L62 Review - Pharmacology.pdf

Lecture 62: Pharmacology - Pharmacology of Hematopoiesis Anemia: significant reduction in functional RBC mass w/ reduction in O2 carrying capacity, due to blood loss or reduced RBC production Physiology of hematopoietic growth factors: Erythropoietin: heavily glycosylated protei...

Lecture 62: Pharmacology - Pharmacology of Hematopoiesis Anemia: significant reduction in functional RBC mass w/ reduction in O2 carrying capacity, due to blood loss or reduced RBC production Physiology of hematopoietic growth factors: Erythropoietin: heavily glycosylated protein synthesized mainly by interstitial fibroblasts in kidney; most important regulator of proliferation of committed progenitors (CFU-E), maturation of erythroblasts, & release of reticulocytes; acts synergistically w/ IL-3 & GM-CSF; binds specific receptor on surface of bone marrow cells Myeloid (colony-stimulating) growth factors (CSFs): glycoproteins that stimulate proliferation & differentiation of several precursor cells Interleukin 3 (IL-3): stimulates colony formation in most hematopoietic cell lines; influences functions of eosinophils & basophils Granulocyte/macrophage CSF (GM-CSF): acts w/ IL-3 & erythropoietin to stimulate GM/BFU-E proliferation, increases phagocytic & cytotoxic potential of mature granulocytes, increases toxicity of eosinophils & leukotriene synthesis Granulocyte CSF (G-CSF): stimulates granulocyte colony formation & production of neutrophils, enhances phagocytic & cytotoxic activities of mature granulocytes Macrophage CSF (M-CSF or CSF-1): stimulates monocyte/macrophage colony formation/ function, induces synthesis of G-CSF & IL-1 & enhances production of interferon & TNF Pharmacology of hemopoietic growth factors: Erythropoietin: highly effective treatment of anemia from chronic renal failure, AIDS, or chemo Administration: IV or SC as recombinant erythropoietin (epoetin alfa) Requires close dosing/monitoring bc of short t1/2 (10 hr), proper response requires adequate iron Adverse effects: HTN & thrombotic phenomena, minimized by raising hematocrit slowly Diseases assoc w/ ↑: HTN, cancers, renal cysts, renal artery stenosis, pulmonary insufficiency, emphysema, congenital heart defects, CHF, Conn’s syndrome, Bartter’s syndrome, carboxyHg Agents that ↑: cobalt, thyroxine, GH, prolactin, ACTH, serotonin, vasopressin, testosterone, cAMP, eicosanoids, angiotensin II, adrenergic 2 agonists, adenosine A2 agonists Agents that ↓: mercurial diuretics, estrogens, adrenergic 2 blockers, adenosine A1 agonists, calcium ionophores, high dose Ca channel blockers, phorbol esters, alkylating agents, DAG Myeloid growth factors: used to restore normal hematopoiesis, reduce morbidity of chemotherapy, assist in defenses against infection, & improve cytotoxicity against tumor cells in chemotherapy Adverse effects: local induration & thrombophlebitis at injection site Dose dependent: fever, myalgias, fatigue, skin rashes, GI distress, bone pain Dose-limiting: pericarditis, pleuritis, pleural effusions, & pulmonary emboli Sickle cell disease (CC): genetic cause of hemolytic anemia due to ↑ erythrocyte destruction Effect: anemia is mostly compensated, primary problem is deformation of erythrocytes & membrane permeability changes → aggregates in microvasculature → veno-occlusive damage & pain Population: individuals of African descent due to associated resistance to malaria Supportive treatments: analgesics, antibiotics, pneumococcal vaccination, & transfusions Hydroxyurea: chemotherapeutic drug which ↓veno-occlusive events by ↑production of fetal Hb Iron deficiency (CC): most common cause of nutritional anemia Effect: characteristic microcytic, hypochromic anemia secondary to ↓Hb synthesis Causes: insufficient dietary intake, blood loss, or interference w/ iron absorption Ferritin: storage protein for iron (1 molecule binds up to 4000 atoms), aggregates into hemosiderin Transferrin: plasma glycoprotein responsible for internal transport of iron Iron deficiency associated w/ ↑transferrin receptors & ↓ferritin receptors Iron requirements: 13 µg/day (adult male) to 21 µg/day (menstruating female) to 80 µg/day (infant) Heme Fe = most bioavailable; nonheme = most of dietary, ascorbate facilitates absorption of nonheme Ferrous sulfate: oral iron, most treatment regimens consist of 200-400 mg daily for 3-6 months Adverse effects: nausea, GI discomfort, abdominal cramps, constipation, & diarrhea Parenteral iron therapy: replenishes iron more rapidly, usually in pt’s that cannot absorb oral iron Vitamin B12, Folic Acid: deficiency causes decreased synthesis of methionine & S-adenosylmethionine → decreased protein & nucleic acid synthesis → megaloblastic anemia Vitamin B12: methyl groups from MeFH4 synthesize methylcobalamin for methionine synthesis Intrinsic factor: required for absorption in distal ileum, transported via transcobalamin II Daily requirement: 3-5 µg, liver stores 1-10 mg, deficiency wouldn’t develop for 3-4 years  Deficiency: abnormal DNA synthesis impacts hematopoietic & nervous system → mega- loblastic anemia; usually caused by IF deficiency or impaired B12-IF complex absorption Diagnosis: measure serum B12 and/or methylmalonic acid, treated w/ parenteral injections Folic acid: derivatives needed for purine synthesis & methylation of dUMP → dTMP (DNA synthesis) Intake: mostly present as reduced polyglutamates in food → transport in intestine requires pteroyl-γ-glutamyl carboxypeptidase → transported to tissues in MeFH4 form for uptake by receptor-mediated endocytosis Deficiency: often caused by inadequate dietary intake, or prolonged cooking (destroys folates) Alcoholics & those w/ liver disease can have diminished capacity to store folates Diagnosis: important to distinguish B12 from B9 deficiency in megaloblastic anemia to treat cause Deficiencies in other vitamins & trace elements: Copper: deficiency extremely rare in humans, may occur after intestinal bypass surgery, in those receiving parenteral nutrition, in malnourished infants, & in Zinc overdose Menke’s disease (CC): aka steely hair syndrome; affects transport of Cu in man Deficiency: associated w/ leukopenia, particularly granulocytopenia, & anemia Treatment: oral or parenteral cupric sulfate Cobalt: deficiency not reported in man, Co may inhibit certain enzymes in oxidative metabolism, resulting in tissue hypoxia & ↑ erythropoietin secretion, but large amounts depress erythropoiesis Pyridoxine (B6): oral therapy can ↑ hematopoiesis in pts w/ sideroblastic anemia Therapy: effective for anemia due to certain drugs (ie. isoniazid, pyrazinamide), but not effective for others Riboflavin: can cause spontaneous red-cell aplasia (rare), but induced hypoproliferative anemia has been observed, administration can help to correct red-cell aplasia in pts w/ protein depletion