Exam (elaborations) NR 566 (NR566WEEK 5 REVIEW.) (NR 566 (NR566WEEK 5 REVIEW.)) Drugs Affecting the Hematopoietic System NR 566 WEEK 5 REVIEW / NR 566 WEEK 5 REVIEW _ Latest Summer 2020/2021 (complete)

Chapter 18: Drugs Affecting the Hematopoietic System I. Anticoagulants (oral & parenteral) Oral Anticoagulants  Warfarin (Coumadin): Inhibits synthesis of vitamin K-dependent clotting factors X, IX, VII, and II (prothrombin)  Pharmacokinetics  Well-absorbed when taken orally  Metabolized by CYP 1A2 and 2C9  Half-life of 3 to 4 days  Precautions and contraindications  Pregnancy category X  Use cautiously in patients with fall risk, dementia, or uncontrolled hypertension.  Avoid in hypermetabolic state.  Adverse drug reactions  Bleeding (Antidote is vitamin K)  Drug interactions: Many  Antiplatelet drugs  Thrombolytic drugs  Anticoagulant effect may be decreased by Oral contraceptives, carbamazepine, Vitamin K-containing foods, etc.  Clinical use and dosing  Drug of choice for deep vein thrombosis (DVT) and pulmonary embolism (PE)  Start at 5 mg per day (7.5 mg/d if weight greater than 80 kg).  Consider lower dose if  Older than 75 years  Multiple comorbid conditions  Elevated liver enzymes  Changing thyroid status  Dose to maintain international normalized ratio (INR) between 2 and 3.  Monitoring  INR daily until in therapeutic range for 2 consecutive days  Then two or three times weekly for 1 to 2 weeks  Then less frequently but at least every 6 weeks  Rivaroxaban (Xarelto): Factor Xa inhibitor  Apixaban (Eliquis): Factor Xa inhibitor  Reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation  Prophylaxis of DVT following knee replacement surgery  Treatment of DVT and PE Parenteral Anticoagulants  Heparin  Binds with the antithrombin III  Inactivates factors IXa, Xa, XIIa, XIII  Pharmacokinetics  Given IV or subcutaneously (SC)  Extensively protein-bound  Metabolized by liver and renally eliminated  Precautions and contraindications  Pregnancy category C  Avoid in advanced hepatic or renal disease.  Avoid in bleeding disorders or active bleeding.  Adverse drug reactions (ADRs)  May cause thrombocytopenia  Life-threatening bleeding  Pain at injection site (SC)  Antidote is protamine sulfate  Drug interactions  Cephalosporins and penicillins; Warfarin, antiplatelets and thrombolytics; Valproic acid  Clinical use and dosing  Given 2 hours pre-operatively  Maintenance every 8 to 12 hours for 7 days after surgery  Heparin is processed into smaller molecules  low molecular-weight heparins (LMWH)  Inactivates factor Xa  Enoxaparin  DVT or PE  Given 2 hours before surgery  Fondaparinux - Selective inhibitor of antithrombin III and factor Xa inhibitor  DVT  Hip fracture surgery or knee replacement  Dalteparin  Prevention of DVT after abdominal surgery or hip replacement  Monitoring for Anticoagulants  Activated partial thromboplastin time  Platelet and hematocrit (Hct) every 2 to 3 days initially  Patient Education for Anticoagulants  Administration  Warfarin dosing may vary day to day.  SC administration instruction for LMWH at home  ADRs for Anticoagulants  Risk for bleeding  Vitamin K-containing foods II. Antiplatelet Drugs  Aspirin: Inhibits cyclooxygenase & interferes with platelet aggregation  Well-absorbed when taken orally  Metabolized in liver  Renally excreted (pH affects excretion)  Aspirin Hypersensitivity -- Cross-sensitivity with NSAIDs  Pregnancy category C (D in third trimester)  Can cause Reye syndrome in children  ADR: Bleeding; May cause gastrointestinal (GI) bleeding; Salicylism (tinnitus)  Drug interactions: Concurrent use of other antiplatelet, anticoagulant, or fibrinolytic drugs  Aspirin: Herbals (ginko, garlic, ginseng), NSAIDs  Clinical use and dosing for aspirin:  Myocardial infarction (MI) prevention: 75 to 162 mg daily  Persistent atrial fibrillation: 75 to 325 mg daily  Stroke or transient ischemic attacks: 50 to 100 mg daily  Patient Education for administration:  Take aspirin with a full glass of water.  Aspirin must be stopped 7 days before surgery.  Ticlodipine & clopidrogrel: reduce platelet aggregation by inhibiting adenosine diphosphate pathway  Ticlopidine: Rapidly absorbed after oral administration; Metabolized in liver; Half-life lengthens with repeated dosing; Decreased renal clearance with age  Clopidogrel: Prodrug: metabolized into active metabolite; Excreted in urine and feces  Ticlopidine ADR: neutropenia; Avoid in patients with liver dysfunction  Clopidogrel ADR: bleeding; Avoid in patients with liver dysfunction  Drug interactions: Concurrent use of other antiplatelet, anticoagulant, or fibrinolytic drugs  Clopidogrel-specific: Proton pump inhibitors (PPIs); CYP 2C19 inhibitors  Ticlopidine-specific: Antacids; Digoxin; Cimetadine  Clinical use and dosing for clopidogrel:  MI prevention: 75 mg daily  ST-elevation acute coronary syndrome: 300 mg daily if less than 75 years of age and 75 mg daily if more than 75 years of age  Clinical use and dosing for ticlopidine:  Prevent stones in patients intolerant of acetylsalicylic acid: 250 mg twice daily Anemias develop when the number or red blood cells, or their ability to carry oxygen, becomes insufficient to meet a person’s needs. This tends to vary person to person and can be due to multiple factors, including blood loss; malnutrition; malabsorption; or be associated with a disease state. Signs and symptoms are also variable and depend upon the rate of development, age and cardiovascular status. • Rapid onset: tachycardia, lightheadedness, breathlessness • Chronic onset: fatigue, weakness, headache, loss of skin tone, etc. There are multiple types of anemia, some of them include: 1. Anemias caused by increased destruction a. Acute post-hemorrhagic anemia/chronic blood loss b. Sickle cell anemia (hydroxyurea for prophylaxis) 2. Anemia due to decreased production of RBC a. Iron-deficiency anemia (most common nutritional deficit worldwide) b. Anemia of chronic renal failure  discussed below c. Vitamin B deficiency (pernicious anemia)  discussed below d. Folate deficiency  discussed below e. Aplastic anemia – condition of bone marrow failure; several causes, including drug-induced i. Mild cases treated with supportive care ii. Need to refer patient to hematologist or oncologist Anemia of chronic renal failure • Due to decreased EPO production in kidney and occurs when the GFR falls below 60ml/min • Measure of microanemia is a good test for the detection of renal disease • Drug therapy: HEMATOPOETIC GROWTH FACTORS o MVI to replace the vitamins not received when on a restrictive diet o Epoetin, Darbopoeitin – recombinant hormones that  Stimulate the production of RBC in erythroid tissues in the bone marrow  Administered either IV or SQ; dosing is weight-based  Darbopoeitin is considered longer-acting; takes 4 weeks to reach steady state  Takes 2-6 weeks for a response  Contraindicated in patients with uncontrolled hypertension  Generally well-tolerated, but ADR may include HTN, headache, seizures, n/v/d, fatigue  Epoetin alfa (Epogen, EPO, Procrit) and darbepoetin alfa (Aranesp)  Stimulates erythropoiesis (red blood cells)  Used for treatment of anemia due to end-stage renal disease, AIDS, or chemotherapy  Preoperatively to prepare for allogenic transfusions  Granulocyte colony stimulating factor (filgrastim [Neuopgen], pegfilgrastim [Neulasta])  Stimulates granulocyte formation  Neutropenia due to bone cancer and chemotherapy  Pharmacokinetics for Hematopoetic Growth Factors  Well-absorbed SC  May be given IV  Metabolism and excretion not well understood  Precautions and contraindications for Hematopoetic Growth Factors  All are well-absorbed SC  Epoetin alfa and darbepoetin alfa: increased risk of tumor growth; Pregnancy category C  Hypertension (HTN) is only contraindication  Filgrastim and pegfilgrastim: hypersensitivity to E. coli; pregnancy category C  ADRs for Hematopoetic Growth Factors  All can produce bone pain  Epoetin alfa and darbepoetin: risk of seizures, HTN  Decreased overall survival rate and/or tumor growth in patients with certain cancers  Filgrastim and pegfilgrastim: risk of hypersensitivity  Drug interactions for Hematopoetic Growth Factors: few  Clinical use and dosing for Hematopoetic Growth Factors  Epoetin alfa to treat anemia  50 to 150 U/kg three times/week depending on diagnosis  For allogenic transfusion: 300 U/kg/day given 10 days prior to surgery, day of surgery, and for 4 days after surgery  Darbepoetin: 0.45 to 2.25 mcg/kg once weekly  Monitoring for Hematopoetic Growth Factors  Darbepoetin alfa: hemoglobin (Hgb) weekly  Eopetin alfa: Hct twice weekly, blood pressure  Ferritin for both  Patient education for Hematopoetic Growth Factors  Self-administration of SC medication  Use of iron supplements  ADRs: HTN and allergic reactions Iron-deficiency anemia (most common nutritional deficit worldwide)  Anemia due to decreased production of RBC  Treatment: dietary supplementation & iron preparations  IRON PREPARATIONS: Build serum iron and iron storage in the body  Pharmacokinetics  Enhanced absorption if iron stores low  Ferrous form is absorbed more readily.  Food affects absorption.  Eliminated via shedding of GI mucosal cells or via bleeding  Precautions and contraindications: hemochromatosis and hemolytic anemia  ADRs: GI symptoms (constipation, GI upset); acute toxicity possible especially in children  mostly GI-related (n/v/d)  take with food to reduce s/e  Food can decrease absorption by up to 66%  Consider a change in the salt form or switch to the SR formulation  Drug interactions: chelation; antacids/PPI b/c they reduce stomach acid  decreased absorption  Clinical use and dosing  Iron deficiency anemia: ferrous iron preferred b/c of increased bioavailability  Treatment for 3 to 4 months after Hgb/Hct return to normal  Therapy should continue for at least 3-6 months  Adults: 150 to 300 mg elemental iron daily  Ferrous sulfate 325mg TID is sufficient  divided doses to increases absorption, preferably 1 hour before meals  Sustained-release formulations dissolve in the small intestine, which leads to decreased absorption  Premature infants: 2 to 4 mg/kg/day  Infants and young children: 4 to 6 mg/kg/day  Reticulocytosis begins in 7-10 days  Monitoring  Reticulocyte count 7 to 10 days after starting therapy  Hgb at 2 weeks, then based on individual risk  Patient education  Prevention: adequate intake of iron in diet  Administration: take on empty stomach, if tolerated; take with vitamin C to enhance absorption; Avoid taking with dairy products, calcium, antacids. Anemia due to folic acid deficiency  Folate deficiency – d/t the development of large, functionally immature erythrocytes (megaloblasts)  Causes: poor intake; impaired absorption; increased demand; impaired utilization  Often associated with poor eating habits and the chronically ill; can also be drug induced  Signs & symptoms are similar to VB12-deficiency, but without the neurological manifestations  Pharmacokinetics: Oral, IM or SC well absorbed  Metabolized by liver & Excreted in urine and stool  Folic Acid Clinical Use  Replacement: found in most citrus fruits and green, leafy vegetables  Deficiency is treated with oral replacement therapy; usual dose is 1 mg  Initial dose: 1 mg/day in adults in children  Maintenance dose  Infants 0.1 mg/day  Pregnant or lactating women: 0.8 mg/day  Prevention of folic acid deficiency: 0.4 mg/day prior to conception and during pregnancy  Duration of treatment depends on cause; May be indefinite for those with chronic malabsorption  Side effects: erythema, rash, nausea, irritability, depression, confusion, impaired judgment Vitamin B deficiency (pernicious anemia)  Vitamin B is essential for maintaining the integrity of the nervous system  Certain populations are at an increased risk of Vitamin B deficiency, including the elderly, alcoholics, malnourished, vegans  Vitamin B12 deficiency etiology  Poor intake (vegans, vegetarians)  Impaired absorption due to lack of intrinsic factor, diseases of the ilium, stasis (constipation)  Gastrectomy, bariatric surgery  Pharmacokinetics  IM, SC or intranasal well absorbed  Stored in liver and excreted in urinE  Vitamin B12 Clinical Use  Parenteral injection required to replenish Vitamin B where malabsorption syndromes are present b/c there is no intrinsic factor present  PO Vitamin B12 can be used if the deficiency is due to inadequate intake  Prevention of deficiency  Pregnancy 2.2 mcg/day, lactation 2.6 mcg/day  Infants 0.3 to 0.5 mcg/day  Children age 1 to 10 years: 0.7 to 1.4 mcg/day  Treatment of deficiency  1000 mcg oral cobalamin daily for 6 to 12 weeks  Pernicious anemia  Initial dose 1000 mcg/day IM or SC x 7 days, then 100 to 1000 mcg IM per week for a month  Maintenance:  1000 mcg IM monthly  500 mcg intranasal cyanocobalamin weekly  1000 mcg PO daily  Clinical improvement is measured via increased alertness, appetite, etc.  Reticulocytosis occurs within 2-3 days and peaks 5-8 days  Hematocrit begins to increase in 2 weeks and is within normal limits ~ 2 months HIV/AIDS • 2 types of HIV: o I – majority of cases worldwide o II – primarily in west Africa; less efficiently transmitted; slower disease progression than type I • HIV transmitted primarily via: sexual contact, bloodborne contact; perinatal contact; breastfeeding o **prevention is key to avoiding transmission • Treatment • Goals of therapy: o Sustained suppression of viral replication to undetectable levels via  Maximal and sustained suppression of viral load  Restoration and perseveration of immune system function  Enhance quality of life  Decrease morbidity and mortality from HIV-related complications  Prevent HIV-transmission • Patient response to antiretroviral therapy (ART) varies o Successful treatment can reduce the viral load in 12-24 weeks o Need to select a regimen based on drug resistance testing, ADR, DDI, comorbidities and conveniences REVERSE TRANSCRIPTASE INHIBITORS • NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs): o interfere with the transcription of viral RNA to DNA via chain termination or competitive inhibition  Abacavir  Didanosine  Emitricitabine  Lamivudine  Stavudine  Zidovudine • NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs): o bind to reverse transcriptionase to interfere with the conversion of RNA to DNA  Delavirdine  Efavirenz  Etravirine  Nevirapine o Most common ADR: GI distress; rash; increase in hepatic transaminaSes • PROTEASE INHIBITORS o act near the final stage of HIV replication via inhibition of protease-mediated cleavage of the polyproteins that are responsible for creating new HIV-RNA copies. Inhibition of this final stage decreases the production of HIV-RNA copies o 10 medications on the market – all vary in their kinetic profile, efficacy and ADR  ADR includes n/v/d (use loperamide); increase in hepatic transaminases  Class effect: lipodystrophy  Most are also associated with hyperlipidemia. Pravastatin is the preferred agent b/c of least DDI concerns  New onset of diabetes mellitus in 3-5% of patients; • Promote therapeutic lifestyle changes and treat according to ADA guidelines • FUSION INHIBITORS – enfuvirtide (Fuzeion) o Inhibits the fusion of the virus to CD4+ T-cells and prevents HIV from entering the cell o Reserved for patients that are resistant to other treatments o Generally well-tolerated • INTEGRASE INHIBITORS – Raltegravir o Prevent integration of viral DNA into the host cell’s genome • CCR5 ANTAGONISTS – Maraviroc o Blocks the CCR5 receptor on the membrane of CD4+ T-cells and prevents the entry of the HIV virus