13 Drugs for Hyperlipidemia (Zarqa University, 2021/2022) PDF

Zarqa University Pharmacy school Clinical Pharmacy Department Pharmacology I Drugs Used in Hyperlipidemia Dr. Haneen Basheer Dr.Shorouk Ibraheem 1ST semester 2021/2022  Background Cholesterol and triglycerides, as the major plasma lipids, a...

Zarqa University Pharmacy school Clinical Pharmacy Department Pharmacology I Drugs Used in Hyperlipidemia Dr. Haneen Basheer Dr.Shorouk Ibraheem 1ST semester 2021/2022  Background Cholesterol and triglycerides, as the major plasma lipids, are essential substrates for cell membrane formation and hormone synthesis, and provide a source of free fatty acids. Cholesterol, triglycerides, and phospholipids are transported in blood as complexes of lipids and proteins (lipoproteins). Of these three, cholesterol plays the central role in the pathogenesis of atherosclerosis  cont The major clinical consequences of hyperlipidemia are acute pancreatitis (Control of triglycerides can prevent recurrent attacks of this life-threatening disease.) and atherosclerosis. Cholestrol plays the central role in the pathogenesis of atherosclerosis Atherosclerosis Leads to CHD or PAD Eventual clinical outcomes may include angina, myocardial infarction (MI), arrhythmias, stroke,, abdominal aortic aneurysm, and sudden death.  Atherosclerotic lesions Atherosclerotic lesions arise from transport and retention of plasma LDL through the endothelial cell layer into the extracellular matrix of the subendothelial space. Once in the artery wall, LDL is chemically modified through oxidation and nonenzymatic glycation. Mildly oxidized LDL recruits monocytes into the artery wall, which transform into macrophages that accelerate LDL oxidation. Oxidized LDL provokes an inflammatory response mediated by chemoattractants and cytokines  Oxidized LDL increases plasminogen inhibitor levels (promotion of coagulation), induces the expression of endothelin (vasoconstrictive substance), inhibits the expression of nitric oxide (a vasodilator and platelet inhibitor), and is toxic to macrophages if highly oxidized  Cont Risk factors such as oxidized LDL, (1) mechanical injury to endothelium, and (2) excessive homocysteine can lead to endothelial dysfunction and cellular interactions culminating in atherosclerosis. Eventual clinical outcomes may include angina, myocardial infarction (MI), arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death.  Cont Repeated injury and repair within an atherosclerotic plaque eventually lead to a fibrous cap protecting the underlying core of lipids, collagen, calcium, and inflammatory cells. Maintenance of the fibrous plaque is critical to prevent plaque rupture and coronary thrombosis An imbalance between plaque synthesis and degradation may lead to a weakened or vulnerable plaque prone to rupture.  Lipoproteins Plasma lipoproteins are spherical particles with surfaces that consist largely of phospholipid, free cholesterol, and protein and cores composed mostly of triglyceride and cholesterol ester  Apolipoproteins Each lipoprotein has various proteins called apolipoproteins (Apos) embedded on the surface that serve four main purposes: (a) Required for assembly and secretion of lipoproteins; (b) Serve as major structural components of lipoproteins; (c) Act as ligands for binding to receptors on cell surfaces; (d) Can be cofactors for inhibition of enzymes involved in the breakdown of triglycerides from chylomicrons and VLDL. Lipoprotein metabolism and transport  Cholesterol synthesis Increased intracellular cholesterol resulting from LDL catabolism inhibits the activity of 3-hydroxy-3- methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme for intracellular cholesterol biosynthesis Additional consequences of increased intracellular cholesterol include reduced synthesis of LDL receptors, which limits subsequent cholesterol uptake from the plasma, and accelerated activity of acyl coenzyme-A: cholesterol acyltransferase to facilitate cholesterol storage within cells.  HDL HDL, which transfers cholesterol to either VLDL and LDL or to the liver for secretion into bile or conversion into bile acids. Apolipoprotein A-I production is increased by estrogens, leading to higher HDL levels in women and in individuals receiving estrogen.  dyslipidemia Elevated blood levels of lipoproteins (cholesterol, triglycerides, phospholipids) - Lipoprotein abnormalities (dyslipidemia): > 1 of the following Elevated total cholesterol (TC) Elevated low-density lipoprotein (LDL) Elevated triglycerides (TG) Reduced high-density lipoprotein (HDL) ↓TC, ↓ LDL, ↑HDL reduces mortality/CHD events  Dyslipidemia – Primary (Familial) or secondary like DM – Total cholesterol (generally ≥ 240 mg/dl [6.2 mmol/L]) – Low-density lipoprotein (LDL) cholesterol (generally > 160 mg/dl [4.14 mmol/L]) – Triglyceride levels (generally > 200 mg/dl [2.3 mmol/L]) – Decreased high-density lipoprotein (HDL) cholesterol levels (generally < 40 mg/dl [1.03 mmol/L])  Pharmacology of Drugs used in Hyperlipidemia The decision to use drug therapy for hyperlipidemia is based on the specific metabolic defect & its potential for causing atherosclerosis or pancreatitis.  hypercholesterolemia dietary changes including reduced intake of saturated fats and refined carbohydrates increased physical activity (for example, 30 minutes of moderate intensity 3-7 days/week) smoking cessation statins are recommended drug of choice by major guidelines and may reduce LDL- cholesterol ≥ 50% HMG-COA REDUCTASE INHIBITORS These compounds are structural analogs of HMG- CoA (3-hydroxy-3-methylglutaryl-coenzyme A Their principal effect is the reduction of LDL. Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. It has become standard practice to initiate high dose reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels. Shown to prevent bone loss.  MOA The effect is mainly on the liver. **Also decrease triglycerides and increase HDL-C  PK Lovastatin and simvastatin are inactive lactone prodrugs that are hydrolyzed in the gastrointestinal tract to the active β-hydroxyl derivatives whereas pravastatin, atorvastatin, fluvastatin, and rosuvastatin are active as given. Absorption of the ingested doses of the reductase inhibitors varies from 40% to 75% with the exception of fluvastatin, which is almost completely absorbed. Lovastatin should be taken with morning or evening meals since its absorption increases with food. All have high first-pass extraction by the liver. Most of the absorbed dose is excreted in the bile; 5–20% is excreted in the urine. Plasma half-lives of these drugs range from 1 to 3 hours except for atorvastatin (14 hours), pitavastatin (12 hours), and rosuvastatin (19 hours). Renal impairment: atorvastatin, fluvastatin, pravastatin, or simvastatin are indicated in patients with chronic kidney disease since they do not undergo renal elimination Liver impairment: pravastatin and rosuvastatin can be used in patients with compensated liver disease since they are metabolized to a lesser extent by the liver in comparison to other statins.  Clinical use These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias. However, patients who are homozygous for familial hypercholesterolemia lack LDL receptors and, therefore, benefit much less from treatment with these drugs.  Adverse effects Mild elevations of serum aminotransferases are common but are not often associated with hepatic damage. Patients with preexisting liver diseases may suffer more An increase in creatine kinase (released from skeletal muscle) is noted in about 10% of patients; in a few, severe muscle pain and even rhabdomyolysis may occur mild transient gastrointestinal symptoms, headache, sleep disturbances, and fatigue HGMCoA reductase inhibitors are metabolized by the cytochrome P450 system; drugs or foods (eg, grapefruit juice) that inhibit cytochrome P450 activity increase the risk of hepatotoxicity and myopathy. Because of no enough evidence that the HMG-CoA reductase inhibitors are teratogenic, these drugs should be avoided in pregnancy. Use shared decision making to discuss benefits versus risks of statin therapy with patients during pregnancy.  PCSK9 inhibitors PCSK9 inhibitors refer to proprotein convertase subtilisin-kexin type 9 inhibitors: PCSK9 inhibitors alirocumab and evolocumab (only SC) Reduce low-density lipoprotein (LDL) cholesterol by preventing binding of PCSK9 to LDL receptors (LDLRs), which in turn increases the number of LDLRs and thereby increases the subsequent clearance of LDL cholesterol Consider PCSK9 inhibitor therapy in patients on maximally tolerated statin therapy (with or without ezetimibe) with persistently elevated LDL cholesterol (≥ 70 mg/dL [1.8 mmol/L]) and with any of atherosclerotic cardiovascular disease (ASCVD), at high risk to very- high risk for ASCVD, and/or with familial hypercholesterolemia S/E: nasopharyngitis, injection-site reactions, and upper respiratory tract infections