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

4. Use

a. Prophylaxis of organ rejection in patients receiving liver transplants
b. Topical treatment of atopic dermatitis
c. Immunosuppressant after kidney transplant
d. May be used as rescue therapy for rejection

5. Highly lipophilic
6. Hepatic metabolism of CYP450 3A4
7. Side effects (similar to cyclosporine)

a. Tremor, insomnia, paresthesia
b. Diarrhea
c. Hyperkalemia, hypomagnesemia

8. Typical adult dose

a. More side effects occur when given IV
b. 0.03 to 0.1 mg/kg/day IV as a continuous infusion or 0.15 to 0.3 mg/kg/day orally, divided and given every 12 hours
c. Doses should be adjusted to maintain trough tacrolimus concentrations of 5 to 20 ng/ml.
d. Convert to oral as soon as possible if the patient is receiving IV administration

9. Converting from cyclosporine to tacrolimus

a. Discontinue cyclosporine 24 hours before starting tacrolimus

10. Therapeutic drug monitoring

a. Early after transplantation
b. Levels correlate with area under the curve concentration (AUC)
c. Target trough: 5–20 ng/mL (10 ng/mL)

C. Sirolimus (Rapamune)

1. mTOR inhibitor
2. Mechanism of action

a. Inhibits delayed T-cell activation by inhibiting signal transduction
b. Blocks response of T and B cells to cytokines

3. Use

a. Renal transplant
b. Combination use with cyclosporine and prednisone; withdrawal protocol in low-risk patients

4. Half-Life (T½): 60 hours; time to reach steady state is 12 days
5. Drug interactions (similar to cyclosporine)

a. CYP 3A4

6. Adverse effects

a. Similar to cyclosporine (less nephrotoxicity)
b. Infections (e.g., herpes simplex virus [HSV])
c. Peripheral edema
d. Hypertriglyceridemia
e. Hypertension
f. Hypersensitivity reactions
g. Thrombocytopenia
h. Constipation, abdominal pain, diarrhea, nausea

7. Typical adult dose

a. Dose of 6 mg PO (loading) followed by 2–5 mg/day (maintenance)
b. Give 4 hours after morning dose of cyclosporine

8. Therapeutic drug monitoring

a. Every 5–7 days

9. Avoid with voriconazole, a potent CYP 3A4 inhibitor, which may ↑ sirolimus levels

IV. Antilymphocyte globulins

A. Lymphocyte immune globulin (Atgam)

1. Typical adult dose ~15 mg/kg per day
2. Side effects

a. Headache
b. Fever
c. Chills
d. Nausea
e. Serum sickness
f. Acute renal failure
g. Acute respiratory distress syndrome
h. Injection site reaction
i. Hemolytic anemia
j. Cytokine release syndrome (CRS) – may limit reaction by use of required premedication; slow infusion

B. Antithymocyte globulin [rabbit] (Thymoglobulin)

1. Typical adult dose 1.5 mg/kg per day
2. Side effects

a. Fever
b. Hyperkalemia
c. Hypertension
d. Leukopenia
e. Peripheral edema
f. Shivering
g. Cytokine release syndrome (CRS) may limit reaction by use of required premedication; slow infusion

3. Benefits

a. Decreases and delays the onset of acute rejection
b. Delays introduction of calcineurin inhibitors
c. Predictable suppression of T cells
d. Better tolerated than Atgam

4. Risks

a. CMV infections and malignancy risks comparable to Atgam
b. Serum sickness
c. Thrombocytopenia
d. First-dose reactions: “shake and bake”
e. Prevention medications: steroids, acetaminophen, antihistamine

V. Monoclonal Antibodies

A. Daclizumab (Zenapax)

1. Humanized monoclonal antibody (mAb)
2. Mechanism of action: block alpha unit of IL-2 receptor on activated T cells; inhibits IL-2 binding and IL-2 activation
3. Dose 1 mg/kg per dose
4. Side effects: well tolerated, anaphylaxis

B. Basiliximab (Simulect)

1. Chimeric mAb
2. Mechanism of action: block alpha unit of IL-2 receptor on activated T cells; inhibits IL-2 binding and IL-2 activation
3. Dose 20 mg per dose
4. Side effects: well tolerated, anaphylaxis

C. Muromonab CD-3 (OKT3)

1. Murine mAb
2. Dose 2.5–5 mg/day
3. Side effects

a. CRS “shake and bake” (fevers and chills)

PATIENT PROFILE

Patient Initials: DR
Sex: Male
Age: 33
Height: 5′ 9″
Weight: 74 kg
Race: Caucasian
Allergies: No known drug allergies (NKDA)
Current Health Conditions:
Hypercholesterolemia
Hypertension
Kidney transplantation 2 years ago, secondary to familial kidney disease
Pharmacy Medication Profile:
Lipitor 20 mg PO once daily
Procardia XL 90 mg PO qam
Neoral solution 185 mg PO twice daily
Prednisone 40 mg PO once daily
Prilosec 20 mg PO once daily

PATIENT PROFILE QUESTIONS

1. What is/are common side effects of treatment with Neoral?

I. High blood pressure
II. Renal toxicity
III. Anemia and neutropenia
a. I only
b. II only
c. I and II
d. I and III
e. II and III
f. I, II, and III

Answer: c. Cyclosporine has no effects on red blood cell counts or on white blood cell counts. Cyclosporine inhibits T-lymphocyte proliferation for its immunosuppressant effect. Hypertension and a potential for nephrotoxicity are commonly recognized side effects; hypertension often requires medical management in these patients.

2. The Prilosec prescription is going to be therapeutically substituted with an H2 antagonist on the family practice clinic formulary. Which of the following would be an appropriate choice for DR?

I. Tagamet
II. Pepcid
III. Zantac
a. I or II
b. II or III
c. I, II, or III

Answer: b. Although all the drugs listed are in the H2 antagonists class of medications, Pepcid (famotidine) and Zantac (ranitidine) are the safest to give to DR due to a lack of drug interactions with his prescribed immunosuppressant drugs. Tagamet (cimetidine) exhibits many drug interactions with medications metabolized by hepatic cytochrome P450 isoenzymes and would not be a good choice for a patient stabilized on important medications to prevent transplantation rejection.

3. What are points that should be included in counseling a patient on appropriate Neoral administration?

I. Take doses at the same time each day, with consistent intervals between doses.
II. Do not take Neoral with grapefruit juice.
III. Mixing the solution in milk will help it taste better.
IV. The solution should be refrigerated.
a. I only
b. III only
c. I and II
d. II and IV
e. I, II, III, and IV

Answer: a. Neoral should not be stored in a refrigerator. It is okay to mix Neoral in apple or orange juice at room temperature, but mixing in milk will result in an unpalatable taste. Doses are usually given twice daily and should be spread 12 hours apart and at consistent times of day each day. Grapefruit juice interacts with Neoral and this juice should be avoided.

REVIEW QUESTIONS

(Answers and Rationales on page 381.)

1. Which of the following is considered an immunosuppressant?

I. Sirolimus
II. Cyclosporine
III. Demeclocycline
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

2. Which of the following is an adverse effect(s) associated with cyclosporine?

a. Nephrotoxicity
b. Hyperlipidemia
c. Gingival hyperplasia
d. Hypertension
e. All of the above are adverse effects.

3. Which of the following statements about cyclosporine are true?

I. It inhibits T cell proliferation.
II. It has a narrow therapeutic window although the range is not absolutely defined.
III. Sandimmune, Neoral, and Gengraf brands of cyclosporine are bioequivalent and may be used interchangeably.
a. I only
b. III only
c. I and II only
d. II and III only
e. I, II, and III

4. The mechanism of tacrolimus is similar to that of:

a. cyclophosphamide.
b. cycloserine.
c. cyclosporine.
d. All of the above
e. None of the above

5. Which of the following are potential benefit(s) of using Thymoglobulin?

I. Better tolerated than ATGAM
II. Predictable suppression of T cells
III. The incidence of CMV infections less than ATGAM
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

6. Azathioprine may be used for which of the following?

I. Renal transplant (adjunct)
II. Rheumatoid arthritis
III. Inflammatory bowel disease
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

7. Which of the following are potential adverse effect(s) with methylprednisolone?

a. Weight gain
b. Cataracts
c. Osteoporosis
d. Growth retardation
e. All of the above

8. Which of the following statements about tacrolimus (Prograf) are true?

I. It is highly lipophilic.
II. Target trough is between 5–20 ng/mL.
III. It is metabolized by CYP 3A4.
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

9. Which of the following statements about the mechanism of mycophenolate mofetil are true?

a. It inhibits purine synthesis.
b. It has minimal effect on cytokine production.
c. It blocks activity of inosine monophosphate dehydrogenase (IMPDH).
d. It inhibits synthesis and proliferation of T and B lymphocytes.
e. All of the above are true.

10. Which of the following drugs is associated with hypertension?

a. Cyclosporine
b. Indapamide
c. Prazosin
d. None of the above
e. All of the above

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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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