3-Pharmacology of Blood Disorder.pdf

blood cell RBC=45% WBC= 1% plasma and pl8late in RBC PHRM 736 Fall 2023 Lunawati Bennett MS; PhD; PharmD; FACN Blessed are the poor in spirit, for theirs is the kingdom of heave. Blessed are the meek, for they will inherit the earth. Blessed are the peacemakers, for t...

blood cell RBC=45% WBC= 1% plasma and pl8late in RBC PHRM 736 Fall 2023 Lunawati Bennett MS; PhD; PharmD; FACN Blessed are the poor in spirit, for theirs is the kingdom of heave. Blessed are the meek, for they will inherit the earth. Blessed are the peacemakers, for they will be called sons of God. Matthew 5:3,5,9  Lecture slides for this course contain roughly 90% of the exam material. The remaining 10 % will come from classroom discussion, class lecture, filling the blank.  Students are encouraged to listen intently, take good notes, and ASK questions.  RBC- red blood cells  THF4- tetrahydrofolate  CSF-Colony stimulating factor  DHFR- dihyrofolate reductase  G-CSF - Granulocyte colony stimulating factor  A.a- amino acids  GM-CSF- Granulocyte macrophage colony  F.a- fatty acids stimulating factor  DNA- deoxyribo nucleic acid  IL- interleukin  PBPC- peripheral blood progenitor cells  EPO- erythropoietin  PEG- polyethylene glycol  rHuEPO- recombinant human erythropoietin  TPO- thrombopoietin  MGF-Myeloid growth factor  ESA- erythropoietin stimulating agent  Hgb-hemoglobin  ANC- absolute neutrophils count  Myb-myoglobin  PEG- polyethylene glycol  BP- blood pressure  WBC- white blood cells  IDA- Iron deficiency anemia  HF- heart failure  HGF- Hematopoietic growth factor  CKD- chronic kidney disease  PCC- prothrombin complex concentrate  CCF-Clotting factor concentrate  APCC- activated prothrombin complex concentrate At the conclusion of this lecture and after studying the material, the student should be able to: 1. Compare and contrast normocytic, microcytic and macrocytic anemias. 2. Describe the causes of IDA 3. Know iron salt conversion to elemental Fe 4. Know DDI of iron and management of drugs when taken with iron 5. Identify IV iron names, use and ADRs 6. Explain function of B12 and B9, what happen if deficient or overdose 7. Identify normocytic, drug names and MOA, toxicity, and factors that response to ESA 8. Identify MOA, ADR and drug name for treatment of beta thalassemia 9. Identify MOA, drug names and ADRs for drugs to treat neutropenia 10. Identify MOA, drug names and ADRs for drugs to treat thrombocytopenia 11. Identify the problems with disorders of coagulation, MOA, drug names, ADRs for drugs to treat this disorder  Anemia: a group of diseases characterized by  Hgb, or volume of RBC that result in oxygen binding capacity of the blood  Normal Hgb in men: 13.5-17.5 g/dL. MCV= size  Normal Hgb women 12-16 g/dL  Severe low Hgb < 8 g/dL blood carries blood so when low these symptoms happen  Acute symptoms of anemia : tachycardia, hypotension, palpitations, angina, lightheadedness  Chronic symptoms of anemia: fatigue, weakness, dyspnea, vertigo, pallor, sensitivity to cold  Serum iron: Serum iron bound to transport protein, transferrin, in the blood. If iron stores are depleted, less is released for circulation. Normal 50-150 g/dL. In iron deficiency anemia (IDA): < 30 ug/dL  Transferrin : transport protein  Total iron binding capacity (TIBC): indirect measurement of iron-binding capacity of serum transferrin  Transferrin saturation (TSAT): ratio of serum iron and transferrin available  Mean Corpuscular volume (MCV): size and average volume of RBC  Hematocrit (Hct): the volume % of RBC in blood  Hemoglobin (Hgb) is the protein molecule in red blood cells that carries oxygen from the lungs to the body's tissues and returns carbon dioxide from the tissues  Iron absorption in restricted to the proximal small intestine. Excretion is due to loss of iron from blood or cells  Daily intake is 15 mg for men, 11 mg for women  Men absorb 6% (1mg), women absorb 12% (1.3 mg) men absorb less than women  The body contain about 3-4 grams of total iron  Majority 2.5 gram is used dont need to memorize for RBC production  Stored 1 gram as ferritin unused iron  iron deficiency anemia ↓in B9 and B6 and B- thalasseium women having period is microcytic https://www.lecturio.com/concepts/anemia-overview/ www.medscape.com/viewarticle/412897_2  FYI https://www.google.com/search?q=iron+route+in+the+body&rlz=1C1GCEU_enUS950US950&sx  Inadequate dietary intake: poor diet (vegetarian), malnutrition, psychosis  Blood loss: GI hemorrhage, heavy menses, drug induced (NSAID, steroids, antiplatelet, anticoagulant)   iron absorption: taking PPI, Celiac disease, IBD, gastric bypass   iron requirement: pregnancy, lactation, rapid growth infants and adolescents  Treatment of IDA- Microcytic ( 2 0f 4) % elemental iron oral  Oral Iron: Fe sulfate, Fe fumarate, Fe Carbonyl Fe, 100 polysaccharide gluconate, carbonyl iron, polysaccharide Fe complex, Fe iron complex maltol Fe-gluconate 12  BBW: accidental overdose of iron, fatal Fe-sulfate 20 poisoning in children, accidental overdose- Fe sulfate, dried 30 call poison control immediately even if asymptomatic Fe-fumarate 33  Antidote for iron overdose are: ▪ New drug Ferric maltol (Accrufer) ✓ Deferoxamine (Desferal®) - IM, SC; 100% elemental, approved 2019 ✓ Deferasirox PO 65 mg elemental Fe sulfate= exam question 325 mg, lease expensive  just mush  ADRs: constipation (use docusate or Bisacodyl), dark and tarry stool, nausea, stomach upset mush and push DDI:  Antacids, →Fe absorption- take Fe 2 hr before or 4 hr after antacids  H2RA, PPI → Fe absorption- does not improve absorption even with separation take it with orange juice, do not take with coffee or tea  Vit C → absorption of Fe – good to take together  Quinolone, tetracycline, cefdinir – separate 2 hr before or 4-8 hr after  Bisphosphonate- can take Fe after 30-60 minutes  Levothyroxine, levodopa, methyldopa- separate by 2 hr before, or 4 hr after  Treatment of IDA- IV iron ( 4 0f 4) IV iron: use oral first before using IV ▪ Iron sucrose (Venofer®), ▪ Ferumoxytol, (Feraheme ®), ▪ Iron dextran complex (INFeD) Indications: CKD on hemodialysis, CKD receiving ESA, unable to tolerate oral, loosing iron too fast ADR: Anaphylaxis rxn (INFeD can cause fatal allergic rxn) Give IV slow to prevent hypotension  b- thalassemia RBC MOA: Erythroid maturation agent  Recombinant fusion protein that binds selectively to TGF-β superfamily ligands to reduce Smad 2/3 signaling  Smad 2/3 abnormally high in β-thalassemia, myelodysplastic syndrome (MDS)/pre-leukemia due to ineffective production of RBC preleukemia Drug: Relozyl ®(luspatercept-aamt) Indications: 1. Anemia in β-thalassemia pts who require regular RBC transfusion, 2. Anemia failing on RBC transfusion 3. MDS (myelodysplastic syndrome)/preleukemia ADR: HTN https://www.youtube.com/watch?v=h1vjwg_eyvE  Kidney is responsible for 90% production of erythropoietin (EPO)  EPO is hormone produce by kidney to stimulate bone marrow to produce RBC  A deficiency in EPO cause anemia of chronic kidney disease (CKD) Treatment need: ✓ Iron therapy, erythropoietin ✓ ESA (erythropoiesis stimulating agent) ▪ EPO helps maintain Hgb level and decrease the need for blood transfusion, but ineffective if Iron store are low  MOA: induce erythropoiesis by stimulating the division and differentiation of erythroid progenitor cells, induce release of reticulocytes from the bone marrow into bloodstream to become mature erythrocytes →  Hct and Hgb level ▪ Recombinant human Erythropoietin (rHUEPO)= ESA, hematopoetic growth factor (HGF) Drugs: ✓ Epoetin  (Epogen®, Procrit®)-t ½ - 4-13 hr ✓ Darbepoetin  (Aranesp®) - t ½ -2-3x of Epogen®- less often in dosing Banned by International Olympic Committee for athlete who try to improve performance ADRs: edema, fever, headache, insomnia, HTN , arthralgia Toxicity: if serum Hgb is  12 g/dL →thrombotic complication (stroke, MI, worsening of CHF, HTN) Too much iron chronic iron toxicity due to -organ failure -inherited disease -death -excessive iron absorption Factors limiting response to ESA: -heart , liver, pancreas failure -RBC tranfusion long time ❖ Iron, folic acid, ❖ vit C or vit B12 deficiencies, ❖ infection, blood loss/hemolysis, Animal better source of iron -Heme iron ❖ AL overload, aluminum can decrease iron ❖ cancer, malnutrition Plant non-heme iron Banned by International Olympic Committee for athlete who try to improve performance  pregnant women  Caused by  Vit B12 or folate (B9) or both  Diagnosis : low Hgb and high MCV  B12 injection is 1st line.  Pernicious anemia should be given life long B12 injection homocystein is bad and want to avoide  water soluble  Function B12: “assist” folate in ▪ Function B9: B9 is converted to TH4 → biosynthesis of DNA, act as coenzyme, involve in RNA and DNA biosynthesis → a.a and f.a metabolism, promotes cell and hematopoietic cells coenzyme in the RBC growth conversion of histidine ↔ glutamate  Deficiency: pernicious anemia- weakness,  Deficiency: limit RBC cell division → bleeding gum, numbness of hand and leg, megaloblastic anemia poor memory, depression, demyelination of CNS - loss of memory and dementia  Overdose: toxic, large dose 10 mg/day IV can induce seizure  Overdose: no toxicity. Doses in excess of 1000 x the RDA appear to be safe.  Together with B12 and B6, folate can ▪ If taking with mega dose of vit C,  risk of nose homocysteine and ear bleed (large dose vit C destroy B12) Vit B12 (cyanocobalamin)  Dosage: IM 100-1000 mcg , oral, Nascobal (nostril weekly)  ADR: pain at site injection, rash,  Monitor: Hgb, Hct, reticulocyte count  DDI: Chloramphenicol and colchicine (decrease efficacy and absorption) Vit B9 (Folate, folic acid)  Dosage: IM , oral  ADR: bronchospasm, flushing, rash, pruritis  Monitor: same as B12  DDI: some chemotherapeutics, phenytoin, green tea, sulfazalazine  biphosphante vitamin C 1) ______, antacid ______, ____, ____ will change the absorption of oral iron, quinolone EXCEPT ______ PPI and H2RA 2) ADR of IV iron are _____, _____, _______, except _______ death anaphylaxis iron overload hypotension chronic kidney diseaase intrinsic or extrinsic 3) Normocytic anemia is due to _________, ______, need iron and ________. ESA 4) EPA can cause _____, HTN _____, Stroke _______,______ HF Arthlgia ESA b9=folic macrocytic anemia 5) Vit B9 is benefit for _____, _______, _______, Text but have ceiling dose (toxicity)of______ 10 mg/day ↓homocysteine can cause seizure  (HGF (1 of 4) - FYI ✓Goodman and Gillman’s. The Pharmacological Basis of Therapeutics. 2023  HGF are glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. white blood cells CMP- common myeloid progenitor CLP- common lymphoid progenitor http://www.bloodlines.stemcells.com/chapters.html  Thrombocytopenia :  platelet, penia= dec  bleeding Neutropenia: neutrophils,  infection Leukopenia : WBC (leukocytes) possible cancer, viral infection too much WBC= sign of infection http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=cmed&part=A14898  Drugs Treatment for Erythropoietin, Darbepoetin  - anemia G-CSF- Filgrastim, Peg-filgrastim - neutropenia GM-CSF- Sargramostim - neutropenia - stem cell transplantation, IL11, Opreivekin - thrombocytopenia Romiplostim - thrombocytopenia Hematopoietic growth factors (HGF): erythropoietin, darbepoetin, granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, Interleukin 11 ✓Katzung BG , et al 2021 Drugs Source t1/2 Serious ADRs Common ADRs Other Filgrastim Recombinant 3.5 hr, need daily Spleen rupture, N, V Excreted by kidney (Neupogen E coli + human G- injection allergic rx, bone pain, Pregnancy C* ®) CSF acute fever, t1/2 of SC= t1/2 of respiratory pain at site IV distress injection syndrome Pegfilgrastim Filgrastim + PEG, 15-80 hr, inject 1 same same Excreted by (Neulasta®) dose per cycle of neutrophils (large Protects the drug chemotherapy molecules due to PG) from enzymatic and phagocytic Pregnancy C* degradation * Must enroll in Amgen’s Pregnancy Surveillance program Info from package insert from Amgen MOA: stimulates proliferation of neutrophils, monocytes/macrophages, and dendritic cells ▪ Neutrophils -active against bacteria ▪ Monocytes/Macrophages- active against fungi ▪ Myeloid derived dendritic cell- active against viruses Drug: sargramostim (Leukine ®)- recombinant (rhu) human and yeast GM-CSF rHu GM-CSF has broader biologic actions than G-CSF ADR: fever, myalgia, capillary leak syndrome (peripheral edema and pericardial effusion), supraventricular tachycardia, pain at site injection Caution: pts with fluid retention, HF, CV, respiratory and renal or hepatic dysfunction MOA: Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways →activates thrombopeitin receptors → platelet production Drug: romiplastim (AMG 531, Nplate®)  Obtain through a restricted usage program called NEXUS Use: - anti-hemorrhagic, - chronic idiopathic thrombocytopenia (refractory to steroids or immunoglobulins) ADR: HA (35%), myalgia, abdominal/shoulder pain, dyspepsia, allergic rx  MOA: act on specific cell surface cytokine receptor to stimulate growth of multiple lymphoid, myeloid cells, platelet and neutrophils  IL-11 is a multifunctional cytokine made from bone marrow. It is a key regulator of hematopoiesis, platelets and megakaryocyte maturation and production = also called adipogenesis inhibitory factor (AGIF) Drugs: Oprelvekin (Neumega®) Eltrombopag (Promacta®), non peptide  Given as SubQ several times, until platelet rise to  50000 cells/L ADR: fluid accumulation (in lung, swelling of hand and feet, dyspenia), NVD, mouth sores, fatigue, HA, dizziness, cardiovascular (anemia due to hemodilution), transient arrhythmias, hypokalemia, capillary leak syndrome (rare)  Dose adjustment in renal dysfunction Hemophilia: bleeding disorder from congenital deficiency in plasma coagulation protein.  Hemophilia A (classic): deficiency in factor VIII.  Hemophilia B (Christmas): deficiency in factor IX Treatment goal of hemophilia: prevent bleeding during surgical, medical, dental procedure, and minimize bleeding and complication when occurred. Treatments: ▪ Non-blood products: Desmopressin, aminocaproic acid ▪ Blood products: Cryoprecipitate, Clotting factor concentrates (CFC)  Factor Synonym t ½, hr Blood product source I Fibrinogen 100-150 cryoprecipitate II Prothrombin 50-80 FFP, PCC V Proaccelerin 24 FFP VII Proconvertin 6 Recombinant VII, FFP, PCC VIII, Hemophia A Antihemophilic factor 12 FFP, PCC, CFC IX, Hemophilia B Christmas factor 24 FFP, PCC, CFC X Stuart power factor 25-60 FFP. PCC XI Plasma tromboplastin 40-80 FFP antecedent XII Hageman factor 50-70 XIII Fibrin stabilizing factor 150 FFP, cryoprecipitate ✓FFP- fresh frozen plasma, CFC- clotting factor concentrate ✓PCC- prothrombin complex concentrate Dipiro JT, et al. Pharmacotherapy. A pathophysiologic approach  FYI ✓Extrinsic Pathway: initiated by tissue Factor, causing cascade activation ✓Intrinsic Pathway: propagation of clot formation ✓Common Pathway Haines ST, Witt DM, Nutescu EA. Venous Thromboembolism. In: DiPiro 1. Desmopressin (DDAVP) MOA: not well understood. Synthetic analog of the antidiuretic hormone vasopressin that causes release of vWF and factor VIII from endogenous storage sites (temporarily  factor VIII by 3 folds) Indication: minor bleeding. Contraindicated: CrCl < 50 ml/min Monitor: bleeding time, Factor VIII , serum Na, urine osmolality ADRs: facial flushing, HA,  heart rate, BP, thrombosis, hyponatremia  2. Aminocaproic acid (Amicar®) MOA: binds to the lysine binding sites within the plasminogen/plasmin molecule which interferes with the ability of plasmin to lyse fibrin clots Indication: treatment of hemorrhage due to hyperfibrinolysis ADRs: dizziness, HA, tinnitus, delirium, hypotension, sinus bradycardia, rhabdomyolysis 3. Cryoprecipitate collection of RBC  Cryoprecipitate Anti Hemophilic Factor, frozen blood product prepared from plasma  Each 15 mL plasma unit contains 100 IU of factor VIII, 250-350 mg of fibrinogen, vWF and factor XIII ✓ Factor VIII is bound to vWF (protects the factor VIII from rapid breakdown within the blood). Deficiency of vWF → factor VIII levels  Not used much, due to increase risk of viral exposure ▪ Over the years, blood products are made better, less viral exposure  FFP → Cryo → Plasma derived products (plasma from thousands of donor) → CFC  Brand name Product type Viral inactivation Other contents Factor VIII concentrates Solvent detergent, monoclonal Ab, Albumin, heparin, vWF. Alphanate, Hemophil M, Profilnate, Plasma pasteurization others reconize what is factoer VIII and IX Classified as: low, intermediate, high and Bioclate, Helixate, others Recombinant DNA from kidney ultrahigh purity or ovary of Chinese hamster Factor IX concentrates Plasma, recombinant Solvent detergent, monoclonal Ab Heparin Benefix, Mononine APCC plasma Dry heat, vapor heat Heparin, II, VII, VIII, IX, Autoplex T, FEIBA X PCC plasma Dry heat, vapor heat Heparin, II, VII, VIII, IX, Bebulin VH, Proplex T, others X Other Recombinant, porcine Freeze dried NovoSeven, Hyate C These are Clotting factor concentrate (CFC) PCC- prothrombin complex concentrate ; APCC- activated prothrombin complex concentrate Dipiro JT, et al. Pharmacotherapy. A pathophysiologic approach.  Text 1) Drugs use to treat thrombocytopenia are ____, _____, ____, while ESA is eltrombopag useful to treat ______ microcytic and IDA opreluekin 2) Capillary leak syndrome is ADR of ______, Text which works by _______ Text Desmopressin 3) _____, __________ aminocapro acid are non blood products; while ____, ________, cryo clotting factor concentrate ________, APCC ___ PCC are drug products used for coagulation disorder ▪ Golan DE et al. Principles of Pharmacology: the Pathophysiologic Basis of Drug Therapy. 3rd ed. 2012 ▪ Dipiro et al. Pharmacotherapy: A pathophysiologicic Approach 8th ed, 2011. ▪ Various internet information as cited Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 14th edition Editors: Brunton, Hilal-Dandan, Knollmann. Publisher: McGraw-Hill, 2023 Katzung BG et al. Basic & Clinical Pharmacology. 15th ed. 2021 1.)microcyte = IDA (iron defiency Anemia) Microcyte Anemia 2.)B-thallsemia -> ↓Smad (Relozyl) Being Vegan, Mensus, baby, and NSAID inhibator absorption: avoid caffiene, tea Induce: take- Vitamin C Oral: Fumarate>Sulfate>Glutomate IV: CKD, Dialysis *Oral is preffered* IV- can cause liver falure, HF, and death Do not use Aluminum product and can cause anemia Normocytic anemia -Anemia -CKD EPO are made in kidney Use ESA too much ESA can cause MI,stroke, death, ↑cancer promotion  Macrocytic Anemia B9, B12 pernecious Anemia because not enough B12 HGF HEMATIC GROWTH FACTOR stem cell -> common lymphoid progenator= production of Tcell and B cell -> common myeloid progenator -> platelet thrombolypenia * Romiplastim ADR= HA, pain *opreluekin etrombag ADR= fluid accumulation Coagulation hemophilia factor VIII and IX problem blood: CRYO, PCC, APCC, FFC