L4 - Pharmacology Of Anemia Flashcards
What the most common sx of anemia?
Fatigue, dizziness, pale skin, cold hands and feet, shortness of breath and irregular heart beat
What are other sx of anemia?
Low BP, palpitations, rapid heart rate, chest pain, angina, heart attack, splenomegaly, yellowing of the eyes, pale skin, cold skin, SOB, muscle weakness, changes in stool color
Iron loss typically occurs via what?
Routine blood loss and sloughing of cells
No renal mechanism for elimination of excess iron
Iron absorption is regulated by what?
Hepcidin
Capacity of hepcidin to block iron absorption can be overwhelmed by excess intake or bypassed by iron infusion
If there is an increase in hepicidin what occurs?
Decreased iron by blocking ferroportin mediated iron absorption
What are the cases of microcytic anemia?
Reduced iron availability (severe iron deficiency is MC)
Reduced heme synthesis due to lead poisoning, conventional or acquired sideroblastic anemia
Reduced globin production due to thalassemic disorders, other hemoglobinopathies
Rare disorders due to defects in iron absorption, transport, utilization and recycling
Why are RBCs so large in macrocytic anemia?
Erythroblasts doubled their protein in anticipation of division but were unable to synthesize new DNA
Extrusion of nucleus leaves behind a large cell
What needs to be measured if a folate or vitamin B 12 deficiency is suspected?
B12 and folate levels as well as MMA and homocysteine levels
Vitamin B12 is important for what?
Metabolism, the formation of RBCs, and the maintenance of the CNS which includes the brain and spinal cord
Where can vitamin B12 be found?
Found in animal products such as fish, meat, poultry, eggs, milk and milk products
Generally not present in plant foods but fortified breakfast cereals are available for vegetarians
How much vitamin B12 do we need daily?
2 ug/day (usual diet contains 5-7)
How much Vitamin B12 does the body store in the liver?
2-5mg
Because the normal body stores greatly exceed the daily requirement it takes years to develop vitamin B12 deficiency after normal absorption ceases
What can inactivate cyanocobalamin (common form of vitamin B12?
Nitrous oxide, inhaled analgesia during surgery
If body stores of Vitamin B12 are depleted what can occur?
Rapid onset of neurologic dysfunction (e.g. paresthesia, weakness, spasticity) that may not fully reverse
Describe the absorption of vitamin B12
Cbl is liberated from food by actions of acid and pepsin
R factors in saliva and gastric juice bind Cbl
Cbl is freed from R factors in alkaline pancreatic enzyme juice of duodenum
Cbl then finds to IF (which is secreted by parietal cells along with gastric acid)
The IF-Cbl complex then binds to a specific receptor, cubulin, in the ileum and is absorbed in an energy requiring process
What is a common cause of vitamin B12 deficiency?
Pernicious anemia
Other causes include gastrectomy or gastritis and H pylori infection
What can cause pernicious anemia?
Auto Ab formation - two types:
- Blocks IF-Cbl interaction
- Blocks IF-Cbl receptors in ileum
Chronic atrophic gastritis due to auto Abs directed against the H K ATPase of the parietal cells
What are the sx of vitamin B12 deficiency?
Vitiligo, hyperpigmentation and jaundice
Glossitis
Anemia (macrocytic, megaloblastic), neutropenia (hypersegmented neutrophils), thrombocytopenia
Paresthesia, numbness, gait abnormalities, cognitive impairment, irritability, weakness
What is the function of folate in the body?
Aids in the production of RBCs and the synthesis of DNA
Works with B12 and vitamin C to help the body digest and utilize proteins
What are the best sources of folate?
Obtained from yeast, liver, kidney, and green leafy vegetables
What are the daily requirements for folate intake?
Daily requirement is 5-50ug/day but recommended daily allowance is 400ug/day for adults and 800ug/day for pregnant and lactating women
Describe folate absorption
Absorbed in jejunum, enters plasma, rapidly cleared by hepatocytes and other cells where its trapped by polyglutamation
Plasma levels fall within 3 weeks of inadequate intake due to metabolism and urinary excretion
Undergoes extensive enterohepatic circulation; levels fall wihtin 6 hrs if this is disrupted
What is the usual cause of folate deficiency?
Inadequate dietary intake or alcoholism
But malabsorption in jejunum can also be its cause
What are the sx of folate deficiency?
Jaundice, mouth ulcers, macrocytic megaloblastic anmeia, neutropenia, thrombocytopenia, neuropsychiatric sx are rare
Deficiency during pregnancy causes neural tube defects in fetus
The kidney releases erythropoietin in response to what?
Hypoxia
What is the MOA of epoetin Alfa?
A 165 amino acid erythropoiesis stimulating glycoprotein
What are the effects of epoetin Alfa?
Stimulates erythropoiesis
Increases reticulocyte counts in <10 days
What are the clinical applications for epoietin Alfa?
Anemia due to CKD or cancer chemo
Use banned by international Olympic committee
What are the pharmacokinetics for epoetin Alfa?
Administered IV or SC
What are the toxicities of epoetin Alfa?
20-50% have increase DAP >10mmHg despite keeping Hct in 3-35 range
Increased risk of death, MI, stroke, VTE, tumor progression
What is the MOA for hydroxyurea?
Boosts levels of HbF
What are the clinical applications for hydroxyurea?
Only disease modifying therapy approved for sickle cell disease
What are the pharmacokinetics for hydroxyurea?
Administered orally (readily absorbed) Distributed widely
What is the MOA for eculizumab?
A monoclonal Ab that binds to C5 with high affinity and inhibits its cleave to C5a and C5b + prevents generation of terminal complement complex C5b-C9
What are the effects of eculizumab?
Inhibits terminal complement mediated intravascular hemolysis in PNH (RBC lack enough CD59 and CD55 to prevent MAC mediated destruction)
Inhibits complement mediated thrombotic microangiopathy in pts with atypical HUS
What are the clinical applications for eculizumab?
PNH
Atypical HUS
Only available under REMS
What ar the pharmacokinetics for eculizumab?
Given IV over 35 min once per week for 1st 4 weeks
Maintenance doses then given IV every 2 weeks
Was the most expensive drug on the market but so effective that private insurers and nationalized health plans pay for it
What are the toxicities for eculizumab?
Viral infections Life threatening meningococcal infections Immunogenic URI MSK pain Anemia, leukopenia HTN, HA, insomnia, fatigue, UTI
What are the causes of neutropenia?
Cancer or other disease that damages bone marrow
Congenital disorders characterized by poor bone marrow function
Viral infections that destroy neutrophils or bone marrow cells
Overwhelming infections that use up neutrophils faster than they can be produced
Drugs that destroy neutrophils or damage bone marrow (bc of their rapid turnover, especially vulnerable to cancer chemo)
What are common presenting sx of neutropenia?
Low grade fever, sore mouth, odynophagia (severe pain when swallowing), gingival pain and swelling, skin abscesses, recurrent sinusitis and otitis, sx of pneumonia (cough, dyspnea), perirectal pain and irritation
What is the MOA for filgrastim?
Human G-CSF
What are the effects of filgrastim?
G-CSF regulates the production of neutrophils wihtin the bone marrow
Affects neutrophil progenitor proliferation and differentiation
What are the clinical applications for filgrastim?
Decreases the incidence of infection as manifested by febrile neutropenia in pts with non-myeloid malignancies receiving myelosuppressive anti cancer drugs or in those receiving a bone marrow transplant
Also used to mobilize hematopoietic progenitor cells into peripheral blood for collection by leukapheresis
Also used in these with severe chronic neutropenia
What are the pharmacokinetics for filgrastim?
Administered as 4 or 24 hr IV infusion or continuous SC infusion
Wait 24 hours after chemo, stop 24 hours beforehand since dividing cells are most vulnerable
What are the toxicities of filgrastim?
Generally well tolerated by can cause allergic reaction and bone pain (treated with NSAIDs)
What is the MOA for sargramostim?
Recombinant form of GM-CSF
What are the effects of sargramostim?
Increase production of neutrophils, eosinophils, and monocytes/macrophages
What are the clinical applications for sargramostim?
Used to accelerate recovery of myeloid cells after autologous bone marrow transplantation
Expanded to include allogeneic bone marrow transplantation
Can be used to mobilize HSC into peripheral blood
Indicated for use following induction of chemo on pts >55 years with AML to shorten time to neutrophil recovery
What are the pharmacokinetics for sargramostim?
Given IV or SC
What are the toxicities for sargramostim?
Edema
Sequestration of granulocyte in pulmonary circulation causing dyspnea
Has worsened pre existing renal and hepatic dysfunction
Contains benzyl alcohol and can cause fatal gasping syndrome in premature infants
There is no role for CSF usage in what kind of patients?
Afebrile pts with neutropenia
When is CSF used as a primary prophylaxis treatment for cancer?
Use only if incidence of febrile neutropenia is estimated at >20%
Individualize decisions if risk is 10-20%
When is CSF used as a secondary prophylaxis treatment for cancer?
Only use if delay or reduction of chemo dose would prevent full doses of potentially curative chemo
What is the MOA for plerixafor?
Partial agonist of the CXCR4 receptor
Important for the homing of HSC to the bone marrow
What are the effects of plerixafor?
Mobilizes HSC from bone marrow to plasma
What are the clinical applications for plerixafor?
Used in pts who dont mobilize sufficient stem cells
Orphan drug
Both thrombopoietin and its PEG derivative variant have been withdrawn from the market due to what?
Auto abs that caused severe thrombocytopenia
Why can’t stem cell factor (c-Kit) be used clinically?
Has potent synergist effects on early progenitor cells
However also found on mast cells and administration causes severe allergic reaction
What is the MOA for oprelvekin?
Recombinant form of IL-11
Mechanism unknown
What are the effects of oprelvekin?
Promotes the formation and maturation of megakaryocytes to increase platelet levels
What are the toxicities associated with oprelvekin?
Significant edema
Cardiac dysrhythmias, severe allergic reactions, blood shot eyes
Which interleukins can also increase platelet levels but are too toxic to use?
IL-3 and IL-6
What is the MOA for romiplostim?
A peptibody which is covalently bound with two identical peptide sequences linked via polyglycine that bind to the TPO receptor
Has no TPO homology
What are the effects of romiplostim?
Increased platelet count in healthy individuals and pts with ITP
What are the clinical applications for romiplostim?
ITP
Typically used after failure of glucocorticoids, immune globin +/- splenectomy
What are the pharmacokinetics for romiplostim?
Administered weekly as a SC injection
What are the toxicities for romiplostim?
Well tolerated
Most serious concern is allergic reaction
What is the MOA for eltrombopag?
Non peptide TPO receptor agonist
What are the clinical applications for eltrombopag?
Excess platelet destruction due to ITP
Cirrhosis due to hepatitis C
What are the pharmacokinetics of eltrombopag?
Orally active
Given once a day
What are the toxicities of eltrombopag?
Hepatotoxicity
What are 2nd/3rd line agents for ITP if glucocorticoids, immune globin (first option) is contraindicated and/or rituximab +/- splenectomy (second line) didn’t work?
Romiplostim and eltrombopag
What is the MCC of drug induced thrombocytopenia?
Heparin
What drugs can cause hemolytic anemia?
Cephalosporins and penicillin derivatives
Which drugs can cause aplastic anemia?
Cancer chemo, chloramphenicol, benzene
