IMMUNOPHARMACOLOGY Flashcards
List 7 different types of immunosuppressive drugs?
Glucocorticoids Calcineurin Inhibitors Proliferation Signal Inhibitors Inhibitors of Angiogenesis Cytotoxic Agents Other Agents Immunosuppressive Antibodies
Glucocorticoids effects and how does it modulate its effects?
• Glucocorticoids have broad anti-inflammatory
effects.
• Glucocorticoids act by binding to the cytosolic
glucocorticoid receptor.
• The glucocorticoid-glucocorticoid receptor
complex translocates to the nucleus and binds to
glucocorticoid response elements (GREs) in the
promoter region of specific genes, either upregulating or down-regulating gene expression
• Glucocorticoids down-regulate the expression
of many inflammatory mediators.
• The overall effect of glucocorticoid administration
is profoundly anti-inflammatory and
immunosuppressive.
GLUCOCORTICOIDS:
ANTI-INFLAMMATORY MOA
• Glucocorticoids relieve pain due to the modulation
of inflammatory responses.
• Glucocorticoids suppress several inflammatory
pathways.
• Glucocorticoids inhibit prostaglandin synthesis
through independent mechanisms:
• Inhibition of PLA2
• Reduction of transcription of COX-2
GLUCOCORTICOIDS: ADVERSE EFFECTS?
• Short-term use: hypertension, hyperglycemia,
immunosuppression, psychotic reactions, and
cognitive impairment.
• Long-term use: myopathy, Cushing’s syndrome,
and osteoporosis.
GLUCOCORTICOIDS: USES?
• Used to prevent and treat transplant rejection.
• Used to treat autoimmune disorders such as
rheumatoid arthritis, SLE, psoriasis, asthma, and
IBD.
• In palliative care glucocorticoids are used to
alleviate pain, nausea, and fatigue.
• Used to treat pain, including neuropathic and bone pain. Dexamethasone is usually preferred because of its long half-life and low mineralocorticoid
effects.
List 2 Calcineurin inhibitors?
- Cyclosporine
* Tacrolimus
Cyclosporine moa?
• Calcineurin is a phosphatase necessary for activation of a Tcell-specific transcription factor: NFAT. • NFAT is required for the induction of cytokine genes. • Cyclosporine forms a complex with cyclophilin, an immunophilin. • This complex inhibits calcineurin
Cyclosporine AE?
• Main adverse reactions: Nephrotoxicity, tremor,
hypertension, hyperglycemia, hyperlipidemia,
osteoporosis, hirsutism, gum hyperplasia.
• Nephrotoxicity is limiting and occurs in the
majority of patients treated. Major indication
for cessation of therapy.
• Very little bone marrow toxicity.
Cyclosporine drug interactions and uses?
• Primarily metabolized by CYP3A4: involved in
many drug interactions.
uses: • Organ transplantation • Uveitis • Rheumatoid arthritis • Psoriasis
Tacrolimus moa?
- Tacrolimus binds to FK-binding protein (FKBP).
- FKBP is an immunophilin.
- The tacrolimus-FKBP complex inhibits calcineurin.
Tacrolimus AE?
- Nephrotoxicity
- Neurotoxicity
- Hyperglycemia
- Hypertension
- Hyperkalemia
- GI complaints
TACROLIMUS: USES?
• Prevention of rejection of transplanted kidneys,
liver or heart.
• Topical formulation is used for atopic dermatitis
and psoriasis.
SIROLIMUS category and moa?
PROLIFERATION SIGNAL INHIBITORS
• Structurally similar to tacrolimus.
• Sirolimus binds to FKBP.
• But the sirolimus-FKBP complex does not inhibit
calcineurin.
• Instead, it inhibits the serine-threonine kinase
mTOR.
• Blockade of mTOR blocks IL-2-driven T-cell
proliferation.
Sirolimus AE?
• Myelosuppression • Hepatotoxicity • Diarrhea • Hypertriglyceridemia • Pneumonitis • Headache. • Nephrotoxicity is less common than with calcineurin inhibitors.
Sirolimus uses?
• Renal transplantation.
• Sirolimus-eluting coronary stents are used to
inhibit restenosis of the blood vessels in patients
with severe CAD by reducing cell proliferation.
Thalidomide category, actions, and uses?
INHIBITORS OF ANGIOGENESIS
- Its mechanism of action is unclear.
- Inhibits synthesis of TNF-α.
- Inhibits angiogenesis.
- Thalidomide is now called an immunomodulatory drug.
- Indicated for the treatment of patients with erythema nodosum leprosum and multiple myeloma
Two categories falling under cytotoxic agents?
- ANTIMETABOLITES
* ALKYLATING AGENTS
Name 4 antimetabolites?
- Azathioprine
- Methotrexate
- Mycophenolate mofetil
- Leflunomide
AZATHIOPRINE: ADVERSE EFFECTS?
- Bone marrow suppression
- GI disturbances
- Increase in infections and malignancies
Azathioprine moa?
• Purine antimetabolite.
• Prodrug of 6-mercaptopurine.
• Converted to 6-MP.
• 6-MP is converted to metabolites that inhibit de
novo purine nucleotide synthesis.
• This leads to suppression of B and T cell
function, of immunoglobulin production and of
IL-2 secretion.
AZATHIOPRINE: DRUG INTERACTIONS?
• Much of the drug’s inactivation depends on
xanthine oxidase.
• Patients who are also receiving allopurinol for
control of hyperuricemia should have the dose of
azathioprine reduced.
AZATHIOPRINE: USES?
- Prevention of organ transplant rejection
* Severe rheumatoid arthritis
Methotrexate moa?
• Methotrexate’s main mechanism of action at the
low doses used in rheumatic diseases is inhibition of aminoimidazolecarboxamide
ribonucleotide (AICAR) transformylase
• AICAR transformylase catalyzes the penultimate
and final steps in de novo purine biosynthesis
which lead to synthesis of IMP.
• Inhibition of AICAR transformylase leads to
accumulation of AMP.
• AMP is released and converted extracellularly to
adenosine
• Adenosine is a potent inhibitor of inflammation.
METHOTREXATE: ADVERSE EFFECTS?
- Nausea
- Mucosal ulcers
- Leukopenia
- Anemia
- GI ulcerations
- Hepatotoxicity
- Cirrhosis is rare.
- Hypersensitivity pneumonitis
Methotrexate contraindicated and how to reduce toxicity?
• Methotrexate toxicity can be reduced with
leucovorin or folic acid.
• Methotrexate is contraindicated in pregnancy.
METHOTREXATE: USES?
- Rheumatoid arthritis
- Psoriasis
- Psoriatic arthritis
- Ankylosing spondylitis
- Systemic lupus erythematosus
MYCOPHENOLATE MOFETIL moa?
• Mycophenolate mofetil is converted into
mycophenolic acid.
• Mycophenolic acid inhibits inosine
monophosphate dehydrogenase, an enzyme in
the de novo pathway of guanosine triphosphate
(GTP) synthesis.
Mycophenolate mofetil action?
• This action suppresses both B- and Tlymphocyte activation.
• Lymphocytes are particularly susceptible to
inhibitors of the de novo pathway because they
lack the enzymes necessary for the salvage
pathway.
MYCOPHENOLATE MOFETIL:
ADVERSE EFFECTS
- Nausea, vomiting, diarrhea, abdominal pain.
- Headache
- Hypertension
- Reversible myelosuppression
MYCOPHENOLATE MOFETIL: USES?
- Prophylaxis of transplant rejection.
* SLE.
LEFLUNOMIDE moa?
• Prodrug of teriflunomide. • Teriflunomide inhibits dihydroorotate dehydrogenase. • This decreases levels of UMP. • UMP is essential for the synthesis of pyrimidines.
LEFLUNOMIDE: ADVERSE EFFECTS?
- Diarrhea.
- Reversible alopecia
- Rash
- Myelosuppression
- Increases in aminotransferase activity.
- CBC and liver function tests should be monitored.
- Carcinogenic and teratogenic in animals.
- Contraindicated in pregnancy.
LEFLUNOMIDE: USES?
- Rheumatoid arthritis
- SLE
- Myasthenia gravis
Cyclophosphamide category and action?
ALKYLATING AGENTS
• Cyclophosphamide is one of the most effective
immunosuppressive drugs available.
• Cyclophosphamide destroys proliferating
lymphoid cells.
• It also alkylates DNA and other molecules in
resting cells.
CYCLOPHOSPHAMIDE: ADVERSE EFFECTS?
• Infertility • Bone marrow suppression • Hemorrhagic cystitis • Rarely, bladder carcinoma. • Acrolein, a metabolite, is responsible for the urinary toxicities. • Long-term use increases the risk of infection and malignancy.
CYCLOPHOSPHAMIDE: USES?
• Used to treat SLE and other autoimmune diseases.
HYDROXYCHLOROQUINE moa and ae?
• Mechanism of anti-inflammatory action is
unclear.
AE:
• Serious adverse effects are rare.
• Hemolysis in patients with G6PD deficiency.
• Retinal damage: vision should be monitored.
HYDROXYCHLOROQUINE: USES?
• Moderately effective for mild rheumatoid arthritis.
• Usually well tolerated.
• Often used with other drugs, particularly
methotrexate and sulfasalazine.
• Also used for lupus erythematosus.
• May require 3-6 months to show clinical benefit
SULFASALAZINE constituents and metabolic activation?
• Sulfasalazine consists of sulfapyridine and 5-
aminosalicylic (5-ASA) connected by a diazo
bond.
• Metabolized by bacteria in the colon to the
constituent moieties.
• The sulfapyridine is probably the active moiety in the treatment of rheumatoid arthritis.
• The 5-ASA moiety is thought to be important in
ulcerative colitis.
SULFASALAZINE: ADVERSE EFFECTS?
- Nausea, vomiting.
- Headache, rash.
- Neutropenia.
- Thrombocytopenia is very rare.
- Drug-induced lupus is rare.
- Hemolysis in patients with G6PD deficiency.
SULFASALAZINE: USES?
- Ulcerative colitis
- Rheumatoid arthritis
- Crohn’s disease
- Ankylosing spondylitis
Name 2 polyclonal antibodies?
- Antilymphocyte & Antithymocyte Antibodies
* Rho(D) Immune Globulin
• Two types of antisera directed against
lymphocytes are available:
uses?
- Antilymphocyte globulin (ALG)
- Antithymocyte globulin (ATG)
- Used for stem cell transplantation.
- Also used for solid organ transplantation.
RHO(D) IMMUNE GLOBULIN preparation and use?
• Rho (D) immune globulin is a preparation of
human IgG containing antibodies against the
Rho
(D) antigen of the red cell.
• Used for prevention of Rh hemolytic disease of
the newborn.
MONOCLONAL ANTIBODIES
- TNF-alpha INHIBITORS
* OTHER MONOCLONAL ANTIBODIES
Lst three tnf-alpha inhibitors?
MOA?
- Adalimumab
- Infliximab
- Etanercept
• TNF-α inhibitors bind to TNF-α and prevent its
interaction with its receptors.
TNF-alpha INHIBITORS: ACTIONS?
• Blocking TNF-α action results in suppression of
inflammatory cytokines and adhesion molecules
involved in leukocyte activation and migration.
Overview adalimumab and uses?
• Fully human IgG1 anti-TNF monoclonal antibody. USES • Rheumatoid arthritis • Psoriatic arthritis • Ankylosing spondylitis • Crohn's disease • Ulcerative colitis
Overview of inflimab and uses?
• Chimeric monoclonal antibody. USES • Rheumatoid arthritis • Psoriatic arthritis • Ankylosing spondylitis • Crohn's disease • Ulcerative colitis
Overview and uses of Etanercept?
• Not a true Mab. • Contains the ligand-binding portion of human TNF-α receptor fused to Fc portion of human IgG1. USES • Rheumatoid arthritis • Ankylosing spondylitis • Psoriatic arthritis
ANTI-TNF-alpha DRUGS: ADVERSE EFFECTS
• Cytopenias can occur. CBC should be monitored.
• TNF inhibitors increase risk of infections.
• TNF inhibitors should not be given to patients with
an active infection.
• Live vaccinations should not be given to patients
on TNF inhibitor therapy.
• Patients should be screened for TB and HBV
infection.
• TNF inhibitors may increase risk of malignancies.
• TNF inhibitors may increase risk of GI ulcers and
large bowel perforation.
• TNF inhibitors can induce formation of anti-drug
antibodies. These antibodies may interfere with
drug efficacy and correlate with infusion site
reactions.
• TNF inhibitors can exacerbate HF.
Omalizumab moa and 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
exposure.
• Used in asthma refractory to inhaled corticoids
and evidence of allergic sensitization.
• Also approved for chronic urticaria.
Basiliximab moa and use?
- IL-2 receptor antagonist.
- Chimeric human-mouse IgG.
- Binds to the IL-2 receptor.
- Used to prevent renal transplant rejection.
Rituximab moa and uses?
• Chimeric murine-human monoclonal antibody that
binds to the CD20 molecule on B lymphocytes.
• Causes depletion of circulating B cells.
• Used for treatment of non-Hodgkin’s lymphoma and
chronic lymphocytic leukemia.
• Also approved for the treatment of rheumatoid
arthritis.
Anakinra action and uses?
• 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 overview and use?
- Fusion protein that interferes with T-cell activation.
* Used for moderate to severe rheumatoid arthritis.
List 3 immunostimulants?
- Aldesleukin
- Interferons
- Bacillus Calmette-Guérin (BCG)
ALDESLEUKIN structure and use?
• Recombinant interleukin-2 (IL-2).
• Indicated for treatment of renal cell carcinoma
and malignant melanoma.
Interferons alpha, beta, and gamma uses?
• Interferon-alpha is used in hairy cell leukemia,
chronic myelogenous leukemia, malignant
melanoma, Kaposi’s sarcoma, and hepatitis B
and C infections.
• Interferon-beta is approved for use in relapsing
multiple sclerosis.
• Interferon-gamma is approved for treatment of chronic
granulomatous disease.
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BACILLUS CALMETTE-GUÉRIN
BACILLUS CALMETTE-GUÉRIN (BCG) uses and ae?
• Attenuated, live culture of Mycobacterium bovis.
• By unclear mechanisms, it is active against
tumors.
• It is indicated for the treatment and prophylaxis
of carcinoma of the urinary bladder.
• Adverse effects include hypersensitivity, shock,
chills, fever, malaise, and immune complex
disease.
