Immunosuppressive drugs.pptx

 Immunosuppressants are drugs or medicines
that lower
 the body's ability to reject a transplanted organ.
Another
 term for these drugs is anti-rejection drugs.
 There are 2 types of immunosuppressants:
 • Induction drugs: Powerful antirejection
medicine used
 at the time of transplant
 • Maintenance drugs: Antirejection
medications used for
 the long term.

 The ability to prolong life by transplanting organs
had
 long been a dream of medical practitioners.
 • Early efforts at transplantation were unsuccessful
 because of inadequacies in surgical technique and
lack of
 fundamental knowledge of the immune system.
 • The kidney was the first such organ to be
successfully
 transplanted.
 • Initial attempts at immunosuppression were with
total
 body radiation, but all the patients died.
 • Steroids alone were then used, also without
success. 4

 1950’s
 • First successful kidney transplant
 • Total body irradiation for immunosuppression
 • Steroids
 1960’s
 • Azathioprine
 1970’s
 • Polyclonal anitbodies – anti-lymphocyte globulin
(now Atgam ,
 Thymoglobulin )
 1980’s
 • Cyclosporine (Sandimmune ), “triple drug therapy”
 • Monoclonal antibody, OKT3 (Orthoclone ) in 1985
 5

 • Tacrolimus (Prograf )
 • Mycophenolate Mofetil (Cellcept )
 • Basiliximab (Simulect )
 • Cyclosporine Microemulsion (Neoral )
 • Daclizumab (Zenapax )
 • Rabbit Antithymocyte globulin
(Thymoglobulin )
 • Sirolimus (Rapamune )

 • Preparation made by immunization of animals
with
 human lymphoid tissue
 Rabbits ➠
 • Thymoglobulin (Genzyme)
 • Anti-T-lymphocyte immune globulin (ATG-
Fresinius)
 Horses ➠ ATGAM
 • Several studies found that rATG was more
effective in
 preventing rejection and was associated with
better graft
 survival than ATGAM.

 • Rapid T-cell depleting agent through
complementdependent
 cell lysis in the blood compartment and
 apoptotic cell death in the lymphoid tissues.
 • Also modulates cell surface molecules that regulate T
cell
 activation as well as adhesion molecules and chemokine
 receptors involved in leukocyte-endothelial interactions.
 • Repopulation leads to expansion of specific T-cell subsets
 that have been shown to exhibit regulatory suppressor
 functions, such as CD8+CD57+CD28- T cells.
 11

 • rATG are antibodies derived from rabbit sources
which
 are commonly used induction agents although they
are
 approved for corticosteroid resistant rejection.
 • These antibodies are FDA approved for treatment of
 acute rejection at dose of 1.5 mg/kg for 7-14 days,
 • Reported induction doses range from 1-6 mg/kg per
 dose over 1-10 days with a more typical regimen of
1.5
 mg/kg for 3-5 days
 Kalluri HV, Hardinger KL. Current state of renal
transplant immunosuppression: 12
 Present and future. World J Transplant 2012; 2(4):
51-68

 • Common adverse events include cytokine release
 • Side effect
 – Leukopenia
 – serum sickness (cross-reactivity with other tissue
antigens)
 – adversely affects the ability of the patient to make
 antibodies against foreign protein
 – thrombocytopenia
 – pruritis
 – fever
 – arthralgias
 – opportunistic infections
 – malignancies

 • BASILIXIMAB has high specificity to the alfa-chain of IL-2
 receptor on the surface of T cells which act by blocking
 activated lymphocytes.
 • Basiliximab has the FDA’s approval for the prophylaxis of
 acute organ rejection in patients with renal
 transplantation when used as part of a triple
 immunosuppressive regimen that includes CsA, MMF and
 corticosteroids.
 • Its use is recommended for other solid organ transplant
 recipients, as well. 20
 Maravic-Stojkovic V, Stojkovic B, Peric M. Modern
immunosuppressive agents
 after heart transplantation. Curr Trend Cardiol.
2017;1(2):41-48.

 • Basiliximab is registered for intravenous administration
 only, as a bolus or as infusion over 30 minutes.
 • It should be administrated only two times: first dose 20
 mg within 2 hours after starting surgery, and second dose
 4 days after transplantation.
 • These saturate receptors and prevent T lymphocytes
from
 replication, and also from activating the B cells, which are
 responsible for the production of antibodies, which would
 bind to the transplanted organ and stimulate an immune
 response against the graft

 • Zenapax
 • Description
 – Humanized monoclonal antibody against CD25
 (interleukin-2– receptor α chain)
 • Mechanism
 – Binds to and blocks the interleukin-2– receptor α
 chain (CD25 antigen) binds with high-affinity to the
 Tac subunit of the high-affinity IL-2 receptor complex
 and inhibits IL-2 binding
 – on activated T cells, depleting them and inhibiting
 interleukin-2–induced T-cell activation

 Daclizumab: IL-2 antagonist: Humanized, 90%
human
 10% murine origin
 • 1 mg/kg within 24 hours of KT plus additional 4
doses
 of 1 mg/kg at a schedule of every 2 weeks after
KT.
 • Causes receptor saturation that lasts up to 120
days
 • Daclizumab was “retired” from market by the
 manufacturer at the end of 2009
 • Basiliximab will remain the only IL-2RA in the
market

 • Orthoclone OKT3
 • Description
 – Murine monoclonal antibody against CD3 component of T-cell–
 receptor signal-transduction complex
 • Mechanism
 – monoclonal IgG2a antibody
 – binds to the T cell receptor-CD3-complex (specifically the CD3
 epsilon chain) on the surface of circulating T cells, interfering
 with the receptor-antigen-interaction
 – resulting in a transient activation of T cells, release of
cytokines,
 and blocking of T-cell proliferation and differentiation
 – T-cell function usually returns to normal within approximately
 48 hours of discontinuation of therapy

 • OKT3 is a murine monoclonal antibody directed
against
 the CD3 receptor.
 • Inert T-cell , removed via
opsonization/phagocytosis.
 • A substantial T-cell loss could occur within the
first few
 hours after an initial dose.
 • As T-cell fall, several T-cell derived cytokines
(eg,TNF,
 IL-2, and IFN-γ) are released into circulation.
 • Dosage: 5mg iv bolus, daily for 10 days
 ITS AN OLD MOLECULE NOT USED NOWADAYS

 • Recombinant DNA-derived humanized
monoclonal
 antibody directed against CD52
 • CD52 is present on all B- and T-cells
macrophages, NK
 cells
 • Trigger antibody-dependent lysis of T cell
 • FDA approved in refractory B cell chronic
lymphocytic
 leukemia treatment
 • DOSING: 20-30 mg on the day of
transplantation infused
 4-8 hr (over peripheral line)

Immunosuppressive drugs.pptx

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