Immunopharm

Question 1

Immunosuppressive Drugs

Answer 1

• Glucocorticoids
• Calcineurin Inhibitors
• mTOR Inhibitors
• Inhibitors of Angiogenesis
• Cytotoxic Agents
• Immunosuppressive Antibodies

Question 2

CALCINEURIN INHIBITORS

Answer 2

• includes Cyclosporine & Tacrolimus

MOA

• Calcineurin is a phosphatase necessary for activation of a T- cell-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 forms a complex with cyclophilin, an immunophilin -> inhibits calcineurin.

Uses: organ transplantation, uveitis, rheumatoid arthritis, and psoriasis.

Question 3

CYCLOSPORINE: ADVERSE EFFECTS

Answer 3

• Main adverse reactions: Nephrotoxicity,tremor, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, hirsutism, gum hyperplasia.
• Nephrotoxicity is limiting and occurs in the majority of patients treated. It is the major indication for cessation or modification of therapy.
• Very little bone marrow toxicity.

Drug interactions: primarily metabolized by CYP3A4: involved in many drug interactions.

Question 4

TACROLIMUS

Answer 4

• Tacrolimus binds to FK-binding protein (FKBP).
• FKBP is an immunophilin.
• The tacrolimus-FKBP complex inhibits calcineurin.

Uses

• organ and stem cell transplantation.
• atopic dermatitis and psoriasis.

Question 5

Sirolimus

Answer 5

• MAMMALIAN TARGET OF RAPAMYCIN (mTOR) 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.

Question 6

Thalidomide

Answer 6

• 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

Question 7

CYTOTOXIC AGENTS

Answer 7

ANTIMETABOLITES

• Azathioprine
• Methotrexate
• Mycophenolate mofetil
• Leflunomide

ALKYLATING AGENTS

• cyclophosamide

Question 8

AZATHIOPRINE including drug interactions

Answer 8

• Prodrug of 6-mercaptopurine.
• 6-MP is metabolized to 6-thioinosinic acid,which inhibits de novo purine nucleotide synthesis.
• This leads to suppression of B and T cell function, of immunoglobulin production and of IL-2 secretion

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 is indicated for prevention of organ transplant rejection and in severe rheumatoid arthritis.

Question 9

METHOTREXATE

Answer 9

MOA @ low doses

• inhibition of amino imidazole carboxamide 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.

Question 10

MYCOPHENOLATE MOFETIL

Answer 10

• Mycophenolate mofetil is converted into mycophenolic acid.
• Mycophenolic acid inhibits inosine monophosphate dehydrogenase, an enzyme in the de novo pathway of GTP synthesis.
• This action suppresses both B-andT- lymphocyte activation.
• Lymphocytes are particularly susceptible to inhibitors of the de novo pathway because they lack the enzymes necessary for the salvage pathway.

Uses

• Prophylaxis of transplan trejection.
• SLE

Question 11

LEFLUNOMIDE

Answer 11

• Prodrug of teriflunomide.
• Teriflunomide inhibits dihydroorotate dehydrogenase.
• This decreases levels of UMP.
• UMP is essential for the synthesis of pyrimidines.

Uses

• Rheumatoid arthritis
• SLE
• Myasthenia gravis

Question 12

Cyclophosphamide

Answer 12

• ALKYLATING AGENTS
• one of the most effective immunosuppressive drugs available.
• Cyclophosphamide destroys proliferating lymphoid cells.

**Uses: **SLE and other autoimmune diseases.

Question 13

POLYCLONAL ANTIBODIES

Answer 13

• Antilymphocyte & Antithymocyte Antibodies
• Immune Globulin Intravenous (IGIV)
• Rho(D) Immune Globulin
• Hyperimmune Immunoglobulins

Question 14

ANTILYMPHOCYTE & ANTITHYMOCYTE ANTIBODIES

Answer 14

• Antilymphocyte globulin (ALG)
• Antithymocyte globulin (ATG)
• Both are produced in horses or sheep by immunization against human thymus cells.
• Antibodies in these preparations bind to T cells involved in antigen recognition and initiate their destruction by serum complement.

Uses

• ALG and ATG are used before stem cell transplantation to prevent graft-versus-host reaction.
• Also used for solid organ transplantation.

Question 15

IGIV

Answer 15

• Immunoglobulin preparation from pools of thousands of healthy donors.
• It is believed to have a normalizing effect on an individual’s immune system.
• Its precise mechanism is not known.

Uses

• Immunoglobulin deficiencies
• Autoimmune disorders
• HIV disease
• Bone marrow transplantation

Question 16

HYPERIMMUNE IMMUNOGLOBULINS

Answer 16

Available for treatment of:

• RSV
• Cytomegalovirus
• Varicella zoster
• Hepatitis B virus
• Rabies
• Tetanus
• Rattlesnake and coral snake bites
• Digoxin overdose

Question 17

TNF-α INHIBITORS

Answer 17

include Infliximab & Etanercept

Risks

• Patients may be at an increased risk of infection or reactivation of M tuberculosis, hepatitis B virus, and invasive systemic fungi.
• Patients may also be at increased risk for malignancies.

Question 18

INFLIXIMAB

Answer 18

• Chimeric monoclonal antibody.
• Binds with high affinity and specificity to human TNF-α
• Used in the treatment of Crohn’s disease, rheumatoid arthritis, ulcerative colitis, ankylosing spondylitis, and psoriatic arthritis.

Question 19

ETANERCEPT

Answer 19

• Not a true Mab.
• Contains the ligand-binding portion of a human TNF-α receptor fused to the Fc portion of human IgG1
• Etanercept binds to TNF-α and prevents it from interacting with its receptors.
• Approved for rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis, and psoriatic arthritis

Question 20

MUROMONAB-CD3

Answer 20

• Binds to the CD3 antigen on the surface of thymocytes and mature T cells.
• Depletes pool of T cells.
• Used to manage acute rejection of kidney, heart and liver transplants.

Question 21

DACLIZUMAB

Answer 21

• IL-2receptorantagonist.
• Humanized IgG that binds to the IL-2 receptor present on the surface of activated lymphocytes and prevents activation by IL-2.
• Used in combination with other immunosuppressants to prevent renal transplant rejection.

Question 22

BASILIXIMAB

Answer 22

• IL-2 receptor antagonist.
• Chimeric human-mouse IgG.
• Binds to the IL-2receptor.
• Used in combination with other immunosuppressants to prevent renal transplant rejection.

Question 23

RITUXIMAB

Answer 23

• 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.

Question 24

IMMUNOSTIMULANTS

Answer 24

• Aldesleukin
• Interferons
• Bacillus Calmette-Guérin (BCG)

Question 25

ALDESLEUKIN

Answer 25

* Recombinant interleukin-2 (IL-2). * IL-2 is a 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.

Question 26

INTERFERONS

Answer 26

used in hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, Kaposi's sarcoma, and hepatitis B and C infections. Interferon-β is approved for use in relapsing multiple sclerosis. Interferon-γ is approved for treatment of chronic granulomatous disease.

Question 27

BCG

Answer 27

* 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.