Immunosuppressants

IMMUNOSUPPRESSANTS


IMMUNOSUPPRESSANTS

  • Drugs lowering body’s immunity, including lowering effect of rejection of transplanted organ.
  • Also referred as “anti-rejection” drugs.
Drugs included: 
  • Glucocorticoids, Calcineurin inhibitors (Cyclosporine & Tacrolimus), proliferation signal inhibitors (Sirolimus, Everolimus), purine synthesis inhibitor (Mycophenolate mofetil), Antimetabolites (Azathioprine), Cytotoxic agents (Cyclophosphamide, chlorambucil & methotrexate), leflunomide, thalidomide, monoclonal antibodies, co-stimulation inhibitor (Abatacept & belatacept), IL-1 inhibitor (Anakinra), Nintedanib & Apremilast.

INDIVIDUAL DRUG DESCRIPTION:

1. GLUCOCORTICOIDS:

  • Most common immunosuppressant.
  • MOA:
    • Acts by inhibiting production of prostaglandins, leukotrienes, histamine, bradykinin & PAF.
    • Also, diminish chemotactic activity of neutrophils & monocytes.
  • Specific effects:
  • Causes sequestration of lymphocytes in lymphoid tissue resulting in lymphopenia
    • By inhibiting IL-1 production –> decrease in IL-2 & IFN-γ production.
    • Continuous administration increases IgG catabolism.
  • Uses:
    • 1st line immunosuppressive drugs for solid organ & hematological stem cell transplant recipients. 
    • Used for treatment of graft rejection & graft versus host disease (GVHD), ITP treatment, rheumatoid arthritis & bronchial asthma.

2. CALCINEURIN INHIBITORS:

  • Calcineurin required for activation of NFAT (nuclear factor of activated T-cells) –> Increases IL-2 transcription (due to activated T-cells).
  • Drugs included:
    • Cyclosporine & Tacrolimus (FK 506).
  • Tacrolimus:
    • Macrolide antibiotic.
    • More potent than cyclosporine.
  • MOA:
    • Inhibits NFAT activation by binding to immunophilins – Cyclosporine binds to cyclophilin; tacrolimus binds to FKBP.
    • Inhibition of IL-2 gene transcription.
  • Uses: 
    • Used as immunosuppressive agents for organ transplantation, GVHD & some autoimmune diseases (rheumatoid arthritis & psoriasis).
  • Comparison of effects between cyclosporine & tacrolimus:
    • Cause nephrotoxicity, hepatotoxicity, hypertension (50% of renal transplant & all cardiac transplant recipients), hyperkalemia, hyperlipidemia, hyperuricemia, hyperglycemia, hirsutism, gum hyperplasia & neurotoxicity (tremor, headache, motor disturbance & seizures).
    • Incidence of hyperglycemia & neurotoxicity is more with tacrolimus than cyclosporine.
    • Hirsutism, gum hyperplasia, hyperuricemia & hyperlipidemia not caused by tacrolimus.
  • Specific adverse effect of cyclosporine:
    • Nephrotoxicity (Major) – Needs cessation or modification of cyclosporine therapy.         
    • Sirolimus aggravates cyclosporine-induced renal dysfunction.
    • Cyclosporine increases sirolimus induced hyperlipidemia & myelosuppression.

3. PROLIFERATION SIGNAL INHIBITORS:

  • MOA:
    • IL-2 stimulates immune system – By activation of T-cells, via activation of mammalian target of rapamycin (mTOR).
  • Drugs included:
    • Sirolimus (rapamycin) & Everolimus.
  • Sirolimus:
  • MOA: 
    • Binds to mTOR & inhibits IL-2 action without affecting its transcription.
  • Uses:
    • Used as immunosuppressive agent in organ transplantation & GVHD.
    • Incorporated in cardiac stents, decreasing reocclusion chances.
  • Major adverse effect: 
    • Thrombocytopenia due to bone marrow suppression & hyperlipidemia.
    • Nephrotoxic – Sirolimus (per se not).
    • Due to increasing lymphocele in dose-dependent fashion.
  • Everolimus:
    • Newer drug with shorter half-life (43 hrs compared to 60hrs with sirolimus).
  • Uses:
    • Recently approved for treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis.
    • Useful in cardiac transplantation.
  • Adverse effect: Increases risk of hemolytic uremic syndrome.

4. PURINE SYNTHESIS INHIBITOR:

  • Drug: Mycophenolate mofetil.
  • MOA:
    • Inhibits inosine monophosphate dehydrogenase enzyme, after conversion to active metabolite (mycophenolic acid).
    • Monophosphate dehydrogenase enzyme necessary for de novo synthesis of purines.
  • Uses: 
    • Used as immunosuppressants for steroid-refractory cases.
  • Major adverse effects: GI disturbances & myelosuppression.

5. ANTIMETABOLITES:

  • Drug: 
    • Azathioprine only antimetabolite as immunosuppressant (not anticancer drug).
    • Prodrug & activated to 6-mercaptopurine (anticancer drug).
    • It lacks anticancer properties because conversion to active metabolite occurs only in lymphoid cells. 
  • Major adverse effect:  Bone marrow suppression.

6. CYTOTOXIC AGENTS:

  • Cyclophosphamide, chlorambucil & methotrexate:
    • Anticancer drugs used as immunosuppressants.
  • Cyclophosphamide – Used for treatment of SLE & Wegner’s granulomatosis.
  • Cyclophosphamide & chlorambucil – Used in treating childhood nephrotic syndrome.

7. LEFLUNOMIDE:

  • Prodrug.
  • Orally active drug.
  • Active metabolite inhibits dihydro-orotate dehydrogenase –> Inhibits pyrimidine synthesis.
  • Used for polyomavirus nephropathy.

8. THALIDOMIDE:

  • Sedative drug.
  • Withdrawn due to teratogenic (phocomelia) effects.
  • Remarketed for its anti-angiogenic, immunomodulatory & anti-inflammatory effects.
  • Used for multiple myeloma, erythema nodosum leprosum & skin manifestations of SLE.
  • Immunomodulatory derivatives of thalidomide termed “IMiDs”.
    • Eg: Lenalidomide: ImiD approved for myelodysplastic syndrome & multiple myeloma.
  • SelCIDs (Selective Cytokine Inhibitory Drugs) – 
    • Group of thalidomide analogs.
    • Are phosphodiesterase-4 (PDE-4) inhibitors with potent anti-TNFα activity.

9. MONOCLONAL ANTIBODIES:

  • Polyclonal antibodies like anti-lymphocyte & anti-thymocyte antibodies, hyperimmune immunoglobulins & Rho (D) immunoglobulin.
  • Useful as immunosuppressive drugs.    
  • Drugs included:
    • Abciximab, Alemtuzumab, Adalimumab, Basiliximab, Belimumab, Bevacizumab, Cetuximab, Daclizumab, Denosumab, Eculizumab, Infliximab, Ibritumomab, Natalizumab, Nimotuzumab, Nivolumab, Palivizumab, Rituximab, Siltuximab, Trastuzumab, Vedolizumab.

10. CO-STIMULATION INHIBITOR:

  • Co-stimulatory molecules present on T-cell surface.
  • Interaction between antigen presenting cells (APCs) & co-stimulatory molecules necessary for T-cell activation.
  • Drug included: 
    • Abatacept & belatacept.
    • Abatacept – For treatment of severe rheumatoid arthritis resistant to DMARDs.
    • Belatacept – For preventing rejection of kidney transplants.
  • MOA: Acts by inhibiting CD-80 & CD-86 co-stimulatory molecules, present on APC.

11. IL-1 INHIBITOR:

  • Anakinra – Used in septic shock & RA.

12. OTHER DRUGS:

  • Nintedanib – 
    • Small molecule kinase inhibitor, blocking multiple pathways involved in lung tissue scarring.
    • Approved for oral treatment of idiopathic pulmonary fibrosis.
  • Apremilast – 
    • Phosphodiesterase-4 inhibitor.
    • Indicated for severe plaque psoriasis & psoriatic arthritis.

Exam Important

  • Glucocorticoids are the most common immunosuppressant.
  • Glucocorticoids cause sequestration of lymphocytes in lymphoid tissue resulting in lymphopenia, by inhibiting IL-1 production –> decrease in IL-2 & IFN-γ production.
  • 1st line immunosuppressive drug for solid organ & hematological stem cell transplant recipients is Glucocorticoids.
  • Glucocorticoids are used for treatment of graft rejection & graft versus host disease (GVHD), ITP treatment, rheumatoid arthritis & bronchial asthma.
  • Calcineurin required for activation of NFAT (nuclear factor of activated T-cells) –> Increases IL-2 transcription (due to activated T-cells).
  • Calcineurin inhibitors include Cyclosporine & Tacrolimus.
  • Tacrolimus is more potent than cyclosporine.
  • Calcineurin inhibitors like Cyclosporine & Tacrolimus are used as immunosuppressive agents for organ transplantation, GVHD & some autoimmune diseases (rheumatoid arthritis & psoriasis).
  • Incidence of hyperglycemia & neurotoxicity is more with tacrolimus than cyclosporine.
  • Hirsutism, gum hyperplasia, hyperuricemia & hyperlipidemia not caused by tacrolimus.
  • Nephrotoxicity is the major cause resulting in stop or modification of cyclosporine therapy.         
  • Sirolimus (rapamycin) & Everolimus are proliferation signal inhibitors.
  • Cytotoxic agents like Cyclophosphamide, chlorambucil & methotrexate are useful as immunosuppressants.
  • Leflunomide is a prodrug, acts by inhibiting pyrimidine synthesis.
  • Thalidomide is remarketed for its anti-angiogenic, immunomodulatory & anti-inflammatory effects.
  • Thalidomide is useful for multiple myeloma, erythema nodosum leprosum & skin manifestations of SLE.
  • Immunomodulatory derivatives of thalidomide termed “IMiDs”, eg: Lenalidomide.
  • Co-stimulatory inhibitors like Abatacept & belatacept are useful as immunosuppressants.
  • Co-stimulatory inhibitors act by inhibiting CD-80 & CD-86 co-stimulatory molecules, present on APC.

 

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