L41- Immunopharmacology Flashcards
list the immunosuppressive agents
- glucocorticoids
- calcineurin inhibitors
- proliferation signal inhibitors
- angiogenesis inhibitors
- cytotoxic agents
- other agents
- immunosuppressive Antibodies
immunosupressive agents are used for the following clinical situations….
(dampen immune response)
- organ transplantation
- auto-immune disease
Glucocorticoids:
- (1) general immune effects
- (2) MOA in terms of immune system
1- anti-inflammatory, immunosuppressive effects
2:
-binds cytosolic glucocorticoid receptor
-receptor complex translocates to nucleus
-binds GREs (glucocorticoid response elements) in promoter region of genes
-down-regulation of many inflammatory mediators
+
-dec PG synthesis
______ is the preferred glucocorticoid for immunosuppression, explain
dexamethasone- long half-life, low mineralocorticoid effects
list the immune uses of glucocorticoids
- prevent/treat transplant rejection
- autoimmune disorders: RA, SLE, psoriasis, asthma, IBD
- neuropathic and bone pain
- palliative care: alleviate pain, nausea, fatigue
Glucocorticoids AEs:
- (1) short term use AEs
- (2) long term use AEs
1- HTN, hyperglycemia, immunosuppression, psychotic reactions, cognitive impairment
2- myopathy, Cushing’s syndrome, osteoporosis
Cyclosporin uses
(calcineurin inhibitor)
- organ transplants
- uveitis
- RA
- psoriasis
list the many AEs for Cyclosporin
(calcineurin inhibitor)
- **nephrotoxicity (most common reason to stop drug –> RAAS activation + endothelin release)
- tremor
- HTN
- hyperglycemia, hyperlipidemia
- osteoporosis
- hirsutism
- gum hyperplasia
-CYP3A4 metabolism –> drug interactions
list the calcineurin inhibitors
- cyclosporin
- tacrolimus
Calcineurin is a (1) type enzyme, which functions to activate (2) that is required for induction of (3).
1- phosphatase (dephosphorylation)
2- NFAT (T-cell specific transcription factor)
3- CK gene upregulation (IL-2 gene)
Cyclosporin MOA
- forms complex with cyclophilin (an immunophilin)
- complex inhibits calcineurin
- prevents dephosphorylation of NFAT
- no CK (IL-2) production
Tacrolimus uses
(calcineurin inhibitor)
- transplant rejection: kidney, liver, heart
- topical: psoriasis, atopic dermatitis
Tacrolimus AEs
(calcineurin inhibitor, less AE severity than cyclosporin)
- nephrotoxicity, neurotoxicity
- HTN, hyperkalemia, hyperglycemia
- GI issues
Tacrolimus MOA
(calcineurin inhibitor)
- forms complex with FKBP (FK-binding protein, an immunophilin)
- complex inhibits calcineurin
- prevents dephosphorylation of NFAT
- no CK (IL-2) production
______ is the main proliferation signal inhibitor
Sirolimus
Sirolimus uses
(proliferation signal inhibitor)
-renal transplant
-Coronary Stents: sirolimus released –> inhibits restenosis of BV via reduction in cell proliferation
Sirolimus AEs
(proliferation signal inhibitor)
- myelosuppression
- hepatotoxicity
- hypertriglyceridemia
- pneumonitis
- diarrhea
- HA
Sirolimus MOA
(proliferation signal inhibitor- note it has similar structure to Tacrolimus a calcineurin inhibitor)
- binds FKBP (FK binding protein, an immunophilin) [–> no calcineurin inhibitor]
- inhibits serine-threonine kinase mTOR
- blocks IL-2 driven T-cell proliferation
______ is the main angiogenesis inhibitor
Thalidomide
Thalidomide uses
(angiogenesis inhibitor)
erythema nodosum leprosum
multiple myeloma
Thalidomide MOA
(angiogenesis inhibitor)
mostly unclear:
-inhibits TNF-α synthesis
-inhibits angiogenesis
technically an immunomodulatory drug
list the Cytotoxic agents
antimetabolites:
- azathioprine
- methtrexate (MTX)
- mycophenolate mofetil
- leflunomide
alkylating agents:
-cyclophosphamide
Azathioprine:
- (purine/pyrimidine) anti-metabolite
- prodrug of (2) which functions to suppress (3)
1- purine
2- 6-MP (6-mercaptopurine)
3- B and T cell function, Ig production, IL-2 secretion
Azathioprine uses
- organ transplant
- severe RA
Azathioprine:
- (1) AEs
- (2) drug interactions
1- BM suppression, GI issues, inc infections and malignancies
2- allopurinol –> give lower dose as inactivation requires xanthine oxidase
MTX uses
- RA
- psoriasis, psoriatic arthritis
- ankylosing spondylitis
- SLE
MTX MOA
(low doses)
Rheumatic Diseases:
-inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase
-AMP accumulation
-converted to adenosine extracellularly
-adenosine is potent inhibitor inflammation
MTX AEs + contraindication
- nausea, GI ulcerations
- mucosal ulcers
- leukopenia, anemia
- hepatotoxicity, (rarely cirrhosis)
- hypersensitivity pneumonitis
Contraindicated in pregnancy
MTX toxicity can be reduced with co-administration of….
- folic acid
- leucovorin
Mycophenolate MOA
- converted to mycophenolic aid
- inhibits ionosine monophosphate dehydrogenase
- dec Guanosine synthesis
-suppresses B, T cell activation – particularly susceptible to inhibition b/c lacking enzymes in salvage pathway
Mycophenolate uses
- prophylaxis transplant rejection
- SLE
Mycophenolate AEs
- n/v/d, abdominal pain
- HTN, HA
- reversible myelosuppression
______ is the simple reason why anti-metabolites are effective as immunosuppressants
B/T-lymphocytes are particularly susceptible to inhibition b/c they lack the necessary enzymes for the salvage pathway
Leflunomide MOA
- prodrug of turiflunomide
- turiflunomide inhibits dihyrdrooroate dehydrogenase
- dec UMP levels
Leflunomide uses
- RA
- SLE
- myasthenia gravis
Leflunomide AEs
- diarrhea
- rash, reversible alopecia
- myelosuppression
- inc aminotransferase activity
- cardiogenic / teratogenic in animals
- contraindicated in pregnancy
Cyclophosphamide MOA (briefly / generally)
- destroys proliferating lymphoid cells
- alkylates DNA / other molecules in resting cells
Cyclophosphamide uses
SLE + others
Cyclophosphamide AEs
- infertility
- BM suppression
- hemorrhagic cystitis via acrolein
- bladder cancer (rare) – general inc of infection and malignancy with long-term use
list the ‘other’ agents of immunosuppression
- hydroxychloroquine
- sulfasalazine
Hydroxychloroquine MOA
unclear anti-inflammatory mechanism
Hydroxychloroquine uses
- RA (moderate effect, well-tolerated)
- SLE
note- often in combination with MTX, sulfasalaxine and may require 3-6 mos to show clinical benefit
Hydroxychloroquine AEs
(serious and rare)
- hemolysis in G6PD deficiency
- retinal damage (monitor vision)
Sulfasalazine:
- (1) structure
- (2) metabolism allows for (3) function
Sulfasalazine = sulfapyridine + 5-aminosalicylic acid (5-ASA)
- connected via diazo bond
- Sulfasalazine is metabolized into moieties by bacteria in colon
Sulfapyridine —> RA Tx
5-ASA –> ulcerative colitis Tx
Sulfasalazine uses
- UC, CD
- RA
- ankylosing spondylitis
Sulfasalazine AEs
- n/v
- HA
- rash
- neutropenia, hemolysis in G6PD def.
Rare: thyrombocytopenia, drug-induced lupus
list the immunosuppressive POLYclonal Abs and their uses
ALG, ATG (antilymphocyte and antithymocyte globulin):
- stem cell transplant
- solid organ transplant
Rho(D) immune globulin: an IgG against Rho(D) Ag on RBCs
-prevents Rh hemolytic disease in newborns
list the TNF-α inhibitor monoclonal antibodies
- adalimumab
- infliximab
- etanercept
list the ‘other’ immunosuppressuve monoclonal antibodies
- omalizumab
- basiliximab
- rituximab
list some of functions TNF-α signalling
-inc inflammation (macrophages)
- inc cell infiltration (endothelium)
- inc angiogenesis (endothelium)
- inc CRP (hepatocytes)
- cartilage degradation via MMPs (synoviocytes)
match the Ab structure with the TNF-α monoclonal antibody:
- (1) contains ligand-binding portion of human TNF-α receptor fused to Fc portion of human IgG
- (2) chimeric monoclonal Ab
- (3) fully human IgG1 anti-TNF monoclonal Ab
1- etanercept (not true mab)
2- infliximab
3- adalimumab
list the uses for monoclonal anti-TNF antibodies
All:
- RA
- psoriatic arthritis
- ankylosing spondylitis
Infliximab, Adalimumab:
-CD, UC
monoclonal Anti-TNF antibodies:
- screen for (1) before starting therapy
- monitor for (2) during therapy
- never give (3) to people on these Abs
- most AEs result from (4) activity
1- Tb, HBV infections
2- CBC for cytopenias
3- live vaccinations + Pts w/ infections
4- TNF inhibition: inc infections, don’t give to infected Pts
list the AEs of TNF inhibitors
- inc risk of malignancies and GI ulcers
- anti-drug Ab complexes formation –> interferes with efficacy + correlates w/ infusion site reaction
- exacerbate HF
Omalizumab:
- (1) MOA
- (2) uses
1- anti-IgE recombinant humanized monoclonal Ab –> prevents IgE from binding/activating mast cells and basophils –> prevents release of inflammatory mediators after allergen exposure
2:
- asthma with allergy sensitization
- chronic urticaria
Basiliximab:
- (1) structure
- (2) MOA
- (3) uses
1- chimeric human-mouse IgG
2- IL-2 receptor antagonist – binds and blocks IL-2 receptor
3- prevent transplant rejection
Ritusimab:
- (1) structure
- (2) MOA
- (3) uses
1- chimeric murine-human monoclonal Ab
2- binds CD20 on B cells –> depletion of circulationg B cells
3:
- non-Hodgkin’s lymphoma
- chronic lymphocytic leukemia
- note: approved for RA
Anakinra:
- (1) structure
- (2) MOA
- (3) uses
1- recombinant human IL-1RA
2- IL-1 receptor antagonist –> prevents IL-1 binding its receptor
3- moderate to severe RA
Abatacept:
- (1) MOA
- (2) uses
1- fusion protein –> interferes with T cell activation
2:
- moderate to severe RA
- polyarticular juvenile idiopathic arthritis
list the immunostimulants
Aldesleukin
IFN-α, β, γ
BCG- bacillus calmette-guerin
Aldesleukin:
- (1) structure / MOA
- (2) uses
1- recombinant IL-2
2- renal cell carcinoma, malignant melanoma
list the functions for each IFN
IFN-α: HBV/HCV infections, hairy cell leukemia, CML, malignant melanoma, Kaposi’s sarcoma
IFN-β: relapsing MS
IFN-γ: chronic granulomatous disease
BCG:
- (1) structure
- (2) MOA
- (3) uses
- (4) AEs
(Bacillus Calmette-Guerin)
1- attenuated live culture of Mycobacterium bovis
2- unknown –> active against tumors
3- Tx/prophylaxis urinary bladder carcinoma
4:
- fever, chills, malaise
- hypersensitivity, immune complex disease, shock
