Week2 Flashcards
PEGylation
the addition of polyethylene glycol (PEG) moieties significantly increases half-life and “masks” the drug from the host’s immune system→ decreased immunogenicity and antigenicity
o 12 drugs have been approved
o Approved PEG’d drugs: L-asparaginase, PEG-liposome containing doxorubicin, Interferon α, Methoxy polyethylene, glycol epoetin, Pegfilgrastim
ERYTHROPOIETIN
MOA:Most important regulator of the proliferation of committed RBC progenitors (interacts with EPO R on red cell progenitors, EPO R is a member of the JAK/STAT superfamily
produced in the kidney, inverse relationship between Hb level and serum EPO level)
- Exception = chronic renal failure when EPO levels are low – kidneys cannot produce the GF
Pharmacokinetics:Produced in response to severe anemia
Relatively short half-life (IV 3-4 x per week)
Therapeutic Uses:- Anemia (secondary to chronic kidney DZ →
nearly all patients will require Fe supplement; some patients may require folate supplement) (due to primary bone marrow disorders and secondary anemias)
- Reduce need for transfusion in high-risk surgical patients
after phlebotomies for autologous transfusion
Fe overload (hemochromatosis)
- M-PEG-epoetin should not be used in patients with anemia due to cancer chemotherapy (clinical trial found increase in deaths)
- Banned by IOC (increased [RBC] may increase O2 delivery to muscles)
Side Effects:Life threatening: thrombosis
Serious
Common: HTN
Rare: faster tumor growth (head and neck ca), allergic rxn (long term SC admin)
FILGRASTIM
G-CSF
MOA: - Regulates production of neutrophils within bone marrow & affects neutrophil progenitor prolif, different, and functional activation
- Also mobilizes hematopoietic SC, increasing their conc. in peripheral blood
- Led to use of peripheral blood SCs rather than bone marrow SCs for transplantation
Pharmacokinetics:
Therapeutic Uses:- Cancer chemo-induced neutropenia (esp. FILGRASTIM) – esp. during autologous SC transplantation following high-dose chemo, objective is to prevent systemic infection (neutrophils are 1st line of defense against infection)
- Congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia
Side Effects:Serious: allergic reations, splenic rupture (rare)
Innoculous: mild/moderate bone pain (F/P better tolerated than S) (common)
INTERLEUKIN 11
MOA: + thrombopoietin → increase platelet production
Pharmacokinetics:
Therapeutic Uses: Thrombocytopenia – particularly following chemo, also idiopathic thrombocytopenia
Side Effects: Serious: A fib (common), hypokalemia (rare)
Innocuous: fatigue, HA, dizziness, mild/mod edema, dyspnea (due to fluid in lungs), anemia (due to hemodilution)
NO FEVER
SAGRAMOSTIM
MOA: Stimulates myelopoiesis generally, and neutrophils and monocytes specifically
Pharmacokinetics: - Conjugation product of filgrastim with polyethylene glycol, much longer half-life, injected once per chemotherapy cycle (instead of daily for several days)
Therapeutic Uses: - Cancer chemo-induced neutropenia (esp. FILGRASTIM) – esp. during autologous SC transplantation following high-dose chemo, objective is to prevent systemic infection (neutrophils are 1st line of defense against infection)
- Congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia
Side Effects: - Cancer chemo-induced neutropenia (esp. FILGRASTIM) – esp. during autologous SC transplantation following high-dose chemo, objective is to prevent systemic infection (neutrophils are 1st line of defense against infection)
- Congenital neutropenia, cyclic neutropenia, myelodysplasia, and aplastic anemia
THROMBOPOIETIN
MOA:
Pharmacokinetics:
Therapeutic Uses:
Side Effects:
• Administration: IV
long half-life (detectable in serum 3-6 mo after completion of tx)
• Side effects:
o Infusion reactions: immediate response during infusion
• Not unique to antibodies; seen particularly with cancer chemotherapy drugs
• Sx:
• CV: chest pain, hypo-/HTN, tachy/bradycardia, arrhythmia, edema, ischemia/infarction, cardiac arrest
• Resp: cough, dyspnea, nasal congestion, rhinitis, sneezing, wheezing, bronchospasm, edema, cyanosis, acute respiratory distress syndrome
• CNS: HA, dizziness, confusion, loss of consciousness, anxiety, sense of impending doom
• Skin: rash, pruritis, urticaria, flushing, local or diffuse erythema, conjunctival erythema
• Endocrine: rigors, diaphoresis, fever, generalized feeling of warmth
• GI: n/v, metallic taste, diarrhea, abdominal cramping, bloating
• Urinary: incontinence, renal impairment
• Genital: uterine cramping
• Musculoskeletal: arthralgias, myalgias, fatigue
• 2 types (sx are similar for both types, and are typically managed by slowing the infusion and by administration of antihistamines and other procedures common to management of type I hypersensitivity reactions):
• Typical IgE mediated type I hypersensitivity reaction occurs within minutes (10-12 hours maximum)
o Increased severity and quicker response with repeated exposure
• Cytokine release due to Fc region recruitment of immune effector cells (esp. granulocytes that release cytokines, obviously!) – occurs during the first few hours after infusion
o Worse on 1st infusion, often decreases in severity with subsequent exposures
o Cytokine release syndrome
- Observed particularly with anti-T cell antibodies that can directly activate the T cell receptor before triggering destruction of lymphocytes)
- Can result in a “cytokine storm”, a kind of positive feedback loop where cytokine release recruits more effector cells that release more cytokines, etc.
- Shaking chills, fever, arthralgia, diarrhea, vomiting, hypotension and respiratory distress
Lim =
immune
Les =
Cir =
Les = infectious lesions Cir = cardiovascular
• Which of the following drugs has the shortest half-life?
o Tumor necrosis factor – half-life in minutes, inject it as close to the tumor as you can
o You are planning to treat a patient who has IBD with infliximab. What test should you perform first?
• Mantoux test – need to worry about reactivation of virus with immune suppression
o Myeloid Growth Factors
filgrastim (G-CSF), pegfilgrastim, sargramostim (GM-CSF)
• Filgramostim: G-M progenitor → neutrophil
• AE: splenic rupture
• Sargramostim: two sites of action – differentiation of common myeloid progenitor and G-M progenitor
• AE: capillary leak syndrome
• AE for both: bone pain (worse with sargramostim because it acts earlier in differentiation process)
o Megakaryocyte Growth Factors
interleukin 11, romiplostim
• IL-11: common myeloid progenitor → megakaryocyte
• AE: A fib
o Allergic reaction and general malaise are AE for all cytokines
MHC 1
interleukin 11, romiplostim
• IL-11: common myeloid progenitor → megakaryocyte
• AE: A fib
o Allergic reaction and general malaise are AE for all cytokines
to make a lymphoid progenitor cell
• Hematopoietic stem cell (bone marrow) + IL-3, IL-7
CTL activation
MHC to CD 4/8
ICAM to LFA
B7 to CD28
= general activators of T cells
o IL-2 & IL-15
drive T helper cells → Th1
IL-12 & IFN-γ
drives T helper cells → Th2
IL-4
down-regulates Th1 & TGF-β, down-regulates both Th1 & Th2 subtypes
o IL-10
• FAS
T cells expressing FAS ligand bind to FAS protein on a target → induce caspase activation & apoptosis
• B cell surface markers
every cell has BCR (antibody), signaling molecules (CD79a, CD79b)
o CD40 = molecule that interacts with Tfh to receive signal to mature into plasma cell
o X-linked agammaglobulinemia =
o CD40 ligand deficiency =
o Activation-Induced Cytidine Deaminase Deficiency =
o Common Variable Immunodeficiency =
o X-linked agammaglobulinemia = an absence of B lymphocytes o CD40 ligand deficiency = failure of immunoglobulin class switching o Activation-Induced Cytidine Deaminase Deficiency = failure of immunoglobulin class switching o Common Variable Immunodeficiency = failure to produce antibodies against particular antigens
