Blood And Lymph- Immunosuppressant Drugs By Boy Bridges

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Blood and Lymph- Immunosuppressant Drugs by Boy Bridges

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Blood and Lymph- Immunosuppressant Drugs by Boy Bridges

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Why immunosuppress?

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Dampen the immune response in …

Solid Organ and Bone Marrow (BM) Transplantation

Prevention of allograft rejection
-More success in preventing response than suppressing an established response
-Usually dealing with life-long immunosuppression

Graft-versus-host disease (GVHD)

Isoimmune disorders; Rh hemolytic disease of newborn

Autoimmune diseases

*LIFE LONG TREATMENT!

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Glucocorticoids:
Prednisone

use, DOC

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Prevent rejection
-Most effective when given at time of transplantation

Acute rejection episodes
-High doses used to treat

GVHD
-Lower doses used to prevent; High doses to treat

DOC for several autoimmune diseases
Acute glomerular nephritis
Autoimmune hemolytic anemia

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prednisone moa

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suppress immune system.
-decrease circulating lymphocyte levels
-dec. T cells (prolif and activ)
-inhibit IL-2 production

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adverse effects of prednisone

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the steroid man. major problem.
*thinning of skin and purpura
-cushing-like syndromes

eye: cataracts (after prolonged use)
GI: gastritis, peptic ulcers, GI bleeding
renal: fluid retention, hypertension
Genitourinary: Amenorrheoa, reduced fertility
Musculoskeletal: osteoporosis (one of most serious), muscle weakness
CNS: euphoria, psychiatric disorders
dislipidemia, hyperglycemia (new onset diabetes)
more susceptible to infection

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Calcineurin Inhibitors

cyclosporine
tacrolimus

do you use this for acute rejection?

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no, you don't use for acute rejection. it's for maintenance therapy.

Uses
Used alone or in combination with other immunosuppressants (maintenance therapy a.k.a. prophylaxis)
Allograft transplantation
not effective in ongoing or acute rejection
GVHD
Certain autoimmune disease
psoriasis
rheumatoid arthritis

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moa of cyclosporine

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Targets intracellular signaling pathways induced by T-cell-receptor activation
-**Selective decrease IL-2 gene transcription
-Binds to *cyclophilin (cytoplasmic receptor) to prevent early stage T cell activation
--Cyclosporin-cyclophilin complex binds calcineurin
Inhibits IL-2 & IL-2 dependent T cell prolif

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pharmacokinetics of cyclosporine

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Pharmacokinetics
Plasma levels are usually monitored to…
Assure maximal desired therapeutic range
Dose must be carefully adjusted to ‘prevent’ rejection
Individualized dosing required for optimal therapy
Avoid toxicity

Mostly eliminated by CYP3A4
So drug interactions can be an issue
Some azoles can inhibit CYP3A4
increase cyclosporine levels ; produce toxicities

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adverse effects

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Adverse effects
**Nephrotoxicity (worst thing)
Neurological/hepatic tox (~20% incidence)
**Gingival Hyperplasia (zebra)
**Hirsutism (zebra)

**Hyperkalemia (reduced excretion)
hypertension
seizures
hyperglycemia

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Tacrolimus, difference between this and cyclosporin?

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Similar MoA and Use as cyclosporine except…
Binds different cytoplasmic protein
-binds FKBP rather than cyclophilin
-Tacrolimus-FKBP complex binds calcineurin

Toxicity similar to cyclosporine
-Nephrotoxicity (dose limiting)
-Glucose intolerance & diabetes mellitus
-No hirsutism or gingival hyperplasia

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Antiproliferative Agents

sirolimus
azathioprine
mycophenolate mofetil

use
what doesnt it do (that tacrolimus does)

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Use: prophylaxis (usually in combo)
-+ calcineurin inhibitor + glucocorticoid

Binds to FKBP like tacrolimus but….
-does NOT block IL-2 production
-Sirolimus-FKBP complex
--binds mTOR
--does not bind to calcineurin

Interrupts T-cell activation downstream of IL-2 receptor
-if other drug can't stop IL-2 production, this stops the IL-2 signal

Inhibits proliferation
-Inhibits protein kinase (mTOR)
--mTOR = mammalian target of rapamycin
-mTor: key enzyme in intracellular signaling pathway for cell-cycle progression; Blocks cell cycle progression (at G1-S)

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Sirolimus

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-hyperlipidemia
-PROFOUND myelosuppression
-no renal tox
-Extensively metabolized by liver
(Mainly CYP3A4)

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Antiproliferative Agents
Azathioprine

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A prodrug
-converted to mecaptopurine
-inhibits DNA synth in the S phase
-maintenance therapy, prevents rejection and maintains transplant

-moa: interferes with purine nucleotide de novo synthesis (inhibit dna synth)

Cytotoxic to proliferating cells: Stimulated lymphoid cells are most sensitive (**especially T-cells)
Depresses both cell mediated and antibody mediated reactions

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Azathioprine pharmacokinetics, adverse effects

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Inactivated by xanthine oxidase
-Dose reduction required when allopurinol is being used

-adverse: bone marrow suppression

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Mycophenolate mofetil

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Selective, noncompetitive inhibitor of IMPDH
-de novo guanine nucleotide synthesis
-deprives rapidly dividing cells of GTP and dGTP
-B & T lymphocytes dependent on (de novo) pathway for proliferation – other cells use salvage

-Selectively inhibits lymphocyte proliferation, including Ab formation
-Used in combo with a glucocorticoid + calcineurin inhibitor

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Antibodies

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Used as ‘adjuvants’ to ↓ # circulating T-cells or impair T-cell function; leave humoral intact

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ALG

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used in **kidney transplants

polyclonal anti-lymphocyte globulin

ANTISERA produced by immunization of large animals.

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ATG

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used in **acute rejection episodes

a polyclonal anti-thymocyte globulin
ANTISERA produced by immunization of rabbits or horses

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ALG & ATG

used to treat

adverse effects:

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Used to treat donor BM prior to transplantation to destroy T cells to avoid GVHD

Used to treat steroid resistant rejections

Adverse effects:
Mostly related to allergic type reactions (foreign proteins); Local pain and erythema

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Muromonab-CD3 (OKT3)

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Muromonab-CD3 (OKT3)

T-cell specific murine monoclonal Ab

Directed against CD3 on surface of human thymocytes & mature T-cells

Shuts down activation of T-cell proliferation and impairs cytotoxic T-cell function

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when is Muromonab-CD3 (OKT3)
used?

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Treat **acute rejection episodes in combination with other drugs

Deplete donor BM of T-cells prior to BM transplant (minimize GVHD occurrence)

Use in US has decreased dramatically
-Due to acute side effects (infection and first-dose reaction – cytokine release)

adverse effects: cytokine storm

doesnt work as well the second time because the body makes antibodies against it.

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Daclizumab

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IL-2 antagonist

use:
-prophylaxis against acute rejection
-acute rejection episodes