Lec 5,6 Toxic response of the blood6_Toxic_response_of_the_blood_.pdfl Oxidative Hemolysis : the...

Assist.Prof. Dr.Bushra Hassan MaroufUniversity of Sulaimani-College of Pharmacy

Toxic response of the blood

February 22, 2020 Toxicology 4th year -Lec 5,6 1

Hematotoxicology:

Hematotoxicology is the study of the adverse effects of exogenous chemicals on blood and blood-forming tissues.


Bone marrow and Blood cells


Why blood or hematopoitic tissue consider as a sensitive target tissue for cytoreductive or antimitotic agents

l The vital functions that blood cells perform.l Blood has high proliferative and regenerative capacity (16

weeks) susceptible to intoxication l Production rate of blood cells is 1 million to 3 million per

second in a healthy adult.l This tissue is also susceptible to secondary effects of toxic

agents that affect the supply of nutrients such as iron, the clearance of toxins and metabolites such as urea, and the production of vital growth factors such as erythropoietin.


What are the consequences of direct or indirect damage to blood cells?

l Hypoxia l Hemorrhage l Infection


Toxicology of Erythron


Xenobiotics may affect

the

• Production of erythrocytes

• Function of erythrocytes

• Survival of erythrocytes

Erythrocytosisor anemia

l There are two general mechanisms that lead to true anemia

l either decreased production or increased erythrocyte destruction.


Toxic responses of erythrocytes include:

Alterations in Red Cell Production: Adult Hb(HbA)


Mechanisms of alteration in RBCs Production and consequences 1. An imbalance between α- and β-chain production of Hb is the basis of congenital thalassemia syndromes and results in decreased hemoglobin production and microcytosis .

2. Xenobiotics can affect globin-chain synthesis and alter the composition of hemoglobin within erythrocytes e.g hydroxyurea, which has been found to increase the synthesis of γ-globin chains.

3. Synthesis of heme requires incorporation of iron into a porphyrin ring. Iron deficiency is usually the result of dietary deficiency or increased blood loss. Any drug that contributes to blood loss, such as NSAIDS, with their increased risk of gastrointestinal ulceration and bleeding, may potentiate the risk of developing iron deficiency anemia.


Mechanisms of alteration in RBCs Production and consequences (cont.)

4. Defects in the synthesis of the porphyrin ring of heme can lead to sideroblastic anemia, with its characteristic accumulation of iron in bone marrow erythroblasts.



5. Hematopoiesis requires active DNA synthesis and frequent mitoses.

l Folate and vitamin B12 are necessary to maintain synthesis of thymidine for incorporation into DNA . Deficiency of folate and/or vitamin B12 results in megaloblastic anemia,

l A number of xenobiotics may contribute to a deficiency of vitamin B12 and/or folate, leading to megaloblastic anemia



6. Many of the antiproliferative drugs used in the treatment of malignancy predictably inhibit hematopoiesis, including erythropoiesis (although new chemicals, such as amifostine, are being developed that may help protect against the marrow toxicity of these agents)

7. Drug-induced aplastic anemia may represent either a predictable or idiosyncratic reaction to a xenobiotic. This lifethreatening disorder is characterized by :

l Peripheral blood pancytopenia,l Reticulocytopenia, l Bone marrow hypoplasia


Predictable vs idiosyncratic aplastic anemia

l Agents such as benzene and radiation have a predictable effect on hematopoietic progenitors, and the resulting aplastic anemia corresponds to the magnitude of the exposure to these agents.

l In contrast, idiosyncratic aplastic anemia does not appear to be related to the dose of the agent initiating the process.


Pure red cell aplasia

l Is a syndrome in which the decrease in marrow production is limited to the erythroid lineage .

l Pure red cell aplasia is an uncommon disorder that may be due to genetic defects, infection, immune-mediated injury, myelodysplasia, drugs or other toxicants.

The drugs most clearly implicated include:l isoniazidl phenytoinl azathioprine. The mechanism of drug-induced pure red cell aplasia is unknown, but some evidence suggests that it may be immune-mediated


Alterations in the Respiratory Function of Hemoglobin

l Hemoglobin transports oxygen and carbon dioxide between the lungs and tissues.

l The ability of hemoglobin is dependent on both 1. intrinsic (homotropic) ?2. extrinsic (heterotropic) ?

l Envoronmental and therapeutic agents associated with Methemoglobinemia ???


Class Activity-Reference: page 532-534 Casarett and Doull's The basis science of Poison edition 8

Alterations in the Respiratory Function of Hemoglobin

Class Activity

Hemoglobin-oxygen dissociation curves ?


Class Activity

• The normal erythrocyte has metabolic mechanisms for reducing heme iron back to the ferrous state; these mechanisms are normally capable of maintaining the concentration of methemoglobin at less than 1% of total hemoglobin, what are these mechanisms?

Alterations in Erythrocyte Survival

l The normal survival of RBC → 120 days.l Then erythrocytes are removed by the spleen, where the iron

is recovered for reutilization in heme synthesis.l Red cell destruction lead to : Anemia


The acquired hemolytic anemias

The acquired hemolytic anemias are often divided

into:

Nonimmune Hemolytic Anemia

Immune Hemolytic Anemia


1. Non-immune Hemolytic Anemia

l Microangiopathic Anemias: The formation of fibrin strands in the microcirculation is a common mechanism for RBC fragmentation

l Mechanical Injuries: March hemoglobinuria. The erythrocytes appear to be destroyed by mechanical trauma in the feet. Major thermal burns, are also associated with a hemolytic process.

l Infectious Diseases: : malaria, babesiosis, clostridial infections


1. Non-immune Hemolytic Anemia (cont.)

l Oxidative Hemolysis : the normal respiratory function of erythrocytes generates oxidative stress on a continuous basis.


1. Non-immune Hemolytic Anemia (cont.)

• Nonoxidative Chemical-Induced Hemolysis• Exposure to some xenobiotics is associated with hemolysis

without significant oxidative injury. • Arsenic hydride is a gas that is formed during several industrial

processes. Inhalation of the gas can result in severe hemolysis, with anemia, jaundice, and hemoglobinuria.

• Lead poisoning is associated with defects in heme synthesis and a shortening of erythrocyte survival.

• Excess copper has been associated with hemolytic anemia• Ingestion of excess chromium may result in a hemolytic anemia

and thrombocytopenia


2. Immune mediated hemolytic anemia

Immunologic destruction of erythrocytes is mediated by the interaction of IgG or IgM antibodies with antigens expressed on the surface of the erythrocyte, In the case of autoimmune hemolytic anemia, the antigens are intrinsic components of the patient's own erythrocytes.


Mechanisms of Immune mediated hemolytic anemia

A number of mechanisms have been implicated in xenobiotic mediated antibody binding to erythrocytes.

1. Some drugs, of which penicillin is a prototype, appear to bind to the surface of the cell, with the “foreign” drug acting as a hapten and eliciting an immune response. The antibodies that arise in this type of response only bind to drug-coated erythrocytes.


Mechanisms of Immune mediated hemolytic anemia

2. Other drugs, of which quinidine is a prototype, bind to components of the erythrocyte surface and induce a conformational change in one or more components of the membrane.

3. A third mechanism, for which α-methyldopa is a prototype, results in production of a drug-induced autoantibody that cannot be distinguished from the antibodies arising in idiopathic autoimmune hemolytic anemia


Immune hemolytic anemia


Toxicology of the Leukon

l Components of Blood Leukocytes


Toxic effects on Granulocytes

Effects on Proliferation lThe high rate of proliferation of neutrophils makes their progenitor and precursor granulocyte pool particularly susceptible to inhibitors of mitosis. Such effects by cytotoxic drugs are generally nonspecific. ? (i.e they similarly affect cells of the dermis, gastrointestinal tract, and other rapidly dividing tissues )


Examples

l Methotrexate,l Cytosine arabinoside, l Daunorubicin, l Cyclophosphamide, l Cisplatin, l Nitrosureasl are toxic to resting and actively dividing cells, in which

maximum effects usually are seen 7 to 14 days after exposure.


l Myelotoxicity in clinical medicine today is most commonly seen with cytoreductive cancer chemotherapy agents.

l However, this is changing ? How?


How ?

l Development of drugs with cancer cell–specific molecular targets that are relatively bone marrow sparing.

l Cotreatment with hematopoietic growth factors successfully rescues patients from the effects of myelosuppression such as granulocyte colony- stimulating factor (G-CSFs) filgrastim and the longer acting pegfilgrastim.


Toxic effects on Granulocytes

• Effects on Function • Ethanol and glucocorticoids, which impair phagocytosis and

microbe ingestion in vitro and in vivo. • Iohexol and ioxaglate, components of radiographic contrast

media, have also been reported to inhibit phagocytosis.• Superoxide production, required for microbial killing and

chemotaxis, has been reported to be reduced in patients using parenteral heroin as well as in former opiate abusers on long-term methadone maintenance


Idiosyncratic Toxic Neutropenia

l Mechanisms of idiosyncratic damage often do not relate to pharmacologic properties of the parent drug, which makes managing this risk a particular challenge to hematologists and toxicologist.

l Chemicals that unexpectedly damage neutrophils and granulocyte precursors are of great concern of inducing agranulocytosis=without granulocyte=granulopenia which is characterized by a profound depletion in blood neutrophils to less than 500 µL−1


Mechanisms of Toxic Neutropenia

l Immune-mediated neutropenia: Antigen-antibody reactions lead to the destruction of peripheral neutrophils, granulocyte precursors or both, An immunogenic xenobiotic can act as a hapten, where the chemical must be physically present to cause cell damage, or may induce immunogenic cells to produce antineutrophil antibodies that do not require the drug to be present. Examples of Drug-induced autoimmune neutropenia

l Fludarabinel Propylthiouracil l Rituximab


Leukemogenesis as a Toxic Response

Human LeukemiasLeukemias are proliferative disorders of hematopoietic tissue that originate from individual bone marrow cells. They have been classified as myeloid or lymphoid, referring to the major lineages for erythrocytes/granulocytes/thrombocytes and lymphocytes, respectively.


Mechanisms of Toxic Leukemogenesis

l Acute myelogenous leukemia (AML) is the dominant leukemia associated with drug or chemical exposure, followed by Myelodysplastic syndrom (MDS). This represents a continuum of one toxic response that has been linked to cytogenetic abnormalities, particularly the loss of all or part of chromosomes 5 and 7.

l Some of the same changes have been observed in AML patients who have been occupationally exposed to benzene.


Leukemogenic Agents

l Most alkylating agents used in cancer chemotherapy can cause MDS and/or AML (cyclophosphamide, melphalan, busulfan,chlorambucil, and nitrosurea compounds such as carmustine).

l Among the aromatic hydrocarbons, only benzene has been proven to be leukemogenic.

l Treatment with the topoisomerase II inhibitors etoposide and teniposide can induce AML.

l Exposure to high-dose - or x-ray radiation has long been associated with ALL, AML, and CML, as has been demonstrated in survivors of the atomic bombings of Nagasaki and Hiroshima.

l Other controversial agents include 1,3-butadiene, nonionizing radiation (electromagnetic, microwave, infrared, visible, and the high end of the ultraviolet spectrum), and cigarette smoking.


Toxicology of Platelets and Hemostasis

• What is Hemostasis? Is a multicomponent system responsible for preventin the loss of blood and maintaining circulating blood in a fluid state

• The major constituents of hemostatic system: 1. Circulating platelets, 2. A variety of plasma proteins, 3. Vascular endothelial cells.

Alterations in these components or systemic activation of this system can lead to the clinical manifestations of deranged hemostasis, including excessive bleeding and thrombosis.


Platelets and platelets aggregation


Toxic Effects on Platelets

Mechanisms of immune-mediated platelet destruction byxenobiotics:

1. Some drugs, such as penicillin, function as haptens, binding toplatelet membrane components and eliciting an immune responsethat is specific for the hapten. The responding antibody thenbinds to the hapten on the platelet surface, leading to removal ofthe antibody-coated platelet from the circulation.


2. A second mechanism of immune thrombocytopenia is initiated by xenobiotic-induced exposure of a neoepitope on a platelet membrane glycoprotein. Change in a platelet membrane glycoprotein caused by the xenobiotic (quinidine is a prototype) elicits an antibody response. The responding antibody binds to the altered platelet antigen in the presence of drug, resulting in removal of the platelet from the circulation by the mononuclear phagocytic system.


3. Thrombocytopenia is an uncommon but serious complication of inhibitors of factors (GPII b/IIIa) involved in the clot-formation cascade (abciximab). These inhibitors can change the comformation of those factors, causing exposure of certain peptides (called neoepitopes because they are newly exposed to the immune system) on the factors that react with endogenous antibodies. This leads to phagocytosis of the platelets associated with these factors. Thus, exposure of epitopes that react with naturally occurring antibodies represents a third mechanism of immune-mediated platelet destruction

l(the reaction is dependent on antibodies formed prior to exposure to drug)


4. Heparin-induced thrombocytopenia represents a fourth mechanism of immune-mediated platelet destruction.

Antibodies react with a multimolecularcomplex formed by the interaction between heparin and a protein; platelet factor 4 (PF 4)

When concentrationof heparin to PF 4 is appropriate, the complex is formed, which is associated with exposure of a neoepitope on PF 4 & IgG developed

During the processof platelet activation, platelet microparticles that promote thrombin generation are released.


Toxic Effects on Platelet Function

Major drug groups that affect platelet function include:

lNonsteroidal anti-inflammatory agents; -lLactam-containing antibiotics; lCardiovascular drugs, particularly beta blockers; lPsychotropic drugs; anesthetics;l Antihistamines; andl Some chemotherapeutic agents.


Toxic Effects on Platelet Function (Cont.)

Xenobiotics may interfere with platelet function through a variety of mechanisms. l Some drugs inhibit the phospholipase A2/cyclooxygenase

pathway and the synthesis of thromboxane A2 (e.g., nonsteroidal anti-inflammatory agents).

l Other chemicals appear to interfere with the interaction between platelet agonists and their receptors (e.g., antibiotics, ticlopidine, clopidogrel).

l As the platelet response is dependent on a rapid increase in cytoplasmic calcium, any agent that interferes with the translocation of calcium may inhibit platelet function (e.g., calcium channel blockers).


Toxic Effects on Fibrin Clot Formation

l The most common toxic effect of xenobiotics on fibrin clot formation are related to a decreased level of one or more of the critical proteins necessary for this process.

l The decrease in clotting factor activity may be due to decreased synthesis of the protein(s) or increased clearance from the circulation.


Decreased Synthesis of Coagulation Proteins

l Most proteins involved in the coagulation cascade are synthesized in the liver. Therefore, any agent that impairs liver function may cause a decrease in the production of coagulation factors.

l Factors II, VII, IX, and X are dependent on vitamin K for their complete synthesis. Anything that interferes with the absorption of vitamin K from the intestine or with the reduction of vitamin K epoxide (oxidized) may lead to a deficiency of these factors and a bleeding tendency .


Decreased Synthesis of Coagulation Proteins

Warfarinandanalogs Intravenous-tocopherol

Rodenticides(e.g.,brodifacoum) Dietarydeficiency

Broad-spectrumantibiotics Cholestyramineresin

N-Methyl-thiotetrazolecephalosporins Malabsorptionsyndromes

Conditions Associated with Abnormal Synthesis of Vitamin K–Dependent Coagulation Factors


Increased Clearance of Coagulation Factors

l Idiosyncratic reactions to xenobiotics include the formation of antibodies that react with coagulation proteins, forming an immune complex that is cleared rapidly from the circulation and resulting in deficiency of the factor.


Toxicology of Agents Used to Modulate Hemostasis

l Oral Anticoagulants (warfarin) interfere with vitamin K metabolism by preventing the reduction of vitamin K epoxide (oxidized), resulting in a functional deficiency of reduced vitamin K.

l Heparin: The major complication associated with heparin therapy is bleeding



l Fibrinolytic Agents: dissolve pathogenic thrombi l The toxicology of the fibrinolytic drugs can be divided into :l Toxic effects of systemic plasmin activation (Systemic

fibrinolysis) l Toxic effects of the activators themselves (Acute allergy).All these effects potentiate the risk of bleeding. l Streptokinase is a protein derived from streptococci and it is

antigenic in humans. Antibody formation to streptokinase occurs commonly in association with streptococcal infections as well as exposure to streptokinase.

l Acute allergic reactions may occur in 1-5% of patients exposed to streptokinase.



plasminogen is an inactive precursor, convert to plasmin, an active proteolytic enzyme. Plasmin is normally tightly regulated and is not freely present in the circulation. However, administration of fibrinolytic drugs regularly results in the generation of free plasmin leading to systemic fibrin(ogen)olysis


l Inhibitors of Fibrinolysisl Tranexamic acid and -aminocaproic acid are small molecules

that block the binding of plasminogen and plasmin to fibrin. Although relatively well tolerated, there is some evidence that administration of these chemicals may increase the risk of thrombosis, due to the inhibition of the fibrinolytic system

l Aprotinin is a naturally occurring polypeptide inhibitor of serine proteases (plasmin) it is immunogenic when administered to humans.


Lec 5,6 Toxic response of the blood6_Toxic_response_of_the_blood_.pdfl Oxidative Hemolysis : the...

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