Renal Pharmacology 2 (post-transplant) Flashcards
What are the 2 calcinurin inhibitors?
Cyclosporine: small (11aa) cyclic polypeptide, fungal origin
Tacrolimus: macrolide isolated from Streptomyces spp
What is calcinurin inhibitors MOA?
- Bind to cytosolic receptor proteins: Cyclophilin (cyclosporine) & FKBP12 (tacrolimus)
- Complex binds to and inhibits action of calcineurin
- Inhibits the transcription of cytokines such as IL-2 that are essential for T-cell activation and proliferation
What are some things to know about Cyclosporine administration?
oral or i.v.
• Concentrates in tissues –liver, kidney, spleen, bone marrow
• Metabolized extensively by CYP3A4 in liver
• Long half-life (27 hours)
What are side effects of cyclosporin?
- Nephrotoxicity – vasoconstriction, induction TGFβ, fibrosis, tubular atrophy
- Hypertension and fluid retention (50%)
- Hepatic Dysfunction
- Tremor, headache, fatigue
- GI - nausea, vomiting, diarrhea
- Hypertrichosis –excessive hair growth
- Gum Hypertrophy (common)
- Hyperlipidemia
- Hypomagnesemia
- Hypokalemia
What are some drugs that interact with cyclosporine?
Nephrotoxic drugs – NSAIDs, aminoglycosides, antimicrobials
Drugs that induce Cyp3A4 – phenytoin, carbamazepine
Drugs that inhibit CYP450 – erythromycin, ketoconazole
What are some things to know about tacrolimus administration?
oral or i.v. • More water soluble • Metabolized by liver • Highly variable half-life (4 - 41 hrs) • Monitor trough blood concentration is essential • Does not stimulate TGFβ
What are the side effects of tacrolimus?
Pleural and pericardial effusions
Cardiomyopathy in children
Which calcineurin inhibitor is used more often?
Tacrolimus
What is the mTOR inhibitor we need to know?
Sirolimus
What is the MOA of Sirolimus?
- Sirolimus binds to FKBP12
- complex binds and modulates the activity of mTOR (mammalian target of rapamycin)
- blocks signal 3: inhibition of cytokine/IL-2 induced cell cycle progression from G1 to S phase
What are some things you should know about siroliums administration?
oral
- gut absorption modulated by p-glycoprotein
- metabolized by intestinal and liver CYP450
- very long half life
What are some side effects of sirolimus?
- Lymphocele (renal transplant complication can cause ureteric compression)
- Edema, ascites, tachycardia, hypertension
- GI – abdominal pain, nausea, diarrhea
What are some overall benefits of sirolimus?
Potent prophylaxis against acute cellular rejection
Less vasoconstriction
Not associated with acute or chronic renal insufficiency
What does Mycophenolate mofetil do?
Antiproliferative Agent: Competitive, reversible inhibition of IMPDH, a critical rate-limiting enzyme in de novo purine synthesis &Lymphocytes dependent on de novo pathway vs. salvage pathway utilized by other cell types
What are some things to know about mycophenolate mofetil administration?
oral or i.v.
• Metabolized by liver
• Long half-life (18 hrs)
What are some side effects of mycophenolate mofetil?
- hypertension, edema, tachycardia
- dyspnea, cough
- dizziness, insomnia, tremor, seizures
- leucopenia, thrombocytopenia, anemia
- opportunistic infections: viral cytomegalovirus, bacterial urinary tract
- lymphoproliferative disease, skin cancer
What does azathioprine do?
Antiproliferative Agent: Purine analog Metabolized in the liver to 6-mercaptopurine and then to thiosinosine monophosphate (TIMP). TMP decreases synthesis of DNA precursors and also incorporates into DNA
Blocks CD28 co-stimulation of T-cells
What are some alternatives to azathioprine?
Methotrexate
Cyclophosphamide
What are some things about azathioprine administration?
oral
• Short half-life (3-5 hrs)
What are some side effects of azathioprine?
- bone marrow suppression leucopenia, thrombocytopenia
- hypersensitivity reactions, malaise, dizziness, GI tract, fever, rash, hypotension
- opportunistic infections
- alopecia
- small risks for lymphomas
What are the drug interactions with azathioprine?
Allopurinol – decreases 6-mercaptopurine metabolism need to reduce azathioprine dose by 75% if used together
What are the anti-CD25- Interleukin-2 Receptor Antibodies?
Basiliximab (Simulect)
Daclizumab (Zenapax)
Alemtuzumab (Campath-
1H)
What should you know about Basiliximab (Simulect) administration?
i.v.
• Very long half-life (1 week)
• Given immediately prior to surgery and 4 days following
What are the side effects of Basiliximab (Simulect)?
hypersensitivity reactions rarely occur
What is Belatacept?
Co-Stimulator Blocker : fusion protein binds CD28 and CD86 molecules and blocks co-stimulatory action with CD28 on T-cell activation
What is Belatacept used for?
used for renal transplant in patients that are seropositive for Ebstein-Barr Virus
What should you know about Belatacept administration?
IV with a Very long half-life (8-10 days)
What are the side effects of Belatacept ?
- hypersensitivity reactions rarely occur
- lymphoproliferative disorder in those with no prior exposure to Ebstein-Barr virus
What is Prednisolone?
Corticosteroid
How do corticosteroids work?
- Inhibits pro-inflammatory transcription factors such as NF-κB
- Activate anti-inflammatory genes by histone acetylation in promoter region of genes
- Reduces T-lymphocyte proliferation and increases T-cell apoptosis
- Reduces T-cell activation and B-cell proliferation
What are side effects of steroids?
Acne Cushingoid facial appearance Hirsutism Mood disorders Hypertension Glucose intolerance Cataracts Osteoporosis Growth retardation in children
Advances in transplant immunosuppression have contributed to what?
decrease in the frequency of acute rejection
increase in graft survival
longevity for renal allograft recipients
More choices for immunosuppression post transplant has lead to what?
more options
different mechanisms of action
more complicated management schemes
increase potential for drug-drug interactions and complex side effect profiles
What are induction agents for immunosuppression?
Monoclonal or polyclonal antibodies
Administered intravenously immediately following surgery
What are the maintenance agents of immunosuppression?
Prednisolone
Calcineurin Inhibitors: form the cornerstone of immunosuppressive therapy
Anti-proliferative agents: mycophenolate mofetil, azathioprine, sirolimus
Triple agents / withdrawal / avoidance / conversion
What are the induction agents we have to know for immunosuppression?
Muromonab Anti-thymocyte globulin Basiliximab (Simulect) Daclizumab (Zenapax) Alemtuzumab (Campath-1H) FTY 720
What is Muromonab ?
humanized anti-CD3
What is Anti-thymocyte globulin (ATGAM)?
deplete circulating lymphocytes
What is FTY 720?
sphingosine-1-phosphate receptor (S1P-R) agonist - lymphocyte homing
