1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

2.  Inhibitors of lymphocyte gene expression-
glucocorticoids- PREDNISOLONE
 Calcineurin Inhibitors-specific T-cell inhibitors-
CYCLOSPORINE, TACROLIMUS
 M-TOR inhibitors- SIROLIMUS, EVEROLIMUS
 Antiproliferative drugs- AZATHIOPRINE,
METHOTREXATE, MYCOPHENOLATE MOFETIL
 CYCLOPHOSPHAMIDE, CHLORAMBUCIL

3.  Biological agents-
 TNFα inhibitors- ETANERCEPT, INFLIXIMAB,
ADALIMUMAB
 IL-1 receptor antagonist: ANAKINRA, RILONACEPT
 IL-2 receptor antagonist: DACLIZUMAB, BACILIXIMAB
 Monoclonal antibodies-
 Anti CD3 antibody: MUROMONAB
 Anti CD52 antibody: ALEMTUZUMAB

4.  Inhibitors of immune cell adhesion- EFALIZUMAB
 Tolerogens or inhibitors of immune cell
costimulation- ABETACEPT, BELATACEPT
 Polyclonal antibodies: Antithymocyte antibody(ATG),
Rho(D) immune globulin

5. _ Inhibition of IL-1 and TNF gene expression and synthesis
1. Activation of T lymphocytes by decreasing IL-1 release
2. Neutrophil functions esp. chemotaxis
3. Antibody production (high doses)
4. Release of kinins and proinflammatory eicosanoids
(prostaglandins and leukotrienes)
5. lymphocyte mobilization out of lymphoid organs
(lymphopenia)

6.  All commonly occur because high doses used for
immunosuppression
 Suppression of hypothalamic-pituitary adrenal axis (HPA)
 Osteoporosis
 Hypertension
 Weight gain
 Hyperglycemia
 Euphoric personality changes
 Cataracts

7. Cyclosporine –cyclic polypeptide
Inhibits T-cell proliferation, IL-2 and other cytokine
production
It binds to cyclophilin inhibits response of helper T-
cells to antigenic stimulation fails
It enhances expression of TGF-β (Transformation
growth factor – β), an inhibitor of IL-2

8. _ other cytokine expression (IL-3, gamma interferon)
_ site of action is a binding protein that inhibits
calcineurin (a phosphatase) involved in signal
transduction upon antigen stimulation of T cell
receptor

9. _ Pharmacokinetics
_ variable, incomplete oral absorption
_ extensive hepatic metabolism, excreted in bile
_ used alone or in combination with prednisone and
azathioprine (or other antineoplastic drugs)
_ Adverse Effects
_ nephrotoxicity, hepatotoxicity, hirsutism, neurotoxicity
_ Drug interactions due to induction and inhibition of
hepatic cytochrome P450

10. Structure-macrolide like (Multi-membered lactone ring )
Mechanism
Similar to cyclosporine except binds to different protein
that inhibits calcineurin (a phosphatase enzyme involved
in gene transcription of IL-2, gamma interferon and other
cytokines)

11. _ given by IV infusion or orally
_ used concomitantly with corticosteroids
Adverse Effects
_ nephrotoxicity, increased risk of lymphomas,
hypersensitivity, hyperglycemia, GI complaints,
hypertension, neurotoxicity (tremor, headache,
motor disturbances, seizures)

12. Structure-macrolide like (Multi-membered lactone ring )
_ Mechanism
_ Binds to FKBP and later binds to calcineurin
_ binds to immunophilin protein that binds to a key
regulatory kinase required for T cell activation
_ (new unique mechanism to inhibit T lymphocyte
activation by IL-2)
_ different site of action than cyclosporine and Tacrolimus
_ Selective blockade of cytokine signal transduction
_ Potential for synergy with other immunosuppressants

13. P/K-low oral absorption
_ hepatic metabolism by CYP4 (drug interactions)
_ long half-life (60 hours)
Adverse Effects
_ thrombocytopenia, hyperlipidemia, rash
_ lacks direct end organ toxicity but increased incidence
impaired renal function when combined with
cyclosporine

14.  MTX is an antifolate belonging to the antimetabolite
class of antineoplastic agents.
 MTX is a cell cycle specific chemotherapeutic agents
that acts on S-phase & thus inhibit DNA synthesis
Metabolism
Methotrexate undergoes hepatic and intracellular
metabolism to active polyglutamated forms and is
partially metabolized by intestinal flora after oral
administration.
Folic acid
Tetrahydrofolic
acid
Dihydrofolate reductase

15. Absorption
Oral absorption is dose dependent. 1 to 2 h (oral) and 30 to 60 min
(IM). The mean bioavailability is 60%. Food delays absorption and
reduces peak concentration.
Distribution
Approximately 50% is protein bound. Methotrexate does not
penetrate the blood-cerebrospinal fluid barrier in therapeutic
amounts when given orally or parenterally, but it has been
detected in breast milk.
Elimination
Renal excretion is the primary route of elimination and is dependent
upon dosage and route of administration. With IV administration,
80% to 90% is excreted unchanged in urine within 24 h and less
than 10% through biliary excretion.
Anti proliferative-Methotrexate

16. Structure-derivative of mycophenolic acid
Mechanism-inhibits inosine monophosphate
dehydrogenase involved in denovo synthesis of purines
_ selectively suppresses T- and B-cell proliferation
_ Also suppresses some macrophage functions (may
explain anti-inflammatory actions)
Pharmacokinetics
_ oral absorption and hepatic metabolism
Adverse Effects-diarrhea, leukopenia and CMV infections
_ increased incidence of lymphomas

17.  New Immunosuppressant
 Recombinant DNA-derived humanized monoclonal
antibody
 Binds to CD52. a nonmodulating antigen present on
surface of all T and B cells
 Some bone marrow cells express CD52 including some
CD34+ cells
 Produces profound T cell depletion
 Used for selected leukemias and lymphomas
also for stem cell transplant procedures

18. _ OKT3 (Muromonab-CD3)
_ monoclonal antibody to CD3 on T cell
_ inhibits cytotoxic T killer cell function
_ opsonizes circulating T lymphocytes and enhances their
removal
_ used to prevent or reverse acute graft rejection
_ Antilymphocyte Globulin
_ polyclonal antibody similar to OKT3
_ Antithymocyte Globulin-Rabbit
_ used to treat acute renal transplant rejection

19.  Hypersensitivity reactions may occur with nonhuman
antibodies resulting in chills, fever, thrombocytopenia,
erythema, pruritus
 Problem with murine monoclonal antibody called OKT3 is
formation of anti-OKT3 antibodies limit its action so only
given by IV infusion for 7-14 days

20. _ Basiliximab
_ Chimeric murine monoclonal antibody against human
IL-2 receptor alpha subunit of activated T to block T cell
_ Blocks activation and inhibits clonal expansion of T cells
_ Used to induce immunosuppression and to prolong
organ transplants in combination with
immunosuppressants

21. Daclizumab
_ a humanized immunoglobulin similar to Basiliximab
which blocks IL-2 receptor
_ Formed by splicing complementary portions of light and
heavy chain variable regions of murine antibody into
human-derived Fab framework and fusing the Fab to the
Fc portion of human IgG

22. _ Immunosuppression by inhibition of lymphocyte
proliferation and cause bone marrow suppression
_ Azathioprine
_ Cyclophosphamide

23. _ Interferon Alpha (prod. by leukocytes)
_ (antiviral, antiproliferative)
_ malignant melanoma, renal cell carcinoma, hairy cell
leukemia, Kaposi’s sarcoma
_ Interferon Beta (prod. by fibroblasts)
_ (antiviral, antiproliferative)
_ relapsing type MS
_ Interferon Gamma (prod. by lymphocytes)
_ (stimulates NK cells and macrophages)
_ chronic granulomatous disease

24.  TNF inhibitors (disease modifiers to treat rheumatoid
arthritis)
 Etanercept
▪ Recombinant version of TNF receptor
 Infliximab
▪ Chimeric human/murine anti-TNF monoclonal
antibody
 Anakinra
 Human IL-1 receptor antagonist
 Disease modifier agent for Rheumatoid arthritis

25. _ Rh(D) Immune Globulin
_ for Rh (neg.) mother after delivery of Rh(pos.) baby
_ Abciximab
_ for surface receptor on activated platelets to prevent
restenosis after coronary angioplasty
_ Rituximab
_ for CD20 on pre-B and mature B cells to treat non-
Hodgkin's lymphoma