1. immunosuppressants Organ transplantation
(immune system-mediated graft rejection)
Autoimmunity
(immune system-mediated diseases)

2. Immunosuppressive drugs
Glucocorticoids
Calcineurin inhibitors
Antiproliferative/antimetabolic agents
Biologics (antibodies)

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The drug should be reduced or withdrawn if its toxicity exceeds its benefit.

4. General approach to organ transplantation therapy
Biologic Induction Therapy
Maintenance Immunotherapy
Therapy for Established Rejection

5. 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.

6. 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.

7. 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.

8. Adrenocortical steroids
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.

9. 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.

10. Adrenocortical steroids
Toxicity
The 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
Poor wound healing
Cataracts
Hyperglycemia
Hypertension

11. 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.

13. 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.

14. Cyclosporine 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.

15. Cyclosporine Toxicity
The principal adverse reactions to cyclosporine therapy are:
Renal dysfunction Hypertension
Tremor Hyperlipidemia
Hirsutism Gum hyperplasia
Combined use of calcineurin inhibitors and glucocorticoids is particularly diabetogenic, with diabetes being more frequent in patients treated with FK than in those receiving cyclosporine.

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

17. Cyclosporine Drug Interactions
Inhibitors Inducers
CCBs Nafcillin
Fluconazole, Ketokonazole Rifampin
Erythromycine Phenobarbital
Methylprednisolone Phenytoin
Indinavir Octreotide
Allopurinol and metoclopramide Ticlopidin
Grapefruit (Juice)
NSAIDs, MTX, Digoxin and Lovastatin

18. 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.

19. 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

20. Tacrolimus Toxicity Nephrotoxicity Hyperkalemia
Neurotoxicity Hyperglycemia
GI complaints Diabetes
Hypertension
As with other immunosuppressive agents, there is an increased risk of secondary tumors and apportunistic infections

21. Tacrolimus Drug Interactions
The potential interactions described for cyclosporine apply for tacrolimus as well

22. 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

23. 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

24. Sirolimus Toxicity Increase in serum cholesterol and TG Lympocoele
Anemia
Leukopenia
Thrombocytopenia
Hypokalemia or hyperkalemia
Fever, Gastrointestinal effects

25. Sirolimus Drug interactions
Dose adjustment may be required with coadministration of sirolimus with CsA, diltiazem or rifampin

26. 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.

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

28. Azathioprine Toxicity
The major side effect of azathioprine is BMD, increased susceptibility to infections, hepatotoxicity, alopecia, GI toxicity, pancreatitis and increased risk of neoplasia

29. 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

30. 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.

31. Mycophenolate Mofetile
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

32. 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

33. Mycophenolate Mofetile
Drug Interactions
Aluminium or magnesium hydroxide
Cholestyramine

34. Other Antiproliferative and Cytotoxic Agents
MTX
Cyclophosphamide
Thalidomide
Chlorambucil
Leflunomide