Objec>ves. Solid Organ Transplant from the Primary Care Perspec>ve. Immunity 101 4/23/15

Transcription

1 Objec>ves Solid Organ Transplant from the Primary Care Perspec>ve Genevieve Pagalilauan MD FACP Associate Professor UWSOM Dept. of Medicine, Div. of General Internal Medicine Review immunosuppressive medica>ons used in solid organ transplant (SOT) Consider SOT medica>on side- effects, interac>ons and toxicity Use common primary care scenarios to illustrate important medica>on management considera>ons for SOT pa>ents Immunity 101 Figure 1 Schema>c of mechanisms of ac>on of immunosuppressive drugs Kobashigawa JA and Patel JK (2006) Immunosuppression for heart transplanta>on: where are we now? Nat Clin Pract Cardiovasc Med 3: doi: /ncpcardio0510 1

2 SOT Meds- Triple Therapy Calcineurin inhibitor tacrolimus (FK506, Prograf ), cyclosporine (Sandimmune, Neoral ) Acts by blocking calcineurin, blocks IL2 produc>on An>prolifera>ve mycophenolate (MMF, Cellcept ), mycophenoloic acid (Myfor=c ) Acts by blocking the cell cycle in the nucleus Cor>costeroid (predinsone, prednisilone) Acts on the APC complex, and blocks IL2 Mechanism of Ac>on Calcineurin inhibitors pep>de Kobashigawa Mechanism of Ac>on An>prolifera>ves SOT Meds - Other Azathioprine (Imuran, Azasan ) Used in pa>ents intolerant to MMF Acts on the cell cycle of the nucleus Sirolimus (Rapamune ), everolimus (Afinitor, Zortress ) Used instead of/ or to lower dose of cyclosporine or tacrolimus Acts by blocking TOR (target of rapamycin) Kobashigawa 2

3 Mechanism of Ac>on An>- TOR Case 48 M s/p an orthotopic liver transplant 2007 for ETOH cirrhosis presents to clinic with a 1 day history of a hot red right 1 st MTP joint. He tells you this is his 3 rd bout of gout this year. Meds: Cyclosporine, Azathioprine, Prednisone Kobashigawa You recommend A) PO prednisone acutely B) Colchicine C) Probenecid D) Allopurinol + prednisone E) Febuxostat (Uloric ) + colchicine Drug Side Effects Med Interac7on Tacrolimus (FK506, Hecoria, Prograf ) Cyclosporine (Gengraf, Neoral, Sandimmune ) Calcineurin Inhibitors Nephrotoxicity K, Mg Drug induced DM Tremor Neurotoxicity GI HTN Hirstu>sm Same as above HTN Nephro and Neurotoxicity levels Phenytoin Carbamazepine Phenobarbital Rifampin levels Azoles Fluoroquinolones Dil>azem Sirolimus Grapefruit Protease inhibitors Same as above Sta7ns contraindicated 3

4 An>prolifera>ves Other SOT Immunosuppressives Medica7on Side Effects Med Interac7on Mycophenolate (MMF, Cellcept ) Mycophenoloic Acid (Myfor>c ) GI GI ulcera>on (PPI) Leukopenia Thrombocytopenia LFTs Neurotoxicity Pancrea>>s (rare) Same as above GI Levels Antacids Cholestyramine As above Drug Side Effects Med Interac7on Azathioprine (Imuran ) Sirolimus (Rapamune ) Leukopenia Anemia Thrombocytopenia GI Rare- hepa>>s, pancrea>>s Same heme issues Hyperlipidemia HTN Nausea Allopurinol Febuxostat contraindicated- blocks metabolism, toxicity Same as calcineurin inhibitors Give sirolimus 4 h aler cyclosporine Voriconazole contraindicated Managing Gout in SOT é risk for gout ê excre>on of uric acid via calcineurin inhibitors, é serum uric acid CKD ê uric acid excre>on Medica>on considera>ons NSAIDs contraindicated in general Colchicine in CKD/AKI é myopathy, neuropathy, cyclosporine levels with calcineurin inhibitors Probenecid is ineffec>ve in CKD Febuxostat (Uloric) + azathioprine contraindicated, é azathioprine levels/toxicity Allopurinol + azathioprine require monitoring and adjustment for é toxicity Case Gout and SOT meds You choose to: A) PO prednisone acutely B) Colchicine C) Probenecid D) Allopurinol + prednisone E) Febuxostat (Uloric) + colchicine 4

5 Case TAKE HOME: For gout in SOT pa>ents a direct steroid injec>on to the joint, or é PO steroid dose for any pa>ent is safe once infec>ons is ruled out. Watch for medica>on interac>ons or toxicity if kidney dysfunc>on is present or if on azathioprine. 62 M pa>ent of your partner s calls. He is s/p renal transplant in 2011 and requests refills of his cyclosporine, and prednisone. He was seen 2 months ago and his cyclosporine trough level was at goal (8-12). When you anempt to refill the prescrip>on in your EMR it indicates that Gengraf is a >er 4 medica>on and generic cyclosporine is >er 1. Case You choose to: A) Refill Gengraf at the previous doses B) Switch to generic cyclosporine at the same dose C) Recheck the cyclosporine level prior to any refill D) Call a transplant pharmacist for advice Case Immunotherapy Refills, It s Not So Simple Cyclosporine Dosing is different between brands Consult a transplant pharmacist before switching Ex: Gengraf (modified), Neoral (modified), Sandimmune (non- modified) Mycophenolate Dosing is different between brands Ex: Cellcept (mycophenolate mofe>l), Myfor>c (mycophenoloic acid) Conversion 720 mg Myfor>c = 1000 mg Cellcept 5

6 Case TAKE HOME: Unlike most prescrip>on medica>ons, there are significant differences in dosing between name brand immunosuppressive medica>ons. Do not switch between products without consul>ng with a transplant pharmacist. 33 M s/p pancreas- renal transplant 18 months prior for DM1 presents with 48 hours of rhinorrhea, cough produc>ve of white sputum, and nasal conges>on. VS are stable, PE is notable for nasal mucosa erythema, clear discharge, post nasal drip, and otherwise normal. Which medica>on should be avoided in SOT pa>ents? a) Diphenhydramine b) Guaifenesin c) Dextromethorphan d) Codeine Case - Cough Acute cough should be assessed aggressively in SOT. Immunosuppressants can dampen infec>ous responses like fever More indolent course, have an atypical origin or have more severe manifesta>ons Low threshold for CXR, influenza assessment, or sinus evalua>on ê immunosuppression >6 mo post transplant Community acquired infec>ons > opportunis>c, reac>va>on, and nosocomial infec>ons Case- Cough Medica>on Medica7on Mechanism Concerns Safety in SOT Guaifenesin Dextromethorphan Diphenhydramine Codeine PMID: é ciliary mo>lity, ê mucous thickness Centrally ac>ng an>- tussive Locally ac>ng anesthe>c and centrally ac>ng Narco>c centrally ac>ng an>tussive, dries secre>ons locally Ques>onable efficacy for cough Poten>al P450 2D6 compe>>ve metabolism An>- cholinergic side- effects Drowsiness, decreased GI mo>lity, orthosta>c hypotension - First line - May cause urinary tract stones - Beware in liver dysfunc>on. - Not helpful in lung txp - Cau>on with calcineurin inhibitors, check levels - Beware in liver dysfunc>on - Not helpful in lung txp 6

7 Case - Depression TAKE HOME: Consider guaifenesin for cough treatment in SOT pa>ents. 57M 9 months post heart transplant presents with 1 month of anhedonia, low mood, sleep disrup>on, loss of hope and passive suicidality. Meds: Cyclosporine, prednisone, mycophenolate. PHQ9 15 In addi7on to counseling your recommend: a) Fluoxe>ne b) Bupropion c) Escitalopram d) Paroxe>ne e) Sertraline SOT and An>depressants é rates of depression pre and post transplant é morbidity related to depression Many an>depressants are P450 inhibitors Fluoxe>ne, paroxe>ne, bupropion, sertraline*, nefazodone* Citalopram, escitalopram and mirtazapine minimally inhibit P450 St. Johns Wort is a potent P450 inducer Beware in combina>on with tacrolimus and cyclosporine Citalopram and TCAs é QT interval. Beware in combina>on with tacrolimus and cyclosporine TAKE HOME: Consider escitalopram or mirtazapine as first line an>depressant or anxiety preven>on medica>ons in SOT pa>ents * Nefazodone and sertraline are P450 CYP3A inhibitors, and tacrolimus is a substrate 7

8 Case- Hypertension 43F s/p cadaveric renal transplant for IgA nephropathy 3 years ago presents for follow- up of elevated BP readings. Her 24 hour blood pressure monitor shows a lack of usual circadian dipping with an average SBP 153 and DBP 95. K 4.5, Cr. 1.5, U alb/cr 20. Meds: Cyclosporine, MMF, prednisone Case - Hypertension Besides diet and lifestyle modifica7ons, what do you recommend to treat HTN? a) HCTZ b) Furosemide c) Lisinopril d) Amlodipine e) Atenolol Hypertension in SOT é risk of HTN 55-85% liver transplant, 70-90% renal transplant Steroids, calcineurin inhibitors, renal impairment Incremental é gral failure with é BP Goal < 130/80 (NICE guidelines) JNC 8 <140/90 é complexity Coordinate care with transplant center May require ê immunotherapy or surgery Consider ambulatory BP monitoring (ABPM) Circadian nondipping in renal transplant PMID: Hypertension Medica>ons in SOT An7hypertensive Considera7ons Helpful for co- morbidi7es Loop diure>c Thiazide diure>c CCB é Serum uric acid levels ê Mg, calcineurin inhibitor CHF, volume overload é Serum uric acid levels é CVD risk Dose adjust cyclosporine and tacrolimus if using dil>azem and verapamil ACE- Inhibitors and ARBs Consider use once renal func>on is stable. If compelling indica>on Cr<2.5, K <5.5 PMID: , PMID: , PMID: é CVD risk, DM - Dihydropyridines preserve gral func>on in renal SOT Proteinuria, post- transplant erythrocytosis, DM, post MI/CVA, CKD 8

9 Hypertension Medica>ons in SOT An7hypertensive Considera7ons Helpful for co- morbidi7es Beta blocker 2 nd line therapy Stable CHF, post MI, é CVD risk, arrhythmia Potassium sparing diure>c Alpha blocker 3 rd line therapy, é K in CKD 3 rd line add- on therapy CHF BPH TAKE HOME: Choose an>hypertensive medica>ons based on co- morbid condi>ons, and side- effects. PMID: , PMID: , PMID: Summary Understand the mechanism of key immunosuppressants Consider primary toxicity issues as well as medica>on interac>ons. Beware medica>ons that require you to check a level Beware of gout medica>ons for those on azathioprine or with renal dysfunc>on Consult a transplant pharmacist if switching between brands for immunotherapy Consider guaifenesin for cough Consider escitalopram for depression or anxiety Choose high blood pressure medica>ons based on co- morbid condi>ons and side- effects You Did It! INSERT PICTURE OF YOU NEXT TO STEVE MCQUEEN 9

10 Addi>onal References/Resources The Transplant Pa>ent and Transplant Medicine in Family Prac>ce Lloyd D. Hughes PMCID: PMC Primary Care of the Transplant Pa>ent Peggy B. Hasley, MD, MHSc, Robert M. Arnold, MD PMID: Primary Care of the Solid Organ Transplant Recipient Christopher Wong An>cipated Medical Clinics of N.A Travel advice for the immunocompromised traveler: prophylaxis, vaccina>on, and other preven>ve measures Rupa R Patel PMID: Safety considera>ons: breas}eeding aler transplant Kris>na (Muñoz- Flores) Thiagarajan, RN, MN, PhD PMID: General Medica>on Interac>ons CYP inducers Rifampin Carbamazepine Dilan>n Phenobarbitol Thiozolidinediones RULE 1: CHECK MED INTERACTIONS WITH SEIZURE MEDS RULE 2: CHECK MED INTERACTIONS WITH ANTIFUNGALS RULE 3: CHECK MED INTERACTIONS WITH HIV MEDS CYP inhibitors Clarithro/Erythromycin Fluconozole/voriconazole/ itraconazole/ketoconazole Dil>azem/verapamil Fluoxe>ne/bupropion/ paroxe>ne > duloxe>ne Gemfibrozil Indinavir/nelfinavir/ ritonavir Amiodarone Substrate RULE 4 Watch out for meds with a narrow therapeu>c index Cyclosporine, tacrolimus Theophylline Warfarin Phenytoin Common medica>ons with risk for toxicity or failure Sta>ns (except pravasta>n, rosuvasta>n, fluvasta>n) Macrolides (except azithromycin) TCAs Calcium channel blockers hnp://medicine.iupui.edu/clinpharm/ddis/clinicaltable.asp 10