Immunopharmacology Flashcards
applications of immunosuppression
- hypersensitivity
- autoimmunity
- organ transplantation
immune tolerance due to
antigen-specific
application of immunostimulation (biological response modifers)
immunodeficiency
see diagram and blurb in pdf
see diagram and blurb in pdf
name 5 immunosuppressive agents
- glucocorticoids
- calcineurin inhibitors
- antiproliferative/antimetabolic agents
- agents affeting lymphocyte distribution
- antibodies
what are the most common glucocorticoids used
- prednisone
- prednisolone
- dexamethasone
how are glucocorticoids administered
- oral
- IV
- topical
what bond is required for glucocorticoid but no mineralocorticoid activity
11Beta-OH
addition — bond selectively increases glucocorticoid activity
1,2 double bond
— bond increases both glucocrticoid and minteralocorticoid activity
9 alpha F
substitution at — eliminates mineralocorticoid activity
C16
the glucocorticoid receptor is a member of
the nuclear hormone receptor superfamily
the cortisol-receptor complex is translocated to
the nucleus where it binds as homodimers to DNA transcripts that contain glucocorticoid response elements (GREs) and regulates gene expression of those genes
cortisol-receptor complex binding influences
transcription factors that act on other response elements. Therefore glucocorticoids influence the expression of genes
what are the anti-inflammatory/Immunosuppressive Effects of Glucocorticoids
- decrease cytokines, other inflammatory mediators
- redistribution of peripheral leukocytes
- decrease activity of peripheral leukocyes at site of inflammation
- impaired macrophage, T-cell, B-cell responses
- vasoconstriction
- decrease capillary permeability
what are the therapeutic uses for immunosuppression (glucocorticoids)
- prevention and treatment of transplant rejection
- graft-versus-host disease in bone-marrow transplantation
- autoimmune disorder (Rheumatoid and other arthritides, systemic lupus erthematosus)
- systemic dermatomyositis
- psoriasis and other skin conditions
- asthma and other allergic disorders
- inflammatory bowel disease
- inflammatory opthalmic disease
- autoimmune hematologic disorders
- acute exacerbation of MS
effective doses of glucocrticoids to relieve symptoms are determined
empirically
short term admin of glucocrticoids (up to 10 days) in the absence of contraindictions does not produce
adverse side effects
for prolonged use of glucocrticoids , benefits must be weighted against production of
iatrogenic Cushing’s
high doses of glucocrticoids cause
mineralcorticoid effects - concern in pts with heart disease
prolonged use of glucocrticoids causes
- increase susceptibility to infection
- inhibits growth
- induces myopathy, osteoporosis, cataracts
what happens when glucocrticoids are used for more than 2 weeks
- adrenal suppression may be induced by negative feedback
- reduced ACTH secretion
- adrenocortical atrophy
- acute adrenal insufficiency in times of stress or upon withdrawal of the corticosteroid
what is cyclosporine
-lipid soluble peptide antibiotic
cyclosporine also known as
cyclosporin A
how is cyclosporine administered
- oral
- IV
- ophthalmic emulsion
cyclosporine binds to
cyclophilin C
binding of cyclosporine to cyclophilin C causes
- decrease calcineurin (cytoplasmic phosphatase)
- decrease production of cytokines
- decrease response of T cells to antigens
therapeutic use of cyclosporine
- graft-versus host disease in bone-marrow transplantation
- aplastic anemia in patients ineligible for transplants
- kidney, liver, heart and heart-lung transplantation
- autoimmune diseases
- dry eye syndrome (opthalmic emulsion)
cyclosporine toxicity can cause
- reversible nephrotoxicity (dose limiting)
- vascoconstriction that may lead to hypertension
- neurotoxicity
- hyperlipidemia
- transient hepatotxicity
- stimulates TGF-beta which may lead to an increase risk of cancer
cyclosporine is metabolized by
cytochrome P450 (especially CYP3A4)
what drugs inhibit metabolism and reduces cyclosporine clearance
- erythromycin
- ketoconazole
- Amphotericin B
- grapefruit juice
“A-KEG”
what drugs increase cyclosporine clearance
- phenobarbital
- rifampin
what is Tacrolimus
a macrolide antibiotic
Tacrolimus binds to
FK506-binding protein-12 (FKBP-12) an immunophilin structurall related to cyclophilin
function of Tacrolimus
- inhibits calcineurin
- decreases production of cytokines
- decreases response of T cells to antigens
administration of Tacrolimus
- oral
- injection
therapeutic use of Tacolimus
SAME AS CYCLOSPORINE:
Graft-versus-host disease in bone-marrow transplantation
Aplastic anemia in patients ineligible for transplants
Kidney, liver, heart and heart-lung transplantation
Autoimmune diseases
Tacrolimus is — times more potent than cyclosporine
10 to 100
toxicity and drug interactions of Tacrolimus
same as for cyclosporine
what is Sirolimus
macrocyclic lactone
Sirolimus binds to
FKBP-12
does Sirolimus inhibit calcineurin
no!
function of Sirolimus
- inhibits mTOR (mammalian target of rapamycin, key enzyme in cell cycle progression)
- inhibit T-cell activation and proliferation
administration of Sirolimus
oral
therapeutic use of Sirolimus
- inhibition of transplant rejection (often include combination with a calcineurin inhibitor and glucocorticoid)
- preservation of graft-versus-host reaction
- treatment of autoimmune disease
effects of Sirolimus persists for —- after discontinuing therapy
several months
toxicity accompanying the use of Sirolimus includes
- dose-dependent thrombocyopenia
- leukopenia
- hyperlipidemia
renal transplant patients on Sirolimus may show
a dose-dependent increase in serum cholesterol and triglycerides
adverse side effects of Sirolimus toxicity
- anemia
- hypotension
- hypokalemia or hyperkalemia
- fever
- gastrointestinal effects
- increase risk of lymphomas
- increased infections
Sirolimus interacts with what substrate
CYP3A4 - see cyclosporine for interactions
what is Azathioprine a derivative of
6 mercaptopurine (6-MP) derivative
Azathioprine has a better — than (6-MP)
oral absorption
Azathioprine inhibits
S phase of DNA synthesis
Azathioprine is converted to
thioinosinic acid
thionosinic acid is a competitive inhibitor of
purine synthesis
Therapeutically thionosinic affects
T cells more than B cells
administration method of Azathioprine
oral
IV
Azathioprine is used in combination with corticosteroids to
inhibit rejection of organ transplants and for rheumatoid arthritis
Azathioprine toxicity can lead to
- bone marrow suppression, gastrointesinal toxicity, mild hepatotoxicity
- lead to severe infection
- mutagenic, carcinogenic
what happens if Azathioprine is co-administered with allopurional
toxicity may increase
Mycophenolate Mofetil is a semisynthetic derivative of
mycophenolic acid
therapeutic use of Fingolimod
treatment of patients with relapsing multiple sclerosis to reduce frequency of exacerbations and delay the physical disability
function of Mycophenolate Mofetil
- inhibits inosine monophosphate dehydrogenase
- decreases purine biosynthesis
- decreases proliferation of T and B lymphocytes
administration of Mycophenolate Mofetil
oral, IV
Mycophenolate Mofetil is used in combination with cyclosporine and corticosteroids to
prevent organ rejection in allogenic renal transplant pts and in liver and cardiac transplant patients
Mycophenolate Mofetil toxicity causes
- diarrhea
- leukopenia
- cytomegalovirus infections and gastrointestinal hemorrhage
what happens when Mycophenolate Mofetil is co-administered with antacids (magnesium, aluminim hydroxides)
decreases absorption
Mechanism of action of Fingolimod
-sphingosine 1-phosphate receptor (S1P-R) agonist
administration of Fingolimod
-oral
what type of vaccine should be avoided when taking Fingolimod
live attenuated vaccines during and for 2 months after stopping due to risk of infection
effects of Fingolimod toxicity
- decrease heart rate and/or AV conduction after first dose
- infections
- macular edema
- decrease in pulmonary function
- hepatotoxicity
why should women of childbearing potential on Fingolimod use contraception during and for 2 months after stopping
bc Fingolimod increases fetal risk
Fingolimod has a pharmacodynamic interaction meaning
Antiarrhythmic drugs and Beta blockers increase risk of additive effects on heart rate
Vincristine used to teat
idiopathic thrombocytopenic purpura
Fingolimod clearance is decreased by
ketoconazole (inhibitor of CYP4F)
other antimetabolites used for immunisuppression
- cyclophosphamide
- methotrexate
- Vincristine
Methotrexate used to treat
rheumatoid arthritis
Vincristine used to teat
idiopathic thrombocytopenic purpura
therapeutic use of ATG
can be used alone or in combination with corticosteroids and azathioprine to prevent renal allograph rejection
ATG toxicity can lead to
hypersensitivity
nephritis and anaphylaxis (occurs rarely)
what is Muromonab-CD3
a mouse monoclonal Ab
mechanism of action of Muromonab-CD3
- blocking Ab
- CD3 localized adjacent to antigen recognition complex, which is blocked as well
- T cells are unable to recognize foreign antigen
what is antithymocyte globulin (ATG)
is a purified equine immunoglobulin against human thymus lymphocytes
name 2 IL-2 Receptor (Anti-CD25) Antibodies
- Basiliximab
2. Daclizumab
both Basiliximab and Daclizumab are
mouse/human monoclonal antibodies
infliximab toxicity causes
- infusion rxn - fever, urticaria, hypotension, dyspnea within 1-2 hrs after administration
- upper respiratory and urinary tract infections
- development of antinuclear Abs, rarely a lupus-like syndrome
therapeutic use of Basiliximab and Daclizumab
- prevention of acute renal transplant rejection
- both are given with cyclosporine and corticosteroids
Basiliximab and Daclizumab toxicity
well tolerated; no significant drug interactions
therapeutic use of Muromonab-CD3
- treatment of acute kidney or hepatic transplant rejection
- prophylaxis in cardiac transplantation
- depletions of T cells in marrow from donors before bone marrow transplantation
name an Anti-TNF reagent
infliximab
Muromonab-CD3 toxicity causes
- fever
- pulmonary edema
- vomiting
- headache
- anaphylaxis
- infection during chronic therapy
what is infliximab
a chimeric anti-TNF -alpha monoclonal antibody
sites of action of immunosuppressive agents of T-cell activation (see slide 26)
- glucocorticoids
- cyclosporine
- tacrolimus
- sirolimus
- Azathioprine
- Fingolimod
- Mycophenolate
- Muromonab- CD3
- Daxlizumab, Basiliximab
infliximab toxicity causes
- infusion rxn - fever, urticaria, hypotension, dyspnea within 1-2 hrs after administration
- upper respiratory and urinary tract infections
- development of antinuclear Abs, rarely a lupus-like syndrome
therapeutic use of Rho immune globulin
prevention of hemolytic disease of Rh-positive newborns
mechanism of action of Etanercept
blocks the effects of TNF-alpha
therapeutic use of Etanercept
rheumatoid arthritis - patients who do not respond to other treatments
Etanercept toxicity cause
- injection site rxns
- infections
BCG toxicity leads to
severe hypersensitivity and shock
what are immune globulins
- human plasma from donors in the general population or hyperimmunized individuals (for specific exposures such as hepatitis B, rabies, tetanus, varicella-zoster, cytomegalovirus, botulism, respiratory syncytial virus)
- replacing missing Abs
what are immunostimulants
biological response modifiers
What is Bacillus Calmette-Guerin (BCG)
- an immunostimulant
- viable attenuated strain of Myobacterium bovis
mechanism of action of BCG
-has an adjuvant effect to stimulate T cells and natural killer cells
therapeutic use of BCG
bladder cancers
BCG toxicity leads to
severe hypersensitivity and shock
therapeutic use of immune globulin
passive immunization
- immunodeficiencies
- prevention of infection in chronic lymphocytic leukemia
- Kawasake disease (acute multisystem inflammatory disease of children)
immune globulin toxicity leads to
- anaphylactoid rxns and severe hypotension
- theoretical risk of infection due to plasma source
name 2 recombinant cytokines
- interleukin-2
2. interferons
name 2 Myeloid Colony Stimulating Factors
Granulocyte-macrophage colony stimulating factor (GM-CSF)
Granulocyte stimulating factor (G-CSF)
what drugs are calcineurin inhibitors
- cyclosporine
- Tacrolimus
what drugs are Antiproliferative & Antimetabolic drugs
- Sirolimus
- Azathioprine
- Mycophenolate Mofetil
- Fingolimod
- Cyclophosphamide
- Methotrexate
- Vincristine
what drugs are antibodies
- antithymocyte gloulin (ATG)
- Muromonab -CD3 (Anti-CD3 Monoclonal Ab)
- Basiliximab (IL-2 Receptor Antibodies)
- Daclizumab (IL-2 Receptor Antibodies)
- Infliximab (Anti-TNF Reagents)
- Rho Immune Globulin
what drugs are Anti-TNF reagents
-Etanercept
what drugs are immunostimulants
immune globulin
