End-Stage Renal Disease: Dialysis & Transplant Pharmacology Flashcards
What is the formula for estimated creatinine clearance? What is this equivalent to? There is another formula too (MDRD) – what does this take into account that the first formula does not? What is true about the use of both of these equations? So, all in all, how can we use these formulas to calculate drug dosing.
estimated creatinine clearance = [(140 - age) x weight (kg)] / (72 x serum creatinine (mg/dL)) – multiply by 0.85 if female. This estimates GFR in ml/min. The MDRD formula takes into account race and body surface area. The GFR is presented as ml/min/1.73m^2. These formulas, and direct measurements, are only valid in stable renal function, i.e. stable Cr. This means that these formulas cannot be used for drug dosing based on creatinine clearance and estimated GFR if unstable renal function. Summary: (1) calculate creatinine clearance, (2) look up the drug in question.
For someone on dialysis, what variables are important in deciding to supplement a drug? What are the major features of a “dialysis diet?”
Size, Volume of Distribution, Protein Binding, Time on Dialysis. Diet while on dialysis: (1) Fluid restriction – there is limited ability to handle water. (2) Salt restriction – increased salt intake leads to increased fluid intake. (3) Potassium restriction – limited ability to excrete potassium, the GI becomes the major excretor. (4) PO4 restriction (we also use phosphate binders to help avoid seondary hyperparathyroidism). (5) Encourage protein intake.
How is the urea reduction ratio calculated?
URR = [(PreBUN - PostBUN) / PreBUN] x 100
When talking about immunosuppression, what are the concepts of induction, maintenance, and antirejection?
Induction: Agents given at the time of transplant, Designed to seriously stun the immune system, but not kill it. Maintenance: Agents used to keep a long-term light reign on the immune system. Antirejection
Spank the system back in line.
What antibodies are used in immunosuppression? What other drug can be used? Side effects?
Pan T-cell Antibodies:
ATGAM: Polyclonal horse serum
ALG: Polyclonal rabbit serum
Muromonab CD3 (OKT3): Murine monoclonal (targets CD3-TCR complex).
Targeted T-cell Antibodies: Anti-IL-2 receptor (this ensures targeting of active T-cells)
Dacluzimab: Humanized murine monoclonal
Basiliximab: Chimeric murine monoclonal
Other:
Alemtuzimab: Humanized anti CD-52 (CD52 is on all T cells)
Methylprednisolone can also be used (systemmic corticosteroid).
Antibodies:
OKT3, ATGAM: Cytokine release syndrome (shake and bake), Lymphopenia
ALG: Lymphopenia (prolonged), Cytokine release syndrome (less than above)
Anti-IL2 receptor: Rare hypersensitivity reactions
What is calcineurin? What are the calcineurin inhibitors used for? What are examples? When should these drugs be initiated and how should they be dosed? Side effects? What is different between these two drugs?
Calcineurin activates nuclear factor of activated T cell, cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors – used for maintenance. Examples: cyclosporine, tacrolimus. Initiate a few days after transplant (give the kidney some time to get going), keep the levels high in the first month and taper over the next two months. Side effects: Nephrotoxicity, Gingival hyperplasia, Hypertrichosis (CsA), Hyperlipidemia, Tremor, Neuropathy, Hyperuricemia/Gout, Glucose intolerance/diabetes (Tacro), Hemolytic-uremic syndrome, Significant drug interactions (any drug metabolized through CYP3A4). Cyclosporine binds to CYCLOPHILIN, and this complex inhibits calcineurin – so, cyclosporine DECREASES THE PRODUCTION OF IL-2. Tacrolimus binds the immunophiln FK506-BINDING PROTEIN RATHER THAN CYCLOPHILIN and this prevents the TRANSCRIPTION of IL-2.
What steroids are used for maintenance immunosuppression? How are they dosed?
Methylprednisolone & Prednisone. High dose early, taper early (1st week - 1st month).
What are the antimetabolites used for? Give examples. Side effects?
Maintenance immunosuppression. These inhibit de novo purine synthesis. Examples: 6-mercaptopurine & azathioprine, mycophenolate mofetil, mycophenolic acid. Azathioprine: Leukopenia/myelosuppression, Hepatotoxicity. Pancreatic toxicity, Interaction with allopurinol. Mycophenolate: Gastrointestinal intolerance,
Leukopenia/myelosuppression.
What are the mTOR inhibitors? MOA? How are they dosed? Side effects?
Sirolimus, Everolimus. Block cell progression from G1 to S. High dose early, lower doses later. Sirolimus: Hyperlipidemia (Responds to therapy, but not to baseline), Impaired wound healing (Contraindicated in lung transplants), Interstitial pneumonitis.
What maintenance drug acts to block T-cell activation? How does this drug work?
Belatacept: Fusion protein of IgG1 FC and the extracellular domain of CTLA-4 – Blocks co-stimulation of T cells by preventing CD28 – CD80/86 interaction. (Abatacept has the same MOA)
What are the strategies for cell-mediated anti-rejection? What about antibody-mediated anti-rejection?
Cell-mediated rejection: Pulse steroids, Thymoglobulin.
Antibody-mediated rejection ; Rituxumab (chimeric ab to CD-20 on B-cells), Plasmapheresis, IVIg.
