigger form of lipoproteins PPRE (Proliferator Response Element): a specific nucleotide sequence in the DNA that functions as a binding site for peroxisome proliferator-activated receptors (PPARs) Clofibrate & Gemfibrozil & Fenofibrate SE ○ GIT (indigestion, abdominal pain, diarrhea) ○ Myositis: can occur resulting in weakness and tenderness of muscles, use of fibrates w/ statins is generally inadvisable Contraindicated w/ combo in statins (statins already cause muscle weakness) ○ Can cause renal toxicity ○ Gallbladder Clofibrate increases cholesterol content of bile Predisposes to gallstones Limited to patients who have cholecystectomy  “good fat” (Omega 3) can lower triglycerides Lovaza: an rx of Omega 3