Transplant Therapeutics Flashcards
What is the goal in general with prescribing drugs for transplant?
Use the lowest dose possible
What does triple/maintenance therapy consist of
- Anti-metabolites: AZA or mycophenolate
- Calcineurin inhibitors: cyclosporine or tacrolimus
- Prednisone
What drug can be a substitute for 1 and 2 of triple therapy?
Sirolimus
What are the anti-metabolite drugs?
- Azathioprine
- Mycophenolate
Azathioprine is a prodrug of
6-mercaptopurine
Azathioprine MOA
↓ circulating B and T lymphocytes, ↓ IG synthesis, and ↓ IL-2 secretion
Clinical indications azathioprine
- Prophylaxis of organ rejection
- Active RA
- Steroid-sparing agent for corticosteroid-dependent IBD
- Tx of various autoimmune diseases
Where are we more likely to see azathioprine than in transplant pts.?
Difficult to manage rheumatologic disorders
What are the various autoimmune disorders AZA can be used to treat?
- Psoriatic arthritis
- Psoriasis
- RA
- Behcet’s dz
- Polymyositis
- SLE
- Sustain remissions in systemic vasculitis
What do we monitor in a pt. on azathioprine?
- CBC w/ diff
- CMP
- Thiopurine methyltransferase (TMPT) genotyping or phenotyping
Pt. w/ absent or reduced TMPT are at risk for what?
Severe life-threatening myelotoxicity
Why are pt. w/ absent or reduced TMPT at risk for myelotoxicity?
These pt. have an inability to degrade the drug fully and clear it; this leads to more immunosuppression
How do we approach prescribing AZA to pt. that are TMPT homozygous for nonfunctional alleles?
Do NOT prescribe
How do we approach prescribing AZA to pt. that are TMPT heterozygous for nonfunctional alleles?
Reduce dose
Drug interactions with azathioprine
- Additive immunosuppression w/ other agents
- ACEI
- Allopurinol/febuxostat
- Aminosalicylates (e.g. Mesalamine - IBD drug)
What happens if you use azathioprine with ACEI?
May induce anemia & severe leukopenia
What happens if you use azathioprine with allopurinol/febuxostat or aminosalicylates?
Increase myelosuppression risk
How does concomitant use of AZA and allopurinol/febuxostat cause increase myelosuppression risk?
Slows elimination of 6-MP by inhibiting xanthine oxidase (XO)
How does concomitant use of AZA and aminosalicylates cause increase myelosuppression risk?
May inhibit TMPT
Azathioprine ADRs
- N/V, anorexia
- Hepatotoxicity
- Pancreatitis
- Myelosuppression (infeciton, malignancy)
Renal transplant pt. have _____ risk of malignant disease
50-100x
Most common tumors associated with renal transplant pt.
- SCC of the skin»_space;»
- NHL
Do we use azathioprine or mycophenolate more commonly?
Mycophenolate
Mycophenolate MOA
↓ B and T cell proliferation
Clinical indications mycophenolate
- Prophylaxis of organ rejection in pts receiving allogenic renal, cardiac, or hepatic transplants
- Tx of lupus nephritis, psoriasis, myasthenia gravis
- Prevention & tx of GVHD
Drug monitoring in a pt. on mycophenolate
CBC w/ diff
Drug interactions with mycophenolate
- Additive immunosuppression w/ other agents
- Fe, antacids, cholestyramine
Adding Fe, antacids, or cholestyramine to mycophenolate does what to the drug and why is this a problem?
Decreases absorption of mycophenolate, increases rejection risk
Mycophenolate ADRs
- N/V/D, abd cramping
- Myelosuppression
- Miscarriages & birth defects (BLACK BOX)
What types if birth defects occur in the fetus of a pregnant women on mycophenolate?
- Cleft lip/palate
- Ear deformities
What are the calcineurin inhibitor drugs?
- Cyclosporine
- Tacrolimus
Are formulations of cyclosporine interchangable?
NO
Cyclosporine is available in what formulations?
Solution, tablet, IV, ophthalmic gtt
Are “old” or “new” cyclosporines preferred and why?
“New” preferred b/c they have a more reliable Pk profile
Cyclosporine MOA
↓ production/release of IL-2 -> inhibits IL-2-induced activation of resting T-lymphs
Clinical indications cyclosporine
- Prophylaxis if organ rejection in kidney, liver, & heart transplants
- Severe, refractory RA, psoriasis, & IBD
- Keratoconjunctivitis sicca-associated ocular inflammation (ophthalmic emulsion)
What do we monitor in pt. on cyclosporine?
- Cyclosporine trough levels
- CMP
- CBC w/ diff
- BP
- FLP
Drug interactions w/ cyclosporine
- Additive immunosuppression w/ other agents
- Additive nephrotoxicity w/ other nephrotoxic agents
- CYP interactions
Cyclosporine is a substrate of CYP____
3A4, also P-gp
Cyclosporine is a moderate inhibitor of CYP____
3A4
Cyclosporine ADRs
- Nephrotoxicity (AKI)
- HTN
- Neurotoxicity
- Metabolic abnormalities
- Myelosuppression
- Gingival hyperplasia
- Hirsuitism
- N/V/D
What cyclosporine ADR is the most common & clinically significant?
Nephrotoxicity (reversible after dose reduction)
Cyclosporine-induced HTN
- Caused by renal vasoconstriction & Na+ retention
- 1st wks of therapy
- Usually responds to dose reductions
Cyclosporine-induced neurotoxicity
- Severe HA, visual abnl, seizuers r/t acute HTN
- Mild tremor common (35-55%)
Cyclosporine-induced metabolic abnormalities
- Glucose intolerance (=post-transplant DM)
- Hyperlipidemia
- Hyperuricemia (exacerbate gout)
Where does tacrolimus come from?
It is a macrolide ABX produced by the bacteria streptomyces tsukubaensis
Tacrolimus MOA
↓ production/release of IL-2 -> inhibits IL-2-induced activation of resting T-lymphs
*binds to immunophilin instead of cyclophilin
Clinical indications tacrolimus
- Immunosuppression for heart, kidney, or liver transplant
- Refractory ulcerative colitis
- Moderate-to-severe atopic dermatitis*
For what clinical indications is the oral/injection form of tacrolimus used?
- Immunosuppression
- Refractory UC
For what clinical indications is the topical form of tacrolimus used?
Atopic dermatitis
What do we monitor in a pt. on tacrolimus?
- CBC w/ diff
- CMP
- BP
- Drug concentration*
Drug interactions w/ tacrolimus
- Additive nephrotoxicity w/ other nephrotoxins
- CYP interactions
Tacrolimus is a substrate of CYP___
3A4, also P-gp
Tacrolimus ADRs
Similar to cyclosporine
- Nephrotoxicity, myelosuppression….
What ADRs are more common with tacrolimus c/t cyclosporine?
- PTDM
- Alopecia
What ADRs are more common with cyclosporine c/t tacrolimus?
- Hirsuitism
- Gingival hyperplasia
- HTN
What is our corticosteroid of choice for transplant therapy?
Prednisone
Prednisone is a prodrug of
Prednisolone
Where in the body is prednisone converted to prednisolone?
In the liver
Prednisone MOA
Not fully understood
- Lower doses inhibit cytokine production
High doses of prednisone are believed to be
Lymphotoxic
Clinical indication of prednisone
Prevention & tx of organ transplant
Drug interactions w/ prednisone
- Additive immunosuppression
- Antagonizes effect of anti-DM meds
How does prednisone antagonize DM drugs?
Induces hyperglycemia
What do we monitor in a pt. on prednisone?
- BP
- Blood glucose
Prednisone “acute” ADRs
- Insomnia, nervousness
- Increased appetite
- Hyperglycemia
Prednisone “chronic” ADRs
- Hirsutism
- Cataracts
- Fat redistribution* (Cushingoid)
- Fluid retention
- Osteoporosis*/AVN
- Poor wound healing
- HPA-axis suppression/growth suppression*
- Myopathy
Pts. on prednisone have the following sx r/t myopathy:
- Proximal muscle weakness
- Muscle wasting
Pts. on prednisone DO NOT have the following sx r/t myopathy:
- Myalgias
- Muscle tenderness
Which occurs first in pt. on prednisone r/t myopathy: UE or LE weakness?
LE weakness (more severe)
What are the implications of LE weakness in pt. on prednisone?
Interferes w/ ADLs
Prendisone-induced myopathy is uncommon at what dose?
<10mg/d
Prednisone-induced myopathy is common at what dose?
> 40-60mg/d for 1 month
Prednisone-induced myopathy is a……
Diagnosis of exclusion
Sirolimus is an example of what type of drug?
mTOR inhibitor (mammalian target of rapamycin)
Sirolimus MOA
Inhibition of mTOR suppresses cytokine-drive T cell proliferation
*binds to immunophilin like tacrolimus
Clinical indications sirolimus
- Prophylaxis of organ rejection in pts receiving renal transplants
- Used in triple therapy maintenance regimens in place of calcineurin inhibitor or antimetabolitc (depends on transplant center)
What do we monitor in a pt. on sirolimus?
- Drug concentration
- CBC w/ diff
- CMP
- FLP
- BP
Sirolimus is a substrate of CYP____
3A4; also P-gp
Sirolimus ADRs
- HA
- Tremor
- HTN
- Edema
- PTDM
- Renal dysfcn
- similar to tacrolimus
Belatacept MOA
- Select T-cell costimulation blocker
- Inhibits cytokine production
Clinical indications belatacept
Prevention of rejection of renal transplant
- Only indicated for use in EBV seropositive pt.
Drug interactions w/ belatacept
- Additive immunosuppression
Belatacept ADRs
- Leukopenia/anemia, N/V/D (20%)
- Myelosuppression (malignancy, infection)
- Post-transplant lymphoproliferative disorder (PTLD) possible
