hematotox - ready to review Flashcards
t/f: blood is not really an important target for hematotoxicity
FALSE! its one of the most important target tissues for chemical toxicity
what are the four main functions of blood/blood cells
delivers oxygen to tissues
delivers immune effectors to tissues
delivers hormonal signals to tissues
delivers drugs to tissues.
why is the hematopoeitic system a prime target for toxic agents affecting cell growth, proliferation, and differentiation
blood has high proliferative and regenerative capacity.
what do all blood cells originate from
multipotential hematopoietic stem cell
what toxicants lead to immune hemolytic anemia
cephalosporins, penicilin, amethylDOPA, oxaliplatin
what toxicants lead to non immune hemolytic anemia
primaquine, chloroqine, dapsone, ribavirin
what toxicants lead to megaloblastic anemia
trimethoprim, pyrimethamine, methotraxate
what toxicants lead to sideroblastic anemia
isoniazid, chloramphenicol, linezolide
what toxicants lead to aplastic anemia
chloramphenicol, gold, NSAIDs, phenytoin
what toxicants lead to immune thrombocytopenia
quinidine, vancomycin, sulfonamides, penicilins.
what toxicants lead to agranulocytosis/neutropenia
rituximab, procainamide, sulfonamide, captopril
what happens in immune hemolytic anemia
RBCs get destroyed. this is triggered by antibodies that react with RBC surface antigens.
what antibodies mediate immune hemolytic anemia
IgG, IgM
this results in complement activation and acute intravascular lysis of the RBC
t/f: all of the antibodies in IHA are drug dependent
false. they can be either drug dep or drug indep
what drugs mediate DIIHA (drug induced immune hemolytic anemia) and what role do they play
drug adsorption - penicillin, cefotetan
autoantibody induction - methyldopa, fludarabine
immune complex - caphalosporin
which drugs are now most responsible for IHA
cephalosporin antibiotics
what are the three key consequences of IHA
anemia - iha leads to a decrease in the number of functional RBCs –> fatigue, weakness, shortness of breath,
jaundice –> the hemolysis releases free hemoglobin, which gets broken down into bilirubin
hemoglobinuria - the kidneys cant handle how much free hemoglobin there is
is favism a type of immune or non immune hemolytic anemia
non immune
what is favism and how is the G6PD involved?
favism = hemolytic anemia assoc with the ingestion of fava beans or inhalation of pollen from fava plants.
when the fava bean glycosides are hydrolysed, this makes divicine and isouramil.
h2o2 gets made in the metabolism of these compounds.
in normal cells (ie: they have normal G6PD), enough NADPH is made, so it can power the GSH that takes care of the ox stress
but in cells with reduced G6PD activity, they have limited NADPH, cant regenerate the GSH, and you get ox stress –> hemolysis.
how does primaquine lead to hemolytic anemia? is this immune or non immune?
non immune
its used to treat malaria.
how it leads:
- oxidized by CYP into 5 hydroxyprimaquine.
- redox cycling leads to ROS production
- ROS attaks the Hb sufhydryl groups and produces Hb - thiyl radicals
- Hb thyil radicals bind to cysteine in the membrane skeletal proteins. the macrophages recognize and destroy the cell
why do anti cancer drugs have adv effects on on blood cells?
bc cancer treatment attacks rapidly proliferating cells ; blood is rapidly prolif.
what role does G6PD play in erythrocyte protection
its the rate limiting enzyme for the production of NADPH in the hexose monophosphate shunt.
NADPH is used by glutathione reductases, converts GSSG to GSH
GSH used for antiox.
how is G6PD deficiency linked to malaria
its an evolutionary advantage against malaria. it increases the toxicith of primaquine and dapsone.
how is G6PD deficiency related to sex
G6PD is found on the X chromosome. so, deficiency is more common and severe in males as they only have one X chromosome
females have two X chroms, thus could be heterozygous for mut, and only intermediate deficiency
what happens in megaloblastic anemia? what deficiencies or drugs can lead to it?
happens when you have deficiences in cobalamin (vit b12) or folate (vit b9). these deficiencies can be drug induced.
can also be when you have drugs that interfere with DNA synthsis. this means they cant progress to M stage of cell cycle. so, the cells grow, but they dont divide, and form megaloblasts.
what are good sources of folate
fruits,s dark leafy green veg and legumes
what are good sources of cabalamin
meat, fish, milk, eggs, fortfied food.
colchicine, cycloserine, ethanol, isoniazid, and metformin are xenobiotics assoc with this contributing factor to megaloblastic anemia:
b12 deficiency
ampicillin, antimetabolites, chloramphenicol, cholestryamine, erythromycin are xenobiotics assoc with this contributing factor to megaloblastic anemia:
folate deficiency
azathioprine, thioguanine, mercaptopurine, fludarabine, pentostatin are xenobiotics assoc with this contributing factor to megaloblastic anemia:
purine metabolism
gemcitabine, hydroxyuream methotrexate, mercaptopurine, fluorouracil are xenobiotics assoc with this contributing factor to megaloblastic anemia:
pyrimidine synthesis.
why is B12 deficiency assoc with megaloblastic anemia (wrt folate)
its needed in the synthesis of TH4 folate.
th4 folate is needed to make dTMP by thymidilate synthase.
this is needed to make DNA. so, imparing DNA synthesis –> megaloblastic anemia.
what happens in sideroblastic anemia
you get impaired synthesis of HEME. this leads to appearance of ring sideroblasts.
- sideroblasts are erthyroblasts that accumulate non heme iron in the mitochondria in a ring around the nucleus.
what chemicals can lead to sideroblastic anemia
lead, isoniazid, pyrazinamide, cycloserine, chloramphenicol, copper deficiency, zinc poisoning, ethanol.
why is copper deficiency related to sideroblastic anemia
coppy is needed for iron metabolism. no copper, you get a build up of iron.
how does lead lead to sideroblastic anemia (what enzymes does it block)
lead blocks the enzymes ALAD and FECH these enzymes are important in the process of making heme.
blocking them, you get impaired heme synthesis, so iron builds up in the mito, and you’ll see rings.
what happens in aplastic anemia (3 key events)
failure of hematopoeisis:
- the blood forming stem cells are replaced by fat cells
- pancytopenia - you get a reduction in circulating RBCs, WBCs, and platelets.
- reticulocytopenia - you get reduced RBC forming reticulocytes.
t/f: aplastic anemia is never fatal
false. fatal if not managed aggressively.
how can you reverse the progress of aplastic anemia
aplastic anemia can occur indirectly via immune mechanims; immunosup therapies can be used to reverse the progress.
what happens in immune thrombocytopenia (specifically, what is the CAUSE)
you get antibody triggered destruction of platelets by phagocytosis. this leads to reduced amount of platelets, which leads to impaired blood clotting.
what kind of drugs can cause immune thrombocytopenia
drugs that covalently bind to platelet surfaces and act as a hapten (marker for antibody) , drugs that expose a novel epitope on the surface of platelt, drugs that increase the protein binding affinity of naturally occuirng antibodies
what is drug dependent antibody binding and whats its role in immune thrombocytopenia
drug binds to the antibody, alters confirmation of antibody. allows the antibody to bind with a higher affinity to the platelet cell surface.
ie: quinine.
what happens in neutropenia
you get a reduction in the number of circulating GRANULOCYTES.
how is neutropenia treated
you treat with granulocyte colony stimulating factor (G- CSF)
what are the drug induced causes of neutropenia; what drugs can cause each
immune mediated neutrophil destruction by penicilin
complement mediated neutrophil destruction by propylthiouracil
increased neutrophil apoptosis by clozapine
dose dep inhibition of granulopoesis by carbamazepine + valproic acid
direct tox to myeloid precursor cells by clopidogrel …
is agranulocytosis a severe or non severe form of neutropenia
severe
does clozapine induce neutrophil apoptosis? what changes the dosage?
yes
more clozapine, more apop. if tehre is an activating system (peroxidase + h2o2) irt takes a low dose to induce apop
if there is no activating system it takes a high dose.
its the reactive metabolites produced by the perox. metabolism that are likley repsonsible for the apop
what does clopidogrel toxicity to myeloid precursor cells depend on
.* reduction of myeloid precursor colonies is BAD!*
clopidogral reduces the colonies , this reduction (ie toxic effect) is ENHANCED when it is metabolised by CYP3A4
are the metabolites of clopidogrel, or clopidogrel responsible for its toxicity
the metabolites - bc w cyp 3a4 the tox effect is enhanced.
