Immunosuppressive Pharmacotherapy Flashcards
2 phases of immunosuppressive pharmacotherapy are…
1) Induction therapy
2) Maintenance therapy
Risk of acute rejection is highest…
In the first 1-3 months after transplant
Induction therapy improves efficacy of immunosuppression by…
Reducing acute rejection, and allowing for reduction in other maintenance medications
Induction therapy consists of…
IL-2 receptor antagonist or lymphocyte depleting antibody
+
Triple therapy
A common IL-2 receptor antagonist used is…
Basiliximab (Simulect)
This is usually standard practice
MOA of IL-2 receptor antagonists is…
Binds to IL-2 receptor on activated lymphocytes, preventing IL-2 binding to receptor
Block T-cell pathway, no proliferation
Safety/tolerability of IL-2 receptor antagonists is…
Usually well tolerated, no DI’s
Possibility of acute hypersensitivity
Most common lymphocyte depleting antibody is…
Anti-thymocyte globulin (ATG, thymoglobulin)
MOA of ATG is…
Antibodies will bind to antigens found on surface of T-cells, and depletes T-cells from circulation
Potency of ATG compared to IL-2 receptor antagonists is…
Greater - can be used for induction or cell-mediated rejection
Safety/tolerability of ATG is…
Bone marrow suppression - platelets/leukocytes may be affected as well
Anaphylaxis, hepatic, infusion related reactions
Think more potent than basiliximab
Dosing for ATG is unique because it is…
Weight-based
Lifetime doses are also counted to balance risk vs. immunosuppression
Maintenance immunosuppression regimens usually consist of…
Triple therapy
Corticosteroid
Antiproliferative (Mycophenolate, azathioprine)
Calcineurin inhibitors (Cyclosporine, tacrolimus)
MOA of corticosteroids for immunosuppression is…
Up-regulates expression of anti-inflammatory proteins, represses expression of proinflammatory proteins
Inhibits antigen presentation, cytokine production, + proliferation of lymphocytes (broad spectrum immunosuppressant)
Dosing of corticosteroids (prednisone) is…
Initially IV, then switched to oral prednisone + tapered to lowest effective dose
Usually 5-10 mg/day
Short-term AE’s with prednisone include…
Insomnia
Personality changes
GI issues
Glucose alterations
Long-term AE’s with prednisone include…
Musculoskeletal changes
Osteoporosis
Cataracts
Are relevant to discuss since usage will be indefinite
To help prevent complications of osteoporosis with long-term prednisone usage, we should…
Do routine bone density measurements
Pharmacotherapy - calcium, vitamin D, bisphosphonates
To help prevent complications of hyperglycemia with long-term prednisone usage, we should…
Hope it resolves with tapering doses
Modify diet, usage of oral hypoglycemis/insulin if needed
Also consider than tacrolimus may increase BG
Mycophenolate is used more commonly than azathioprine because…
Mycophenolate does not affect other rapidly dividing cells
An important drug interaction to remember with azathioprine is…
Allopurinol - risk of myelosuppression, need to dose adjust
MOA of azathioprine and mycophenolic acid derivatives is…
Purine analog - affects purine synthesis + metabolism, suppresses T and B cells
Mycophenolate is more specific than azathioprine
AE’s of mycophenolate include…
GI - diarrhea, nausea, indigestion
Neutropenia
Anemia
When taking mycophenolate, this is required for both males and females…
Birth control - teratogenic
Relevant drug interactions with mycophenolate include…
Divalent cations (iron, calcium)
Cholestyramine
Food - decreases rate, but not extent of absorption
Food/drugs can help minimize GI since adherence is super important
GI AE’s with mycophenolate can be managed via…
Rule out infectious cause
Administer with food or acid suppressive medication
Divide total daily dose into 3/4 doses, or decrease if possible
Try alternate formulation
Diarrhea = loperamide if non-infectious
Maybe change to azathioprine
Neutropenia can be managed via…
Reducing dose if possible
Look for other drug causes + eliminate if possible
Filgrastim/GCSF if needed (proliferates WBC’s)
MOA of calcineurin inhibitors (CNI’s)
Tacro, cyclo
Forms complex that binds with calcineurin - inhibition of calcineurin impairs expression of several cytokine genes that promotes T-cell activation
CNI’s require ____ for safety.
Therapeutic drug monitoring - narrow therapeutic index
Cyclosporine drug levels can be taken at…
Trough (C0) or 2 hour post dose (C2)
Timing of cyclosporine drug levels is important to obtain accurate levels. C0 and C2 timing is…
C2 - no more than 15 minutes from 2 hour mark
C0 - 11.5-12.5 hours after last dose
Cyclosporine drug levels are dependent on…
Various patient factors - time since transplant, match, AE’s, history, type of organ transplant
Individualized levels
An important factor to note about tacrolimus formulations is that…
They are NOT bioequivalent !
Advagraf = once daily dosing
Prograf = Q12hours
Envarsus is newer and is also once daily
Tacrolimus drug levels can be taken at…
Trough level only (C0).
No C2
Timing of tacrolimus drug levels is important to obtain accurate levels. C0 timing is…
Preferably no more than 30 minutes from the C0 hour mark
Tacrolimus drug levels are dependent on…
Various patient factors - time since transplant, match, AE’s, history, type of organ transplant
Individualized levels
AE’s with CNI’s include…
Nephrotoxicity - acute + chronic
Neurotoxicity (dose-related), headache, tremor, dizziness, fatigue
HTN
Electrolyte imbalances
GI issues
Hepatotoxicity
Cyclosporine unique AE’s include…
Higher rates of increased lipid levels, BP, and uric acid
Hirsutism, acne, gingival hyperplasia unique
Tacrolimus unique AE’s include…
Higher rates of headache, GI issues (diarrhea), BG levels
Alopecia unique
HTN, Increased BG, and increased lipid levels from CNI are treated…
Similar to general population
With statin, use lowest dose possible and monitor lab values (higher rates of muscle aches/weakness)
Notable DI’s with CNI’s include…
CYP3A4 drugs - most common = erythromycin, clarithromycin, diltiazem, verapamil, antifungals, rifampin, grapefruit juice
Avoid if possible - dose adjustment/drug level management if cannot be avoided
Take DI’s seriously in this population !
PD interactions with CNI’s include…
NSAID’s, nephrotoxic medications
Think similar to CKD population
Sirolimus is an mTor inhibitor, where the MOA is to…
Engage TOR to reduce cytokine-dependent cellular proliferation of G1-S phase of the cell division cycle. Does not block calcineurin
Considered “less potent” than a CNI
DI’s with sirolimus are…
Similar to CNi’s
mTor inhibitors would be used when…
CNI’s cannot be used - declining renal function
Malignancy (?anti-tumour properties)
Potentially as add-on therapy for those needing increased immunsuppression despite triple therapy
Notable AE’s with sirolimus include…
Proteinuria
Increased BP, lipids
Anemia, thrombocytopenia
Arthralgia
Rash - possibly dose related
Mouth sores
Edema, non-responsive to diuretic
Delayed wound healing
If experiencing, may need to reduce dose or just stop drug
If a patient experiences acute cellular rejection, we can give…
High dose steroids
Antibody therapy - ATG
If a patient experiences humoral rejection, we could give…
Plasmapheresis
High dose steroids
ATG, IV immune globulin
Could also give other antibodies directed against B lymphocytes
If a patient experiences chronic rejection, we could try…
Increasing maintenance immunosuppression
All transplant patients are required to have bloodwork for life - frequency depends on…
Time post-transplant
Clinical status of the patient
Type of organ transplant
Bloodwork assists in monitoring…
For rejection
For toxicity from immunosuppressive medications
Standard bloodwork consists of…
Drug levels (CNI, mTor)
Renal function
Hematology/CBC
Electrolytes
May also include cholesterol panel, etc.
