Immunosuppressive Therapy

Question 1

Immunosuppressive Drug

Answer 1

A drug used to prevent the production of antibodies
One primary use is in the field of organ transplants
Immunosupprissive drugs prevent transplanted organs from being rejected by the recipient
Also used to treat graft-versus-host-disease
The other area where these drugs are used is to treat autoimmune disorders

Question 2

Calcineurin Inhibitors

Answer 2

Cyclosporine
Lipophylic cyclic peptide of 11 AA
Isolated from a fungi

Tacrolimus
Macrolide antibiotic
isolated from fungus
MOA similar to cyclosporine

Question 3

Calcineurin Inhibitors MOA

Answer 3

both bind with cytoplasmic proteins
drug protein complex specifically inhibits calcineurin (calcium &calmodulin dependent phosphate)
causes reduced transcriptional activity for IL-2, TNF alpha and granulocyte macrophage colony-stimulating factor
# of T lymphocytes is reduced!!!
T cell dependent B cell responses are inhibited
Immune response decreased

Question 4

Cyclosporine administration

Answer 4

IV
Oral
Opthalmic formulations available
Initially given IV because it is variably & incompletely absorbed orally
Opthalamic preperation used for keratoconjunctivitis sicca

Question 5

Cyclosporine use

Answer 5

For solid organ transplant, GVHD and several autoimmune diseases (RA)
Toxic!–generally not used as 1st line agent

Question 6

Cyclosporine SE

Answer 6

Nephrotoxicity: most common/concerning
HTN-use Ca2+ channel blockers fro treatment
Neurotoxicity: mild tremor, HA/seizures, blindness
Infection: viral (CMV) and fungal common
Benign and malignant lymphoproliferative disease
Others: hyperkalemia, hypomagnesemia, glucose intolerance, hyperuricemia

Question 7

Cyclosporine Monitoring Parameters

Answer 7

renal function
BP
Serum electrolytes and magnesium
LFT (may elevate bilirubin)

Question 8

Tacrolimus

Answer 8

IV, oral and topical prep
Use: for prevention of organ rejection (with availability for newer agents w/ less toxicity use has declined)
Used w/ methotrexate for prevention of acute GVHD
Topical preparations used for severe, plaque, psoriasis and severe atopic dermatitis

Question 9

Tacrolimus SE

Answer 9

Nephrotoxicity:
Neurotoxicity-HA, tremors, paresthesias, coma
HTN
Pulmonary–dyspnea
GI–N/V diarrhea, abd discomfort
Fatigue
Other: hyperkalemia, hypomagnesemia, hyperglycemia

Question 10

Tacrolimus Monitoring Parameters

Answer 10

Renal function
Electrolytes and magnesium
BP
Fasting blood glucose
Tacrolimus levels

Question 11

Sirolimus

Answer 11

Macrolide antibiotic struct similar to tacrolimus but not an inhibitor of calcineurin
Sirolimus binds to intracellular proteins and Inhibits Growth of Hematopoietic and lymphoid cells
2nd line Agent for use in combination with other immunosuppressive agents for phrophylactic organ rejection

Question 12

Sirolimus SE

Answer 12

GI: N/V, diarrhea, elevation of LFTs
Hypertriglyceridemia
Throbocytopenia
Leucopenia
BP changes
HA, mucous membrane irritation, infx, epistaxis
Nephrotoxicity (not often encountered)
THROMBOCYTOPENIA & NEUTROPENIA dose limiting toxicity

Question 13

Prednisolione MOA

Answer 13

Glucocorticoids: diffuse across cell membrane

bind to specific receptors then enter the nucleus and interacts w/ DNA

Question 14

Prednisolone MOA cont

Answer 14

antiinflammatory effectsL inhibts production of most cytokines and proinflamm mediators

Inhibits innate immunity by suppressing phagocytic function of neutrophils and macrophages
causes neutrophilic leukocytosis
decreases number of circulating T cells
w/ chronic admin decreases IgG and IgA

Question 15

Prednisolone uses

Answer 15

undesirable immunological 
Prophylaxis for prevention of rejection of a transplanted organ in a recipient
Autoimmune diseases
Inflammatory disorders
Allergic conditions
Malignancies

Question 16

Prednisolone SE

Answer 16

related to dosage and more common for long term therapy
Skin and thinning and purpura (bleeding underskin)
Cushingoid appearance/ wt gain
Cataracts and glaucoma
HTN 7 Hyperlipidemia leading to atherosclerosis
GI: gastritus, ulcers, may initially increase appetite

Question 17

Prednisolone

Answer 17

Osteoporosis
Neuropsychiatric
Initailly may cause euphoria/insomnia
May lead to depression and mania or psychosis
Hyperglycemia leading to development of DM
Hypothalamic pituitary adrenal insufficiency
Heightened risk of typical and opportunistic infection

Question 18

Prednisolone Monitoring Parameters

Answer 18

BP
CMP
Lupids
Long Term
   Opthalamic exam
    DEXA scan

Question 19

Azathioprine (Imuran)

Answer 19

Class: antimetabolite
MOA: acts as a purine antagonist and inhibits the sythesis of proteins, RNA and DNA
Clinical uses
   Immunosupression in renal homografts
   Autoimmune disease (SLE, RA)

Question 20

Azathioprine SE

Answer 20

Fever
Nausea
Bone marrow supression
Hepatotoxicity (diagnosis of exclusion)
Skin cancer

Question 21

Azathioprine Monitoring Parameters

Answer 21

CBC w/ platelet counts initially weekly

• If significant neutropenia occurs the drug is held until the WBC count has risen
• Rare, persistant or recurrent neutropenia then azithioprine has to be discontinued

LFTs total bilirubin and alkaline phosphatase

Question 22

Cyclophosphamide MOA

Answer 22

alkylating agent
MOA: one of the most potent immunosuppressive therapies
Inhibits DNA sythesis by binding and damaging DNA itself
Able to damage DNA in any phase of the cycle although preferes highly dividing cells

Question 23

Cyclophosphamide uses

Answer 23

Treating leukemias and lymphomas
Others: severe glomerulonephritis
Rheumatoid vasculitis and other types of systemic vasculitis
Given intermittently or as a daily dose

Question 24

Cyclophosphamide SE

Answer 24

Severe N/V
Myelosuppression
Hemorrhagic cystitis
Hepatitis
Cardiac Damage
Pulmonary fibrosis
Development of opportunistic infx
Development of later malignancies

Question 25

Cyclophosphamide Monitoring parameters

Answer 25

Frequent CBCs with a differential (lymphopenia more concerned w/ neutropenia)
Renal function including a UA to check for
LFTs
After off CYC annual UA and if hematuria either gross or microscopic occurs need to have cystoscopy

Question 26

Cyclophosphamide (CYC) and the Bladder

Answer 26

One of the metabolites of CYC is acrolein
Acrolein is toxic to the human bladder it can cause:
Hemorrhagic cystitis
Bladder cancer (even long after treatment)
Risk of acrolein toxicity can be reduced by:
Adequate hydration
Concordant administration of MESNA (sodium 2-mercaptoethane sulfonate