Immunosuppressants and Hypertension

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Overview

• Immunosuppressive drugs
• Cardiovascular disease hyperlipidemia
• Hypertension
• Diabetes
• Vaccines

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Immunosuppressive Drugs

• Corticosteroids
• Antiproliferative agents
• Azathioprine
• Mycophenolate mofetil (MMF)
• Mycophenolic acid (MPA)

• Calcineurin inhibitors
• Cyclosporine
• Tacrolimus
• mTOR inhibitors
• Sirolimus
• Everolimus

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Mycophenolate Mofetil (Cellcept)

• Prodrug converted to active moiety mycophenolic
  acid (MPA)
• Typical Dose 1000mg BID
• Monitoring CBC, MPA levels /-

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Mycophenolic Acid (Myfortic)

• Enteric coated product that provides active
  moiety
• Typical Dose 720mg BID
• Monitoring CBC, MPA levels /-

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Adverse Effects of MMF MPA

• Gastritis, anorexia, cramping, diarrhea
• Neutropenia, thrombocytopenia, anemia
• Trend toward ? incidence of infections
• CMV, HSV
• Progressive multifocal leukoencephalopathy (PML)
  - rare

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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

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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

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Adverse Effects of Calcineurin Inhibitors

• Cyclosporine gt Tacrolimus
• Hypertension and hyperlipidemia
• Gingival hyperplasia, hirsutism
• Tacrolimus gt Cyclosporine
• Hyperglycemia, neurotoxicity, and GI side effects
• Alopecia
• Tacrolimus Cyclosporine
• Nephrotoxicity (?Serum Cr)
• Hyperkalemia
• Hypomagnesemia

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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)

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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

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Adverse Effects of Sirolimus

• Hyperlipidemia (cholesterol and TGs)
• Hypertension
• Thrombocytopenia, leukopenia, anemia
• Constipation, diarrhea, nausea
• Impaired wound healing

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Cyclosporine, Tacrolimus, and Sirolimus
Interactions

• Decreased immunosuppressive drug levels by
  induction of CYP3A4
• Antibiotics
• Rifampin
• Nafcillin
• Anti-convulsants
• Phenobarbital, phenytoin, and carbamazepine
• Herbs
• St. Johns Wort

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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

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Complications of Immunosuppression

• Cardiovascular disease (CVD)
• Hypertension
• Dyslipidemia
• Diabetes
• Renal failure

• Infection
• Anemia
• Osteoporosis
• Malignancy
• Gout

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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

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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

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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

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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

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Immunosuppressive Drugs Contribute to
Hyperlipidemia

• Increased LDL-C
• Cyclosporine gt prednisone
• Lower HDL-C
• Cyclosporine gt prednisone
• Increased triglycerides
• Sirolimus gt prednisone

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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

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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

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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

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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

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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 lt 100 mg/dl is optimal

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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

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Risk Factors for Developing HTN in Transplant
Recipient

• Obesity
• Ethnicity/Race
• Genetics
• Immunosuppressive medications
• Cyclosporine gt tacrolimus, steroids
• Preexisting hypertension
• Development of renal failure

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Hypertension in Organ Transplant Recipients

• Effective antihypertensive treatment
• Reduces target organ damage
• Decreases cardiovascular events
• Promotes long-term allograft and patient survival

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Management of Hypertension

• JNC-7 Guidelines
• Life style modifications
• Diet including salt reduction
• Weight management
• Increased physical activity
• Moderation of alcohol consumption
• Medications

www.nhlbi.nih.gov/guidelines/hypertension
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Calcium Channel Blockers (CCBs)

• Dihydropyridine
• amlodipine, felodipine, nifedipine
• Non-dihydropyridine
• verapamil, diltiazem

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CCB Adverse Effects

• Gingival hyperplasia
• Peripheral edema
• Decreased heart rate (verapamil diltiazem)
• Increases immunosuppressant drug levels
  (verapamil diltiazem)

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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

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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

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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

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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

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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

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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

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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

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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 lt 126mg/dL

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Risk Factors

• African American, Hispanic, Native American
• Family history
• Pre-transplant glucose intolerance
• Obesity or presence of other components of
  metabolic syndrome
• Age gt 40 years
• HCV infection, CMV infection
• Immunosuppressant medications
• Prednisone, tacrolimus gt cyclosporine

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Consequences of Diabetes Mellitus

• Infection
• Microvascular complications
• Neuropathy, nephropathy, retinopathy
• Macrovascular complications
• CVD

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Treatment Goals
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• In general, should follow established guidelines
• Blood glucose goals
• A1c lt 7 (not always accurate after blood
  transfusions, hemolysis, or anemia)
• FPG 70-130mg/dL
• Postprandial lt180mg/dL
• Blood pressure lt130/80 mmHg
• LDL lt100mg/dL

Diabetes Care 2007 30S4-S41
www.oqp.med.va.gov/cpg/cpg.htm
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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)

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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

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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

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Insulin

• Pros
• Allows for tight glucose control
• Easy to titrate
• NPH insulins 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

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Immunosuppressive Alterations by Transplant Center

• Possible options
• Taper or discontinue steroids
• Decrease calcineurin inhibitor dose
• Change tacrolimus to cyclosporine

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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

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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

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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

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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
  hasnt previously received it AND is lt65 yrs
• Hepatitis A and B
• If not previously immunized

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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

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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

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When to Contact the Transplant Center

• Dysfunction of the transplanted organ
• Immunosuppressive drug-related issues
• Life threatening infections
• Malignancy
• Major organ failure

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• September 4, 2008October 28, 20081-800-767-175
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