Immunesuppressive Drugs - Regal Flashcards
What is the general MOA of Anti-Inflammatory Steroids?
- They bind to the cytosolic glucocorticoid receptor (GR)
- type nuclear receptor that is activated by ligand binding
- After a hormone binds to the corresponding receptor, the newly formed complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements (GRE) in the promoter region of the target genes resulting in the regulation of gene expression.
- Regulates gene transcription in T-cells
What effects on synthesis and/or release of inflammatory mediators do Anti-Inflammatory Steroids have?
- Effects on synthesis and/or release of inflammatory mediators
- reduce the expression of COX-2 (preferentially over COX-1)
- inhibit release of arachidonic acid from phospholipids (i.e. stop prostaglandin and leukotriene formation)
- inhibit degranulation of mast cells & basophils
- inhibit synthesis and release of TNF, IL-1, IL-2, and IFN
What are the generic names of the 6 Anti-Inflammatory drugs that we need to know?
- Cortisol
- Hydrocortisone
- Prednisone
- Methylprednisolone
- Betamethasone
- Dexamethasone
What is the duration of Anti-Inflammatory Steroids?
- Cortisol (Hydrocortisone)
- short half life: 8-12 hours
- Betamethasone
- long half life: 36-72 hours
- Dexamethasone
- long half life: 36-72 hours
- Methylprednisolone:
- intermediate half life: 12-36 hours
- Prednisone:
- intermediate half life: 12-36 hours
What is the distribution of Anti-Inflammatory Steroids?
- Inhaled glucocorticoids
- prolonged tissue binding in the airway
- nearly complete hepatic first pass inactivation
- Glucocorticoids can be administered orally, parenterally, and topically
- some systemic absorption occurs with all forms
- metabolized in liver
How are Anti-Inflammatory Steroids eliminated?
- In general:
- Metabolized in the liver
- Excreted by the kidney
What are the major toxicities associated with Anti-Inflammatory Steroids fom continued use of large doses?
- Primarily associated with systemic administration
- increased susceptibility to infection (immunosuppressive)
- peptic ulceration
- behavioral disturbances
- cataracts
- osteoporosis and vertebral compression fractures
- inhibition of growth
What are the major toxicities associated with Anti-Inflammatory Steroids fom withdrawal or discontinuation of long term use?
- Primarily associated with systemic administration
- fever
- myalgia
- arthralgia
- malaise
- death can occur with hypotension and shock
What are the four synthetic steroids used as anti-inflammatory drugs?
- Betamethasone
- Dexamethasone
- Methyloprednisolone
- Prednisone
What are the two Calcineurin Inhibitors used as Immunosuppressive Drugs that we need to know?
- Cyclosporine
- Tacrolimus
What is the MOA of Cyclosporine?
- Binds to a cytoplasmic receptor protein called cyclophilin
- results in the inhibition of calcineurin activit
- this blocks the dephosphorylation events critical for cytokine gene expression and T-cell activation
What is the MOA of Tacrolimus?
- Binds to a cytoplasmic receptor protein called FKBP (FK506 binding protein)
- results in the inhibition of calcineurin activity
- blocks the dephosphorylation events critical for cytokine gene expression and T-cell activation
How is Cyclosporine eliminated?
- Metabolized extensively in the liver
- potential for numerous drug interactions
What are the major toxicities of Calcineurin Inhibitors, Cyclosporine & Tacrolimus?
- Cyclosporine
- renal toxicity
- different from graft rejection in kidney transplantation
- occurs in as many as 75% of patients being treated with cyclosporine
- renal toxicity
- Tacrolimus
- toxicity similar to cyclosporine with nephrotoxicity
- 100x more potent than Cyclosporine
What are the two Antiproliferative/Antimetabolic drugs used as Immunosuppressive Drugs that we need to know?
- Sirolimus (a.k.a. Rapamycin)
- Mycophenolate Mofetil