Bio 117 Module 6 PDF

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY Drugs Affecting the Blood and Antihyperlipidemic Drugs MODULE 6  Table of Contents Content Page Learning Objectiv...

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY Drugs Affecting the Blood and Antihyperlipidemic Drugs MODULE 6  Table of Contents Content Page Learning Objectives ………………………………………………………. 2 Overview ………………………………………………………………....... 3 I. Drugs Affecting the Blood............................................................... II. Antihyperlipidemic Drugs............................................................... Learning Check 3.1......................................................................... Evaluation ………………………………………………………………….. Grading Rubric.................................................................................... Reflection............................................................................................ References ……………………………………………………………….... 2 Page 1  Discussion I. DRUGS AFFECTING THE BLOOD Overview In this unit, we will describe drugs that are useful in treating three important dysfunctions of blood: thrombosis, bleeding, and anemia. Thrombosis - the formation of an unwanted clot within a blood vessel – is the most common abnormality of hemostasis. Thrombotic disorders include acute myocardial infarction, deep-vein thrombosis, pulmonary embolism, and acute ischemic stroke. These are treated with drugs such as anticoagulants and fibrinolytics. Hemostasis is the physiological process that stops bleeding at the site of an injury while maintaining normal blood flow elsewhere in the circulation. Blood loss is stopped by formation of a hemostatic plug. Bleeding disorders involving the failure of hemostasis are less common than thromboembolic diseases. These disorders include hemophilia, which is treated with transfusion of Factor VIII prepared by recombinant DNA techniques, and vitamin K deficiency, which is treated with dietary supplements of the vitamin. Anemias caused by nutritional deficiencies, such as the commonly encountered iron-deficiency anemia, can be treated with either dietary or pharmaceutical supplementation. However, individuals with anemias that have a genetic basis, such as sickle-cell disease, can benefit from additional treatment. Figure 3.17 Summary of drugs used in treating dysfunctions in the blood. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 4  Discussion I. DRUGS AFFECTING THE BLOOD Thrombus vs. Embolus  A clot that adheres to a vessel wall is called a thrombus, whereas an intravascular clot that floats in the blood is termed an embolus. Thus, a detached thrombus becomes an embolus.  Both thrombi and emboli are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients.  Arterial thrombosis most often occurs in medium-sized vessels rendered thrombogenic by surface lesions (damage) on endothelial cells caused by atherosclerosis. Arterial thrombosis usually consists of a platelet-rich clot.  Venous thrombosis is triggered by blood stasis (stagnant) or inappropriate activation of the coagulation cascade, frequently as a result of a defect in the normal hemostatic defense mechanisms. Venous thrombosis typically involves a fibrin-rich clot, with fewer platelets than are observed with arterial clots. Figure 3.18 thrombus vs embolus Source: https://solano.networkofcare.org/mh/library/article.aspx?hwid=tp12576. Figure 3.19 Arterial thrombosis vs venous thrombosis Source: https://www.researchgate.net/publication/311986292_Thrombosis_and_platelets_An_update/figures?lo=1 Page 5  Discussion I. DRUGS AFFECTING THE BLOOD Platelet Response to Vascular Injury  Physical trauma to the vascular system, such as a puncture or a cut, initiates a complex series of interactions between platelets, endothelial cells, and the coagulation cascade. This results in the formation of a platelet-fibrin plug (clot) at the site of the puncture.  The creation of an unwanted thrombus involves many of the same steps as normal clot formation, except that the triggering stimulus is a pathologic condition in the vascular system rather than an external physical trauma.  Platelets act as vascular sentries, monitoring the integrity of the endothelium. In the absence of injury, resting platelets circulate freely. Figure 3.19 Scanning electron micrographs of (A) resting and (B) temperature-activated platelets Source: https://www.researchgate.net/publication/6923881_Portable_Dyna mic_Light_Scattering_Instrument_and_Method_for_the_Measure ment_of_Blood_Platelet_Suspensions/figures?lo=1 Figure 3.20 Basic steps in hemostasis Page 6 Source: https://www.pinterest.ca/amp/pin/514606694899870062/  Discussion I. DRUGS AFFECTING THE BLOOD Figure 3.21 Coagulation cascade Page 7 Source: https://www.differencebetween.com/difference-between-hemostasis-and-vs-coagulation/  Discussion I. DRUGS AFFECTING THE BLOOD I. PLATELET AGGREGATION INHIBITORS  Platelet aggregation inhibitors decrease the formation or the action of chemical signals that promote platelet aggregation.  The most important of these is the GP IIb/IIIa receptor that ultimately regulates platelet- platelet interaction and thrombus formation.  Platelet activation agents, such as thromboxane A2, ADP, thrombin, serotonin, and collagen, all promote the conformational change necessary for the GP IIb/IIIa receptor to bind ligands, particularly fibrinogen.  Fibrinogen simultaneously binds to GP IIb/IIIa receptors on two separate platelets, resulting in platelet cross-linking and aggregation (Figure 3.22).  The platelet aggregation inhibitors inhibit cyclooxygenase-1 (COX-1) or block GP IIb/IIIa or ADP receptors, thereby interfering in the signals that promote platelet aggregation.  Therapeutic uses: prevention and treatment of occlusive cardiovascular diseases, in the maintenance of vascular grafts and arterial patency, and as adjuncts to thrombin inhibitors or thrombolytic therapy in myocardial infarction. Figure 3.22 Activation and Figure 3.23 Aspirin irreversibly inhibits platelet aggregation of platelets. cyclooxygenase-1. GP = glycoprotein. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 8  Discussion I. DRUGS AFFECTING THE BLOOD I. PLATELET AGGREGATION INHIBITORS Aspirin  inhibits thromboxane A2 synthesis from arachidonic acid in platelets by irreversible acetylation of a serine, resulting in a blockade of arachidonate to the active site and, thus, inhibition of COX-1 (Figures 3.23 & 3.24).  for prophylactic treatment of transient cerebral ischemia, to reduce the incidence of recurrent myocardial infarction, and to decrease mortality in pre- and post- myocardial infarct patients.  Adverse effect: Bleeding time is prolonged, causing complications such as increased incidence of hemorrhagic stroke and gastrointestinal bleeding, especially at higher doses. Ticlopidine and Clopidogrel  Although similar in both structure and mechanism of Figure 3.24 Acetylation of action, their therapeutic uses are different (Figure 3.25). cyclooxygenase-1 by aspirin. Source: Lippincott’s Illustrated Ticlopidine Reviews: Pharmacology. 4th ed  for the prevention of transient ischemic attacks and strokes for patients with prior cerebral thrombotic event.  used as adjunct therapy with aspirin following coronary stent implantation to decrease the incidence of stent thrombosis.  due to its life-threatening hematologic adverse reactions, it is generally reserved for patients who are intolerant to other therapies. Clopidogrel  for prevention of atherosclerotic events following recent myocardial infarction, stroke, or established peripheral arterial disease;  for prophylaxis of thrombotic events in acute coronary syndrome;  preferred agent in ischemic heart disease events. Figure 3.25 Mechanism of action of ticlopidine and clopidogrel. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 9  Discussion I. DRUGS AFFECTING THE BLOOD I. PLATELET AGGREGATION INHIBITORS Abciximab  given intravenously along with heparin or aspirin as an adjunct to percutaneous coronary intervention for the prevention of cardiac ischemic complications  Adverse effect: potential for bleeding, especially if the drug is used with anticoagulants or if the patient has a clinical hemorrhagic condition. Eptifibatide and tirofiban  act similarly to abciximab, namely, blocking the GP IIb/IIIa receptor (Figure 3.26).  Eptifibatide is a cyclic peptide that binds to GP IIb/IIIa at the site that interacts with the arginine-glycine-aspartic acid sequence of fibrinogen.  Tirofiban is not a peptide, but it blocks the same site as eptifibatide.  These compounds, like abciximab, can decrease the incidence of thrombotic complications associated with acute coronary syndromes.  Only intravenous formulations are available, because oral preparations of GP IIb/IIIa blockers are too toxic.  major adverse effect: bleeding Dipyridamole  a coronary vasodilator employed prophylactically to treat angina pectoris.  usually given in combination with aspirin or warfarin;  ineffective when used alone. Figure 3.26 Mechanism of action of glycoprotein (GP) IIb/IIIa-receptor blockers. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 10  Discussion I. DRUGS AFFECTING THE BLOOD BLOOD COAGULATION  The coagulation process that generates thrombin consists of two interrelated pathways - the extrinsic and the intrinsic systems.  The extrinsic system, which is probably the more important system in vivo, is initiated by the activation of clotting Factor VII by tissue factor, or thromboplastin.  Tissue factor is a lipoprotein that is expressed by activated endothelial cells, activated leukocytes, subendothelial fibroblasts, and subendothelial smooth muscle cells at the site of vascular injury.  The intrinsic system is triggered by the activation of clotting Factor XII, following its contact in vitro with glass or highly charged surfaces.  In vivo, this pathway may be initiated by Factor XII contact with charged cell surfaces containing phospholipids. ANTICOAGULANTS The anticoagulant drugs either (Figure 3.27):  inhibit the action of the coagulation factors (the thrombin inhibitors, such as heparin and heparin-related agents) or ;  interfere with the synthesis of the coagulation factors (the vitamin K Figure 3.27 Mechanism of action of antagonists, such as warfarin). glycoprotein (GP) IIb/IIIa-receptor blockers. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 11  Discussion I. DRUGS AFFECTING THE BLOOD II. ANTICOAGULANTS A. Thrombin inhibitors Heparin  its anticoagulant effect is a consequence of binding to antithrombin III, with the subsequent rapid inactivation of coagulation factors;  major antithrombotic drug for the treatment of acute deep-vein thrombosis and pulmonary embolism;  (and LMWHs) anticoagulants of choice for treating pregnant women with prosthetic heart valves or venous thromboembolism, because these agents do not cross the placenta (due to their large size and negative charge);  Adverse effects: bleeding complications, hypersensitivity reactions, thrombosis, thrombocytopenia Low-molecular weight heparins (LMWHs)  produced by the chemical or enzymatic depolymerization of unfractionated heparin.  they are free of some of the drawbacks associated with the polymer and are replacing the use of heparin in many clinical situations;  Include enoxaparin and dalteparin  can be conveniently injected subcutaneously on a patient;  do not require the same intense monitoring that heparin needs, subsequently saving laboratory costs as well as nursing time and costs. These advantages make LMWHs useful for inpatient and outpatient therapy. Figure 3.28 Heparin accelerates inactivation of coagulation factors by antithrombin. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 12  Discussion I. DRUGS AFFECTING THE BLOOD II. ANTICOAGULANTS B. Other parenteral anticoagulants Lepirudin  A polypetide; highly specific, direct thrombin antagonist;  produced in yeast cells by recombinant DNA technology;  One molecule of lepirudin binds to one molecule of thrombin, resulting in blockade of the thrombogenic activity of thrombin.  has little effect on platelet aggregation.  Administered intravenously, it is effective in the treatment of heparin-induced thrombocytopenia (HIT) and other thromboembolic disorders, and it can prevent further thromboembolic complications. Argatroban  a small molecule that directly inhibits thrombin;  used prophylactically for the treatment of thrombosis in patients with HIT, and it is also approved for use during percutaneous coronary interventions in patients who have or are at risk for developing HIT. Fondaparinux  the first in a new class of pentasaccharide anticoagulants that is purely synthetically, derived with no variable biologic activity;  has been recently approved by the U.S. Food and Drug Administration for use in the prophylaxis of deep-vein thrombosis that could lead to pulmonary embolism in patients undergoing hip fracture surgery, hip replacement surgery, and knee replacement surgery;  contraindicated in patients with severe renal impairment;  Adverse effect: bleeding Page 12  Discussion I. DRUGS AFFECTING THE BLOOD II. ANTICOAGULANTS C. Vitamin K antagonists Coumarin anticoagulants: warfarin  owe their action to their ability to antagonize the cofactor functions of vitamin K;  Initially used as a rodenticide, warfarin is now widely employed clinically as an oral anticoagulant;  Warfarin is used to prevent the progression or recurrence of acute deep-vein thrombosis or pulmonary embolism after initial heparin treatment;  also used for the prevention of venous thromboembolism during orthopaedic or gynecologic surgery;  Prophylactically, it is used in patients with acute myocardial infarction, prosthetic heart valves, or chronic atrial fibrillation;  The potential morbidity associated with the use of warfarin makes it important to identify those patients who are truly at risk for thrombosis  Adverse effect: bleeding disorders (hemorrhage)  Contraindication: Warfarin should never be used during pregnancy, because it is teratogenic and can cause abortion as well as birth defects. Page 13  Discussion I. DRUGS AFFECTING THE BLOOD III. THROMBOLYTIC DRUGS  Acute thromboembolic disease in selected patients may be treated by the administration of agents that activate the conversion of plasminogen to plasmin - a serine protease that hydrolyzes fibrin and, thus, dissolves clots (Figure 3.27).  Unfortunately, thrombolytic therapy is unsuccessful in about 20% of infarcted arteries, and about 15% of the arteries that are opened will later close again.  In the case of acute myocardial infarction, the thrombolytic drugs are reserved for those instances when angioplasty is not an option or until the patient can be taken to a facility that performs percutaneous coronary interventions.  Fibrinolytic drugs may lyse both normal and pathologic thrombi.  Adverse effect: do not distinguish between the fibrin of an unwanted thrombus and the fibrin of a beneficial hemostatic plug, thus, hemorrhage is a major side effect;  Contraindications: contraindicated in patients with healing wounds, pregnancy, history of cerebrovascular accident, or metastatic cancer. Alteplase  formerly known as tissue plasminogen activator, or tPA)  a serine protease originally derived from cultured human melanoma cells;  now obtained as a product of recombinant DNA technology  for the treatment of myocardial infarction, massive pulmonary embolism, and acute ischemic stroke;  Adverse effects: Bleeding complications, including gastrointestinal and cerebral Figure 3.29 Activation of plasminogen by hemorrhages, may occur. fibrinolytic agents. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Streptokinase  an extracellular protein purified from culture broths of Group C β-hemolytic streptococci.  used in acute pulmonary embolism, deep-vein thrombosis, acute myocardial infarction, arterial thrombosis, and occluded access shunts;  Adverse effects: bleeding disorders ; hypersensitivity reactions – rashes, fever, and rarely, anaphylaxis Page 14  Discussion I. DRUGS AFFECTING THE BLOOD IV. DRUGS USED TO TREAT BLEEDING  Bleeding problems may have their origin in naturally occurring pathologic conditions, such as hemophilia, or as a result of fibrinolytic states that may arise after gastrointestinal surgery or prostatectomy.  The use of anticoagulants may also give rise to hemorrhage.  Certain natural proteins and vitamin K, as well as synthetic antagonists, are effective in controlling this bleeding.  For example, hemophilia is a consequence of a deficiency in plasma coagulation factors, most frequently Factors VIII and IX. Concentrated preparations of these factors are available from human donors. However, these preparations carry the risk of transferring viral infections.  Blood transfusion is also an option for treating severe hemorrhage. A. Aminocaproic acid and tranexamic acid  Can control fibrinolytic states  Both agents are synthetic, inhibit plasminogen activation, are orally active, and are excreted in the urine.  potential side effect: intravascular thrombosis. B. Protamine sulfate  antagonizes the anticoagulant effects of heparin.  This protein is derived from fish sperm or testes and is high in arginine content;  Adverse effects: hypersensitivity as well as dyspnea, flushing, bradycardia, and hypotension when rapidly injected. C. Vitamin K (phytonadione)  The response to vitamin K is slow, requiring about 24 hours (time to synthesize new coagulation factors). Thus, if immediate hemostasis is required, fresh-frozen plasma should be infused. D. Aprotinin  a serine protease inhibitor that stops bleeding by blocking plasmin.  It can inhibit streptokinase.  It is approved for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass surgery.  Adverse effect: renal dysfunction and hypersensitivity (anaphylactic) reactions. Page 15  Discussion I. DRUGS AFFECTING THE BLOOD IV. AGENTS USED TO TREAT ANEMIA Anemia  defined as a below-normal plasma hemoglobin concentration resulting from a decreased number of circulating red blood cells or an abnormally low total hemoglobin content per unit of blood volume.  can be caused by chronic blood loss, bone marrow abnormalities, increased hemolysis, infections, malignancy, endocrine deficiencies, renal failure, and a number of other disease states.  can be at least temporarily corrected by transfusion of whole blood.  A large number of drugs cause toxic effects on blood cells, hemoglobin production, or erythropoietic organs, which in turn may cause anemia;  Nutritional anemias are caused by dietary deficiencies of substances such as iron, folic acid, or vitamin B12 (cyanocobalamin) that are necessary for normal erythropoiesis. A. Iron  Iron is stored in intestinal mucosal cells as ferritin (an iron-protein complex) until needed by the body.  Iron deficiency results from acute or chronic blood loss, from insufficient intake during periods of accelerated growth in children, or in heavily menstruating or pregnant women.  Iron deficiency results from a negative iron balance due to depletion of iron stores and/or inadequate intake, culminating in hypochromic microcytic anemia (due to low iron and small-sized red blood cells).  Supplementation with ferrous sulfate is required to correct the deficiency.  Adverse effects of iron supplements: gastrointestinal disturbances caused by local irritation. Figure 3.30 Symptoms of iron-deficiency anemia. Source: https://healthscopemag.com/health-scope/iron- deficiency-anemia/ Page 16  Discussion I. DRUGS AFFECTING THE BLOOD IV. AGENTS USED TO TREAT ANEMIA B. Folic acid  its primary use is in treating deficiency states that arise from inadequate levels of the vitamin.  Folate deficiency may be caused by: 1) increased demand (for example, pregnancy and lactation), 2) poor absorption caused by pathology of the small intestine, 3) alcoholism, or 4) treatment with drugs that are dihydrofolate reductase inhibitors (for example, methotrexate or trimethoprim).  A primary result of folic acid deficiency is megaloblastic anemia (large-sized red blood cells), which is caused by diminished synthesis of purines and pyrimidines.  This leads to an inability of erythropoietic tissue to make DNA and, thereby, proliferate (Figure 3.29).  Folic acid is well absorbed in the jejunum unless pathology is present. If excessive amounts of the vitamin are ingested, they are excreted in the urine and feces.  Oral folic acid administered has no known toxicity. Figure 3.31 Causes and consequences of folic acid depletion. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 17  Discussion I. DRUGS AFFECTING THE BLOOD IV. AGENTS USED TO TREAT ANEMIA C. Cyanocobalamin (vitamin B12)  Deficiencies of vitamin B12 can result from either low dietary levels or, more commonly, poor absorption of the vitamin due to the failure of gastric parietal cells to produce intrinsic factor (as in pernicious anemia) or a loss of activity of the receptor needed for intestinal uptake of the vitamin.  Intrinsic factor is a GP produced by the parietal cells of the stomach and it is required for vitamin B12 absorption.  In patients with bariatric surgery (surgical gastrointestinal treatment for obesity), vitamin B12 supplementation is required in large oral doses, sublingually or once a month by the parenteral route.  The vitamin may be administered orally (for dietary deficiencies), intramuscularly, or deep subcutaneously (for pernicious anemia).  Folic acid administration alone reverses the hematologic abnormality and, thus, masks the B12 deficiency, which can then proceed to severe neurologic dysfunction and disease. Therefore, megaloblastic anemia should not be treated with folic acid alone but, rather, with a combination of folate and vitamin B12.  Therapy must be continued for the remainder of the life of a patient suffering from pernicious anemia.  There are no known adverse effects of this vitamin. D. Erythropoietin and darbepoetin  Erythropoietin is a GP normally made by the kidney, that regulates red blood cell proliferation and differentiation in bone marrow.  Human erythropoietin, produced by recombinant DNA technology, is effective in the treatment of anemia caused by end-stage renal disease, anemia associated with HIV infection, and anemia in some cancer patients.  Darbepoetin is a long-acting version of erythropoietin that differs from erythropoietin by the addition of two carbohydrate chains, which improves its biologic activity. Due to its delayed onset of action, darbepoetin has no value in acute treatment of anemia. Supplementation with iron may be required to assure an adequate response.  The protein is usually administered intravenously in renal dialysis patients, but the subcutaneous route is preferred.  Side effects are generally well tolerated but may include elevation in blood pressure and arthralgia in some cases. Page 18  Discussion I. DRUGS AFFECTING THE BLOOD V. AGENTS USED TO TREAT SICKLE-CELL ANEMIA Hydroxyurea  Clinical trials have shown that hydroxyurea can relieve the painful clinical course of sickle-cell disease  Hydroxyurea is currently also being used to treat chronic myelogenous leukemia and polycythemia vera.  In sickle-cell disease, the drug apparently increases fetal hemoglobin levels, thus diluting the abnormal hemoglobin S (HbS). This process takes several months.  Polymerization of HbS is delayed in the treated patients so that painful crises are not caused by sickled cells blocking capillaries and causing tissue anoxia.  side effects: bone marrow suppression and cutaneous vasculitis.  It is important that hydroxyurea is administered under the supervision of a physician experienced in the treatment of sickle-cell disease. Figure 3.32 Sickle-cell anemia. Page 19 Source: https://medlineplus.gov/genetics/condition/sickle-cell-disease/  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Overview  The incidence of coronary heart disease (CHD) is correlated with elevated levels of low-density lipoprotein (LDL) cholesterol and triacylglycerols and with low levels of high-density lipoprotein (HDL) cholesterol.  Other risk factors for CHD: cigarette smoking, hypertension, obesity, and diabetes.  Cholesterol levels may be elevated as a result of an individual's lifestyle (for example, by lack of exercise and consumption of a diet containing excess saturated fatty acids).  Hyperlipidemias can also result from a single inherited gene defect in lipoprotein metabolism or, more commonly, from a combination of genetic and lifestyle factors.  Appropriate lifestyle changes in combination with drug therapy can lead to a reduction in mortality due to CHD by 30% to 40%.  Antihyperlipidemic drugs must be taken indefinitely; when therapy is terminated, plasma lipid levels return to pretreatment levels.  The lipid-lowering drugs are listed in Figure 3.33.  Figure 3.34 illustrates the normal metabolism of serum lipoproteins and the characteristics of the major genetic hyperlipidemias.  Clinically important lipoproteins, in decreasing order of Figure 3.33 Summary of atherogenicity: LDL, very-low-density lipoprotein antihyperlipidemic drugs. (VLDL) and chylomicrons, and HDL. HMG CoA = 3-hydroxy-3-  The occurrence of CHD is positively associated with high methylglutaryl coenzyme A. total cholesterol, and even more strongly with elevated LDL cholesterol in the blood. Source: Lippincott’s Illustrated  In contrast, high levels of HDL cholesterol have been Reviews: Pharmacology. 4th ed associated with a decreased risk for heart disease.  Primary goal of cholesterol-lowering therapy: reduction of the LDL level Page 20  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Treatment Goals A. Treatment options for hypercholesterolemia  In patients with moderate hyperlipidemia, lifestyle changes, such as diet, exercise, and weight reduction, can lead to modest decreases in LDL levels and increases in HDL levels.  However, most patients are unwilling to modify their lifestyle sufficiently to achieve LDL treatment goals (Figure 3.34), and drug therapy may be required.  Patients with LDL levels higher than 160 mg/dL and with one other major risk factor, such as hypertension, diabetes, smoking, or a family history of early CHD, are candidates for drug therapy.  Patients with two or more additional risk factors should be treated aggressively, with the aim of reducing their LDL level to less than 100 mg/dL and, in some patients, to as low as 70 mg/dL. B. Treatment options for hypertriacylglycerolemia  Elevated triacylglycerol (triglyceride) levels are independently associated with increased risk of CHD.  Diet and exercise are the primary modes of treating hypertriacylglycerolemia.  If indicated, niacin and fibric acid derivatives are the most efficacious in lowering triacylglycerol levels.  Triacylglycerol reduction is a secondary benefit of the statin drugs (the primary benefit being LDL cholesterol reduction).  The major lipid component of VLDL is composed of triacylglycerol. Figure 3.34 Goal lipoprotein levels achieved with dietary or drug therapy for the prevention of coronary heart disease. Page 21 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Figure 3.35 illustrates the normal metabolism of serum lipoproteins. Figure 3.35 Metabolism of plasma lipoproteins and related genetic diseases. Roman numerals in the white circles refer to specific genetic types of hyperlipidemias. CM = chylomicron, TG = triacylglycerol; VLDL = very-low density lipoprotein, LDL = low-density lipoprotein, IDL = intermediate density lipoprotein, apo CII = apolipoprotein CII found in chylomicrons and VLDL. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 22  xanthomas Discussion II. ANTIHYPERLIPIDEMIC DRUGS Figure 3.36 illustrates the characteristics of the major genetic hyperlipidemias. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 23  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Drugs that Lower the Serum Lipoprotein Concentration Antihyperlipidemic drugs:  decrease production of the lipoprotein carriers of cholesterol and triglyceride;  increase the degradation of lipoprotein;  decrease cholesterol absorption; or  directly increase cholesterol removal from the body;  may be used singly or in combination;  always accompanied by the requirement that dietary saturated and trans fats be low, and the caloric content of the diet must be closely monitored. A. HMG CoA reductase inhibitors  3-Hydroxy-3-methylglutaryl (HMG) coenzyme A (COA) reductase inhibitors (commonly known as statins) lower elevated LDL cholesterol levels, resulting in a substantial reduction in coronary events and death from CHD.  Mechanism of action: inhibits the first committed enzymatic step of cholesterol synthesis, and they are the first-line and more effective treatment for patients with elevated LDL cholesterol.  Therapeutic benefits: plaque stabilization, improvement of coronary endothelial function, inhibition of platelet thrombus formation, and anti-inflammatory activity. Figure 3.37 Inhibition of HMG CoA reductase by the statin drugs. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 24  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Drugs that Lower the Serum Lipoprotein Concentration A. HMG CoA reductase inhibitors  Lovastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, and rosuvastatin are analogs of HMG, the precursor of cholesterol.  Because of their strong affinity for the enzyme, all compete effectively to inhibit HMG CoA reductase, the rate-limiting step in cholesterol synthesis.  By inhibiting de novo cholesterol synthesis, they deplete the intracellular supply of cholesterol (Figure 3.38).  Rosuvastatin and atorvastatin are the most potent LDL cholesterol-lowering statin drugs, followed by simvastatin, pravastatin and then lovastatin and fluvastatin.  Adverse effects: liver failure, myopathy and rhabdomyolysis (disintegration or dissolution of muscle);  Contraindications: contraindicated during pregnancy and in nursing mothers; should  not be used in children or teenagers. B. Niacin (nicotinic acid)  can reduce LDL (the “bad” cholesterol carrier) levels by 10% to 20%;  the most effective agent for increasing HDL (the “good” cholesterol carrier) levels;  can be used in combination with statins; a fixed-dose combination of lovastatin and long-acting niacin is available.  Mechanism of action: Niacin strongly inhibits lipolysis in adipose tissue - the primary producer of circulating free fatty acids.  The liver normally utilizes these circulating fatty acids as a major precursor for triacylglycerol synthesis. Thus, niacin causes a decrease in liver triacylglycerol synthesis, which is required for VLDL production (Figure 21.9). Figure 3.38 Niacin inhibits lipolysis in adipose tissue, resulting in decreased hepatic VLDL synthesis and production of LDLs in the plasma. Page 25 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Drugs that Lower the Serum Lipoprotein Concentration B. Niacin (nicotinic acid)  Therapeutic uses: Niacin lowers plasma levels of both cholesterol and triacylglycerol. It is particularly useful in the treatment of familial hyperlipidemias. It is also used to treat other severe hypercholesterolemias, often in combination with other antihyperlipidemic agents. In addition, it is the most potent antihyperlipidemic agent for raising plasma HDL levels, which is the most common indication for its clinical use.  Adverse effects: intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) and pruritus; nausea and abdominal pain; hyperuricemia and gout; impaired glucose tolerance and hepatotoxicity have also been reported. C. The fibrates: Fenofibrate and gemfibrozil  derivatives of fibric acid that lower serum triacylglycerols and increase HDL levels.  Both have the same mechanism of action but fenofibrate is more effective than gemfibrozil in lowering plasma LDL cholesterol and triglyceride levels.  Therapeutic uses: treatment of hypertriacylglycerolemias, causing a significant decrease in plasma triacylglycerol levels. These are particularly useful in treating Type III hyperlipidemia (dysbetalipoproteinemia), in which IDL particles accumulate. Patients with hypertriacylglycerolemia [Type IV (elevated VLDL) or Type V (elevated VLDL plus chylomicron) disease] who do not respond to diet or other drugs may also benefit from treatment with these agents.  Adverse effects: mild gastrointestinal disturbances; formation of gallstones (lithiasis); myositis (inflammation of a voluntary muscle); myopathy and rhabdomyolysis;  Contraindications: should not be used in patients with severe hepatic and renal dysfunction or in patients with preexisting gallbladder disease. Page 26  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Drugs that Lower the Serum Lipoprotein Concentration D. Bile acid-binding proteins  Bile acid sequestrants (resins) have significant LDL cholesterol-lowering effects, although the benefits are less than those observed with statins.  Mechanism of action: Cholestyramine, colestipol, and colesevelam are anion- exchange resins that bind negatively charged bile acids and bile salts in the small intestine (Figure 3.39). The resin/bile acid complex is excreted in the feces. Lowering the bile acid concentration causes hepatocytes to increase conversion of cholesterol to bile acids, which are essential components of the bile. Consequently, the intracellular cholesterol concentration decreases, leading to a fall in plasma LDL.  Therapeutic uses: drugs of choice (often in combination with diet or niacin) in treating Type IIa and Type IIb hyperlipidemias.  Adverse effects: gastrointestinal disturbances, such as constipation, nausea, and flatulence. Colesevelam has fewer gastrointestinal side effects than other bile acid sequestrants. At high doses, cholestyramine and colestipol (but not colesevelam) impair the absorption of the fat-soluble vitamins (A, D, E, and K). Figure 3.39 Mechanism of bile acid-binding resin. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 27  Discussion II. ANTIHYPERLIPIDEMIC DRUGS Drugs that Lower the Serum Lipoprotein Concentration E. Cholesterol absorption inhibitor (Ezetimibe)  Ezetimibe selectively inhibits intestinal absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood.  Ezetimibe lowers LDL cholesterol by 17% and triacylglycerols by 6%, and it increases HDL cholesterol by 1.3%.  Contraindication: Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe.  A formulation of ezetimibe and simvastatin has been shown to lower LDL levels more effectively than the statin alone. Figure 3.40 Characteristics of antihyperlipidemic drug families. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 28  References Textbooks  Brunton L, Hilal-Dandan R, Knollman BC. 2018. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill-Education, United States of America.  Katzung, Bertram G. 2018. Basic and Clinical Pharmacology. 14th ed. McGraw Hill- Education, United States of America YouTube links  Hemostasis: Control of Bleeding, Coagulation and Thrombosis, Animation at https://www.youtube.com/watch?v=x8TLTTyyPfI  Platelet Activation and Factors for Clot Formation at https://www.youtube.com/watch?v=R8JMfbYW2p4  Coagulation Cascade Animation - Physiology of Hemostasis at https://www.youtube.com/watch?v=cy3a__OOa2M  Platelet Adhesion and Aggregation at https://www.youtube.com/watch?v=0pnpoEy0eYE  How deep vein thrombosis (DVT) forms at https://www.youtube.com/watch?v=0QEo9QAqA3k  DVT and Pulmonary Embolism at https://www.youtube.com/watch?v=uS1RGbW8UbQ  Myocardial Infarction and Coronary Angioplasty Treatment at https://www.youtube.com/watch?v=mLmKq5bQOg0  Understanding and Diagnosing Venous Thromboembolism (VTE) at 29 https://www.youtube.com/watch?v=pHddAMauvFk&t=5s  ANTICOAGULANTS & ANTIPLATELET DRUGS (MADE EASY) at https://www.youtube.com/watch?v=eZBtQ0rDnG4  Hemophilia - causes, symptoms, diagnosis, treatment, pathology at https://www.youtube.com/watch?v=nkC1vZaUpxs  Red Blood Cell Life Cycle and Disorders at https://www.youtube.com/watch?v=W9kGIaGG5Lc  What is Blood? And What are Blood Disorders? At https://www.youtube.com/watch?v=06gtqiIWd0I Page 34  References YouTube links  Vitamin K and blood clotting at https://www.youtube.com/watch?v=eI8kZIqa-VU  Hematology | Types of Anemias at https://www.youtube.com/watch?v=mOrRJBqm744  The Role of Red Blood Cells in Anemia at https://www.youtube.com/watch?v=_ZV5140OykE  Sickle Cell Disease at https://www.youtube.com/watch?v=mky_YWAp4UA  Sickle cell anemia - causes, symptoms, diagnosis, treatment & pathology at https://www.youtube.com/watch?v=fIIJmg_1hv0  Cholesterol Metabolism, LDL, HDL and other Lipoproteins at https://www.youtube.com/watch?v=9dghtf7Z7fw  Hyperlipidemia (High Cholesterol) at https://www.youtube.com/watch?v=-8-3G8voUHs  DRUGS FOR HYPERLIPIDEMIA (MADE EASY) at https://www.youtube.com/watch?v=Of1Aewx-zRM  Statins Mechanism Of Action at https://www.youtube.com/watch?v=GGujNNt_q9Q  Statins, Fibrates, Niacin, etc. - Easy Pharm at https://www.youtube.com/watch?v=fTA5HOa87pM  Kidney Homeostatic Functions at https://www.youtube.com/watch?v=iKusxCtH62c  Nephron Structure and functions at https://www.youtube.com/watch?v=QsSdAXv5BEM  10 Signs Your Kidneys Are Crying for Help at https://www.youtube.com/watch?v=6_NknP0zVVA  Kidney animations at https://www.youtube.com/watch?v=O_PwXsy0Bdc  8 Foods that Are Actually Damaging Your Kidneys at https://www.youtube.com/watch?v=tKoUcEcz1dM  Early Warning Signs of Kidney Problems at https://www.youtube.com/watch?v=Uf0- 2HBxL2s 30  Glomerular Filtration at https://www.youtube.com/watch?v=j9qZwRooBXc  Chronic Kidney Disease at https://www.youtube.com/watch?v=G3_iuZTgKoQ  Kidney Function Tests at https://www.youtube.com/watch?v=zVXY7xLwNJQ  Formation of Urine - Nephron Function at https://www.youtube.com/watch?v=9_h0ZXx1lFw  Diuretics - Mechanism of Action of Different Classes of Diuretics at https://www.youtube.com/watch?v=NyS2wjR7ezA  Diuretics - Part 1 - Osmotic Diuretics & Carbonic Anhydrase Inhibitors at https://www.youtube.com/watch?v=zLqO0z0CbyY  Diuretics - Part 2 - Loops, Thiazides, K+ Sparing, and ADH antagonists at https://www.youtube.com/watch?v=irUFh-lWfvw Page 6