Pharm II (Immunosupression) Ia
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What are the generic uses of Immunosupressents?
They are used to prevent/treat the rejection of transplanted organs and to treat autoimmune diseases (e.g. rheumatoid arthritis, myasthenia gravis).
List the Immuno supressents.
- 1. Calcineurin Inhibitors
- -Cyclosporine, Tacrolimus
- 2. mTOR inhibitor
- 3. Antiproliferative/antimetabolites
- 4. Antibodies
- 5. Steroids
What is Cyclosporines mech of action?
What is it matabolized by?
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
What is Cyclosporine used for?
What is the most common Toxicity?
What can this drug induce?
What substance increases the Blood level of Cyclosporin?
- used to prevent rejection of kidney, liver and cardiac transplantation.
- severe dry eye syndrome
It induces Hypertension, Hyperlipidemia and hirsutism
What is Tacrolimus (FK506)Mech of action?
What is its major toxicity?
What is it the standard treatment for?
What do we have preparations for?
It binds to an immunophilin, FKBP -12,
followed by the binding of the complex to calcineurin and inhibition of its phosphatase activity.
- -Standard for treatment of Graft verses host disease.
- -have ointment preparations for atopic dermatitis and psoriasis.
What are the differences between Cyclosporine and Tacrolimus?
- -100X more potent
- -Binds to FKBP12 and blocks Calcineurin mediated gene transcription.
- -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.
What is interleukin-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
Name the mTOR inhibitor
What is its mech of action?
- 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.
What are the differences of Sirolimus to the other immunosupressants?
- 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)
When is Sirolimus used?
What is its common toxicity?
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.
Name the antiproliferative/Antimetabolites
- -Mycophenolate Mofetil
WHat is methotrexate?
- Folic acid derivative
- -Inhibits DHFR--> prevents the reduction of THF that is needed in dTMP synthesis--> no DNA is made.
What is Azathioprine?
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.
What is the effect of Allopurinol on Azathioprine?
Allopurinol inhibits Xanthine oxidase that takes 6-MP to thiouricil--> prolongs the activity of Azathioprine
What is the major enzyme that metabolizes 6-MP?
Takes 6-MP --> 6-Thiouricil
What is Mycophenolate Mofetil (MMF)?
WHat is its Mech of action?
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 verse Azathioprine
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.
What is Leflunomide?
What does it inhibit?
What is it used for?
What is its toxicity?
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
What is Cyclophosphamide?
What is it used for?
-most efficacious immunosuppressant drugs available.
-effective against autoimmune diseases like SLE, autoimmune hemolytic anemia
-effective in treatment of transplant rejection reactions
What are the Two types of Antibodies?
- 1.Polyclonal antibodies
- -Anti-Thymocyte globulin
- - Rh
- 2. Monoclonal antibodies
- -T-cell receptor directed antibodies
- -IL-2 receptor directed antibodies
What are the differences between the Two types of Antibodies?
- -Many B cell clones
- -Multiple epitopes
- -High potential for cross reactivity
- -Single Bcell clone
- -single epitope
- -low potential for cross reactivity.
ANTITHYMOCYTE GLOBULINs (ATG)
What are they used for?
What are the two drugs that are replacing this? Why?
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.
Rh immuno globulin
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.
What is the drug that does not follow this pattern?
- - 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.
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