Pharm II (Immunosupression) Ia

They are used to prevent/treat the rejection of transplanted organs and to treat autoimmune diseases (e.g. rheumatoid arthritis, myasthenia gravis).

• 1. Calcineurin Inhibitors
• -Cyclosporine, Tacrolimus
• 2. mTOR inhibitor
• -Sirolimus
• 3. Antiproliferative/antimetabolites
• 4. Antibodies
• 5. Steroids

binds to the cyclophilin of T- cells

It inhibits synthesis and secretion of IL-2 leading to a reduced function of T-cells.

Cyclosporine is metabolized by cytochrome P450

• used to prevent rejection of kidney, liver and cardiac transplantation.
• RA
• psoriasis
• severe dry eye syndrome
• _____________________
• Nephrotoxicity

It induces Hypertension, Hyperlipidemia and hirsutism

-Grapefruit juice

It binds to an immunophilin, FKBP -12, followed by the binding of the complex to calcineurin and inhibition of its phosphatase activity.

• -Nephrotoxicity
• -Standard for treatment of Graft verses host disease.
• -have ointment preparations for atopic dermatitis and psoriasis.

• Tacrolimus
• -100X more potent
• -Binds to FKBP12 and blocks Calcineurin mediated gene transcription.

• Cyclosporine
• -Binds Cyclophilin and interferes with cytokine gene transcription in T cells

• BOTH have hepatotoxicity (dont use together)
• BOTH eventually inhibit Calcineuria--> inactive NFAT --> decreased production of IL-2.

IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes, the cells that are responsible for immunity.--> activation of the immune system

Sirolimus (Rapamycin)

• Binds to the immunophilin FKBP 12, resulting in active complex that blocks mammalian target of rapamycin (mTOR) but does not inhibit calcineurin.
• -Block of mTOR--> inhibition of IL-2
• -Inhibits T Lymphocyte kinases and phosphatases--> preventing the signal for cells to move from G1 to S phase.

- Doesnt decrease IL-2, rather decreases its responsivness.

-Prevents B-cell differentiation into Plasma cells--> decreasing Ab production


Sirolimus affects the Second phase (signal trasduction), where as Cyclosporines and Tacrolimus affect the 1st phase (activation)

Sirolimus coated stents are put into the cardiac vasculature -->inhibits re-stenosis of the BV by reducing the proliferation of endothelial cells.

Hyperlipidemia. unlike the others, has low Nephrotoxicity.

• -Methotrexate
• -Azathioprine
• -Cyclophosphamide
• -Mycophenolate Mofetil
• -Leflunomide

• Folic acid derivative
• -Inhibits DHFR--> prevents the reduction of THF that is needed in dTMP synthesis--> no DNA is made.

Prodrug that is converted to 6-mercaptopurine that is a purine analogue,--> a inhibitor of DNA synthesis.

inhibits the proliferation of Lymphocytes--> affects both cell and humoral immunity.

Allopurinol inhibits Xanthine oxidase that takes 6-MP to thiouricil--> prolongs the activity of Azathioprine

Xanthine Oxidase

Takes 6-MP --> 6-Thiouricil

It is safe and very effective in decreasing organ rejections.

• MMF is a inhibitor of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in guanosine synthesis in B and T lymphocytes.
• -It is a STEROID SPARING agent

MMP is increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infections, and a lower incidence of acute rejection.

Prodrug and its active metabolite has a very long half life of weeks.

inhibitor of pyrimidine synthesis

• used for rheumatoid arthritis and Organ rejection reactions
• Toxicity includes liver damage and renal impairment

-most efficacious immunosuppressant drugs available.

-effective against autoimmune diseases like SLE, autoimmune hemolytic anemia

-effective in treatment of transplant rejection reactions

• 1.Polyclonal antibodies
• -Anti-Thymocyte globulin
• - Rh

• 2. Monoclonal antibodies
• -T-cell receptor directed antibodies
• -IL-2 receptor directed antibodies

• Polyclonal
• -Many B cell clones
• -Multiple epitopes
• -High potential for cross reactivity

• Monoclonal
• -Single Bcell clone
• -single epitope
• -low potential for cross reactivity.

Used in the prevention and treatment of acute rejection in organ transplantation (Aplastic anemia)

IL-2 receptor antibodies such as basiliximab and daclizumab are being used in place of ATG, Because they have less cytokine release syndrome.

Is a human IgG immunoglobulin that contains antibodies against Rh (D) antigen of the red cell

The response to the foreign antigen can be blocked if specific antibody to that antigen is administered at the time of exposure to antigen.

Sensitization of Rh– mothers occurs usually at the time of birth of an Rh+ infant when fetal cells may leak into the mother blood.--> leads to Hemolytic disease of the next Rh+ child.

• - Murine (all rat)
• - Chimeric (tips are rat)
• - Humanized (tips have alittle rat)
• - Human (No rat at all)

• Muromunab (OKT3)
• - Murine
• -Binds to CD3 receptor on human T lymphocytes
• - Used in Rejection reactions of Kidney, Heart and liver
• -Toxicities are: severe cytokine release.