SOT4_Adverse Effects_54.pptx

Solid Organ Transplantati on Adverse Effects and Management Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Recognize common adverse effects of immunosuppressant medications • Understand the management of these adverse effects in practice • U...

Solid Organ Transplantati on Adverse Effects and Management Yasar Tasnif, PharmD, BCPS, FAST Associate Professor of Practice | UTEP School of Pharmacy Objectives • Recognize common adverse effects of immunosuppressant medications • Understand the management of these adverse effects in practice • Understand long-term adverse effects of immunosuppression and management Induction Immunosuppressive Agents Poly/Monoclonal Antibodies COMMON • Gastrointestinal: Abdominal pain, Diarrhea, Nausea • Musculoskeletal: Myalgia (muscle pain) • Neurologic: Headache • Fever 2015. DrugPoints® System. Thomson Reuters. STAT!Ref Online Electronic Medical Library Poly/Monoclonal Antibodies • During infusion, monitor patient closely for allergic reaction - anaphylaxis has been reported • May cause over-immunosuppression resulting in severe infections • May increase incidence of lymphoma or posttransplant lymphoproliferative disease (PTLD) or other malignancies • Thymoglobulin® is less immunogenic than ATGAM® • Infusion may produce fever and chills 2015. DrugPoints® System. Thomson Reuters. STAT!Ref Online Electronic Medical Library Poly/Monoclonal Antibodies SERIOUS • Cardiovascular: Hypertension, Peripheral edema, Tachycardia • Metabolic: Hyperkalemia, Shivering • Leukopenia (decreased WBCs), Thrombocytopenia (decreased platelets) • Anaphylaxis, Cytokine Release Syndrome (CRS; in rare instances, severe CRS can be fatal) 2015. DrugPoints® System. Thomson Reuters. STAT!Ref Online Electronic Medical Library Anaphylaxis Cytokine Release Syndrome • Cytokine-release syndrome is a symptom complex associated with the use of antibody medications • When cytokines are released into the circulation, symptoms such as fever, nausea, chills, hypotension, tachycardia, asthenia, headache, rash, scratchy throat, and dyspnea can result • Mild to moderate symptoms are managed easily Breslin S. Cytokine-release syndrome: overview and nursing implications. Clin J Oncol Nurs. 2007 Feb;11(1 Cytokine Release Syndrome • Some patients may experience severe, life-threatening reactions that result from massive release of cytokines • Severe reactions occur more commonly during the first infusion in patients who have not received prior therapy • Severe reactions are marked by their rapid onset and the acuity of associated symptoms • Massive cytokine release is an emergency Breslin S. Cytokine-release syndrome: overview and nursing implications. Clin J Oncol Nurs. 2007 Feb;11(1 Suppl):37-42. Pre-Medications • Always make sure the following premedication are given at least one hour prior: • • • • Acetaminophen (Tylenol®) Diphenhydramine (Benadryl®) Methylprednisolone (Solu-Medrol®) Doses as indicated by physician • Pre-medications may decrease both the incidence and severity of adverse reactions Thymoglobulin® (Anti-thymocyte Globulin [Rabbit]) Product Basiliximab • Few adverse effects have been reported with basiliximab. • In contrast to lymphocyte-depleting agents, basiliximab has not been associated with infusion-related reactions. • However, since the marketing of basiliximab, an increased number of hypersensitivity reactions have been reported. • No increased risk of malignancy has been reported. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Maintenance Immunosuppressio n Calcineurin Inhibitors (CNIs) – Common Adverse Effects Cyclosporine • • • • • • • Hyperlipidemia Nephrotoxicity Tremor Hypertension Hyperglycemia Gingival hyperplasia Hirsutism Tacrolimus • • • • • • • • Diarrhea, nausea Hepatotoxicity Nephrotoxicity Tremor, headache Hypertension Hyperglycemia Hyperkalemia Hypomagnesemia Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Calcineurin Inhibitors (CNIs) • Cyclosporine appears to have a greater propensity to cause or worsen hypertension and hyperlipidemia compared with tacrolimus. • On the other hand, hyperglycemia is more common with tacrolimus than with cyclosporine. • Cyclosporine is associated with cosmetic effects, such as hirsutism and gingival hyperplasia. • Tacrolimus, in contrast, has been reported to cause alopecia. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Calcineurin Inhibitors (CNIs) • The nephrotoxic potential of both drugs is equal and is often related to the dose and duration of exposure. • Neurotoxicity typically manifests as tremors, headache, and peripheral neuropathy; occasionally, however, seizures have been observed. • Tacrolimus may be associated with an increased occurrence of neurologic complications compared with cyclosporine. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Mechanism of CNI Nephrotoxicity Pallet et al. / Pharmacological Research64 (2011) 25–30 Management of CNIs Adverse Effects • Two types of nephrotoxicity can occur with CNIs • Acute nephrotoxicity is frequently seen early and is dose-dependent and reversible • Chronic nephropathy is more common. • Clinical manifestations of CNI nephrotoxicity include elevated serum creatinine and blood urea nitrogen levels, hyperkalemia, hyperuricemia, mild proteinuria, and a decreased fractional excretion of sodium. • CNI nephrotoxicity is recognized as the leading cause of renal dysfunction following nonrenal solid-organ transplant. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Effects • Measures to reduce CNI nephrotoxicity include delaying administration immediately postoperatively in patients at high risk for nephrotoxicity. • Monitoring CNI trough blood levels and reducing the CNI dosage. • Avoiding other nephrotoxins (e.g., aminoglycosides, amphotericin B, and NSAIDs) when possible. • Currently, no proven therapies consistently prevent or reverse the nephrotoxic effects of CNIs. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Effects • Cyclosporine associated cosmetic effects • Hirsutism and gingival hyperplasia managed by converting from cyclosporine to tacrolimus. • Or by proper hygiene in patients who cannot be switched to tacrolimus. • Tacrolimus induced alopecia, is usually selflimiting and reversible • May use Biotin (also called vitamin B₇ / B₈) • Topical minoxidil (Rogaine®) Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Effects • Hyperglycemia is often reversible when doses of CNIs (more tacrolimus than cyclosporine) and/or corticosteroids are reduced. • Some patients may develop NODAT (new onset of diabetes after transplant; ~ 40% of patients). • Lifestyle modifications are necessary. • Patients may need to be started on oral antidiabetic medications such as metformin (monitor and adjust for renal function/diarrhea) or sitagliptin. • Some patients (especially those with a diagnosis of T2DM pre-transplant) may need to Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Effects • Most cases of CNI associated neurotoxicity have occurred at high doses of either drug. • First step may be to get a trough level and evaluate if elevated • If supra-therapeutic reduce the dose and monitor levels • If presenting as a seizure/altered mental status discontinue the immunosuppressant, correct electrolyte abnormalities, control hypertension, and treat the seizure. • In many cases, discontinuation or dose reduction results in resolution of symptoms; unfortunately, this approach has not been https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1432-2277.2000.tb01004.x Management of CNIs Adverse Effects • Hyperkalemia (reduced efficiency of urinary potassium excretion) • Reduction in potassium intake and hydration • Administration of a cation exchange resin (SPS, Lokelma®) • Diuretics such as furosemide • Hypomagnesemia (suppression of reabsorption of magnesium from renal tubules) • Magnesium oxide and increased dietary intake • Hypophosphatemia (induced urinary phosphate wasting) • Phosphate supplementation (K-Phos Neutral®) • Increased dietary intake of phosphorus Lee CH, Kim GH. Electrolyte and Acid-base disturbances induced by calcineurin inhibitors. Electrolyte Blood Press. 2007;5(2):126–130. doi:10.5049/EBP.2007.5.2.126 Management of CNIs Adverse Effects • Primary mechanism of CNI-associated hypertension • Peripheral vasoconstriction • Sodium retention, resulting in extracellular fluid volume expansion • Tacrolimus appears to have less potential to induce hypertension following transplantation than cyclosporine • Multiple antihypertensive agents are usually necessary to achieve the goal blood pressure in transplant recipients • Calcium channel blockers are first-line agents • Ameliorate the nephrotoxic effects of CNIs Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Management of CNIs Adverse Effects Effects • ACEIs ARBs are avoided in kidney ACEIsand and ARBs are avoided intransplantation kidney recipients, especially in the perioperative phase, of transplantation recipients, especially in because the the potential for hyperkalemia and their potentially perioperative phase, because of the potential negative influence onand GFR. their potentially negative for hyperkalemia GFR.are used in patients after • influence When ACEIson or ARBS • transplantation, serum creatinine andin potassium levels When ACEIs or ARBS are used patients after should be monitoredserum closely. creatinine and transplantation, potassium levels should be monitored closely. • If the increase in serum creatinine is greater than 30%within • If 1 to 2 weeks after in initiating ACEIs or ARBs, other alternatives the increase serum creatinine is greater than must be considered. 30% within 1 to 2 weeks after initiating ACEIs or ARBs,ofother alternatives be considered. • Addition a B-blocker, diuretic,must or centrally acting • antihypertensive is usually necessary . or centrally Addition of a B-blocker, diuretic, acting antihypertensive is usually necessary. Schonder KS, Johnson HJ. Chapter 70.HJ. Solid-Org an Transplantation. In: DiPiroJT, Talbert RL, Yee GC,In: Matzke GR, Wells BG, Posey L. eds. Pharm A Pathophys Approach, New York, Schonder KS, Johnson Chapter 70. Solid-Organ Transplantation. DiPiro JT, Talbert RL, Yee GC,acotherapy: Matzke GR, Wells iologic BG, Posey L. 9e eds. Pharmacotherapy: A Pathophysiologic Approach, NY: McGraw-H ill; 209e 14. New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Effects • CNIs may decrease the activity of the lowdensity lipoprotein (LDL) receptor or lipoprotein lipase, altering LDL catabolism. • Aggressive lipid lowering arrests the progress or prevents the complications of atherosclerosis and promotes graft survival • Combination of dietary intervention and an HMG-CoA reductase inhibitor should be considered the treatment of choice. • HMG-CoA reductase inhibitors as a class also have immunomodulatory effects on MHC expression and T-cell activation and may reduce rejection Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of CNIs Adverse Effects • HMG-CoA reductase inhibitors are used with caution (reports of rhabdomyolysis when combined with CNIs); use low doses. • Concurrent use of simvastatin and cyclosporine is contraindicated; due to the increased risk of rhabdomyolysis. • Gemfibrozil should be avoided (due to myopathy). • Inform patients of signs and symptoms of rhabdomyolysis. • Pravastatin preferred as a result of its lower interactive potential with CNIs because it is not metabolized by CYP3A4. • Statin induced hepatotoxicity – close monitoring of Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Corticosteroids GI bleeding Hyperlipidemia Leukocytosis Hypertension Hyperglycemia Weight gain • Increase appetite, sodium and fluid retention • Mood changes • Osteoporosis • GI Ulceration • • • • • • Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of Corticosteroid AEs • The advent of combined glucocorticoid/calcineurin inhibitor regimens has allowed reduced doses or rapid withdrawal of steroids, resulting in lower steroid-induced adverse effects seen at higher doses. • Osteoporosis • Calcium supplementation • Bone density scans to determine treatment with bisphosphonate • Hypertension and hyperlipidemia treatment similar to CNIs • Maintenance therapy will never be with steroid alone Krensky AM, Azzi JR, Hafler DA. Immunosuppressants and Tolerogens. In: Brunton LL, Hilal-Dandan R, Knollmann BC. eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e New York, NY: McGraw-Hill. Anti-Proliferative Agents Mycophenolate • Diarrhea, nausea • Leukopenia • Thrombocytopenia • Has a higher rate of viral infections Azathioprine • Nausea, vomiting • Anemia • Leukopenia • Thrombocytopenia • Rare: Increase liver function tests (AST, ALT, Alk Phos) Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of Mycophenolate AEs • GI side effects occur with similar frequency during IV and oral therapy. • Strategies to reduce GI symptoms include • Dose reduction • Division of the total daily dose into three or four doses • Administration with food, or titration upward from lower doses during initial therapy • Hematologic effects, such as leukopenia and anemia, particularly with higher doses • Leucopenia may be exacerbated when combined with prophylactic anti-CMV therapy (valganciclovir) • May require G-CSF therapy and dosage reduction Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of Azathioprine AEs • Dose-limiting adverse effects of azathioprine are often hematologic. • Leukopenia, anemia, and thrombocytopenia can occur within the first few weeks of therapy and can be managed by dose reduction or discontinuation of azathioprine. • Nausea and vomiting can be minimized by taking azathioprine with food. • Alopecia, hepatotoxicity, and pancreatitis are less common adverse effects of azathioprine and are reversible on dose reduction or discontinuation. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of Azathioprine AEs • Activity of TPMT can affect the occurrence of adverse effects with azathioprine. • Approximately 10% of the population has intermediate TPMT activity and 0.3% has low activity of the enzyme. • In both scenarios, the incidence of leukopenia and hepatotoxicity is increased. • As a result, TPMT genotyping may be useful to guide dosing of azathioprine to minimize adverse effects. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. mTOR Inhibitors • Hyperlipidemia • Thrombocytopenia • Leukopenia Management of mTOR AEs • Both everolimus and sirolimus are associated with dose-related myelosuppression. • Thrombocytopenia is usually seen within the first 2 weeks of sirolimus therapy but generally improves with continued treatment; leukopenia and anemia are also typically transient. • Sirolimus trough serum concentrations greater than 15 ng/mL (15 mcg/L; 16 μmol/L) have been correlated with thrombocytopenia and leukopenia • Dose reduction and close monitoring of trough levels are helpful Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of mTOR AEs • Hypercholesterolemia and hypertriglyceridemia are also common in patients receiving everolimus or sirolimus. • Peak cholesterol and triglyceride levels are often seen within 3 months of initiation but usually decrease after 1 year of therapy • Managed by reducing the dose • Discontinuing mTOR • Or initiating therapy with an HMG-CoA reductase inhibitor Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of mTOR AEs • Delayed wound healing and dehiscence could be a result of inhibition of smooth muscle proliferation and intimal thickening. • Do novo regimens for maintenance are not common • Mouth ulcers are reported in as many as 60% of patients treated with sirolimus and appears to be dose-related. • Good oral care; salt-soda mouth wash; pain medication • Reversible interstitial pneumonitis has been described in kidney, liver, and heart–lung transplantation recipients. • Diagnosed by Chest X-Ray or CT Scan Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Management of mTOR AEs Stomatitis/Mucositis Pneumonitis https://www.semanticscholar.org/paper/Stomatitis-Associated-With-Use-of-mTOR-Inhibitors%3A-Divers-O'shaughnessy/ 196603d1fe84705743eee1ef423d1e0238c83d33 https://www.sciencedirect.com/science/article/abs/pii/S0959804915009296 Management of mTOR AEs • mTORs can worsen proteinuria and should be used with caution in patients with GFR below 30% or proteinuria. • Renal function and proteinuria therefore must be monitored closely in such patients. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Belatacept • Diarrhea • Neutropenia • Anemia • Peripheral edema • Urinary tract infection • Infusion-related reactions are rare Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Long-Term Adverse Effects of Immunosuppressio n Cardiovascular • Comorbidities such as cardiovascular disease, malignancy, recurrent disease, drug toxicities (namely nephrotoxicity), and chronic rejection are the primary causes of mortality in patients who have a functioning graft 5 or more years after transplantation. • Cardiovascular disease is a leading cause of morbidity and mortality in transplant patients. • Preexisting cardiovascular disease, which is common in end-stage organ failure, is not reversed with transplantation. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Cardiovascular • Additionally, hypertension, hyperlipidemia, and diabetes are common complications in transplantation recipients and are independent risk factors that contribute significantly to cardiovascular disease. • All of these conditions warrant attention and aggressive treatment post-operatively and long-term. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Malignancy • Although advances in immunosuppression have decreased the incidence of acute rejection and increased patient survival, they have also increased the patient’s lifetime exposure to immunosuppression. • Post-transplantation malignancy seems to be related to the overall level of immunosuppression, as evidenced by a difference in the rates of malignancy associated with quadruple versus triple versus dual immunosuppressant regimens. • The risk of de novo malignancy in transplantation recipients is increased 3-5-fold Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Malignancy • Skin cancers are the most common tumors. • Factors that may predispose transplant recipients to skin cancers include copious sun exposure and therapy with azathioprine. • mTORs have a theoretical benefit in terms of the development of malignancy (have antiproliferative effects). • Conversion to mTORs from CNIs can result in regression of Kaposi’s sarcoma. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Malignancy • Factors that predispose patients to PTLD include EBV seronegativity at transplantation and intense immunosuppression, particularly with lymphocyte-depleting agents. • One analysis showed a lower risk of PTLD with MMF compared with AZA. • Treatment of life-threatening PTLD generally includes severe reduction or cessation of immunosuppression. • Other options include systemic chemotherapy or rituximab. Schonder KS, Johnson HJ. Chapter 70. Solid-Organ Transplantation. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw-Hill; 2014. Question s • Please contact me at: [email protected] u