Hematology Flashcards
Oral Iron Therapy
Subject to the regulatory mechanism provided by the intestinal uptake system
No need to monitor iron storage levels
Ferrous iron (Fe2+) is used, because it is best absorbed Ferrous sulfate, Ferrous gluconate
Iron therapy should be continued for 3-6 months after correction of iron loss
Adverse Effects: Oral Iron Therapy
Adverse effects: epigastric discomfort, abdominal cramps, constipation, diarrhea
Dose-related-can be remedied by backing off the dose
Patient may have fewer adverse effects with one iron salt than another
Parenteral Iron Therapy: Iron Dextran
Adverse effects: headache, light-headedness, fever, nausea, vomiting
rarely anaphylaxis may occur due to the dextran component-a small test dose should always be given
Caution with patients with a strong history of allergy or who have previously received iron dextran
Since the intestinal regulatory system is bypassed, more iron can be delivered than can be safely stored in intestinal cells and macrophages
Parenteral Iron Therapy: Iron Sucrose Complex,
Sodium Ferric Gluconate Complex
Iron Sucrose Complex, Sodium ferric gluconate complex
May only be given IV
Less likely to induce a hypersensitivity reaction
Iron Toxicity
As few as 10 tablets of commonly available oral iron salts can be lethal in young children
Starts with necrotizing gastroenteritis, followed by lethargy, shock, dyspnea-there is then improvement, but this may be followed by severe metabolic acidosis, coma, death
Urgent treatment is necessary-whole bowel irrigation and treatment with deferoxamine
Chronic iron toxicity (e.g., hemochromatosis) can be treated with deferasirox
Deforoxamine
Treatment for iron toxicity
Urgent treatment is necessary-whole bowel irrigation and treatment with deferoxamine
Deferasirox
Chronic iron toxicity (e.g., hemochromatosis) can be treated with deferasirox
Vitamin B12 Deficiency
Megaloblastic, macrocytic anemia
Leukopenia and/or thrombopenia
Hypercellular bone marrow
Neurological deficits: paresthesia, weakness, spasticity, ataxia, dementia
Usually due to malabsorption rather than a nutritional deficiency, especially in the elderly
Vitamin B12
B12-porphyin-like ring w/ a central cobalt atom + a nucleotide-organic groups may covalently bind to cobalt, forming different cobalamins
Deoxyadenosyl-cobalamin and methylcobalamin are the active forms of the vitamin in humans
Cyanocobalamin and hydroxycobalamin are found in food sources and drugs-converted to active form
Source of B12 is from microbial synthesis-not made by plants or animals-get it from microbially derived b12 found in meat, egg, dairy-sometimes called extrinsic factor
B12 Absorption
Absorbed only after complexing with intrinsic factor, which is secreted by the cell of the gastric mucosa
B12-intrisic factor complex is absorbed in the distal ileum via a receptor-mediated transport system
Once absorbed, B12 is transported to the various cells of the body bound to transcobalamin II
Excess B12 goes to the liver for storage
Erythropoietin
Endogenous erythropoetin is produced by the kidneys
When there is tissue hypoxia, erythropoietin synthesis is increased in order correct the anemia
There is an inverse relationship between hematocrit/hemoglobin levels and erythropoietin levels, except in renal failure
Stimulates erythroid proliferation and differentiation by interacting with erythropoietin receptors on red cell progenitors; can also induce induce release of reticulocytes from the bone marrow
EPO receptors signal through the JAK/STAT kinase pathway
Darbepoetin alpha
Glycosylated EPO
Mainly used in patients with anemia of chronic renal failure
May also be useful for treatment of anemia due to primary bone marrow disorders and secondary anemias, if the patient has disproportionally low serum EPO levels for their degree of anemia
Romiplostim
Peptide bound to a Fc portion of a human antibody that activates thrombopoetin receptors on megakaryocytes to stimulate platelet production
For use in pts with chronic immune thrombocytopenia, but NOT for use in pts with thrombocytopenia due to myelodysplastic syndrome or chemotherapy
Eltombopag
Small molecule thrombopoeitin receptor agonist
Reserved for pts with severe ITP that fail to respond to other tx
IL-11/Oprelvekin (recombinant IL-11)
Stimulates the growth of multiple lymphoid and myeloid cells for patients with thrombocytopenia due to chemotherapy
Acts synergistically with other growth factors to stimulate the growth of primitive megakaryocytic precursors
Increases the number of peripheral platelets and neutrophils
Side effects: fatigue, headaches, dizziness
Indirect Thrombin Inhibitors
Examples: Heparin, LMWH, Fondaparinux
inhibitors-bind to antithrombin and increases the rate at which antithrombin inhibits coagulation factors
Antihrombin can inhibit factors Xa, IIa, IX, VII and V
conformational change occurs that exposes the active site on antithrombin for more rapid interaction with proteases- particularly factor Xa
Act as cofactor for the antithrombin-protease reaction without being consumed; released intact from the complex for renewed binding to more antithrombin
Heparin
All of these compounds have the pentasaccaride-this is what binds to antithrombin and induces the conformational change;
heparin, because of its large size efficiently accelerates the rate of Xa and IIa inhibition
must monitor activated partial thromboplastin time to ensure therapeutic level has been reached
Usually given via continuous IV infusion
Can be reversed with Protamine Sulfate
Can cause Heparin-induced thrombocytopemia; development of IgG antibodies against heparin bound to platelet factor 4, leading to thrombosis and thrombocytopenia
LMWH, fondaparinux:
More predictable pharmacokinetics vs. heparin when given subcutaneously
No monitoring needed
Heparin-induced thrombocytopenia
Immune complex formation between heparin and platelet factor 4
Complex is seen as a foreign substance
Antibodies are formed against the complex=destruction of platelets
Platelet disruption leads to formation of new clots and may result in a deep vein thrombosis, pulmonary embolism, heart attack or stroke
An alternative anticoagulant must be used, e.g., a direct thrombin inhibitor
Lepuridin, Desirudin
Recominant derivatives of hirudin
Directly inhibits thrombin by competitively binding to thrombin’s catalytic site and the extended substrate recognition site
May be used in patients with HIT
Caution in those with renal insufficiency
Treatment of Rocky Mountain Spotted Fever
-low threshold for treatment if symptoms after dog-tick or wood-tick bite (abdominal pain, rash on ankles)
Doxycycline for adults and children (risk of brown teeth vs high risk of death)
Chloramphenicol for pregnant women
other blood-borne bacteria:
- Orientia Tsutsugasmushi: doxycycline or chloramphenicol
- Coxiella Burnetii: doxycycline
- Ehrlichia chaffeensis: doxycycline
Bartonella sp.: azithromycin or erythromycin
Tetracycline
inhibits protein synthesis in bacteria
mRNA attaches to the 30s subunit or rRNA. The P site of 50s rRNA contains nascent polypeptide chain. Tetracycline binds the A site, therefore charged tRNA cannot enter to add to the polypeptide
Chloramphenicol
Binds 50s rRNA subunit at peptidyltransferase site and inhibits the transpeptidation rxn.
Same binding site as clindamycin and macrolides so these agents interfere with binding of chloramphenicol.
Toxicity: anemia, leukopenia, thrombocytopenia; also an idiosyncratic response by aplastic anemia.
Chloroquine
Antimalarial
1-2 month half life
Accumulates in the food vacuole of parasite and inhibition of the formation of hemozoin from the heme released by digesting hemoglobin.
Resistance: decreased accumulation in the food vacuole.
Does not eradicate hepatic forms so must be used with primaquine to eradicate P. vivax and P. ovale
mefloquine, lumefantrine, quinine have similar MOA’s
Primaquine
Antimalarial
converted to electrophiles that generate ROS that interferes with e- transport in parasite
Atovaquone
Antimalarial
interferes with e- transport in the mitochondria of malarial protozoa
Artesunate
release of actice oxygen species from endoperoxide bond kills the malarial parasite
Artemether-lumefantrine
ACT partner drug combo that assures sustained antimalarial action by overcoming Artemether’s short half-life and is actice against multi-drug resistant P. falciparum
Pyrimethamine-sulfadoxine
synergistically inhibits plasmodial DHF reductase/thymidylate synthase and PABA utilization.
Resistance has limited its use
Proquanil
Inhibits DHF reductase/ thymidylate synthase; actice against both primary liver and asexual red cell stages.
Clindamycin
Binds 50s subunit of bacterial ribosomes to suppress protein synthesis by inhibiting translocation step like the macrolides.
Babesia have eukaryotic cytoplasmic ribosome so cilndamycin is ineffective; however, their mitochondria and plastid ribosomes are prokaryotic.
Azithromycin
same MOA as macrolides but differs from erythromycin b/c of its lactone ring, which reduces drug interactions due to cytochrome P-450
Quinine and Quinidine
same MOA as chloroquine
differ from each other at the carbon bearing the secondary alcohol
Acute Lymphoblastic Leukemia
Hoezler/Linker based protocol
Phase 1 (1-4 weeks): vincristine, prednisone, daunorubicin, L-asparaginase
Phase II (5-8 weeks): cyclophospamide, cytarabine and 6-mercaptopurine
prednisone induces apoptosis in lymphocytes to produce quick but short lived remission
L-Asparaginase
deprives lymphoblastic leukemic cells of Asparagine by converting it to Asparatate
Tumor cells can’t synthesize Asparagine
Asparaginase is a tetramer made of a pair of dimers. Each dimer binds one molecule of asparagine.
Treatment for ALL phase I
Acute Myelogenous Leukemia
For most types, AML is treatment is built around cytarabine (Ara-C):
7+3: Cytarabine for 7 days and daunorubicin or idarubicin or mitoxanthrone days 1-3.
HDAC: High-Dose Ara-C (cytarabine)
Gemtuzumab ozogamicin – accelerated FDA-approval agent that was recently removed from the market due to prolonged myelosupression and hepatocellular damage in 40% of patients.
For acute promyelocytic leukemia (APL) with an aberrant retinoic acid receptor-alpha, treatment is by all-trans-retinoic acid (ATRA) plus daunorubicin or idarubicin. Arsenic trioxide for a second remission in relapsed patients after ATRA treatment.
Cytarabine
The trans 2’ OH group of cytarabine inhibits DNA chain elongation after the activated cytarabine-triphosphate is incorporated into DNA (steric hindrance of base rotation). Resistance is by cytidine deaminase and dCMP deaminase as well as deficiency of deoxycytidine kinase (no phosphorylation to active form).
Idarubicin and Mitoxantrone
Idarubicin acts like doxorubicin
Like doxorubicin and idarubicin, mitoxanthrone intercalates with DNA and binds to topoisomerase II to inhibit chromosome separation in mitosis, but it cannot be reduced in the presence to iron to form semiquinones (no 4th ring). Hence, no oxygen radicals are formed yielding lower cardiac toxicity.
Chronic lymphocytic leukemia (CLL)
Withhold treatment in asymptomatic, early-stage patients (watchful waiting).
CLL is treated with fludarabine, cyclophosphamide, rituximab (sometimes in combination), alemtuzumab, ofatumumab, chlorambucil, bendamustine.
Chlorambucil is metabolized to active phenyl acetic acid mustard. Given orally, it generally is well tolerated
Bendamustine and its active metabolites act as an alkylator with rapidly reversible myelosuppression and mucositis that are tolerable.
Fludarabine/ Cladribine
A fluorinated purine analog is fludarabine. It inhibits DNA polymerase, is incorporated in DNA and RNA, and promotes apoptosis. It is used to treat chronic lymphocytic leukemia. Cladribine is the chlorinated version of fludarabine. Both agents are resistant to deamination, which is the major resistance for cytarabine.
CML
Chemotherapy with Gleevec (imatinib mesylate)- first-choice therapy, often in combination with hydroxyurea. Imatinib resistance has led to the use of dasatinib or nilotinib.
Allogeneic stem cell transplantation (allo-SCT)
Interferon-alpha and busulfan treatments- no longer used
CML is characterized by a 9;22 translocation known as the Ph chromosome. The product of this fusion gene is Bcr-Abl tyrosine kinase, which is thought to be leukemogenic
Gleevec is an inhibitor of Bcr-Abl kinase
Inhibition of Bcr-Abl kinase is an effective therapy for CML
Hydroxyurea
Hydroxyurea inhibits ribonucleoside diphosphate reductase to block the conversion of ribonucleotides to deoxyribonucleotides, a crucial step in DNA synthesis
Imatinib/ Dasatinib/ Nilotinib
Imatinib inhibits the closed or inactive configuration of BCR-ABL kinase. It binds the ATP site to inhibit the tyrosine kinase actiivity. Used to treat Chronic Myelogenous Leukemia.
Dasatinib inhibits both the closed and open (active) configurations of BCR-ABL kinase.
Nilotinib has increased potency and specificity for BCR-ABL kinase due to rational design based on the structure of the enzyme and overcomes mutations that cause imatinib resistance.
Hairy Cell Leukemia (HCL)
First choice drugs: cladribine and pentostatin if disease progresses and symptoms appear.
Rarely, patients who don’t respond to chemotherapy or have discomfort because of a very enlarged spleen (caused by leukemia cells growing in the spleen) may have the organ removed by surgery (splenectomy).
Rituximab also shows promise.
Pentostatin
Pentostatin is a potent inhibitor of adenosine deaminase, which leads to build-up of adenosine and deoxyadenosine nucleotides. This blocks DNA synthesis by inhibiting ribonucleotide reductase that produces the deoxynucleotides.
Hodgkin’s Disease or Lymphoma
Treatment by MOPP: Mechlorethamine, vincristine (Oncovin), procarbazine, prednisone. (Classic)
ABDV: Doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine. (Newer)
Non-Hodgkin’s Lymphoma (NHL)
Treatment depends on the grade of NHL: low, low/intermediate, high/intermediate or high-grade.
For advanced high/intermediate-grade NHL: R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone
R-EPOCH (dose adjusted): Rituximab, etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide, filgrastim using neutrophil count as a marker.
Multiple Myeloma
bortezomib, dexamethasone and thalidomide or lenalidomide.
bortezomib, pegylated liposomal doxorubicin, dexamethasone
High-dose melphalan or cyclophosphamide and prednisone, followed by bone marrow or peripheral blood stem cell rescue (transplantation).
Melphalan is a direct alkylator similar to mechorethamine
Thalidomide
More than a teratogen
Anti cancer drug:
. Direct anti-MM effect on tumor cells including G1 growth arrest and/or apoptosis, even against MM cells resistant to conventional therapy. This is due to the disruption of the anti-apoptotic effect of Bcl-2 family members, blocking NF-B signaling, and inhibition of the production of IL-6. B. Inhibition of MM cell adhesion to bone marrow stromal cells due partially to the reduction in IL-6 release. C. Decreased angiogenesis due to the inhibition of cytokine and growth factor production and release. D. Enhanced T-cell production of cytokines, such as IL-2 and IFN-, that increase the number and cytotoxic functionality of natural killer (NK) cells.
Bortezomib
inhibitor of proteasome-mediated protein degradation of IκB, preventing the activation of NF-κB, leading to apoptosis. Central role in treatment of multiple myeloma.
Naked Monoclonal Antibodies (Mab)
Rituximab is used to treat B cell non-Hodgkin lymphoma. It is a monoclonal antibody against the CD20 antigen, found on B cells.
Ofatumumab is a Mab that binds to CD20 at different site from that targeted by rituximab.
Alemtuzumab is an antibody against the CD52 antigen, which is present on both B cells and T cells. It is used to treat B cell chronic lymphocytic leukemia (B-CLL).
Naked monoclonal antibodies kill tumor cells by:
ADCC: antibody-dependent cellular cytotoxicity
CDC: complement-dependent cytotoxicity
Rituximab
RITUXIMAB bound to a protein on the CD20 antigen found on the surface of normal and malignant B lymphocytes. The Fab domain of Rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro.
Conjugated monoclonal antibodies
Conjugated monoclonal antibodies are joined to drugs, toxins, or radioactive atoms. They are used as delivery vehicles to take those substances directly to the cancer cells. The MAb acts as a homing device, circulating in the body until it finds a cancer cell with a matching antigen. It delivers the toxic substance to where it is needed most, minimizing damage to normal cells in other parts of the body.
Gemtuzumab ozogamicin consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic, linked to a recombinant monoclonal antibody. HP67.6 represents the humanized monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML).
Bivalirudin
Directly inhibits thrombin
Alternative to heparin in patients undergoing coronary angioplasty
Agatroban
Binds reversibly to the catalytic site of thrombin
Metabolized by P450-caution in those with hepatic insufficiency
Warfarin
MOA: inhibits Vitamin K reductase. No reduced vitamin K for use in carboxylation reactions.
Clinical use: to prevent progression/reoccurrance of deep vein thrombosis or pulmonary embolism; also used in acute MI and chronic atrial fibirllation. Given orally
Toxicity: birth defects; bleeding
Drug Interactions, C/I
Avoid drugs that inhibit CYP2C9 (e.g., fluxoetine, cimetidine, clopidogrel)
No vitamin K: will reduce anticoagulant effects by increasing activation of clotting factors
Reversal of Action: excess bleeding can be stopped by vitamin K or recombinant Factor VIIa
Due to warfarin’s long t1/2, a single dose may not be sufficient to reverse its effect
oral anticoagulants
Dabigatrin etexilate
MOA: reversible blockade of thrombin active site_._No monitoring needed
Rivaroxaban
MOA: oral Xa inhibitor
No monitoring needed
Fibrinolytics
Lyse thrombi by catalyzing the formation of plasmin from plasminogen
Clinical uses:
Acute MI
Acute ischemic stroke
Tissue plasminogen activator (t-PA): preferentially activates plasminogen bound to fibrin, which confines fibrinolysis to the thrombus BUT at therapeutic concentrations, the level of t-PA is high, creating a systemic lytic state
Recombinant forms of t-PA: Alteplase, Reteplase, Tenecteplase
Toxicity: hemmorrage, treat OD with aminocaproic acid, an inhibitor of fibrinolysis
Antiplatelet Drugs
Aspirin: COX-1 inhibitor
Dipyramidole, Cilostazol: blocks reuptake of adenosine, leading to increased cAMP
Abciximab: Monoclonal antibody directed against IIb/IIIa receptor complex.
Eptifibatide: Analog of the extreme carboxy terminal sequence of the delta chain of fibrinogen
Platelet ADP Receptor Inhibitors
Ticlopidine: blocks ADP receptors, can cause neutropenia
Clopidogrel: a more potent inhibitor of ADP receptors
Prasugrel: also inhibits ADP receptors; prodrug
Ticagerlor: another ADP receptor antagonist
Inhibit platelet aggregation by irreversibly blocking ADP receptors. Inhibit fribrinogen binding by preventing glycopretoin IIb/IIIa from binding to fibrinogen. (Remember Ib binds vWF)
Used in acutre coronary syndrome, decreasing incidence or recurrence of thrombotic stroke
Tranexamic acid, Aminocaproic acid
Fibronolysis inhibitors used to treat bleeding disorders
MOA: block the interaction of plasmin with fibrin
May also be used to treat bleeding from fibrinolytic therapy
toxicity: intravascular thrombosis, hypotension, abdominal discomfort, diarrhea
Vitamin K
used to treat bleeding disorders
Confers biological activity upon prothrombin and factors VII, IX, and X
Two natural forms exist: K1 and K2
K1-found in food
K2-found in human tissues, and is made by intestinal bacteria
K1 is available clinically in oral and parental forms
Rapid infusion of K1 can produce dyspnea, chest and back pain, death, so go slow when infusing iv
Deficiency occurs most frequently in patients in intensive care units
Plasma fractions used to treat bleeding disorders: Desmopressin, Autoplex, Cryprecipitate
Plasma-derived, heat- or detergent-treated factor concentrates or recombinant factor concentrates are standard therapy for bleeding associated with hemophilia
Desmopressin acetate
Increases factor VIII activity in those with mild hemophilia A or von Willebrand disease
Autoplex, FEIBA (factor eight inhibitor bypassing activity)
Factor IX concentrates that contain activated clotting factors
Used for treating patients with inhibitors or antibodies to factor VIII or IX
Cryoprecipitate
Plasma protein fraction from whole blood
Used to treat deficiencies or qualitative abnormalities of fibrinogen or in patients with factor VIII deficiency and von Willebrand disease
Dimercaprol
Chelator
Antidote against arsenic poisoning
May also be used for acute lead intoxication in conjunction with EDTA
Unstable in aqueous solution, so given as a 10% solution in peanut oil
Must be given i.m. (painful!)
Readily absorbed, metabolized and excreted by the kidney within 4-8h after administration
High incidence of adverse effects:
Hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever (especially in children), pain @ injection site
Succimer
Water-soluable analog of dimercaprol
Protects against the lethal effects of acute arsenic poisoning
Can also be used to increase excretion of lead
Oral formulation only in U.S.
May not be advisable for use in acute arsenic poisoning when severe gastroenteritis and splanic edema may limit its absorption
Adverse side effects are uncommon, but may include:
GI disturbances
Rashes
Edetate Calcium Disodium (EDTA)
Primarily used for the chelation of lead
Should only be administered as calcium disodium salt
Life-threatening depletion of calcium can occur if not given as the calcium disodium salt
Chelates extracellular metal ions due to poor penetration of cell membranes
Poor oral absorption due to highly polar nature
administered i.v.
Oral administration may actually increase lead absorption in the gut
EDTA is rapidly excreted by glomerular filtration; also induces rapid excretion of lead in the urine
Excretion of drug and metals may be delayed in patients with renal insufficiency
C/I in anuric patients
Unithiol
Another water soluble analog of dimercaprol
Increases excretion of arsenic and lead
May be given orally or i.v.
Has no FDA-approved indications, but may be advantageous over i.m. dimercaprol or oral succimer in treating severe acute arsenic poisoning
Can also serve as an alterative to oral succimer in the treatment of lead intoxication
Has a low incidence of side effects
When given i.v., must be given slowly over 15-20 min, as it may cause vasodialation and hypotension
Penicillamine
Derivative of penicillin
Readily absorbed, resistant to metabolic degradation
Primarily used to prevent copper accumulation, but can increase excretion of lead
One-third of patients show adverse effects
Hypersensitivity-exercise caution in patients with a history of penicillin allergy
Nephrotoxicity
Pancytopenia with prolonged use
Deferoxamine
Binds iron avidly
Poorly absorbed when given orally
Can increase iron absorption when given via this route
Does not compete for biologically chelated iron
Chelator of choice for iron poisoning
Usually given i.v. or i.m.
If given i.v., it must be done slowly, as rapid administration can cause hypotension
Adverse idiosyncratic responses have been observed, but generally side effects are minimal
Acute inorganic lead poisoning
Initial therapy-parenteral-limited to <5 days
I.V. EDTA (~30-50 mg/kg/d) by continuous infusion OR
I.M. dimercaprol, followed 4h later by concurrent administration of dimercaprol and EDTA
After 5 days-oral therapy
succimer
*The end point for chelation therapy is the resolution of symptoms or the return of blood lead concentration to the pre-morbid range
RHo(D) immune globulin
Prevents Rh hemolytic disease of the newborn
Consists of plasma-derived IgG that contains a high titer of antibodies against the Rh (D) antigen found on the surface of RBCs
When given 24-72h after the birth of a Rh-(+) infant, Rho (D) immune globulin will suppress the Rh (-)mother’s antibody response to foreign Rho (D)-positive cells
Infant’s RBCs will be cleared from circulation before the mother can generate memory B cells that could produce anti-Rho (D) antibodies if they were to be activated during a subsequent pregnancy with an Rho (D)-positive fetus
Mother must be Rho (D)-negative, or not previously immunized to the Rho (D) factor
Treatment is advised for Rh-negative mothers that have had miscarriage, ectopic pregnancy or abortion; basically, any time when the blood type of the fetus is unknown
Must not be given to the infant
Infrequent adverse reactions
Vemurafenib
Small molecule inhibitor of forms of the B-Raf kinase with the V600E mutation
Used to treat metastatic melanoma
