Renal Pharmacology Part 2 Flashcards
What types of T cells are most significant in kidney transplant rejection?
Memory T cells
What are the three signal approaches to immunosuppression?
- Calcineurin
- Cyclosporine, Tacrolimus
- mTOR
- Sirolimus
- Cell Cycle
- Azathioprine
What type of drug is cyclosporine?
How is it metabolized?
What is it’s half life?
Calcineurin inhibitor (binds to cyclophlin)
Metabolized by CYP3A4 in liver
Long half life (27 hours)
How does Cyclosporine lead to nephrotoxicity?
What are its other side effects?
Nephrotoxicity - vasoconstriction, induction of TGF-ß, fibrosis, and tubular atrophy
- Other SE
- HTN
- Hepatic dysfunction
- Hypertrichosis (excessive hair growth)
- GI
- Gum hypertrophy
- Hyperlipidemia
What are drug interaction that occur with cyclosporine?
Nephrotoxic drugs - NSAIDs, aminoglycosides
Drugs that induce CYP3A4 - phenytoin, carbamazepine
Drugs that inhibit CYP450 - erythromycin, ketoconazole
What is tacrolimus?
How is the same as cyclosporine?
How is it different?
- Tacrolimus - calcineurin inhibitor (binds to FKBP)
- Similarities
- Metabolized by liver
- Given orally or IV
- Differences
- Highly variable half life (must monitor)
- Does not stimulate TGF-ß
- More water soluble
Tacrolimus SE
Pleural and pericardial effusions
Cardiomyopathy in children
What events should be monitored for when administering calcineurin inhibitors?
- Hepatotoxicity
- Cardiovascular (hypertension and hypercholesterolemia)
- Tacrolimus has less cardiovasc. SE
- Glucose intolerance
- Neurotoxicity - seen more often with tacrolimus
Why are the following be monitored for drug interaction with calcineurin inhibitor drugs?
Nephrotoxic agents:
Potassium sparing diuretics:
Antacids:
HMG-CoA reductase inhibitors (Statins):
- Nephrotoxic agents:
- NSAIDS may have increased toxicity with hepatic impairment
- Potassium sparing diuretics:
- hyperkalemia has been reported
- Antacids: May inhibit absorption of CNIs (take 2 hours after CNI dose)
- HMG-CoA reductase inhibitors (Statins):
- Increased risk of rhabdomyolysis and bone marrow suppression
The calcineurin inhibitor most commonly used today is
Tacrolimus
What is the MOA of Sirolimus?
- Binds to FKBP12
- Complex binds and modulates the acitivity of mTOR
- Blocks signal 3 leading to inhibition of cytokine/IL-s induced cycle progression from G1 to S phase
How is Sirolimus administered?
How is it metbolized?
What is its half life?
Oral
Metabolized by intestinal and liver CYP450
Very long half-life (60 hours)
What are some SE for Sirolimus?
- Edema, ascites, HTN
- GI
- Hyperlipidemia
- Hypokalemia
- Hypophosphatemia
What drugs interact with Sirolimus?
Drugs that induce CYP3A4 - rifampicin
Drugs that inhibit CYP450 - itraconazole, ketoconazole
What are the benefits of Sirolimus over calcineurin inhibitors?
- Potent prophylaxis against acute cellular rejection
- Less vasoconstriction
- No associated with acute or chronic renal insufficiency (sustained GFR)
What side effect of sirolimus is not a side effect of cyclosporine or tacrolimus?
Bone marrow suppression
Name two antiproliferative agents?
Mycophenolate Mofetil
Azathioprine
What is the MOA of mycophenolate mofetil?
- Competitive, reversible inhibition of IMPDH, a critical rate limiting enzyme in de novo purine synthesis
- Lymphocytes dependent on de novo pathway vs. salvage pathway
- Inhibits proliferation of B and T cells
Where are the origins of mycopheonolate mofetil?
Mycophenolic acid (MPA) isolated from penicillim spp.
Mycopheonolate mofetil (MMF) is a prodrug of MPA
Mycophenolate Mofetil administration?
Metabolized by?
Half life?
Oral or IV
Liver
Long (18 hours)
What are some unwanted SE for Mycophenolate Mofetil?
- HTN, edema, tachy
- dyspnea
- Leucopenia, thrombocytopenia, anemia
- Opportunistic infections
- Lymphoproliferative disease
How does Mycophenolate Mofetil interact with the following?
Antacids:
Rifampin, phenytoin, phenobarbital:
Corticosteroids:
Tacrolimus, sirolimus:
Antacids: Decrease MPA levels
Rifampin, phenytoin, phenobarbital: decrease MPA levels
Corticosteroids, cyclosporine: decrease MPA levels
Tacrolimus, sirolimus: no change to MPA levels
What is the MOA of azathioprine?
- Purine analog that is metabolized in the liver to 6-mercaptopurine and then to thiosinosin monophosphate (TIMP)
- TIMP decreases synthesis of DNA precursors and incorporates into DNA
- Blocks CD28 co-stimulation of T cells
Azathioprine administration?
Half life?
Oral
Short half life (3-5 hours)
SE of azathioprine?
- Bone marrow suppression, leucopenia, thrombocytopenia
- Hypersensitivity reactions, malaise, diziness
- Opportunistic infections
- Alopecia
What drug interaction affects azathioprine?
Allopurinol - decreases 6-mercaptopurine metabolism - need to reduce azathioprine dose by 75% if used together
What are the clinical implications of the SE of…
Azathioprine:
MMF:
Azathioprine: Complete blood counts should be performed regularly to montior for hematologic side effects
MMF: Same as above but note that GI side effects are more common when dose is high and respond to dose reduction or more frequent administration in smaller doses
What are three IL2 receptor antibodies and what are they made up of?
Basiliximab (anti CD-25) - 75% human; 25% mouse
Daclizumab (anti CD-25) - 95% human; 5% mouse
Alemtuzumab (anti CD52) - humanized
Basiliximab administration?
Half life?
SE?
IV
Very long half life (1 week)
Hypersensitivity reactions (rare)
What is the MOA and use for Belatacept?
- Fusion protein that binds CD80 and CD86 molecules - blocks co-stimulatory action with Cd28 on T-cell activation
- Used for renal transplantation in patients seropositive for Ebstein-Barr virus
Belatacept half life?
SE?
Very long (8-10 days)
- SE:
- hypersensitivity reactions rarely occur
- Lymphoproliferative disorder
What is the MOA of corticosteroids (prednisolone)?
- Inhibits pro-inflammatory transcription factors such as NF-kB
- Activates anti-inflammatory genes
- Reduces T-lymphocyte proliferation and increases apoptosis
What are the SE of prednisolone?
- Cushing syndrome effects
- acne
- hirsutism
- HTN
- osteoporosis
- cataracts
- glucose intolerance
What types of agents are used to induce immunosuppression for kidney transplants?
How and when are they administered?
Monoclonal or polyclonal antibodies
Administered intravenously immediately following surgery
What agents are used to maintain immunosuppression in kidney transplants?
Prednisolone
Calcineurin inhibitors (cornerstone of immunosuppressive therapy)
Anti-proliferative agents: MMF, azathioprine, sirolimus
What are some induction agents used to combat kidney transplant rejection?
- Muromonab
- Anti-thymocyte globulin
- Basiliximab
- Daclizumab
- Alemtuzumab
- FTY270
What type of induction agents are the most commonly used today?
Which were most common in 2003?
T-cell depleting type is most common today
IL-2 RA types was most common in 2003
What is used more today, MMF or azathioprine?
Mycophenolate mofetil
What diseases that we have learned about are treated with only ACEi?
Which can treated with both ACEi and ARB?
- IgA nephropathy and Focal segmental glomerulosclerosis - Only ACEi
- Nephrotic syndrome and membranous nephropathy - ACEi or ARB
Which diseases that we have learned about are treated with only corticosteroids?
Which can be treated with both corticosteroids and immunosuppressants?
Anti-GBM/Goodpastures syndrome and Lupus Nephritis (Class V) - only corticosteroids
IgA nephropathy, membranous nephropathy and FSGS - corticosteroids or immunosuppressants
