Applied Therapeutics I Lec. 4 PDF

Fifth stage First semester Applied Therapeutics I Lec. 4 Kirkuk University College of Pharmacy  Introduction: Dyslipidemia is defined as elevated total cholesterol, lowdensity lipoprotein (LDL) cholesterol, or triglycerides; a low high-density lipoprotein (HDL) cho...

Fifth stage First semester Applied Therapeutics I Lec. 4 Kirkuk University College of Pharmacy  Introduction: Dyslipidemia is defined as elevated total cholesterol, lowdensity lipoprotein (LDL) cholesterol, or triglycerides; a low high-density lipoprotein (HDL) cholesterol; or a combination of these abnormalities. Abnormalities of plasma lipids can result in a predisposition to coronary, cerebrovascular, and peripheral vascular arterial disease. Lipid Transport And Lipoprotein Metabolism: Cholesterol is an essential substance manufactured by most cells in the body. Cholesterol is used to maintain cell wall integrity and for the biosynthesis of bile acids and steroid hormones. Other major lipids in our body are triglycerides and phospholipids. Cholesterol, triglycerides, and phospholipids are transported in the bloodstream as complexes of lipids and proteins known as lipoproteins (large carrier proteins) because they are not readily soluble in serum and are rendered miscible by incorporation into lipoproteins Page 2 of 10 Page 3 of 10 TREATMENT: - ACC/AHA, NLA, and AACE/ACE guidelines emphasize that lifestyle therapies are an important element of risk reduction efforts in ASCVD prevention, whether or not pharmacotherapy is also used. - Begin therapeutic lifestyle changes (TLCs) on the first visit, including dietary therapy (decrease intake of total fat ≤ 30% of total energy intake (TEI), saturated fat ≤ 10% TEI, Trans fat ≤ 0.5% TEI and cholesterol ≤ 300mg/day while increase fiber intake and fish oil, also consume large amount of fruit and vegetables as a natural antioxidants , weight reduction, and increased physical activity. Advise overweight patients to lose 10% of body weight. Page 4 of 10 - Assist patients with smoking cessation and control of hypertension. If all recommended dietary changes were instituted, the estimated average reduction in LDL would range from 20% to 30%. - Exercise decrease TG and increase HDLc. - Diet modification should always be encouraged in a patient with dyslipidaemia but is rarely successful alone in bringing about a significant improvement in the lipid profile. - Therapeutic lifestyle changes and exercise should be considered in all patients; additional therapeutic interventions should not be delayed in high-risk patients - It is usually advised to start with dietary and life style modification for 3 – 6 months in patients who are in need for primary prevention, start pharmacological therapy if the goal is not reached. Page 5 of 10  INTENSITIES OF STATINS: STATINS: Statins are well tolerated, with less than 4% of patients in clinical trials discontinuing therapy due to adverse side effects. Elevations in liver function tests (LFTs) and myopathy, including rhabdomyolysis, are important adverse effects associated with statins. Liver toxicity, defined as LFT elevations greater than three times the upper limit of normal, is reported in less than 2% of patients. LFTs should be obtained at baseline and as clinically indicated thereafter. Myopathy, defined as muscle weakness not necessarily associated with creatine kinase (CK) elevations, is reported to range from 0% to less than 0.5% for the currently marketed statins at approved doses. Page 6 of 10 Rhabdomyolysis, defined as muscle symptoms with marked elevation in CK at 50 times the upper limit of normal and creatinine elevation usually associated with myoglobinuria and brown urine, is very rare. Rhabdomyolysis Risk factors: - Small body frame and frailty. - Multisystem disease (eg, chronic kidney disease, especially due to DM). - Perioperative periods. - 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, macrolide antibiotics, protease inhibitors, nefazodone, verapamil, amiodarone, large quantities of grapefruit juice (usually > 1 quart [about 950 mL] per day), and alcohol abuse (independently predisposes to myopathy) CHOLESTEROL ABSORPTION INHIBITORS: Ezetimibe reduces LDL cholesterol by an average of 18%. However, larger reductions can be seen in some individuals, presumably due to higher absorption of cholesterol. These individuals appear to have a blunted response to statin therapy. Ezetimibe lowers triglycerides by 7% to 9% and modestly increases HDL cholesterol. Most recently, ezetimibe combined with simvastatin was shown to further reduce ASCVD events in patients who have suffered a recent myocardial infarction (MI) compared to simvastatin alone. Ezetimibe is primarily used in combination with a statin when adequate reductions in atherogenic cholesterol is not achieved or in those patients who are intolerant to statin therapy. The time until maximum effect on lipids for ezetimibe is generally 2 weeks. BILE ACID SEQUESTRANTS: Resins [cholestyramine, colestipol, and colesevelam] are moderately effective in lowering LDL cholesterol but do not lower triglycerides. Moreover, in patients with elevated triglycerides, the use of a resin may increase triglyceride. Resins are highly charged molecules that bind to bile acids in the gut. The resin–bile acid complex is then excreted in the feces. The loss of bile causes a compensatory conversion of hepatic cholesterol to bile, reducing hepatocellular stores of cholesterol and resulting in an upregulation of LDL receptors which then results in a decrease in serum cholesterol. Page 7 of 10 Fluid intake should be increased to minimize constipation. Colesevelam is better tolerated with fewer GI side effects, although it is more expensive. Colesevelam also has an indication for improvement of glycemic control in type 2 DM. All resins have the potential to prevent absorption of other drugs such as digoxin, warfarin, thyroxine, thiazides, β-blockers, fat-soluble vitamins, and folic acid. Potential drug interactions can be avoided by taking a resin either 1 hour before or 4 hours after these other agents. The time until maximum effect on lipids for resins is generally 2 to 4 weeks. Patients should be instructed to prepare the powder formulations in 6 to 8 ounces (~180–240 mL) of noncarbonated fluids, usually juice (enhances palatability) or water. PROPROTEIN CONVERTASE SUBTILIS IN / KEXIN TYPE 9 ( PCSK9 ) INHIBITORS: Alirocumab and evolocumab are subcutaneous injectable human monoclonal antibodies that bind to PCSK9. PCSK9 binds to the LDL receptors on hepatocyte surfaces to promote low-density lipoprotein receptor (LDLR) degradation. LDLR is the primary receptor that clears circulating LDL; therefore, the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL. By inhibiting the binding of PCSK9 to LDLR, these agents increase the number of LDLRs available to clear LDL, thereby lowering LDL levels. In clinical trials, these agents have produced an additional 48% to 71% decrease in LDL levels when used in combination with statin therapy, compared with statin monotherapy Page 8 of 10  NIACIN: Niacin (vitamin B3 ) has broad applications in the treatment of lipid disorders when used at doses higher than those used as a nutritional supplements. In general, niacin reduces LDL cholesterol from 5% to 25%, reduces triglycerides by 11% to 60%, and increases HDL cholesterol by 14% to 39%. Niacin monotherapy has been shown to reduce CHD events and total mortality, as well as the progression of atherosclerosis when combined with a statins. Several different niacin formulations are available: immediate release (IR), sustained- release (SR), and extended-release (ER). These formulations differ in terms of dissolution and absorption rates, metabolism, efficacy, and side effects. Limitations of niacin IR and SR are flushing and hepatotoxicity, respectively. Niacin ER (Niaspan) was developed as a once-daily formulation to be taken at bedtime, with the goal of reducing the incidence of flushing without increasing the risk of hepatotoxicity. Niaspan is the only long-acting niacin product approved by the FDA for dyslipidemia. Niacin should be instituted at the lowest dose and gradually titrated to a maximum dose of 2 g daily for ER and SR products and no more than 6 g daily for IR products. FDA-approved niacin products are preferred because of product consistency. Moreover, niacin products labeled as “no flush” do not contain nicotinic acid and therefore have no therapeutic role in the treatment of lipid disorders. The time until maximum effect on lipids for niacins is generally 3 to 5 weeks. FIBRATES: Fibrates are the most effective triglyceride lowering drugs and are used primarily in patients with elevated triglycerides and low HDL cholesterol. The predominant effects of fibrates are a decrease in triglyceride levels by 20% to 60% and an increase in HDL cholesterol levels by 9% to 30%. If a fibrate is used with a statin, fenofibrate is preferred because it appears to inhibit the glucuronidation of the statins less than gemfibrozil. A CK level should be checked before therapy is started and if symptoms occur. Liver dysfunction has been reported, and LFTs should be monitored. Fibrates increase cholesterol in the bile and have caused gallbladder and bile duct disorders, such as cholelithiasis and cholecystitis. Unlike niacin, these agents do not increase glucose or uric acid levels. Fibrates are contraindicated in patients with gallbladder disease, liver dysfunction, or severe kidney dysfunction. The risk of bleeding is increased in patients taking both a fibrate and warfarin, specifically with gemfibrozil based on a CYP 2C9 interaction which can result in an increase in a patient’s international normalized ratio (INR) if adding gemfibrozil to warfarin therapy. Page 9 of 10 Increased INR monitoring is suggested after initiation of gemfibrozil in patients currently taking warfarin. The time until maximum effect on lipids is generally 2 weeks for fenofibrate and 3 to 4 weeks for gemfibrozil. LONG - CHAINOMEGA - 3 FATTY ACIDS ( OM3FA ): M3FA (eicosapentaenoic acid and docosahexaenoic acid), the predominant long- chain FA in the oil of cold-water fish, lower triglycerides by as much as 45%. Long-chain OM3FA may be useful for patients with high triglycerides despite diet and weight loss, alcohol restriction, and fibrate therapy. Long-chain OM3FA have other cardiac effects such as reduced platelet aggregation and antiarrhythmic properties. Patients taking anticoagulant or antiplatelet agents should be monitored more closely when consuming these products because excessive amounts of long-chain OM3FA (eg, > 3 g daily) may lead to bleeding and may increase risk of hemorrhagic stroke. Page 10 of 10