IMMUNOSUPPRESSIVE AGENTS

1. IMMUNOSUPPRESSIVE AGENTS

4. Clinical indications of immunosuppressive agents: l-To prevent rejection of organ transplants in allograft transplantation. 2-To manage a wide variety of autoimmune disorders. Autoimmune diseases arise when the immune system is sensitized by "foreign antigens". 3-To prevent Rh hemolytic disease of the newborn (Erythroblastosisfetalis).

5. Hazards of immunosuppressive agents: Nonspecific suppression of the immune responses produces: l-An increased risk of infection by bacterial, viral and fungal organisms. 2-An increased incidence (3-100 fold) of malignant neoplasms in patients after allograft transplantation. This generally occurs after 4-7 years of therapy and cancers most likely to occur are those thought to have viral origin (lymphoma, leukemia, skin).

6. SPECIFIC IMMUNOSUPPRESSIVE AGENTS Four classes of immunosuppressive drugs are currently used: (1) Corticosteroids. (2) Calcineurin inhibitors. (3) Antimetabolites and antiproliferative drugs. (4) Antibodies.

7. I-Corticosteroids 1-Block the processing of antigen by phagocytic cells (macrophages, monocytes) and its subsequent presentation to T cells. 2-Block the activation of Tcells by interleukin-l derived from macrophages. 3-Inhibit the actions of cytotoxic Tcells.

8. Therapeutic uses: 1-Glucocorticoids are useful in autoimmune diseases asidiopathic thrombocytopenic purpura and rheumatoid arthritis due to both immunosuppressive and anti-inflammatory effects. 2-In organ transplant recipients particularly during rejection crisis. 3-Modulate allergic reactions and are useful in the treatment of diseases like asthma or as premedication for other agents (eg, blood products, chemotherapy) that might cause undesirable immune responses.

9. II-CALCINEURIN INHIBITORS A-CYCLOSPORINE (SANDIMMUNE):

10. Pharmacokinetics: Given as intravenous infusion or orally (slowly and incompletely absorbed (bioavailability 20–50%). The absorbed drug is primarily metabolized by the P450 3A enzyme system in the liver with multiple drug interactions that contributes to significant interpatient variability in bioavailability, such that cyclosporine requires individual patient dosage adjustments.

11. Side effects: l-Nephrotoxicity 2-Hypertension, hyperglycemia, neurological toxicity (altered mental status and seizures), hepatotoxicity, hyperuricemia may lead to worsening of gout, hirsutism and gingival hyperplasia may occur. 3-Cyclosporine causes very little bone marrow toxicity. While an increased incidence of lymphoma and other cancers (Kaposi's sarcoma, skin cancer) have been observed in transplant recipients receiving cyclosporine.

12. Therapeutic uses: 1-Cyclosporine is used primarily in combination with other immunosuppressive agents, particularly glucocorticoids, to prevent rejection of renal, hepatic and cardiac transplants. 2-In a variety of autoimmune diseases as in rheumatoid arthritis and psoriasis, cyclosporine may be useful but relapses occur in a significant number of patients when therapy is terminated.

13. B-TACROLIMUS: Mechanism of action: It binds to an intracellular protein, FK-binding protein-l2 (FKBP-12), that leads to inhibition of the phosphatase, calcineurin i.e. it is calcineurin inhibitor. (10-100 fold more potent). Therapeutic uses: 1-When cyclosporine has proved ineffective or too toxic. 2-It is now considered a standard prophylactic agent (usually in combination with methotrexate or mycophenolatemofetil) for graft-versus-host disease.

14. III-ANTIMETABOLITES AND ANTIPROLIFERATIVE DRUGS These drugs have their effects on actively dividing cells and at low doses appear to have a relatively selective action on lymphocytes. A-Sirolimus: Mechanism of Action: Sirolimus inhibits T-lymphocyte activation and proliferation downstream of the IL-2 and other T-cell growth factor receptors. It binds FKBP-12, this complex does not affect calcineurin activity but rather inhibits a protein kinase that is a key enzyme in cell-cycle progression, called (mTOR).

15. Side effects: A common side effect of sirolimus is hyperlipidemia. Therapeutic uses: 1-Indicated for prophylaxis of organ transplant rejection in combination with a calcineurin inhibitor and glucocorticoids. 2-In patients experiencing or at high risk for calcineurin inhibitor–associated nephrotoxicity, it has been used with glucocorticoids and mycophenolatemofetil to avoid permanent renal damage.

16. B-AZATHIOPRlNE (IMURAN): Mechanism of action: Azathioprine is a prodrug for the purine antagonist 6-mercaptopurine. It thus exerts its effects by interfering with the synthesis of DNA and RNA. It kills rapidly dividing cells and so inhibits proliferation of lymphocytes as well as macrophages. Pharmacokinetics: The dose of azathioprine reduced by 25-33% in patients who are receiving the xanthine oxidase inhibitor, allopurinol.

17. Side effects: The major toxic effect of azathioprine and mercaptopurine is bone marrow suppression (commonly leukopenia ). Therapeutic uses: 1-Azathioprine is used to suppress organ transplantation rejection. 2-Treat severe refractory rheumatoid arthritis.

18. C-MYCOPHENOLATE MOFETIL: Mechanism of action: Mycophenolatemofetil is a prodrug that is rapidly hydrolyzed to the active drug, mycophenolic acid, which is a selective inhibitor of inosine monophosphate dehydrogenase, an enzyme critical for de novo synthesis of purines. It is, therefore, more effective in inhibiting T and B cells which depend on this pathway for cell proliferation.

19. Side effects: The principal toxicities of mycophenolatemofetil are leukopenia, diarrhea, and vomiting. Therapeutic uses: The drug is approved for oral use in the prophylaxis and treatment of organ rejection following renal and cardiac transplantation. It is usually given in combination with glucocorticoids and a calcineurin inhibitor.

20. Other Cytotoxic Drugs Most of the cytotoxic drugs used in cancer chemotherapy are immunosuppressive due to their actions on lymphocytes and other cells of the immune system. • Methotrexate has been used to induce remission in refractory rheumatoid arthritis and in treatment of severe disabling psoriasis. • Cyclophosphamide is a very potent immunosuppressive drug and is used to prevent organ transplant rejection. It is also used in rheumatoid arthritis, systemic lupus erythematosus and nephrotic syndrome in children

21. ANTIBODIES l-Antithymocyte globulin: It is used primarily to treat and prevent acute renal transplant rejection in combination with other immunosuppressive agents 2-Monoclonal antibodies: i-Anti-CD3 monoclonal antibodies, as Muromonab CD3 have been used in the treatment of acute organ transplant rejection. ii-Anti-TNF α monoclonal antibodies, as lnfliximab, are used in patients with rheumatoid and patients with Crohn's disease.

22. iii-Anti-IL-2-receptor monoclonal antibodies, as Daclizumab, are used to prevent organ transplant rejection as a part of combination therapy with other immunosuppressive agents. 3-Rh(D) immune globulin: It is used specifically in Rh-negative mothers sensitized to Rh(D) antigen of the red cell. As this sensitization occurs at the time of birth or abortion, the Rh(D) antibody is administered IM to the mother within 72 hours after birth of an Rh-positive baby.

23. ANTHELMINTICS

24. BENZIMIDAZOLES: This group includes drugs like albendazole, mebendazole and thiabendazole. that have various anthelmintic activities, particularly against GIT nematodes. Mechanism of action: Their primary action is to inhibit microtubule synthesis by binding to β-tubulin. As a result, immobilization and death of susceptible GIT parasites occur slowly, and their clearance from GIT may not be complete until a few days after treatment.

25. 1-ALBENDAZOLE: Albendazole is irregularly absorbed following oral administration. After absorption, the drug is rapidly metabolized to the active metabolite, albendazolesulfoxide. This metabolite is well distributed into various tissues, including hydatid cysts. Side effects: 1-In short-term therapy: Mild and include nausea, diarrhea, headache and dizziness. 2-In long-term therapy: Liver dysfunction may occur.

26. Therapeutic uses: 1-Therapy of intestinal and tissue nematodes including ascaris, hookworm, enterobius (oxyuris) and trichuris infections, whether they are single or mixed infections. 2-Drug of choice for medical treatment of cysticercosis and cystic hydatid disease and is a useful adjunct to surgical removal or aspiration of cysts. 3-Control of lymphatic filariasis and related tissue filarial infections.

27. 2-MEBENDAZOLE: Mebendazole is poorly absorbed following oral administration so it does not cause significant systemic toxicity. Therapeutic uses: The drug is highly effective against GIT nematode infections as albendazole and is particularly valuable for the treatment of mixed infections.

28. 3-THIABENDAZOLE: This drug is absorbed rapidly after oral administration. Therapeutic uses: It is mainly used: 1-Topically in cutaneous larva migrans of hookworm infections 2-Orally in strongyloidesstercoralis infection. Although thiabendazole is active against a wide range of nematodes that infect GIT, its use against these parasites has declined markedly because of its toxicity relative to that of other equally effective drugs.

29. DIETHYLCARBAMAZINE Mechanism of action: It immobilizes the microfilaria by altering its surface structure and makes it more susceptible to destruction by host defense mechanisms. Side effects: Fever, headache, malaize, urticaria, vomiting, ocular complications and lymphadenitis may follow the first dose and are due to products of destruction of parasite. Therapeutic uses: Diethylcarbamazine kills both microfilaria and adult worms of susceptible filarial species.

30. IVERMECTIN: Mechanism of action: It produces tonic paralysis of musculature of the nematode by acting on a group of glutamate-gated Cl- channels. It also binds with high affinity to GABA receptors, but the significance of this is poorly understood. Ivermectin is microfilaricidal. It does not effectively kill adult worms but blocks the release of microfilariae for some months after therapy.

31. Side effects: Ivermectin appears to have a wide margin of safety. Untoward effects include skin rashes, headache, dizziness, pains in muscles and joints. Therapeutic uses 1-Ivermectin is an antifilarial drug. The drug is curative with a single oral dose. 2-It is also used, and is a drug of choice, in the therapy of intestinal strongyloidiasis.

32. NICLOSAMIDE: Mechanism of action: It probably acts through inhibition of oxidative phosphorylation of the parasite. Worms in the gut deteriorate such that the scolex and segments may be partially digested. Side effects: Infrequent, mild and transient and include GIT manifestations.

33. Therapeutic uses: 1-This drug is effective against most cestodes but it is a second choice to praziquantel. In case of taeniasolium a purgative is better given after 3-4 hours of drug administration since viable ova are released into the gut lumen following digestion of segments and may lead to cysticercosis.

34. METRIFONATE: Metrifonate is an organophosphorus compound used as an insecticide and then as an anthelmintic, especially for S. haematobium. Metrifonate is a prodrug that is converted nonenzymatically to dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP), a potent cholinesterase inhibitor. It was withdrawn from market due to adverse effects (respiratory paralysis and defects in neuromuscular transmission)

35. OXAMNIQUINE: Mechanism of action: The drug might act through binding and alkylating DNA. It induces shift of the worms from the mesentery to the liver where many die; surviving females cease to lay eggs. Side effects: Infrequent. Occasional headache, dizziness, drowsiness, nausea, vomiting, hallucinations and excitation have been reported. Therapeutic uses: 1-Oxamniquine is a second choice drug to praziquantel for the treatment of schistosomamansoni infections. Adult male worms are more susceptible to the action of oxamniquine than are the female worms.

36. PIPERAZINE: Mechanism of action: Piperazinc is a GABA agonist. It increases chloride conductance and produces hyperpolarization of ascaris muscle membrane; this leads to flaccid paralysis. The paralyzed worms are expelled live by normal peristalsis. Because pyrantelpamoate and piperazine are mutually antagonistic with respect to their neuromuscular effects on parasites, the two should not be used together.

37. Side effects: It has a wide margin of safety; very occasionally GIT upset, transient neurological effects and urticarial reaction have been reported. Therapeutic uses: The drug is highly effective against both ascaris and enterobius. Contraindicated: In patients with a history of epilepsy, pregnancy, impaired renal or hepatic function.

38. PRAZIQUANTEL: Mechanism of action: Praziquantel increases the influx of Ca++ across the tegument of schistosomes. This leads to marked contraction followed by paralysis of worm musculature. Vacuolization and disintegration of the tegument occur and parasite death follows. Side effects: It may cause nausea, headache, dizziness and drowsiness. Therapeutic uses: Praziquantel has the unique characteristic of being effective in the treatment of :1-All species of schistosoma. 2-Most other trematode and cestode infections.

39. PYRANTEL PAMOATE: Mechanism of action: Pyrantel is a neuromuscular blocking agent that causes release of acetylcholine and inhibition of cholinesterase in susceptible nematodes; this results in spastic paralysis, which is followed by expulsion of worms. Side effects: It may induce GIT disturbances, headache, dizziness, drowsiness, rash and fever. Therapeutic uses: Pyrantelpamoate is an alternative to mebendazole in the treatment of: 1-Ascaris 2-Enterobius and 3-Hookworm infections.