immunosuppressants

Organ transplantation(immune system-mediated graft rejection)

Autoimmunity(immune system-mediated diseases)

Immunosuppressive drugs

Glucocorticoids

Calcineurin inhibitors

Antiproliferative/antimetabolic agents

Biologics (antibodies)

General Approach to Organ Transplantation Therapy Careful patient preparation and selection of

the best available ABO type-compatible HLA match for organ donation.

Combination therapy. Greater immunosuppression is required to

gain early engraftment and/or to treat established rejection, than to maintain long term immunosuppression.

Careful investigation of each episode of transplant dysfunction is required.

The drug should be reduced or withdrawn if its toxicity exceeds its benefit.

General approach to organ transplantation therapy

Biologic Induction Therapy

Maintenance Immunotherapy

Therapy for Established Rejection

Adrenocortical Steroids

Mechanism of Action: Steroids lyse and possibly induce redistribution

of lymphocytes, causing a rapid, transient decrease in peripheral blood lymphocyte count.

Steroids bind to receptors inside cells; either these receptors, glucocorticoid-induced proteins, or interacting proteins regulate the transcription of numerous other genes.

Adrenocortical Steroids

Mechanism of Action Glucocorticoid-receptor complexes increase

IkB expression, thereby curtailing activation of NF-kB1 which increases apoptosis of activated cells.

Downregulation of important proinflammatory cytokines, such as IL-1 and IL-6. T cells are inhibited from making IL-2 and proliferating.

Adrenocortical steroids

Mechanism of Action The activation of cytotoxic T lymphocytes is

inhibited. Neutrophil and monocytes display poor

chemotaxis and decreased lysosomal enzyme release.

Therefore, glucocorticoids have broad anti-inflammatory effects on cellular immunity.

In contrast, they have relatively little effect on humoral immunity.

Therapeutic Uses Glucocorticoids commonly are used in combination

with other immunosuppressive agents to both prevent and treat transplant rejection.

High doses of intravenous methylprednisolone sodium succinate (pulses) are used to reverse acute transplant rejection and acute exacerbations of selected autoimmune disorders.

Adrenocortical steroids

Therapeutic Uses They are efficacious for treatment of GVH

disease in BMT.

Glucocorticoids are used routinely to treat RA, SLE, systemic dermatomycositis, psoriasis, asthma, and other allergic disorders, IBD, inflammatory ophthalmic diseases, autoimmune hematologic disorders, and acute exacerbations of MS.

Adrenocortical steroids

ToxicityThe extensive use of steroids has resulted in

disabling and life-threatnening adverse effects in many patients. These effects include:

Growth retardation Avascular necrosis of bone Osteopenia

Increased risk of infection

Adrenocortical steroids

•Poor wound healing•Cataracts•Hyperglycemia•Hypertension

Calcineurin Inhibitors

Cyclosporine and Tacrolimus (FK506) After binding to cyclophilin or FKBP-12 block

the activity of calcineurine (a phospahtase).

Calcineurine-catalysed dephosphorylation is required for movement of a component of the nuclear factor of activated T lymphocytes (NFAT) into nucleus.

NFAT is required for induction of a number of cytokine genes, including that for IL-2 and T-cell GF and DF.

Cyclosporine

Is a cyclic polypeptide. Is lipophilic and highly hydrophobic. Can be administered intravenously or orally. Cyclosporine is extensively metabolized in the

liver by the cytochrom-P450 3A enzyme system. Cyclosporine and its metabolites are excreted

principally through the bile. In the presence of hepatic dysfunctions, dosage

adjustments are required.

Therapeutic Uses

Clinical indications for cyclosporine are kidney, liver, Heart and other organ transplantation; RA and psoriasis.

Cyclosporine usually is used in combination with other agents, especially glucocorticoids and either azathioprine or mycophenolate mophetile, most recently, sirolimus.

Cyclosporine

ToxicityThe principal adverse reactions to cyclosporine therapy are:Renal dysfunction HypertensionTremor HyperlipidemiaHirsutism Gum hyperplasiaCombined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic, with diabetes being more frequent in patients treated with FK than in those receiving cyclosporine.

Cyclosporine

Drug Interactions

Any drug that affects microsomal enzymes, especially the CYP3A system, may affect cyclosporine blood concenterations.

Cyclosporine

Inhibitors InducersCCBs NafcillinFluconazole, Ketokonazole RifampinErythromycine PhenobarbitalMethylprednisolone PhenytoinIndinavir OctreotideAllopurinol and metoclopramide

TiclopidinGrapefruit (Juice)

NSAIDs, MTX, Digoxin and Lovastatin

CyclosporineDrug Interactions

Tacrolimus (FK506)

Is a macrolid antibiotic. Is available for oral administration and

solution for injection. FK is extensively metabolized in liver by

CYP3A The bulk of excretion of parent drug and

metabolites in the feces. Less than 1% of administered drug is excreted unchanged in the urine.

Tacrolimus

Therapeutic Uses

Tacrolimus is indicated for the prophylaxis of solid-organ allograft

rejection in a manner similar to CsA and as rescue therapy in patients with

rejection episodes despite “ therapeutic” levels of CsA

Tacrolimus

Toxicity

Nephrotoxicity HyperkalemiaNeurotoxicity HyperglycemiaGI complaints DiabetesHypertension

As with other immunosuppressive agents, there is an increased risk of secondary tumors and apportunistic infections

Tacrolimus

Drug Interactions

The potential interactions described for cyclosporine apply for tacrolimus as well

Antiproliferative and Antimetabolic Drugs

Sirolimus (Rapamycin; RAPAMUNE) Is a macroyclic lactone Sirolimus inhibits T-lymphocyte activation

and proliferation downstream of the IL-2 and other T-cell growth factor receptors

The sirolimus-FKBP-12 complex binds to and inhibits the mammalian kinase (mTOR), which is a key enzyme in cell-cycle progression

Sirolimus

Therapeutic uses

Sirolimus is indicated for prophylaxis of organ transplant rejection in combination therapy with a calcineurin inhibitor and glucocorticoids.

Inhibition local cell proliferation

Toxicityo Increase in serum cholesterol and TGo Lympocoeleo Anemiao Leukopeniao Thrombocytopeniao Hypokalemia or hyperkalemiao Fever, Gastrointestinal effects

Sirolimus

Drug interactions

Dose adjustment may be required with coadministration of sirolimus with CsA, diltiazem or rifampin

Sirolimus

Azathioprine (IMURAN)

Mechanism of action

Following exposure to nucleaphiles (gluthathione), azathioprine is cleaved to 6-MP, which in turn, is converted to additional metabolites that inhibit de novo purine synthesis.

Azathioprine

Therapeutic Uses

It is indicated as an adjunct for prevention of organ transplant rejection and in sever RA.

Azathioprine

Toxicity

The major side effect of azathioprine is BMD, increased susceptibility to

infections, hepatotoxicity, alopecia, GI toxicity, pancreatitis and increased risk

of neoplasia

Azathioprine

Drug Interactions

Allopurinol

Adverse effects resulting from co- administration of azathioprine with other myelosuppressive agents or ACEIs include:

Leukopenia, thrembocytopenia and anemia as a result of myelosuppression

Mycophenolate Mofetile

Mechanism of action

Is a prodrug (MFA).

Is a selective, uncompetitive and reversible inhibitor of IMPDH, an important enzyme in the de novo pathway of guanine nucleotide synthesis.

Therapeutic Uses

Mycophenolate mofetile is indicated for prophylaxis of transplant rejection and is typically used in combination with glucocorticoids and a calcineurine inhibitor, but not with azathioprine

Mycophenolate Mofetile

Toxicity

The principal toxicities of mycophenolate mophetile are GI and hematologic. These include:

Leukopenia, diarrhea and vomiting. There also is an increased incidence of some infections, especially sepsis associated with cytomegalovirus

Mycophenolate Mofetile

Drug Interactions

Aluminium or magnesium hydroxide

Cholestyramine

Mycophenolate Mofetile

Other Antiproliferative and Cytotoxic Agents

MTX

Cyclophosphamide

Thalidomide

Chlorambucil

Leflunomide