Transplant Therapeutics Flashcards
What are the two types of transplantation
thoracic and abdominal
What organs are transplanted in thoracic
heart and lung
What organs are transplanted in abdominal
Liver, small bowel, kidney, pancreas
What are the overall goals of immunosupression
improve graft survival, improve patient survival, maintain good Quality of life
What are the three pathways to immunosuppression
depletion of lymphocytes, diversion of lymphocyte traffic, blocking of lymphocyte proliferation and response
What are the four phases of immunosuppression
desensitization (prn), induction, maintenance, rejection (prn)
When are induction drugs used
utilized in peri-operative period
What drug is universally administered to all patients in the induction phase
methylprednisolone
What antibody agents deplete lymphocytes in the induction phase
thymoglobulin, Atgam, Alemtuzumab
What antibody agents are non lymphocyte depleting in the induction phase
Basiliximab
What is the pharmacology of corticosteroids
decrease cytokine gene expression, redistribute T-cells from circulation to lymphoid tissue, decrease inflammation
What is the dosing for corticosteroids that is most commonly used
250mg-1000mg IVPB, followed by a steroid taper or IV MP
How long are lymphocytes suppressed after steroids are given
24 hours
T/F: If prednisone by mouth is greater than 30mg it may be split between every 6 hours to minimize ADRs
False: If prednisone by mouth is greater than 50 mg it may be split to every 12 hours to minimize ADRs
What are ADRs of corticosteroids
hyperglycemia, high blood pressure/fluid retention, leukocytosis
Which immunosuppresants are polyclonal antibodies, what type are they
thymoglobulin and Atgam, IgG
What is the MOA of polyclonal antibodies, what is the result
polyspecific binding to T cell leads to opsonization and elimination, T-cell depletion
How is Thymoglobulin and Atgam dosed, which drug causes longer and greater T-cell depletion
Thymoglobulin: 1.5mg/kg IV for 3-7 days, Atgam: 10-15mg/kg for 3-days, thymoglobulin
T/F: Due to their nature polyclonal antibodies can cause a depletion in other cells, lymphoproliferative disease, and even trigger T cell activation
True
What are the ways to limit infusion reactions and cytokine release for polyclonal antibodies
Pre-medicate (acetaminophen and diphenhydramine), prolong the infusion rate, infuse via central access
What lab level is monitored when using polyclonal antibodies, what is the goal
Absolute lymphocyte count (ALC), less than 200 cells/ul
Which immunosuppressants are monoclonal antibodies
Basiliximab and Alemtuzumab
What is the MOA of basilximab
Acts as IL-2 receptor antagonist to CD25 protein found on the alpha chain on the surface of an activated T cell, blocks signal 3 and T-cell proliferation
What is the dosing for basiliximab
20mg IVPB on Day 0 and Day4
How is Alemtuzumab different from Basiliximab, what is the MOA
binds nearly all T and B lymphocytes, targets CD52 leading to antibody- dependent lysis following cell surface binding
What is the dosing for Alemtuzumab
single 30mg dose on Day 0
T/F: Maintenance drugs are for lifelong immunosuppresion and are administered in the post-transplant period
True
What calcineurin inhibitors is used more often, what is the other medication used
Tacrolimus, cyclosporine
What antimetabolite is used most often, what is the other medication used
Mycophenolic acid, azathiprine
T/F: For CNIs formulations are not interchangeable and errors can lead to graft failure
True
What does tacrolimus complex with to inhibit calcineurin, what does cyclosporine complex with
FKBP-12, cyclophilin
T/F: CNI’s inhibt transcription directly
False: CNIs inhibit calcineurin -> inhibit IL-2 synthesis -> prevention of T-cell proliferation
What are the three formulations for tacrolimus
Prograf (immediate release), Astagraf-XL (extended release), Envarsus- XR (extended release with the best bioavailability)
How is prograf dosing converted when switched to Astagraf
1:1, total dose per day is the same but instead of twice a day it’s once a day
How is Prograf dosing converted when switched to Envarsus
1:0.8, total dose per day is reduced by 20 percent once a day due to the better bioavailability
When would a patient receive CNIs IV, what is the danger of this formulation
bone marrow transplant patients with severe Mucositis, high risk of nephrotoxicity
What CNI route of administration is used via NG tube, where is it made
Suspension, compounded in the pharmacy
What are key guidelines for giving tacrolimus sublingual
can only administer immediate release (Prograf) and decrease the dose by 50%
What CYP3A4 induces will decrease the levels of CNIs
Phenytoin and carbamazepine, rifampin, Nafcillin
What CYP3A4 inhibitors will increase the levels of CNIs
ketoconazole and fluconazole, erythromycin and clarithromycin, dilitizaem and verapmil, ritonavir
What are ADRs of CNIs
Nephrotoxicity, neurotoxicity, electrolytes, diabetes, hypertension
What is the acute nephrotoxicty caused by CNIs, chronic
reduced GFR/ reversible, interstitial fibrosis and scarring/irreversible
Why is diabetes more likely when taking CNIs
lowered insulin secretion via direct Beta-cell toxicity or DNA inhibition (dose dependent)
What CNI should pediatric patients less than 5 receive
cyclosporine
When should tacrolimus be switched over to cyclosporine
For patients with Diabetes, hair loss, tremors/falls
T/F: When IMS agents are changed they should be checked everyday
False: Check levels 7 days after change and then monthly
What are the antimetabolites
azathioprine and mycophenolic acid
What is the MOA of azathioprine
inhibition of de novo purine synthesis (adenine and guanine), incorporation into DNA; all through conversion to 6-MP
What enzyme is responsible for inactivating and action steps for 6-MP, why must it be screen for before using azathioprine
TPMT, slow inactivation of 6MP can lead to accumulation of myelosuppressive metabolites leading to death
What is the mycohphenolic acid MOA
only inhibits the DeNovo pathway inhibiting synthesis of guanosine in active T cells, inhibits inosine 5’ monophosphate dehydrogenase (IMPDH)
What drug should be avoided when taking azathioprine
Allopurinol
T/F: For Antimetabolites dose adjustments are based on side effects
True
What drug has two peaks and a trough, what drug inhibits enterohepatic recirculation that causes this effect
MPA, cyclosporine a
What is a main side effect of MPA
diarrhea and nausea
What drugs are is more likely to cause a cytokine storm due to their mechanism of action
Thymoglobulin and Atgam
Which of CNIs causes the most problems with hypertension
Cyclosporine
What are the major side effects of Tacrolimus
Alopecia and diarrhea
