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Immunosuppressive Drugs. CorticosteroidsAntiproliferative agentsAzathioprineMycophenolate mofetil (MMF)Mycophenolic acid (MPA). Calcineurin inhibitorsCyclosporine Tacrolimus mTOR inhibitorsSirolimus Everolimus. Mycophenolate Mofetil (Cellcept). Prodrug converted to active moiety mycophenol
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2. Overview Immunosuppressive drugs
Cardiovascular disease & hyperlipidemia
Hypertension
Diabetes
Vaccines
3. Immunosuppressive Drugs Corticosteroids
Antiproliferative agents
Azathioprine
Mycophenolate mofetil (MMF)
Mycophenolic acid (MPA) Calcineurin inhibitors
Cyclosporine
Tacrolimus
mTOR inhibitors
Sirolimus
Everolimus In the interest of time we will only be covering mycophenolate/mycophenolic acid, the calcineurin inhibitors and sirolimus
In the interest of time we will only be covering mycophenolate/mycophenolic acid, the calcineurin inhibitors and sirolimus
4. Mycophenolate Mofetil (Cellcept®) Prodrug converted to active moiety mycophenolic acid (MPA)
Typical Dose: 1000mg BID
Monitoring: CBC, MPA levels +/-
Does not require extra monitoring when switching between formulations
Does not require extra monitoring when switching between formulations
5. Mycophenolic Acid (Myfortic®) Enteric coated product that provides active moiety
Typical Dose: 720mg BID
Monitoring: CBC, MPA levels +/-
6. Adverse Effects of MMF & MPA Gastritis, anorexia, cramping, diarrhea
Neutropenia, thrombocytopenia, anemia
Trend toward ? incidence of infections
CMV, HSV
Progressive multifocal leukoencephalopathy (PML) - rare PML is a rare disorder that affects the central nervous system. When it occurs, it is usually in patients with immune systems suppressed by disease or medicines. It happens when the polyomavirus, also known as the JC virus, is activated. The JC virus is found in most adults but does not usually cause symptoms. Scientists do not know exactly how the JC virus is activated. Once activated, the JC virus attacks the cells that make myelin, the protective coating around nerve cells. Signs and symptoms of PML can include localized neurologic signs and symptoms including vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and weakness in the legs. Many patients who develop PML die. Patients who survive may have permanent disability due to irreversible nerve damage. More information on PML can be found at the National Institutes of Health website.
PML is a rare disorder that affects the central nervous system. When it occurs, it is usually in patients with immune systems suppressed by disease or medicines. It happens when the polyomavirus, also known as the JC virus, is activated. The JC virus is found in most adults but does not usually cause symptoms. Scientists do not know exactly how the JC virus is activated. Once activated, the JC virus attacks the cells that make myelin, the protective coating around nerve cells. Signs and symptoms of PML can include localized neurologic signs and symptoms including vision changes, loss of coordination, clumsiness, memory loss, difficulty speaking or understanding what others say, and weakness in the legs. Many patients who develop PML die. Patients who survive may have permanent disability due to irreversible nerve damage. More information on PML can be found at the National Institutes of Health website.
7. Practical Tips for MMF & MPA Take with food
Do not crush, cut or chew tablets (MPA)
Transplant center may reduce dose, split into TID dosing, or convert to MPA
Equimolar dosing
500mg MMF = 360mg MPA
Do not take with iron
8. Calcineurin Inhibitors Tacrolimus (Prograf®, FK506)
Usual Starting Dose
0.05mg/kg q 12 hours
Cyclosporine (Sandimmune®, Neoral®, Gengraf®)
Usual Starting Dose
2.5mg/kg q 12 hours
Dose adjustment
By the transplant center based on drug level
9. Adverse Effects of Calcineurin Inhibitors Cyclosporine > Tacrolimus
Hypertension and hyperlipidemia
Gingival hyperplasia, hirsutism
Tacrolimus > Cyclosporine
Hyperglycemia, neurotoxicity, and GI side effects
Alopecia
Tacrolimus ~ Cyclosporine
Nephrotoxicity (?Serum Cr)
Hyperkalemia
Hypomagnesemia
10. Calcineurin Inhibitor Monitoring Drug levels (12-hr trough drug level)
BUN, creatinine, electrolytes, Mg
Blood sugar, lipid profile, blood pressure
CNS toxicity (tremor, headache, seizures)
11. mTOR Inhibitor: Sirolimus (Rapamune®) Typical dose
6-15mg loading dose, then 2-5mg/day maintenance dose (once daily)
Monitoring
24-hr trough level (goal 5-15ng/mL)
Check levels 5-7 days after dose adjustments
Lipid profile, CBC
Dose adjustment
By the transplant center based on drug level
12. Adverse Effects of Sirolimus Hyperlipidemia (cholesterol and TGs)
Hypertension
Thrombocytopenia, leukopenia, anemia
Constipation, diarrhea, nausea
Impaired wound healing
13. Cyclosporine, Tacrolimus, and Sirolimus Interactions Decreased immunosuppressive drug levels by induction of CYP3A4
Antibiotics
Rifampin
Nafcillin
Anti-convulsants
Phenobarbital, phenytoin, and carbamazepine
Herbs
St. John’s Wort
14. Cyclosporine, Tacrolimus, and Sirolimus Interactions Increased immunosuppressive drug levels by inhibition of CYP3A4
Antihypertensives: verapamil, diltiazem
Azole Antifungals: e.g., fluconazole
Antibacterial: erythromycin, clarithromycin
Antiretroviral: ritonavir, nelfinavir
Anti-arrhythmic: amiodarone
Other: grapefruit/ grapefruit juice
15. Complications of Immunosuppression Cardiovascular disease (CVD)
Hypertension
Dyslipidemia
Diabetes
Renal failure Infection
Anemia
Osteoporosis
Malignancy
Gout
16. CVD in Transplant Recipients Prevalence:
Kidney transplant recipient
5 yr risk of CV event with hyperlipidemia: 12%
5 yr CV mortality with hyperlipidemia: 5%
5 yr mortality (all cause): 8 -15%
Heart or liver transplant recipient
5 yr mortality (all cause): 25% 5 yr risk of CV event with hyperlipidemia: ALERT study 12% (cf USRDS 11% at 3 yrs)
5 yr risk of CV event with hyperlipidemia: ALERT study 12% (cf USRDS 11% at 3 yrs)
17. CVD in Transplant Recipients Many patients die of CVD with an otherwise functioning transplant
e.g., 40% of kidney transplant patients die with a functioning kidney 5 yr risk of CV event with hyperlipidemia: ALERT study 12% (cf USRDS 11% at 3 yrs)
5 yr risk of CV event with hyperlipidemia: ALERT study 12% (cf USRDS 11% at 3 yrs)
18. Risk Factors for CVD are Highly Prevalent in Transplant Recipients Prevalence in kidney transplant patients:
Hypertension 80%
Hypercholesterolemia 80%
Diabetes Mellitus 55%
Obesity 30%
Smoking 20%
19. Reasons for Hyperlipidemia in Transplant Recipients Reflects incidence in general population
DM, obesity, lifestyle
Diabetes and atherosclerosis contributes to end organ failure necessitating transplant
Increased incidence of DM after transplantation
Weight gain after organ transplant
Use of prednisone and tacrolimus
Direct effect of immunosuppressive agents
20. Immunosuppressive Drugs Contribute to Hyperlipidemia Increased LDL-C
Cyclosporine > prednisone
Lower HDL-C
Cyclosporine > prednisone
Increased triglycerides
Sirolimus > prednisone
21. Hyperlipidemia in Transplant Recipients Why treat?
Statins are effective in reducing CV mortality
Transplant recipients are at high risk for CV events
What is the data in transplant recipients?
Excluded from large hyperlipidemia trials
Recent randomized prospective studies in transplant pts are just beginning to demonstrate reductions in CV events
22. Management of Hyperlipidemia: NCEP (ATPIII) Guidelines Therapeutic lifestyle changes (TLC)
Diet, weight loss, physical activity
Drug therapy
HMG CoA reductase inhibitors
Bile acid sequestrants
Fibric acid derivatives
Omega 3 fatty acids
23. Management of Hyperlipidemia HMG-CoA reductase inhibitors (statins)–preferred for LDL-C
Low dose pravastatin or simvastatin are generally well tolerated in transplant patients
Increased risk of myopathy & rhabdomyolysis when combined with cyclosporine or tacrolimus
Bile acid sequestrants e.g. cholestyramine
Reduces LDL-C but may increase triglycerides
May interfere with immunosuppressive drug absorption
24. Management of Hyperlipidemia Fibric acid derivatives e.g. gemfibrozil
More effective for hypertriglyceridemia
Avoid combining with a statin in patients on cyclosporine or tacrolimus
Omega 3 fatty acids
Useful for hypertriglyceridemia
Decreased risk of rhabdomyolysis when combined with CSA or tacrolimus
25. Hyperlipidemia Summary Immunosuppressive medications contribute to hyperlipidemia
Transplant recipients should be screened yearly and 2-3 months after changes in therapy that affect lipid levels
NCEP guidelines should be followed as a guide to therapy; transplant recipients should be considered high risk
LDL-C < 100 mg/dl is optimal No randomized studies on cholesterol lowering in organ transplant recipients except ALERT study – transplantation or CKD is an exclusion criteria for hyperlipidemia trialsNo randomized studies on cholesterol lowering in organ transplant recipients except ALERT study – transplantation or CKD is an exclusion criteria for hyperlipidemia trials
26. Hyperlipidemia Summary HMG-Co reductase inhibitors (statins) should be used as first line therapy to lower LDL-C after lifestyle changes
Monitor for myopathy and rhabdomyolysis No randomized studies on cholesterol lowering in organ transplant recipients except ALERT study – transplantation or CKD is an exclusion criteria for hyperlipidemia trialsNo randomized studies on cholesterol lowering in organ transplant recipients except ALERT study – transplantation or CKD is an exclusion criteria for hyperlipidemia trials
27. Risk Factors for Developing HTN in Transplant Recipient Obesity
Ethnicity/Race
Genetics
Immunosuppressive medications
Cyclosporine > tacrolimus, steroids
Preexisting hypertension
Development of renal failure
28. Hypertension in Organ Transplant Recipients Effective antihypertensive treatment
Reduces target organ damage
Decreases cardiovascular events
Promotes long-term allograft and patient survival
29. Management of Hypertension JNC-7 Guidelines
Life style modifications
Diet – including salt reduction
Weight management
Increased physical activity
Moderation of alcohol consumption
Medications
30. Calcium Channel Blockers (CCBs) Dihydropyridine:
amlodipine, felodipine, nifedipine
Non-dihydropyridine:
verapamil, diltiazem
31. CCB Adverse Effects Gingival hyperplasia
Peripheral edema
Decreased heart rate (verapamil & diltiazem)
Increases immunosuppressant drug levels (verapamil & diltiazem)
32. Beta Blockers Cardioselective preferred - metoprolol, atenolol
Beneficial in patients with heart failure or post MI
Adverse effects
Bradycardia
Significant sinus bradycardia or heart block when combined with non-dihydropyridine CCB
May increase bronchospasm
33. ACE Inhibitors (ACEI)/ Angiotension II Receptor Blockers (ARBs) Long acting ACEI preferred
Especially beneficial in:
Patients with heart failure or post MI
Patients with kidney disease and proteinuria
ARBs can be used for ACEI-induced cough
34. ACEI/ARBs Adverse Effects May decrease renal function, especially if renal artery stenosis present
May contribute to anemia
May cause hyperkalemia, esp. with tacrolimus, cyclosporine
ACEI may lead to cough
35. Alpha-1 Blockers Long acting agents preferred
e.g. doxazosin, terazosin
Often used as add-on therapy
Beneficial in patients with BPH
Adverse effects:
First dose hypotension: begin with low dose at bed time
Increased risk for orthostatic hypotension
36. Diuretics Low dose thiazide diuretics preferred
e.g. HCTZ (12.5-25mg)
Beneficial in patients with edema or resistant hypertension
May be ineffective with severe renal disease
Adverse effects:
May cause volume depletion and elevate creatinine, BUN
May cause hypokalemia
37. Hypertension Summary Common in transplant patients
Follow JNC7 guidelines for the mgmt. of HTN, beginning with lifestyle changes
Many will require combination drug therapy
Monitor for side effects and drug interactions
Contact transplant center or hypertension specialist for difficult cases
38. Diabetes Mellitus Increasing in the general population
Diagnostic criteria redefined
Increased obesity
More common after transplant
Immunosuppressive drug therapy
Incidence of new onset diabetes
Renal transplant 4-25%
Liver transplant 2.5-25%
In Hepatitis C patients 40-60%
39. Working Definitions Diabetes mellitus
FPG = 126mg/dL OR
Random plasma glucose level = 200mg/dL and symptoms of diabetes
Impaired fasting glucose (IFG)
FPG = 100mg/dL and < 126mg/dL
40. Risk Factors African American, Hispanic, Native American
Family history
Pre-transplant glucose intolerance
Obesity or presence of other components of metabolic syndrome
Age > 40 years
HCV infection, CMV infection
Immunosuppressant medications
Prednisone, tacrolimus > cyclosporine
41. Consequences of Diabetes Mellitus Infection
Microvascular complications
Neuropathy, nephropathy, retinopathy
Macrovascular complications
CVD
42. Treatment Goals In general, should follow established guidelines
Blood glucose goals
A1c < 7% (not always accurate after blood transfusions, hemolysis, or anemia)
FPG 70-130mg/dL
Postprandial <180mg/dL
Blood pressure <130/80 mmHg
LDL <100mg/dL
43. Treatment Strategies Non-pharmacologic
Counseling on weight control, diet, and exercise
Pharmacologic
Oral or insulin monotherapy
Combination therapy
Altering immunosuppressive regimens (in consultation with the transplant center) Treatment options include adjustment of immunosuppression
May be effective, but insulin necessary in up to 40% of patientsTreatment options include adjustment of immunosuppression
May be effective, but insulin necessary in up to 40% of patients
44. Sulfonylureas (Glipizide, Glyburide) Pros
Does not require injection
Cons
Less effective in patients on high dose prednisone
Risk for hypoglycemia lower with glipizide than glyburide
45. Biguanides (Metformin) Pros
Beneficial in obese patients with insulin resistance
Cons
Increased risk of lactic acidosis with renal impairment
Use with extreme caution in transplant patients, as renal function can change rapidly Cr > 1.4 in females
Cr > 1.5 in malesCr > 1.4 in females
Cr > 1.5 in males
46. Insulin Pros
Allows for tight glucose control
Easy to titrate
NPH insulin’s onset and duration follows blood glucose rise caused by steroids
Cons
Patients have to learn to self inject
Risk of severe hypoglycemia
Often requires multiple injections
Requires intensive blood glucose monitoring
47. Immunosuppressive Alterations by Transplant Center Possible options
Taper or discontinue steroids
Decrease calcineurin inhibitor dose
Change tacrolimus to cyclosporine
48. Diabetes Summary Diabetes is common in the transplant population
Goals for the diabetic transplant patient should follow standard guidelines
Treating diabetes is important for preventing complications & promoting survival
Insulin and glipizide are safe first-line agents for post-transplant patients
49. Vaccines in Solid Organ Recipients: General Principles Transplant recipients are more susceptible to infections, including those that can be prevented by vaccination
Optimal time to vaccinate is before transplantation
After transplantation
Killed vaccines are less effective
Live viral vaccines are contraindicated
50. Vaccines in Solid Organ Recipients: General Principles Seasonal, periodic or booster doses of common killed vaccines should be administered after transplant
Vaccines required for specific risk factors or for travel should be given after consultation with transplant center or ID specialist
51. Inactivated (Killed) Vaccines Inactivated Influenza vaccine
Yearly during influenza season
Pneumococcal vaccine
2 doses with the second dose after 5 yr
Tetanus/Diptheria
Td every 10 years as booster
Tdap should be given once instead of Td if pt hasn’t previously received it AND is <65 yrs
Hepatitis A and B
If not previously immunized
52. Live Vaccines Contraindicated MMR
Nasal influenza
Oral Polio
Oral typhoid
Rotavirus
Varicella
Zoster
Household contacts who receive a live vaccine present a risk to the transplant patient
53. Long Term Health of the Transplant Recipient Optimize length and quality of life for Veterans
Transplant Center focuses on long term immunosuppression and monitoring transplant function
Primary Care Team focuses on preventive healthcare and management of common problems
54. When to Contact the Transplant Center Dysfunction of the transplanted organ
Immunosuppressive drug-related issues
Life threatening infections
Malignancy
Major organ failure
55. VANTS Calls
September 4, 2008October 28, 20081-800-767-1750Access code: 86360#