Drug-Induced Hematologic Disorders (DIHDs) PDF

DRUG-INDUCED HEMATOLOGIC DISORDERS (DIHDs) Lec:6 ❖The most common DIHDs include: ▪ Aplastic anemia ▪ Megaloblastic anemia ▪ Hemolytic anemia ▪ Agranulocytosis ▪ Thrombocytopenia. ▪ The mechanisms of DIHDs can be the result of: ✓ either direct drug or ✓ metabolite toxicity or ✓ an immun...

DRUG-INDUCED HEMATOLOGIC DISORDERS (DIHDs) Lec:6 ❖The most common DIHDs include: ▪ Aplastic anemia ▪ Megaloblastic anemia ▪ Hemolytic anemia ▪ Agranulocytosis ▪ Thrombocytopenia. ▪ The mechanisms of DIHDs can be the result of: ✓ either direct drug or ✓ metabolite toxicity or ✓ an immune reaction. ▪ Some agents cause predictable hematologic disease (e.g., anti-neoplastics), ▪ DIHDs can affect any cell line, including RBCs, WBCs, & platelets. When a drug causes ↓ in all 3 cell lines accompanied by a hypoplastic bone marrow, the result is drug-induced aplastic anemia.  Drugs can affect RBCs by causing a number of different anemias, including: drug-induced immune hemolytic anemia, drug-induced oxidative hemolytic anemia, or drug-induced megaloblastic anemia. The ↓ in WBC count alone by a medication is drug-induced agranulocytosis. A drug-induced ↓ in platelet count is drug-induced thrombocytopenia. DRUG-INDUCED APLASTIC ANEMIA ▪ is a rare, serious disease of unclear etiology. ▪ is the most serious DIHDs because of its associated high mortality rate compared with other blood dyscrasias. Acquired aplastic anemia: ▪ is characterized by pancytopenia (anemia, neutropenia, & thrombocytopenia) with a hypocellular BM. Bone marrow ▪ Its major etiologies: 1-direct toxicity, 2- metabolite toxicity, & 3- immune-mediated mechanisms (most common cause) Examples: Antineoplastic agents represent the dose-dependent mechanism for the development of aplastic anemia. Many of these agents have the ability to suppress one or more cell lines in a reversible manner. The degree of suppression & the cell line involved depend on the nature of the particular drug & its potential for inhibiting BM proliferation.  Chloramphenicol causes: (i) dose dependent & reversible BM suppression which is usually mediated through intermediate metabolites that bind to proteins & DNA to cause BM failure. (ii) Idiosyncratic drug-induced aplastic anemia secondary to direct toxicity can be characterized by: ▪ dose independence, ▪ a latent period before the onset of anemia, & ▪ continued BM injury after drug discontinuation. The idiosyncratic mechanism is believed to result from abnormal metabolism of chloramphenicol. The nitrobenzene ring on chloramphenicol is thought to be reduced to form a nitroso group on the chloramphenicol molecule.  The nitroso group may then interact with DNA in the stem cell, causing chromosomal damage & eventually cell death. Phenytoin & carbamazepine thought to induce aplastic anemia through toxic metabolites. Drugs Associated with Aplastic Anemia: Antineoplastic agents, Carbamazepine, Captopril, Chloramphenicol, Chloroquine, Chlorpromazine, Dapsone, Furosemide, Gold salts, Lisinopril, Lithium, Penicillamine, Phenobarbital, Phenytoin, Propyl thiouracil, Sulfonamides, Pentoxifylline DRUG-INDUCED HEMOLYTIC ANEMIA Its causes can be divided into two categories: I. Drug-Induced Immune Hemolytic Anemia ▪ IgG or IgM (or both) binds to antigens on the surface of RBCs & initiates their destruction through the complement & mononuclear phagocytic systems. ▪ involve the formation of antibodies directed against RBCs. Such antibodies are of two main types: (i)Drug-independent antibodies are those that are found even in the absence of the drug. (ii)Drug-dependent antibodies are those will only react in the presence of drug, and are the more common form of antibodies causing drug-induced immune hemolytic anemia.  penicillin & cephalosporin derivatives, when given in high doses, are primarily associated with this type of immune reaction. Of the cephalosporins, cefotetan & ceftriaxone are the agents most commonly associated with drug-induced immune hemolytic anemia. Other drugs that have been reported to cause drug-induced immune hemolytic anemia by this process include minocycline, tolbutamide & streptomycin. II. Drug-Induced Oxidative Hemolytic Anemia: - As a hereditary condition, drug-induced oxidative hemolytic anemia, most often accompanies a glucose-6-phosphate dehydrogenase (G6PD) enzyme deficiency, that can occur because of other enzyme defects (reduced nicotinamide adenine dinucleotide phosphate [NADPH] methemoglobin reductase or reduced glutathione peroxidase). - A G6PD deficiency is a disorder of the hexose monophosphate shunt, which is responsible for producing NADPH in RBCs, which in turn keeps glutathione in a reduced state.  Reduced glutathione is a substrate for glutathione peroxidase, an enzyme that removes peroxide from RBCs, thus protecting them from oxidative stress. Without reduced glutathione, oxidative drugs can oxidize the sulfhydryl groups of hemoglobin, removing them prematurely from the circulation (i.e., causing hemolysis). Drugs Associated with Oxidative Hemolytic Anemia: Dapsone, ascorbic acid, metformin, nalidixic acid, nitrofurantoin, Primaquine, Sulfamethoxazole DRUG-INDUCED MEGALOBLASTIC ANEMIA the development of RBC precursors called megaloblasts in the BM is abnormal. - Deficiencies in either vitamin B12 or folate are responsible for the impaired proliferation & maturation of hematopoietic cells→ cell arrest. - These megaloblastic changes are caused by the direct or indirect effects of the drug on DNA synthesis. - Because of their pharmacologic action on DNA replication, the antimetabolite class of chemotherapeutic agents is most frequently associated with drug- induced megaloblastic anemia. Methotrexate, an irreversible inhibitor of dihydrofolate reductase, causes megaloblastic anemia in 3% - 9% of patients.  Drugs Associated with Megaloblastic Anemia: Azathioprine, Chloramphenicol, Colchicine, Co-trimoxazole, Cyclophosphamide, 5-Fluorouracil, Hydroxyurea, 6-mercaptopurine, Methotrexate, Phenytoin, Vinblastine ▪ DRUG-INDUCED AGRANULOCYTOSIS ▪ Agranulocytosis is defined as a reduction in the number of mature myeloid cells in the blood (granulocytes & immature granulocytes) to a total count of (0.5 × 109/L) or less. ▪ The cause of drug-induced agranulocytosis is not fully understood, but two mechanisms have been proposed: (i) Direct toxicity to myeloid cells, particularly neutrophils, has been shown with medications such as chlorpromazine, procainamide, dapsone, sulfonamides, carbamazepine, phenytoin, indomethacin, & diclofenac The severity of neutropenia associated with these drugs is often dose dependent. (ii) Immune-mediated subset of agranulocytosis, there are 3 proposed mechanisms of toxicity: 1 hapten mechanism (aminopyrine, penicillin, & gold compounds): involves the drug or its metabolite binding to the membrane of neutrophils or myeloid precursors → antibodies are induced →destroy the cell. 2 immune-complex mechanism (quinidine & quinine): antibodies form complexes with the causative drug, then the immune complex adheres to the target cell, →cell destruction. 3 autoimmune mechanism (levamisole): the drug triggers the production of autoantibodies that react with neutrophils  Drugs Associated with Agranulocytosis β-Lactam antibiotics, Carbamazepine, Carbimazole, Captopril, Chloramphenicol, Chlorpromazine, Clindamycin, Digoxin, Ganciclovir, Gentamicin, Gold salts, Hydralazine, Imipenem– cilastatin, Lamotrigine, NSAIDs, Penicillamine , Phenytoin, Propranolol, Rifampin, Streptomycin, Valproic acid, Vancomycin, DRUG-INDUCED THROMBOCYTOPENIA Thrombocytopenia is usually defined as a platelet count below (100 × 109/L) or greater than 50% reduction from baseline values. Drug-induced thrombocytopenia can result from: ▪ immune- mediated mechanisms: Hapten type reactions: the offending drug binds covalently to certain platelet GPs→ Antibodies are generated → bind to these drug-bound GP epitopes. After the binding of antibodies to the platelet surface, lysis occurs through complement activation or through clearance from the circulation by macrophages.  Hapten-mediated immune thrombocytopenia usually occurs at least 7 days after the initiation of the drug, although it can occur much sooner if the exposure is actually a re-exposure to a previously administered drug. The agents most commonly implicated in immune-mediated thrombocytopenia are quinine, quinidine, gold salts, sulfonamide antibiotics, rifampin, Abciximab ((glycoprotein (GP) IIb/IIIa (GPIIb/IIIa) receptor antagonists)), & heparin ▪ nonimmune-mediated mechanism: such as direct toxicity-type reactions, are commonly associated with chemotherapeutic agents that cause BM suppression→ suppressed thrombopoiesis & ↓ number of megakaryocytes.  Drugs Associated with Thrombocytopenia: Chemotherapeutic agents, Carbamazepine, Phenytoin, Valproic acid, Abciximab, Acyclovir, Amiodarone, Amphotericin B, Aspirin, Atorvastatin, Captopril, Chlorpromazine , Ciprofloxacin, Clopidogrel, Danazol, Digoxin, Heparin, Hydrochlorothiazide, Interferon-α, Isoniazid, Lithium, Low-molecular-weight heparins, Measles, mumps, & rubella vaccine, NSAIDs, Pentoxifylline, Piperacillin, Rifampin, Simvastatin, Tamoxifen, Vancomycin.