Immunosuppressants

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CHAPTER 25 Immunosuppressants

I. Antiproliferative Antimetabolites

A. Azathioprine (Imuran)

1. Prodrug converted to 6-mercaptopurine
2. Mechanism of action

a. Inhibits purine synthesis, incorporates into DNA as “false” purine
b. Inhibits synthesis and proliferation of T and B lymphocytes

3. Use

a. Renal transplant (adjunct; prophylaxis)
b. Rheumatoid arthritis
c. Inflammatory bowel disease (non-FDA approved)

4. Side effects (after 7–14 days of therapy)

a. Neutropenia
b. Anemia
c. Thrombocytopenia
d. Hepatotoxicity
e. Cholestasis
f. Pancreatitis
g. Infectious disease

5. Adult Dose is initially 3–5 mg/kg per day IV or PO. maintenance 1–3 mg/kg per day PO

a. White Blood Cell count (WBC) 3000–5000 → decrease dose by 50%
b. Dosage in renal failure: Patients with oliguria may have delayed elimination of azathioprine and may require lower doses.

B. Mycophenolate mofetil (CellCept)

1. Prodrug of mycophenolic acid (MPA)
2. Mechanism of action

a. Inhibits purine synthesis
b. Blocks activity of inosine monophosphate dehydrogenase (IMPDH)
c. Inhibits synthesis and proliferation of T and B lymphocytes
d. Minimal effect on cytokine production

3. Side effects

a. Neutropenia
b. Anemia
c. Diarrhea, heart burn, abdominal pain
d. Hypertension
e. Peripheral edema
f. Rash
g. Herpes
i. Hypercholesterolemia
j. Hyperglycemia
k. Hyperkalemia, hypocalcemia, hypomagnesemia
l. Viral infections (CMV)

4. Drug interactions

a. Cyclosporine: ↓ MPA levels
b. Steroids: ↓ MPA levels
c. Tacrolimus: ↑ MPA levels

5. Dose

a. IV 1 g twice daily (liver, kidney) or 1.5 g twice daily (heart)
b. PO 1.5 g twice daily (heart, liver) or 1 g twice daily (kidney)
c. Dosage in renal failure: Patients who had a renal transplantation with severe chronic renal impairment (Glomerular filtration rate [GFR] <25 mL/min/1.73 m2) should not receive doses greater than 1 gram twice a day.

II. Glucocorticoids

A. Mechanism of action

1. Blocks cytokine activation by binding to glucocorticoid response elements

a. Inhibits secretion of Interleukin (IL)-1, IL-2, IL-3, and IL-6, γ-interferon, Tumor Necrosis Factor (TNF)-α

2. Interferes with cell migration
3. Suppresses antibody and complement binding

B. Use: first-line therapy for treatment of acute graft rejection

1. High-dose methylprednisolone: 250–1000 mg daily for 3 days

C. Side effects: immediate (1–3 months)

1. Increased appetite, weight gain, Cushing-like features
2. Sodium and water retention
3. Hypertension
4. Hyperlipidemia
5. Diabetes
6. Acne
7. Hirsutism
8. Cataracts
9. Infections
10. Mood changes

D. Side effects: long-term

1. Osteoporosis
2. Avascular necrosis
3. Growth retardation
4. Skin atrophy

III. Calcineurin inhibitors

A. Cyclosporine (Sandimmune, Neoral, Gengraf)

1. Mechanism of action

a. Inhibits T-cell proliferation; inhibits IL-2 and IL-2–induced activation
b. Binds to cyclophilin, inhibits antigenic response of helper T cells

2. Use

a. Prevention of allograft rejection in solid organ recipients of kidney, liver, or heart
b. Prevention of graft-versus-host disease in bone marrow transplant recipients
c. Management of autoimmune diseases
d. Severe recalcitrant plaque psoriasis in non-immunocompromised adults

3. Hepatic metabolism via cytochrome P-450 (CYP)
4. Side effects

a. Nephrotoxicity (major side effect)
b. Gingival hyperplasia
c. Hypertension
d. Hyperlipidemia
e. Diabetes mellitus
f. Neurotoxicity
g. Alopecia
h. Hyperkalemia
i. Hypomagnesemia
j. Hemolytic uremia syndrome

5. Typical adult dose

a. Various dosing regimens
b. Titrate based on trough levels
c. Sandimmune, Neoral, and Gengraf brands of cyclosporine are not bioequivalent and cannot be used interchangeably.
d. Patients with hepatic insufficiency or renal failure should receive doses at the lower end of the dosing recommendations.

6. Therapeutic drug monitoring

a. Concentration-based rather than dose-based
b. Narrow therapeutic window; range not absolutely defined (general range 100–400 ng/mL)
c. Monitor troughs

B. Tacrolimus (Prograf)

1. More potent than cyclosporine
2. Similar activity to cyclosporine
3. Mechanism of action: Inhibits the activity of calcineurin

a. Reduces production and release of IL-2

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