Module 9: Immunomodulating Agents (Immunopharmacology)

Tasks
Study tip: For each chapter, read "Special Concerns for Rehabilitation Patients" and "Case Study" prior to chapter content. Answer the
case study questions while you read the chapter, then compare your answers to Appendix C.
Ch. 37 (Immunomodulating Agents)

Medication Cabinet
azathioprine (Imuran)
cyclophosphamide (Cytoxan, Neosar)
cyclosporine (Neoral)
prednisone (Deltasone)
dexamethasone (Decadron)
methylprednisolone (Medrol)
methotrexate (Rheumatrex)
tacrolimus (Prograf)
immune globulin (Gamimune)

Select the 2 other modules in which cyclophosphamide, prednisone, and methotrexate all appear.
Cancer Chemotherapy, immunomodulating Agents, and Pain Medications
Assessment
Immunomodulating Agents module is included in Examination 2 on Dec. 8. Practice questions are available.

Learning Objectives
1. Identify clinical indications for immunosuppressive agents vs. immunostimulants.
1. Immunosuppressive agents
1. Prevention or treatment of transplant rejection
1. Azathioprine (Imuran)- primary action (especially kidney)
1. Kidney, heart, liver, pancreas
2. Cyclophosphamide (Cytoxan, Neosar)
1. Bone marrow; other organ transplants
3. Cyclosporine (Neoral)- Primary action
1. Kidney, liver, heart, lung, pancreas, bone marrow
4. Tacrolimus (Prograf)
1. Liver, kidney, heart, lung, pancreas
5. Glucocorticoids: Prednisone (Deltasone); Dexamethasone (Decadron); Methylprednisolone (Medrol)
1. Heart, kidney, liver, bone marrow
2. Diseases that have an autoimmune response (RA, DM, myasthenia gravis, SLE, scleroderma, polymyositis/
dermatomyositis)
1. Azathioprine (Imuran)
1. RA; IBS; myasthenia gravis; systemic lupus erythematosus (SLE); dermatomyositis,
inflammatory myopathy, hepatic disease, ulcerative colitis
2. Cyclophosphamide (Cytoxan, Neosar)
1. RA; multiple sclerosis; SLE; dermatomyositis; glomerulonephritis; hematologic disorders
3. Cyclosporine (Neoral)- not used this way as much
1. Psoriasis; RA; glomerulonephritis, IBS, and autoimmune hepatitis
4. Tacrolimus (Prograf)
1. Uveitis
5. Methotrexate (Rheumatrex) (not indicated for prevention or treatment of transplant rejection)
1. RA, psoriasis
6. Glucocorticoids: Prednisone (Deltasone); Dexamethasone (Decadron); Methylprednisolone (Medrol)
1. MS; RA; SLE; IBS; hemolytic disorders; others
2. Immunostimulants
-beneficial in patients with compromised immune function (such as those with AIDS or certain cancers) or chronic infections
1. Immune globulin (Gamimune)
1. Boost immune function in several conditions, including primary immunodeficiency syndromes
(congenital agammaglobulinemia, common variable immunodeficiency, and severe combined
immunodeficiency), idiopathic thrombocytopenic purpura, Kawasaki disease, chronic lymphocytic
leukemia, and HIV infection in children
2. Other possible indications include dermatomyositis, Guillain-Barre syndrome, demyelinating
polyneuropathies, Lambert-Eaton myasthenia syndrome, and relapsing-remitting multiple sclerosis
2. Explain mechanisms of action and adverse effects for specific immunomodulating agents.
1. azathioprine (Imuran)
1. MOA: probably interferes with DNA synthesis in cells mediating the immune response (acts like
antimetabolic drugs in cancer)
1. Structurally similar to purines which are endogenous substances the cell normally uses (so it acts
as a false ingredient that competes with the naturally occurring substances to slow down and
disrupt DNA synthesis
2. Impaired nucleic acid synthesis slows down the replication of lymphocytes and other substances
that direct the immune response
1. Azathioprine directly limits the cellular proliferation through this inhibitory effect on DNA
synthesis and ultimately limits the production of humoral components (antibodies)
produced by these cells
2. AE: related to suppression of bone marrow function, including leukopenia, megaloblastic anemia, and similar
blood dyscrasias
1. Others include skin rash and GI distress (appetite loss, N/V); hepatic dysfunction (at high doses)
2. cyclophosphamide (Cytoxan, Neosar)- anticancer alkylating agent
1. MOA: causes the formation of strong cross-links between strands of DNA and RNA thus inhibiting DNA/RNA
replication and function in lymphocytes and other key cells, thus limiting the rapid proliferation of these cells
during the immune response- treats transplants, and autoimmune response of uveitis
2. AE: carcinogenic effects during long term use
1. Others include hematologic disorders (leukopenia, thrombocytopenia), cardiotoxicity,
nephrotoxicity, and pulmonary toxicity
3. cyclosporine (Neoral)- calcineurin inhibitor
1. MOA: inhibit calcineurin in lymphoid tissueàultimately suppresses T-cell activation, thus limiting the ability of
T cells to produce other chemical mediators that promote immune cell activity
1. Cyclosporine is one of the premier immunosuppresants because it is relatively selective for T cells
and its inhibition of a key component of the immune response
2. AE: nephrotoxicity (can range from mild, asymptomatic cases to severe kidney dysfunction); hypertension,
neurotoxicity; gingival hyperplasia; hair growth (hirsutism), and increased infections (these tend to be less
severe with cyclosporine than with other less-selective immunosuppressants
4. Glucocorticoids: Prednisone (Deltasone); Dexamethasone (Decadron); Methylprednisolone (Medrol)
1. MOA: probably interrupt the immune response by a complex effect on the genomic level of various cells
1. Drugs enter immune system cells where they bind to cytoplasmic receptors
2. This drug-receptor complex then migrates to the cell’s nucleus, where it acts directly on specific
immunoregulatory genes (influence the expression of cytokines and other chemicals that
orchestrate the immune response
1. They inhibit the transcription of mRNA units that normally translate into immunostimulatory
signals, such as interleukin-1, gamma interferon
2. These signals activate the cells responsible for mediating the immune response
1. These drugs disrupt the production of chemical signals that activate and control
various immune system cellular components
2. AE: produce catabolic effect on collagenous tissues, and breakdown of muscle, bone, skin
1. Hypertension, adrenocortical suppression, growth retardation in children, an increased chance of
infection, glaucoma, decreased glucose tolerance, and gastric ulcer
5. methotrexate (Rheumatrex)- DMARD
1. MOA: antimetabolic that interferes with production of DNA and RNA precursors in rapidly proliferating cells
1. This interference produces a general inhibition of the replication of lymphocytes inherent in the
immune response
2. AE: hepatic and pulmonary toxicity (dose-related) and serious adverse effects occur less frequently as
doses used for immunosuppression than for those used for anticancer treatment
6. tacrolimus (Prograf)- calcineuin inhibitor
1. MOA: acts like cyclosporine by binding to a specific protein (calcineurin) in lymphoid tissues and ultimately
inhibiting the production of key cytokines such as IL-2 which promotes the growth and proliferation of
activated T lymphocytes and other immune cells, such as NK cells
1. This binding provides selective inhibition of immune function that other drugs that exert a general or
nonselective inhibition of immune response
2. AE: GI disturbances (cramps, nausea, diarrhea, constipation), weakness, fever, and skin rashes and itching
1. More serious include renal and CNS toxicity (headache, anxiety, nervousness, seizures)
2. Also associated with problems with glucose metabolism (hyperglycemia, glucose intolerance) and
can cause DM
7. immune globulin (Gamimune)
1. MOA: mimic normal role of endogenous immunoglobulins
1. Directly act as antibodies against infectious agents
2. Can also help modulate the activity of T lymphocytes, macrophages, and other immune system
cells to maintain immune system competence
3. Primary Indication: Prevention of Rh hemolytic disease of the newborn
2. AE: joint and muscle pain, headache, general malaise, and GI disturbances; care must be taken to prevent
transmission of HIV and hepatitis from infected donors; allergic reactions, including anaphylaxis
3. Identify lab values that are important to monitor for patients who take immunomodulating agents.
1. azathioprine (Imuran)
1. CBC including platelet count
-leukopenia- decreased leukocytes (< 5000/ml)- normal is 4500-11,000
-megaloblastic anemia- RBC decreased in anemia (normal is 4.5-5.3)
-Hgb- normal- male= 14-18; female= 12-16 (decreased levels < 8)
-Hgb for anemia; male < 13.5; females < 12
-Hematocrit (normal= males= 37-49 men; 36-46 female)- decreased in anemia (<25% means no exercise)
-Sedimentation rate- normal= male 0-17; female= 1-25 (increased ESR means there is inflammation somewhere in body)
-hepatic failure- hepatic function panel
-serum bilirubin- 0.1-1.0 mg/dl normal (increased with cirrhosis, hepatitis, hemolytic anemia, transfusion reactions)
-serum albumin- 3.5-5.5 g/dl normal (decreased with liver damage)
-total serum protein- 6-8 g/dl normal (decreased in liver damage)
-AST- 8-20 U/L (increased with liver damage)
-ALT- 5-25 U/L normal (increased with liver damage)
-alkaline phosphatase- 30-85 U/L is normal (increased with liver problem)
-thrombocytopenia= platelet count less than 150,000
-also coagulation profile- Platelet count: normal = 150,000-400,000 cells/mm (<20,000= no activity)
-INR- 0.9-1.1 = normal (2-3 therapeutic range for pt on warfarin) >3= no exercise
-PT- 12-15 sec is normal (therapeutic range is 1.5-2.5 x normal)- prolonged in liver damage, intake of warfarin
-aPTT- 30-40 sec is normal (therapeutic level 2-2.5 times normal)- prolonged in disease
2. cyclophosphamide (Cytoxan, Neosar)
1. hematologic profile (leukopenia and platelets) to determine degree of hematopoietic suppression
-leukopenia- decreased leukocytes (< 5000/ml- no exercise)
-thrombocytopenia= platelet count less than 150,000
2. urine should be analyzed for red blood cells which may precede hemorrhagic cystitis
RBC- hematuria- presence of RBC in urine is bad
-nephrotoxicity- increased BUN (normal is 10-20) and increased creatinine (normal is male= 0.6-1.2; female= 0.5-1.1)
3. cyclosporine (Neoral) and tacrolimus
1. renal and liver function should be assessed
1. serume creatinine (if increases greater than 50% above pretreatment level), BUN, serum bilirubin,
and liver enzymes should be monitored
2. Blood concentrations should be routinely monitored in transplant patients and periodically in RA
4. tacrolimus (Prograf)
1. hyperglycemia- monitor BG levels- normal is 70-100 mg/dl; Hemoglobin A1C (normal= 4-6%; anything more is bad)
2. renal toxicity- BUN and serum creatinine
5. methotrexate (Rheumatrex)
1. CBC including differential and platelet, hepatic enzymes, renal function tests and chest x-ray
-WBC differential
-neutrophils (1800-7000 is normal with 50-60 differential)
-neutropenia is decreased levels (<1500)
-lymphocytes (1500-4000 is normal with 30-40 differential)
-renal function- BUN and serum creatinine
-hepatic enzymes- AST, ALT,
-LDH- normal= 45-90 U/L (increased with disease)
-GGH (5-38 is normal- elevated with liver disorder)
-alkaline phosphatase (30-85 is normal- disease increases it)
6. immune globulin (Gamimune)

4. Describe precautions and modifications to PT management of patients who are immunocompromised.

1. Musculoskeletal disorders
2. Catabolic effects of glucocorticoids
3. Cyclosporine and tacrolimus are neurotoxic and can cause peripheral neuropathies and CNS-related problems in
balance and posture
4. Rehab management
1. Institute strengthening and general conditioning exercises to prevent breakdown of muscle, bone, other
tissues, as well as maintain cardiovascular function
2. Problems associated with peripheral neuropathies such as pain and weakness may respond to TENS and
other electrotherapeutic stimulation
3. Balance and gait training may help patients overcome problems caused by CNS toxicity and vestibular
problems