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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5258_Библиотеки_им_академика_М_И_Перельмана.pdf
45
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
ACE-I/ARB Additive risk for
nephrotoxicity in
combination with
immunosuppression
(practices vary:
dihydropyridine calcium
channel blockers such as
amlodipine, and sometimes
beta blockers, are often used
initially after transplant. In a
stable patient >3–6months
after transplantation, ACE-I
and ARB may be used with
careful monitoring of
potassium and renal
function)
No interaction No interaction No interaction
Diltiazem, verapamil Inhibition of CYP3A4,
formation of metabolic
intermediate complex leads
to ↑ tacrolimus/cyclosporine
levels
No interaction Verapamil-sirolimus
combination is associated
with increased blood levels
of verapamil. Monitor
therapy
No interaction
Nifedipine Inhibition of CYP3A4 leads
to ↑ tacrolimus/cyclosporine
levels
No interaction No interaction No interaction
(continued)
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
46
Table 3.4 (continued)
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Carvedilol Inhibition of P-gp and
CYP3A4 leads to mildly ↑
tacrolimus/cyclosporine
levels due to increased
absorption of tacrolimus/
cyclosporine
No interaction Inhibition of P-gp and
CYP3A4 leads to mildly ↑
tacrolimus/cyclosporine
levels due to increased
absorption of tacrolimus/
cyclosporine. Monitor
therapy
No interaction
Psychiatric medications
Carbamazepine Strong induction of
CYP3A4 will lead to ↓
No interaction Strong induction of
CYP3A4 will lead to ↓
sirolimus/everolimus levels.
Consider alternative
anticonvulsant
No interaction
tacrolimus/cyclosporine
levels. Consider alternative
anticonvulsant
Selective serotonin reuptake
inhibitors (SSRIs):
Sertraline, escitalopram, citalopram Generally preferred SSRIs
in transplant recipients
because of minimal drug
interactions
No interaction Generally preferred SSRIs
in transplant recipients
because of minimal drug
interactions
No interaction
Fluoxetine Weak inhibition of CYP3A4
leads to mildly ↑ tacrolimus/
cyclosporine levels
No interaction Weak inhibition of
CYP3A4 leads to mildly ↑
sirolimus/everolimus levels
No interaction
Fluvoxamine Moderate inhibition of
CYP3A4 leads to
theoretical ↑ tacrolimus/
cyclosporine levels. Use
alternative SSRI
No interaction Moderate inhibition of
CYP3A4 leads to
theoretical ↑ sirolimus/
everolimus levels. Use
alternative SSRI
No interaction
L. Sun et al.
47
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Serotonin-norepinephrine reuptake
inhibitors (SNRIs):
Duloxetine May be helpful in those
with chronic pain, may
cause hepatotoxicity
No interaction May be helpful in those
with chronic pain, may
cause hepatotoxicity
No interaction
Venlafaxine Total daily doses exceeding
225mg of venlafaxine can
increase BP. (Drug-induced
HTN already common with
CNIs)
No interaction Total daily doses exceeding
225mg of venlafaxine can
increase BP. (Drug-induced
HTN already common with
mTOR inhibitors)
Total daily doses
exceeding 225mg of
venlafaxine can
increase BP. (Drug-
induced HTN already
common with
corticosteroids)
Norepinephrine+dopamine
reuptake inhibitor:
Bupropion Lowers seizure threshold
and can exacerbate CNS
adverse effects of CNIs.
Assess pt. carefully for
immunosuppressant
associated neurotoxicity
before bupropion is
considered
No interaction Lowers seizure threshold
and can exacerbate CNS
adverse effects of mTORIs.
Assess pt. carefully for
immunosuppressant
associated neurotoxicity
before bupropion is
considered
Lowers seizure
threshold and can
exacerbate CNS adverse
effects of
corticosteroids. Assess
pt. carefully for
immunosuppressant
associated neurotoxicity
before bupropion is
considered
α
2
antagonist:
(continued)
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
48
Table 3.4 (continued)
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Mirtazapine May exacerbate
immunosuppressant-
induced metabolic changes
(weight gain), can also
cause hyperlipidemia
No interaction May exacerbate
immunosuppressant-
induced metabolic changes
(weight gain), can also
cause hyperlipidemia
May exacerbate
immunosuppressant-
induced metabolic
changes (weight gain),
can also cause
hyperlipidemia
Tricyclic antidepressants:
Amityriptyline, imipramine,
desipramine, nortriptyline
Signicant anticholinergic and cardiovascular side effects, orthostatic hypotension, sedation and weight gain make
TCAs last line therapy and reserved for refractory cases of depression in the transplant recipient
Other:
Divalproex sodium, valproic acid AVOID in liver transplant recipients as valproate has been associated with hepatic failure
Lithium Avoid due to nephrotoxicity and renal failure
Other medications
Anti-gout medications:
Colchicine Unclear mechanism,
possible inhibition of
colchicine transport by P-gp
and/or inhibition of
colchicine metabolism by
CYP3A4 and leads to ↑
colchicine levels
No interaction No interaction No interaction
Avoid use if possible. After
the immediate post-
transplant period, short
courses of colchicine can
sometimes be used in
patients for the treatment of
acute gout if no other options
L. Sun et al.
49
Interacting drug
Calcineurin inhibitors
(tacrolimus, cyclosporine)
Anti-metabolites
(mycophenolate, azathioprine)
mTOR inhibitors
(sirolimus, everolimus)
Corticosteroids
(prednisone,
methyl-prednisolone)
Allopurinol No interaction Inhibition of xanthine oxidase
leads to ↑↑↑ levels of
azathioprine and life-
threatening myelotoxicity
(bone marrow suppression).
Allopurinol is contraindicated
with azathioprine
No interaction No interaction
Herbal and natural products:
St. John’s wort Induction of CYP3A4 leads
to ↓ CNI levels
No interaction Induction of CYP3A4 leads
to ↓ mTORi levels
No interaction
Grapefruit, pomelo, pomegranate,
star fruit
Inhibition of CYP3A4 leads
to ↑ CNI levels
No interaction Inhibition of CYP3A4 leads
to ↑ mTORi levels
No interaction
Proton-pump inhibitors:
Omeprazole, lansoprazole,
rabeprazole
Inhibition of CYP2C19,
may increase CNI levels,
but magnitude and clinical
severity of interaction
appears to be dependent on
individual patient’s
CYP2C19 and/or CYP3A5
genotypes
PPIs increase gastric pH that
impairs MMF/MPA absorption
and may ↓ levels of MMF, but
clinical signicance of
interaction is unclear
No interaction No interaction
PPIs are given routinely
with CNI in clinical practice
PPIs are given routinely with
MMF in clinical practice
NSAIDS:
Ibuprofen, naproxen, full dose
aspirin
Additive risk for
nephrotoxicity in
combination with
immunosuppression (avoid
if possible, use
acetaminophen)
No interaction Additive risk for
nephrotoxicity in
combination with
immunosuppression (avoid
if possible, use
acetaminophen)
No interaction
Note: the primary care provider should not be adjusting anti-rejection medications—the above table is given for awareness; concerning drug interactions should
be addressed by coordinating with the transplant team
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
50
Table 3.5
Management of immunosuppression while patient is initiated on concomitant
nirmatrelvir-ritonavir [1, 2, 20]
Day of
nirmatrelvir-
ritonavir therapy Immunosuppression management
Day 1 Tacrolimus or mTORi: HOLD
Cyclosporine: REDUCE total daily dose by 80%
Initiate Paxlovid 12h after last tacrolimus or cyclosporine dose and 24h
after last sirolimus dose
Day 6–8 Check CNI/mTORi level
• If anticipated lab turnaround is same day; await results to guide
CNI/mTORi resumption
– If level within goal range, consider restarting ~50% of CNI/mTORi
home dose
– If level below goal range, consider restarting CNI/mTORi at home dose
– If level ABOVE goal range, conrm with patient the timing of CNI/
mTORi holding and Paxlovid discontinuation and use clinical judgment
as to whether or not the immunosuppression should be restarted at a
reduced dose (consider 75% reduction) or if another level should be
obtained rst
• If anticipated lab turnaround is >24h; consider resuming CNI/mTORi at
50% of pre-Paxlovid dose starting the evening after lab draw
Day 10 If CNI/mTORi restarted at reduced dose, consider increasing back to 100%
of pre-paxlovid dose
Day 14 Check CNI/mTORi level
Continue to monitor CNI level once weekly until stabilized at goal range
Day 21 Check CNI/mTORi level
Continue to monitor CNI level once weekly until stabilized at goal range
Note: In most cases, the transplant team should be involved in initial decision-making regarding
whether to treat with nirmatrelvir-ritonavir as well as ongoing immunosuppressant dose adjust-
ment and monitoring
3.7 Pregnancy andBreast-Feeding
Pregnancy is generally discouraged in the rst year after transplantation, and after-
ward may be considered in select patients. Immunosuppression may need to be
adjusted during pregnancy. The primary care provider should discuss the desire for
pregnancy with solid organ transplant recipients who have the potential for child-
bearing, especially if they are taking mycophenolate or mTOR inhibitors, both of
which are contraindicated during pregnancy. In almost all cases, the patient should
be referred back to their transplant specialist as well as an obstetric specialist (e.g.,
maternal-fetal-medicine or high-risk obstetrics specialist) who has experience with
the transplant population. Often immunosuppressive drug levels are checked more
frequently during pregnancy.
L. Sun et al.
51
Breast-feeding cautions are similar to those during pregnancy, with mycopheno-
late and mTOR inhibitors generally avoided. Patients should work closely with their
transplant team, as well as obstetrics and pediatrics (contraception is discussed in
Chap. 13).
3.8 Pearls forthePrimary Care Provider
For the primary care provider who takes care of solid organ transplant recipients,
the most important medications to be familiar with are tacrolimus, mycophenolate,
and prednisone, as these are the most commonly used. Sirolimus may occasionally
be used to augment CNI induced nephrotoxicity or as an adjunctive immunosup-
pressant for patients with a history of malignancy. In heart transplant recipients,
sirolimus can be used to prevent cardiac allograft vasculopathy and decrease acute
coronary events (see Chap. 6). At each clinic visit, adherence should be assessed in
a nonjudgmental fashion, with recognition that pill burden and side effects may be
factors in how consistently patients take their medications. Laboratory studies may
be conducted at external facilities, requiring the primary care provider to coordinate
and share information with the transplant specialist documentation is critical to
identifying the target drug levels for immunosuppressive therapy, as patients are
often unaware of their specic therapeutic ranges. As primary care providers gain
more experience managing transplant recipients, they will naturally develop col-
laborative relationships with the transplant team. These communication bridges are
essential for ensuring continuity and optimizing patient care. New medications
should always be screened for drug interactions with the anti-rejection medications
using the information in this chapter and other available databases. In general, if it
is possible to choose a medication that does not disrupt the patient’s immunosup-
pressive treatment, this is preferable. If there is uncertainty, then it is advisable to
contact the patient’s transplant specialist. In larger centers, a transplant pharmacist
may be available to eld questions. Table3.6 provides the recommendations for
medication assessment at outpatient visits.
Table 3.6 Checklist for assessing medication use at outpatient clinic visits for solid organ
transplant recipients
Ask about
• Adherence (“how often do you miss a dose of ___?”)
• Side effects (know and ask about common side effects)
• Supplements and prescriptions from other providers
Review
• Transplant team’s lab monitoring schedule, goal trough levels
• Potential drug interactions before starting any new medications
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
52
3.9 Conclusion
The success of a patient who receives organ transplantation depends on many fac-
tors and can be enhanced under the care of an attentive primary care provider as well
as with an adherent patient. Primary care clinicians can play a pivotal role in sup-
porting the immunosuppressive medication regimen by simplifying non- transplant
medications, creating a psychologically safe atmosphere, and providing appropriate
follow-up based on the patient’s medical literacy [22–24]. Communication around
medical prescribing between the primary care physician and transplant team is key
to better patient outcomes and quality of life [23].
References
1. Halloran P. Immunosuppressive drugs for kidney transplantation. N Engl J Med.
2004;351:1215–29.
2. Enderby C.An overview of immunosuppression in solid organ transplantation. Am J Manag
Care. 2015;21:S12–23.
3. Wiesner RH, Fung JJ.Present state of immunosuppressive therapy in liver transplant recipi-
ents. Liver Transpl. 2011;17(suppl 3):S1–9.
4. Mahmud N, Klipa D, Ahsan N. Antibody immunosuppressive therapy in solid-organ trans-
plant: part I.MAbs. 2010;2(2):148–56.
5. OPTN/SRTR 2023 Annual Data Report. https://www.srtr.org/reports/optnsrtr- annual- data-
report/. Accessed 25 June 2024.
6. Madariaga M, Kreisel D, Madsen J.Organ-specic differences in achieving tolerance. Curr
Opin Organ Transplant. 2015;20(4):392–9. https://doi.org/10.1097/MOT.0000000000000206.
7. Moini M, Schilsky ML, Tichy EM. Review on immunosuppression in liver transplantation.
World J Hepatol. 2015;7(10):1355–68. https://doi.org/10.4254/wjh.v7.i10.1355.
8. Mika A, Stepnowski P.Current methods of the analysis of immunosuppressive agents in clini-
cal materials: a review. J Pharma Biomed Anal. 2016;127:207–31.
9. Christians U, Pokaiyavanichkul T, Chan l. Tacrolimus. In: Burton ME, Shaw LM, Schentag
JJ, Evans WE, editors. Applied pharmacokinetics and pharmacodynamics: principles of thera-
peutic drug monitoring. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2006. p.563–94.
10. Nawrocki A, Korecka M, Solari S, Kang J, Shaw LM.Mycophenolic acid. In: Burton ME,
Shaw LM, Schentag JJ, Evans WE, editors. Applied pharmacokinetics and pharmacodynam-
ics: principles of therapeutic drug monitoring. 4th ed. Philadelphia: Lippincott Williams &
Wilkins; 2006. p.563–94.
11. Foster BJ, Dahhou M, Zhang X, Platt RW, Samuel SM, Hanley JA.Association between age and
graft failure rates in young kidney transplant recipients. Transplantation. 2011;92(11):1237–43.
https://doi.org/10.1097/TP.0b013e31823411d7.
12. Dew MA, DiMartini AF, De Vito DA, etal. Rates and risk factors for nonadherence to the
medical regimen after adult solid organ transplantation. Transplantation. 2007;83(7):858–73.
https://doi.org/10.1097/01.tp.0000258599.65257.a6.
13. Girlanda R.Complications of post-transplant immunosuppression. In: Andrades JA, editor.
Regenerative medicine and tissue engineering. London: IntechOpen; 2013.
14. Veroux M.Infective complications in renal allograft recipients: epidemiology and outcome.
Transplant Proc. 2008;40:1873–6.
15. Engels EA, Pfeiffer RM, Fraumeni JF Jr, Kasiske BL, Israni AK, Snyder JJ, Wolfe RA,
Goodrich NP, Bayakly AR, Clarke CA, Copeland G, Finch JL, Fleissner ML, Goodman MT,
L. Sun et al.
53
Kahn A, Koch L, Lynch CF, Madeleine MM, Pawlish K, Rao C, Williams MA, Castenson D,
Curry M, Parsons R, Fant G, Lin M.Spectrum of cancer risk among US solid organ transplant
recipients. JAMA. 2011;306(17):1891–901. https://doi.org/10.1001/jama.2011.1592. PMID:
22045767; PMCID: PMC3310893.
16. Wang JH, Pfeiffer RM, Musgrove D, Castenson D, Fredrickson M, Miller J, Gonsalves L,
Hsieh MC, Lynch CF, Zeng Y, Yu KJ, Hart A, Israni AK, Snyder JJ, Engels EA. Cancer
mortality among solid organ transplant recipients in the United States during 1987-2018.
Transplantation. 2023;107(11):2433–42. https://doi.org/10.1097/TP.0000000000004694.
Epub 2023 Jun 9. PMID: 37291711; PMCID: PMC10615843.
17. Jiyad Z, Olsen CM, etal. Azathioprine and risk of skin cancer in organ transplant recipients:
systematic review and meta-analysis. Am J Transplant. 2016;16:3490–503.
18. Manitpisitkul W.Drug interactions in transplant patients: what everyone should know. Curr
Opin Nephrol Hypertens. 2009;18:404–11.
19. Monostory K.Metabolic drug interactions with immunosuppressants. In: Tsoulfas G, editor.
Organ donation and transplantation: current status and future challenges. London: IntechOpen;
2018. https://doi.org/10.5772/intechopen.74524.
20. Sheikhalipour Z, Faghihdinevari M, Salehi-Pourmehr H, Khameneh M, Vahedi L.Covid-19in
kidney transplant recipients with immunosuppressive therapy. Caspian J Intern Med.
2022;13(Suppl 3):161–72. https://doi.org/10.22088/cjim.12.4.509.
21. Tang Y, Li Y, Song T.Optimizing the use of nirmatrelvir/ritonavir in solid organ transplant
recipients with COVID-19: a review of immunosuppressant adjustment strategies. Front
Immunol. 2023;14:1150341. https://doi.org/10.3389/mmu.2023.1150341. PMID: 37081880;
PMCID: PMC10111375.
22. McCashland TM.Posttransplantation care: role of the primary care physician versus transplant
center. Liver Transpl. 2001;7(Suppl 1):S2–12.
23. Martin LR, Williams SL, Haskard KB, DiMatteo MR. The challenge of patient adherence.
Ther Clin Risk Manag. 2005;1:189–99.
24. Hughes L.The transplant patient and transplant medicine in family practice. J Family Med
Prim Care. 2014;3(4):345–54.
https://doi.org/10.4103/2249- 4863.148106.
3 Anti-Rejection Medication Therapy intheAdult Solid Organ Transplant Recipient
55© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2025
C. J. Wong (ed.), Primary Care of the Solid Organ Transplant Recipient,
https://doi.org/10.1007/978-3-031-98076-3_4
Chapter 4
Primary Care oftheAdult Kidney
Transplant andKidney-Pancreas
Transplant Recipient
BoonphiphopBoonpheng andIrisC.De Castro
4.1 Kidney Transplant Recipients
4.1.1 Introduction
The existence of dialysis as a widely available treatment for end-stage kidney dis-
ease (ESKD) makes kidney failure unique when compared to other types of solid
organ failure. Although signicant advancements have been made in recent years
with respect to mechanical support devices for heart failure, and to a lesser extent
liver failure, these treatments pale in comparison to dialysis as a form of treatment
for end-stage organ failure.
Still, dialysis is clearly not enough. While mortality trends for patients on dialy-
sis have improved over time, with data varying by country, mode and intensity of
dialysis, and patient age and comorbidities, the overall mortality remains high. In
the USA in 2019, all-cause mortality of ESKD patients undergoing dialysis is 159.1
per 1000 person-years [1]. In sharp contrast, the all-cause mortality with kidney
transplantation is 47.7 per 1000 person-years, and as such, transplantation is consid-
ered the treatment of choice for all suitable candidates with ESKD [2–4].
Furthermore, transplantation is endorsed by the Kidney Diseases Improving Global
Outcomes (KDIGO) working group, and, in the USA, the Centers for Medicare and
B. Boonpheng
Division of Nephrology and Hypertension, University Hospitals Cleveland Medical Center,
Cleveland, OH, USA
e-mail: boonphiphop.boonpheng@Uhhospitals.org
I. C. De Castro (
*)
Division of Nephrology, Department of Medicine, University of Washington,
Seattle, WA, USA
e-mail: icastro@uw.edu