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FCP557/2: PHARMACOTHERAPEUTIC V DRUG INDUCED HAEMATOLOGICAL DISORDERS (DIHD) Presented by Hafzan Hanafiah [email protected]  To discuss the various types of drug- 01 induced haematological disorders. learning (C2) To recommend the appropriate...

FCP557/2: PHARMACOTHERAPEUTIC V DRUG INDUCED HAEMATOLOGICAL DISORDERS (DIHD) Presented by Hafzan Hanafiah [email protected]  To discuss the various types of drug- 01 induced haematological disorders. learning (C2) To recommend the appropriate 02 Outcome laboratory analysis, diagnostic assessment and management in DIHD. (C3) To propose appropriate 03 pharmacotherapy plans based on the different types of DIHD using the latest references. (C6)  Let's meet... Mrs. Yikes A 45 year-old-lady presented to the clinic complaining of weakness, fatigue, and shortness of breath for the past two weeks. She reports easy bruising and petechiae on her skin. She is a known case of T2DM and HPT. She is currently on Amlodipine 10 mg OD and Metformin 500 mg BD. She had went to the Pharmacy near her house to get some Ibuprofen for occasional joint pain. Some agents cause predictable hematologic disease (e.g., antineoplastics), but others induce idiosyncratic reactions not directly related to the drugs’ pharmacology Associated with significant drug related morbidity and mortality Aplastic anemia was the leading cause of death, followed by thrombocytopenia, agranulocytosis, and hemolytic anemia The risk of getting DIHD and the risk of death from DIHD is higher with increasing age Drug-induced hematologic disorders can affect any cell line, including white blood cells (WBCs), red blood cells (RBCs), and platelets. Drug-induced hematologic disorders Mintzer DM, Billet SN, Chmielewski L. Drug-induced hematologic syndromes. Adv Hematol. 2009;2009:495863. doi: 10.1155/2009/495863. Epub 2009 Jul 7. PMID: 19960059; PMCID: PMC2778502.  TYPES OF DIHD Drug-induced agranulocytosis Drug-induced thrombocytopaenia Drug-induced haemolytic anaemia DI immune haemolytic anaemia DI oxidative haemolytic anaemia Drug-induced megaloblastic anaemia Drug-induced aplastic anaemia Lu, S., Park, J. S., Feng, Q., & Lanza, R. (2008). Red Blood Cells. Essentials of Stem Cell Biology (Second Edition), 217-222. https://doi.org/10.1016/B978-0-12-374729-7.00025-1 Drug-induced agranulocytosis Definition: Leucopenia: TWBC less than 3000/l Neutropenia: neutrophil count less than 1500/l Granulocytopenia: Granulocyte count less than 1500/l (includes eosinophil & basophil) Agranulocytosis: (severe neutropenia) a reduction in the number of mature myeloid cells in the blood (granulocytes and immature granulocytes [bands]) to a total count of 500 cells/mm3 or less.  Examples of drugs and their mechanisms: Drug-induced Penicillin – hapten-type reaction (onset 7-15 days) Quinidine, phenothiazine – innocent bystander agranulocytosis phenomenon High dose B-lactam antibiotics, carbamazepine, Symptoms: sore throat, fever, valproic acid – autoimmune reaction malaise, weakness, chills Clozapine, ticlopidine – direct toxicity to progenitor stem cells Duration: Occurs within 1-3 months of initiation Can appear within days to weeks Discontinue – counts return within 2-4 weeks after initiation of therapy Propylthiouracil, methimazole – mechanism Usually resolves over time with unknown supportive care and management antithyroid medications accounted for 7% to of infection 23% of drug-induced agranulocytosis cases Neutrophil count recovery: ranged investigated from 4 to 24 days More frequent in older patients Appear within 2 months of initiation  Treatment: Drug-induced Removal of offending drug agranulocytosis Symptomatic treatment (e.g, Abx for infection) Colony-stimulating factors E.g. GM-CSF (Sargramostin), G- CSF (Filgastrim) Recommended in patients with a neutrophil nadir (50% reduction from baseline values. Incidence: The incidence of drug-associated thrombocytopenia is 10 cases per 1,000,000 population Symptoms: Early phase: increased bruising, petechiae, ecchymoses, and epistaxis Later phase: bleeding of mucous membrane and purpura DRUG-INDUCED THROMBOCYTOPENIA Examples of drugs and their mechanisms: Immunologic reactions: Quinidine, quinidine, sulfonamides, rifampin, heparin Vancomycin, penicillin, cephalosporin - Hapten-type immune reaction - usually occurs at least 7 days after the initiation of the drug, median recoverytime~1week Gold compounds, procainamide– platelet specific antibody - drug induces the production of autoantibodies that bind to platelet membranes and cause destruction Antineoplastics – direct toxicity reaction - suppressed thrombopoiesis and produce a decrease in the number of megakaryocytes in the bonemarrow. Heparin – Type I & type II DRUG-INDUCED THROMBOCYTOPENIA  DRUG-INDUCED THROMBOCYTOPENIA Heparin-induced thrombocytopenia Type I Non-immunologic response, mild, reversible This occurs in 10-20% of patients on heparin Occurs within the first 2 days of therapy à platelet count slowly returns to baseline Usually asymptomatic Type II Immunologic response, more severe Less common (1 to 5% for heparin, 0.8% for LMWH) Platelet count generally begins to decline 5 to 10 days after the start Risk factors: patients who had recent major surgery (e.g. cardiac, peripheral vascular or orthopedic surgery) DRUG-INDUCED THROMBOCYTOPENIA Heparin-induced thrombocytopenia Complications: Thrombosis (20-50% patients with HIT), continues for days to weeks after heparin discontinuation heparin-induced skin necrosis and venous gangrene of the limbs Management Goal of management: reduce the risk of thrombosis or thrombosis- associated complication Removal of the offending drug Alternative anticoagulant: direct thrombin inhibitors (e.g. lepirudin, argatroban, bivalirudin) DRUG-INDUCED HAEMOLYTIC ANEMIA Premature RBC destruction (hemolysis). Symptoms: fatigue, malaise, pallor, shortness of breath Can occur Causes: immune or metabolic Defective RBCs Types of hemolysis: Abnormal changes in the Intravascular hemolysis (lysis of RBC in the circulation) intravascular extravascular hemolysis (ingestion of environment RBCs by macrophages) Intravascular Hemolysis Mostly due to hereditary or genetic RBC defect and for some immune mediated variety. RBC destroyed within the blood vessels and free hemoglobin released into blood stream which overwhelm mechanism that usually are capable of removing Hb from circulation. Extravascular Hemolysis Most immune-mediated drug induced RBC destruction An exaggeration of normal mechanism of RBC removal. i.e. RE system prematurely destroy RBC Jaundiced  DRUG-INDUCED IMMUNE HAEMOLYTIC ANEMIA Immunoglobulins (IgG and/or Examples of drug and its mechanism: IgM) bind to antigens on the High dose penicillin or cephalosporin, surface of RBCs and initiate minocycline - hapten- type reaction their destruction through the Quinidine, sulfonamides - Innocent bystander complement and Methyldopa, levodopa, mefenamic acid, mononuclear phagocytic diclofenac – autoimmune systems DRUG-INDUCED IMMUNE HAEMOLYTIC ANEMIA Diagnosis: Coombs test (Antiglobulin Test)  High-Affinity Hapten-Type Reaction: Penicillin: Penicillin or metabolite covalently binds strongly to RBC membrane in dose-related fashion Dose related and patient on > 10 million/day or > 10MU/day or with high penicillin blood level could develop hemolytic anemia. Usually complement not activated Extravascular anemia caused by IgG Anemia gradually 7 –10 days and reverses after a couple of weeks after stopping drug. Direct Coombs test remain positive for several weeks Penicillin or metabolite binds strongly to RBC membrane in dose-related fashion  Low Affinity Binding Hemolytic Anemia: Quinidine Binding of drugs or metabolites to circulating serum protein to form a complete antigen. RBC is lysed and the immune complex (low affinity for cell membrane ) dissociates and goes on to second RBC to repeat process ie recycling. Antibodies is not directed against the RBC but is destroyed as an innocent bystander. Small doses can cause large scale hemolysis (intravascular)  Formation of RBC autoantibodies in 10-20% patients on > 4 months therapy Treatment: Discontinuation Autoimmune Reaction Resolves over several weeks Methyldopa to months RBC Transfusion  DRUG-INDUCED IMMUNE HAEMOLYTIC ANEMIA Management: Removal of offending agent Supportive care – folic acid supplements, glucocorticoid Patients who do not respond can be managed with: Azathioprine or cyclophosphamide Monoclonal antibody(e.g. rituximab) and immunoglobulin treatments Example: glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency Inherited through sex-linked chromosome The most common types of G6PD deficiency occur in American and African blacks (approx. 10%) A deficiency in G6PD reduces the ability of glutathione to help RBCs deal with oxidative stress When the RBCs are exposed to an oxidising agent (drugs), the cell membrane becomes damaged, the haemoglobin becomes oxidised and hemolysed The degree of hemolysis depends on: E.g. drugs: the severity of the enzyme deficiency Nitrofurantoin Sulfamethoxazole the amount of oxidative stress Primaquine DRUG-INDUCED HAEMOLYTIC ANEMIA Features/Manifestations Blood: Reduced Hb and Heinz body in RBC (damaged hemoglobin) Hyperbilirubinemia Reticulocytosis Urine Dark (urobilinogen) Symptoms Jaundice Weakness; abdominal pain, back pain – severe DRUG-INDUCED HAEMOLYTIC ANEMIA G6PD Hemolytic Anemia - WHO Classification The degree of hemolysis in all classes related to degree of enzyme deficiency and strength of stimulus. Severity caused by drugs depends on oxidant potential and dose. Non-Drug: infection, diabetic ketoacidosis and fave beans or broad beans (Vicia faba) Antimalarial drugs such as primaquine, pamaquine, chloroquine, fansidar, maloprim and quinine. Antibiotics such as sulphonamide, co-cotrimoxazole, sulfanilamide, dapsone, nitrofurans., chloramphenicol, cprofloxacin. Analgesics such as asprin, acetanilide, phenacetin Antihelminths like stibophen and β-naphthol. Others: vitamin K, probenecid, naphthalene, nalidixic acid, dimercaprol, and phenylhydrazine. G6PD RELATED HEMOLYTIC ANEMIA  Drug-induced megaloblastic anemia Definition: The development of RBC precursors called megaloblasts in the bone marrow is abnormal. Deficiencies in either vitamin B12 or folate are responsible for the impaired proliferation and maturation of hematopoietic cells, resulting in cell arrest and subsequent sequestration. E.g. cotrimoxazole, phenytoin, barbiturates Cotrimoxazole has been reported to cause drug-induced megaloblastic anemia with both low and high doses, particularly in patients with a partial vitamin B12 or folate deficiency. Treatment: If caused by chemotherapy - A trial course of folinic acid 5mg – 10mg up to 4 times a day If caused by other drugs – folic acid supplementation  Drug-induced aplastic anemia Rare, serious disease Incidence: 2-7 cases per million inhabitants, incidence is higher among 60yearsold The presence of two of the following criteria: WBC count of 3,500 cells/mm3 or less, Platelet count of 55,000 cells/mm3 or less, HHb value of 10 g/dL or less with a reticulocyte count of 30,000 cells/ mm3 or less Pancytopenia (presence of anemia, neutropenia, and thrombocytopenia)  Drug-induced aplastic anemia Mechanisms: Damage to the pluripotent hematopoietic stem cells before their differentiation to committed stem cells Direct, dose-dependent toxic effect Suppression of proliferating cell lines, leading to bone marrow failure E.g. chemotherapy, chloramphenicol Metabolites of phenytoin and carbamazepine bind to macromolecules in the cell and cause direct toxic effects on the cell à cell death Idiosyncratic (not dose-dependent) E.g. chloramphenicol - The nitrobenzene ring on chloramphenicol is reduced to form a nitroso group which interacts with DNA in the stem cell causing damage to the chromosomes à cell death Drug- or metabolite-induced immune reaction  Drug-induced aplastic anemia Onset Symptoms appear from days to months after the initiation of the offending drug (average 6.5 weeks) Neutropenia presents first, followed by thrombocytopenia, and finally anemia Management Should be initiated immediately Remove the offending agent Supportive care (e.g. antibiotics for infection) Transfusion support with erythrocytes and platelets Treatment: hematopoietic stem cell transplantation (HSCT) for young patients Immunosuppressive therapy (e.g. antithymocyte globulin (ATG) and cyclosporine)  Assessment Questions addressing the patient’s drug use along with a thorough review of systems are essential. Causality Severity: Preventability Naranjo scale, Hartwig scale Schumockand WHO UMC Thornton scale Assessment scale Naranjo scale WHO UMC criteria Hartwig scale Assessment of preventability Schumockand Thornton scale General management 1 Remove the offending agent 2 Supportive care (e.g antibiotics, blood transfusion) 3 Alternative treatments