L26 Drugs used in immune disorderss →↑↓

Question 1

Maintenance immunosuppression

Answer 1

combinations of immunosuppressive agents.
Example
1. cyclosporine
2. azathioprine
3. glucocorticoid

→minimize side-effects of any single drug

Question 2

Limitations of immunosuppressive therapy

Answer 2

Increased risk of infections with uncommon pathogens (e.g. cytomegalovirus)

Increased risk of lymphomas and related malignancies

Others including hepatotoxicity, renal toxicity
and pulmonary edema.

Question 3

Name of immunosuppressant (microbial products)

Answer 3

Cyclosporine
Tacrolimus
Sirolimus

Inhibitors of cytokine production and function

Question 4

MoA , adverse effect of Cyclosporine

Answer 4

first line therapy in prophylaix and treatment of transplant rejection

combined in a double-drug or triple drug regimen with corticosteroids and antimetabolites

an alternative for treatment of severe autoimmune disease that does not respond to other therapies such as rheumatoid arthritis and recalcitrant psoriasis

MoA
binds to a cytoplasmic receptor protein called (CpN) cyclophilin
→ inhibits calcineurin (CaN) phosphatase
→→ prevents activation of nuclear factor (NFATc)
→→→ inhibits synthesis of IL-2 which is critical for T-cell mediated immunity

Adverse effects:
nephrotoxicity
infections
viral infection due to herpes group
lymphoma
hypertension, hyperkalemia, tremor, glucose interolerance and gum hyperplasia

Question 5

MoA, adverse effect of Tacrolimus

Answer 5

10-100 fold more effective than cyclosporine, thus lower doses of corticosteroids can be used

given with corticosteroids
and/or an antimetabolite

MoA:
binds to FKBP (FK-binding protein)
→ inhibits calcineurin
phosphatase
→→ prevents activation
of nuclear factors
→→→ inhibits synthesis of
IL-2 in T-cells

Adverse effect:
→more severe nephrotoxicity and neurotoxicity
(tremor, seizures, and hallucinations) than cyclosporine

→development of posttransplant insulin-
dependent diabetes mellitus
lower incidence of cardiovascular toxicities such
as hypertension and hyperlipidemia

cyclosporine & tacrolimus share a mechanism of action and metabolic route - never given together (additive nephrotoxicity)

Question 6

MoA, adverse effect and drug interaction of Sirolimus

Answer 6

together with cyclosporine /
tacrolimus and corticosteroids for
kidney / heart transplantation

MoA
→ binds to the cytoplasmic FK- binding protein, but interfering with mTOR signal (a serine- threonine kinase controlling T-cell proliferation)
→→blocks the ability of T-cells to proliferate in response to IL-2 stimulus

adverse effects: hyperlipidemia (important), leukopenia,
thrombocytopenia and infection

drug interactions:
sirolimus aggravates cyclosporine-induced renal dysfunction, while
cyclosporine increases sirolimus-induced hyperlipidemia

Question 7

Name of Antimetabolites and Cytotoxic agents

Answer 7

Azathioprine

Mycophenolate mofetil

Cyclophosphamide

Question 8

MoA and Adverse effect of Azathioprine

Answer 8

a prodrug

MoA
→converted to 6 -mercaptopurine
and then to a nucleotide
analogue, 6-thioinosinic acid →blocks the de novo purine
synthesis in lymphocytes.

Major side effect
myelosuppression
increased risk of cancer, and
GI irritation.

In patients receiving allopurinol, the xanthine oxidase inhibitor, the dose needs to be decreased by 75
percent for avoiding accumulation of the drug.

in combination with
corticosteroids and cyclosporine or tacrolimus for kidney transplantation and autoimmune disorders, such as hemolytic anemia

Question 9

MoA and Adverse effect of Mycophenolate mofetil

Answer 9

used in combination with corticosteroids and
the calcineurin inhibitors, cyclosporine or tacrolimus

MoA
→rapidly hydrolyzed in the
gastrointestinal tract to mycophenolic acid (MPA), which inhibit inosine monophosphate dehydrogenase

→blocking de novo formation of guanosine phosphate, thus depriving T
and B cell of a key component of nucleic acids

Adverse effects
most common adverse effects include
→diarrhea, nausea, vomiting, abdominal pain, leukopenia, and anemia

Question 10

MoA and Adverse effect of

Cyclophosphamide

Answer 10

→an anti-neoplastic drug

→activated by cytochrome P450

→for treatment of autoimmune diseases including hemolytic anemia, systemic lupus erythematosus (SLE), rheumatoid arthritis, and
organ transplantation

Question 11

Name, MoA and adverse effect of Polyclonal & Monoclonal antibodies

Answer 11

→Antithymocyte globulins
→→mediate antibody-dependent cytotoxicity
→→Antibody-bound cells are depleted in liver and spleen
→→→Adverse effects include chills and fever, leukopenia,
thrombocytopenia, infections, and skin rashes

→IL2 receptor antagonists,
daclizumab/basiliximab
→monoclonal antibodies, e.g. basiliximab and daclizumab, which are anti-CD25 antibodies and bind to the α chain of the IL-2 receptor on activated T cells
→→inhibit IL-2 mediated T-cell activation and proliferation

→induction therapy in transplantation, not used
for the treatment of ongoing rejection

→effective in decreasing the incidence of acute rejection

→→given intravenously; very well tolerated, virtually no
side effects

Question 12

Name, MoA and Adverse effect of Corticosteroids

Answer 12

prednisone or methylprednisolone

→inhibit cytokine production by T cells and macrophages,
→→disrupting T cell activation and macrophage-
mediated tissue injury.
→→→This effect is mediated through inhibition of nuclear factor kappa B activation and by binding to glucocorticoid response elements in the promoter regions of cytokine genes.

effective in suppressing both acute rejection and in chronic graft-versus-host disease, as well as autoimmune diseases

Adverse effects :
diabetogenic, hypercholesterolemia, cataracts, osteoporosis,
and hypertension.