IMMUNOPHARMACOLOGY Flashcards
Cytotoxic Agents
Antimetabolites
Alkylating agents
Azathioprine
MOA
Drug interactions
Purine antimetabolite
Prodrug of 6-mercaptopurine converted to 6-MP
- 6-MP is converted to metabolites that inhibit de novo puine nucleotide synthesis–> suppression of B and T cell function of immunoglobulin production and of IL-2 secretion.
DI: Inactivation of drugs has to do with Xanthine oxidase
Glucocorticoids anti-inflammatory MOA
Inhibition of PLA2
Reduction of transcription of COX-2 (inflammatory cancer)
Glucocorticoids AE
Short term use: HTN hyperglycemia immunosuppresion psychotic reactions cognitive impairment
Long term use:
Myopathy
Cushing’s syndrome
osteoporosis
Glucocorticoids uses:
Prevent treat transplant rejection Treat autoimmune disorders such - RA - SLE - Psoriasis - Asthma - IBD In palliative care glucocorticoids arae used to alleviate pain; nausea and fatigue
Calcineurin inhibitors
MOA?
Cyclosporine - primarily metabolized by CYP 3A4 - forms a complex w/ cyclophilin (immunophilin). - complex inhibits calcineurin Tacrolimus - Binds to FK-binding protein (FKBP) - FKBP is an immunophilin - Tacrolimus -FKBP complex inhibits calcineurin
Calcineurin
Phosphatase used to activat T- Cell specific Transcription factor (NFAT)
NFAT is required for induction of cytokine genes
Cyclosporine adverse effects
Nephrotoxicity*: limiting and occurs in majority of patients tremor HTN Hyperglycemia Hyperlipidemia Osteoporosis Hirsutism* Gum Hyperplasia* - Very little bone marrow toxicity
Cyclosporine USES?
Organ transplant
Uveitis
Rheumatoid Arthritis
Psoriasis
Tacrolimus Adverse Effects
Nephrotoxicity Neurotoxicity* Hyperglycemia HTN Hyperkalemia GI complaints
Tacromlimus uses
- transplant rejection prevention of kidneys liver and heart
- topical formulation is used for topical dermatitis and psoriasis
MOA of sirolimus a Proliferation signal inhibitor:
Sirolimus
- structurel similar to tacrolimus
- also binds to FKBP but does not inhibit calcineurin
- inhibits Serine-threonine kinase mTOR*–>blocks IL-2-driven T- cell proliferation.
Sirolimus Adverse Effects?
Myelosuppresion* Hepatotoxicity Diarrhea Hypertriglyceridemia Pneumonitis Headache
- Nephrotoxicity is less common than w/ calcineruin inhibitors!!!
Sirolimus uses
Renal transplantation
Sirolimus-eluting stents are used to inhibit restenosis of the blood vessels in patients with severe CAD by reducing cell proliferation.
Inhibitors of Angiogenesis MOA?
Thalidomide
- MOA unclear
- inhibits synthesis of TNF-a
- now called an immunomodulatory drug
Thalidomide indications
“MEL”
Erythema nodosum
Leprosum
multiple myeloma
Cytotoxic agents
Antimetabolites:
- Azathioprine
- Methotrexate
- Mycophenolat mofetil
- Leflunomide
Alkylating agents:
Cyclophosphamide
Azathioprine AE:
AE:
- Bone marrow suppression
- GI disturbances
- increase in infections and malignancies
Azathioprine inactivation depends on the action of what enzyme?
What drug interaction should be avoided when taking AZA?
Xanthine oxidase
Allopurinol: used for control of hyperuricemia. Patients receiving allopurinol should have the dose of azathioprine reduced.
AZAthioprine uses
Prevention of organ transplant rejection
severe RA
Methotrexate MOA
At low doses is used in Rheumatic diseases to inhibit Aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase.
- accumulation of AMP–> increased adenosine–> immunosuppressive (potent inhibition of inflammation by adenosine).
AICAR tranformylase catalyzes the penultimate and final step in de novo purine biosynthesis which lead to synthesis of IMP.
Methotrexate AE
Mucosal ulceration Hypersensitivity pneumonitis GI ulcerations Nausea Leukopenia Anemia cirrhosis is rare Hepatotoxicity
Methotrexate toxicity can be reduced with?
Leucovorin
Folic acid
Methotrexate CIs
Pregnancy
Methotrexate uses
"RAPPS" RA Psoriasis Psoriasis arthritis Ankylosing spondylitis SLE
Mycophenolate Mofetil
MOA?
converted to mycophenolic acid
mycophenolic acid inhibits inosine monophosphate DH an enzyme in the de novo pathway of guanosinentriphosphate (GTP) synthesis.
This suppresses both B and T lymphocyte activation.
- lymphocytes lack enzymes necessary for the salvage pathway so they are susceptible to inhibitors of the de novo pathway
Mycophenolate Mofetil AE
Nausea vomiting diarrrhea abdominal pain headache HTN Reversible myelosuppression
Mycophenlate mofetil uses
Prophylaxis of transplant rejection
SLE
Leflunomide MOA
Pro drug of teriflunomide
Teriflunomide inhibits dihydroorotate DH
decreases levels of UMP
UMP is essential for the synthesis of pyrimidines
Leflunomide AE
Diarrhea Reversible alopecia Rash Myelosupression Increases in aminotranferases activity CBC and liver function tests should be monitored Carcinogenic and teratogenic in animals Contraindicated in pregnancy
Leflunomide USES
“RaMS”
RA
SLE
Myasthenia Gravis
Alkylating agents
Cyclophosphamide
- one of the most effective immunosuppressive drugs available
- destroys proliferating lymphoid cells
- alkylates DNA and other molecules in resting cells
Cyclophosphamide AE
Infertiltiy
Bone marrow suppression
Hemorrhagic cystitis
Rarely bladder carcinoma
Acrolein a metabolite is responsible for urinary toxicities
Long term use increases risk of infection and malignancy
Cyclophosphamide USEs
treat SLE and other autoimmune diseases.
may take 3-6 months to show benefit.
Hydrochloroquine AE
Hemolysis in patients w/ G6PD defeciency
Retinal damage: vision should be monitored
Sulfasalazine structure
consists of sulfapyridine and 5-aminosalicylic (5-ASA) connected by diazo bond.
Sulfasalazine MOA
Metabolized by bacteria in the colon to constituent moieties:
- sulfapyridine is probably the active moiety in the tx. of rheumatoid arthritis.
- 5-ASA moiety important in ulcerative colitis.
Sulfasalazine AE
Nausea vomiting Headache rash Neutropenia Thrombocytopenia is very rare Drug induced lupus is rare Hemolysis in patients with G6PD def.
Sulfasalazine uses
Ulcerative colitis
Rheumatoid arthritis
Crohn’s disease
Ankylosing spondylitis
Immunosuppressive Antibodies
Polyclonal antibodies:
- Antilymphocyte (ALG) and Antithymocyte (ATG) Antibodies
- Rho(D) Immune Globulin
Monoclonal antibodies
Antilymphocytic globobulin (ALG) and Antithymocyte Globulin (ATG) uses
- Used before stem cell transplantation to prevent graft-versus-host reaction.
- Also use for solid organ transplantation
Monclonal antibodies
TNF-a inhibitors
- Infliximab
- Adalimumab
- Etanercept
Anti-TNF-a drugs adverse effects
- Cytopenias can occur: CBC should be monitored regularly
- Serious infections are the most important potential adverse effects of TNF inhibition
- Drugs should not be given to patients with an active infection
- *Patients should be screened for latent TB infection before and during tx. w/ a TNF inhibitor.
- Patients may be at risk for malignancies
Infliximab
- Chimeric monoclonal antibody
- Binds with high affinity and specficity to humna TNF-a
- Used in the tx. of rheumatoid arthritis; psoriatic arthirtis; ankylosing spondylitis; Crohn’s disease; and ulcerative colitis.
Adalimumab
Fully humna IgG1 anti-TNF monoclonal antibody
- Binds soluble TNF-a and prevents its interation with TNF receptors.
- Used in the tx. of rheumatoid arthritis; psoriatic arthritis; ankylosing spondylitis; Crohn;s disease and ulcerative colitis.
Etanercept
Not a true Mab
- Ligand-binding portion of a human TNF-a receptor fused to the Fc portion of human IgG1.
- Binds to TNF-a and prevents it from interacting w/ its receptors.
Etanercept uses
RA Ankylosing spondylitis Plaque psoriasis polyarticular juvenile idiopathic arthritis psoriatic arthritis
Omalizumab
MOA?
USE?
- Anti-IgE recombinant humanized monoclonal antibody
- Binds to IgE and prevents IgE from binding to mast cells and basophils thereby preventing release of inflammatory mediators after allergen expopsure
- Used in asthma refractory to inhaled corticoids and evidence of allergic sensitization
- also approved for chronic urticaria
Basiliximab
- IL-2 receptor antagonist
- Chimeric human-mouse IgG
- Binds to the IL-2 receptor
- Used in combination w/ ther immunosuppressants to prevent transplant rejection.
Rituximab
- Chimeric murine-human monoclonal antibody that binds to the CD20 molecule on B lymphocytes.
- Causes depletion of circulating B cells
- Used for tx. of non-hodgkins lymphoma and chronic lymphocytic leukemia
- Also approved for rheumatoid arthritis.
Anakinra
MOA
USE
- IL-1 receptor antagonist
- Recombinant version of the naturally occurring human IL-1RA that prevents IL-1 from binding to its receptor.
- Approved for moderate to severe rheumatoid arthritis
Abatacept
MOA?
USE?
- Fusion protein that interferes w/ T-cell activation
- Used for moderate to severe rheumatoid arthritis
- Used for moderate to severe polyarticular juvenile idiopathic arthritis.
Immunostimulants
Aldesleukin
Interferons
Bacillus Calmette-Guerin (BCG)
Aldesleukin
MOA?
USE?
- Recombinant interleukin-2 (IL-2)
- IL-2 is lymphokine that promotes the production of cytotoxic T lymphocytes and activates NK cells.
- Aldesleukin is indicated for the adjunctive treatment of renal cell carcinoma and malignant melanoma
Interferons
USE?
Hairy cell leukemia chronic myelogenous leukemia malignant melanoma Kaposi sarcoma hep B and C infections
Bacillus Calmette-Guerin (BCG)
attenuated live culture of Mycibacterium bovis
- active against tumors MOA unknown
- indicated for tx. and prophylaxis of carcinoma of the urinary bladder.
AE: hypersensitivity shock chills fever malaise immune complex disease
Drugs used to stop transplant rejection:
Glucocorticoids - prevent and treat Tacrolimus - prevention of rejection for HLK (heartLiverKidney) Azathioprine Mycophenolate - prophylaxis Basiliximab - renal transplant
Drugs used for rheumatoid arthritis
Glucocorticoids Cyclosporine Azathioprine (SEVERE) Methotrexate Leflunomide hydroxychloroquine (MILD) sulfasalzine Infliximab adalimumab Etanercept Rituximab Anakinra (moderate-->severe) Abatacept (moderate to severe)
Renal transplant drugs
Sirolimus
Basiliximab
