Adrenal Steroids and Immunosuppressants

Question 1

Mifepristone

Answer 1

Antagonist of Adrenal Steroids
Competitive antagonist at progesterone and glucocorticoid receptor
Termination of pregnancy
Treats Cushing Disease

Question 2

Spironolactone

Eplerenone

Answer 2

Competitive antagonist at mineralocorticoid receptor
Diuretics
Treat hypertension
Cardiac hypertrophy and heart failure

Question 3

Drospirenone

Answer 3

Progesterone receptor agonist–> Used with estrogen to suppress ovulation and as hormone replacement therapy in post menopausal women
Mineralocorticoid receptor antagonist –> diuretic and antagonizes the salt retaining effects of estrogen
Androgen receptor antagonist

Question 4

Prednisolone

Answer 4

Corticosteroid class of immunosuppressant drugs

1. Cell traffic or accumulation- reduce access of cells to target tissue–> lymphocytopenia and monocytopenia with redistribution of cells out of vascular space and prevent neutrophil adherence to endothelium no inhibit action of chemotactic factors
2. Cell function–> interferes with macrophage antigen processing and blocks the actions of lymphokines and inhibits binding to Fc receptors
3. Used in combination with other drugs in autoimmune disease and to prevent graft rejection
4. Toxicity–> suppression of adrenal pituitary axis and acute adrenal insufficiency on abrupt withdrawal and Cushing’s Syndrome
5. Contraindicated with preexisiting infection

Question 5

Cytotoxic Agents Immunosuppresants

Answer 5

In response to antigen the immune cells proliferate in a synchronized manner with a burst of mitotic division which kill rapidly proliferating cells
Best used at initial exposure to antigen
Relevant clone stimulated by antigen will be killed and other immune cells and clones not stimulated so will be spared
Low daily dosage to block immune proliferation continually

Question 6

Azathioprine

Answer 6

Immunosuppresants cytotoxic agent
Metabolized to 6-mercaptopurine
Orally active
Purine anti-metabolite that inhibits purine biosynthesis and inhibits DNA synthesis so inhibits BOTH de novo and salvage pathways
Used to inhibit rejection of transplanted organs and in some autoimmune diseases as rheumatoid arthritis
Bone marrow depression is a major side effect and GI and hepatic toxicity may occur

Question 7

Cyclophosphamide

Answer 7

Immunosuppresant Cytotoxic agents
Alkylating agent results in cross-linking of DNA to kill replicating and non-replicating cells
Toxic effect more pronounced on B-cells so more effective in suppressing humoral immunity
Orally active
Treat autoimmune disease in combination with other drugs but not effective in preventing graft rejection
Bone marrow depression is major side effect

Question 8

Methotrexate

Answer 8

Immunosuppressant cytotoxic agent
Inhibitor of dihydrofolate reductase–> inhibits folate dependent steps in purine synthesis which inhibits DNA synthesis
Used to treat autoimmune disease
Hepatic toxicity

Question 9

Mycophenolate Mofetil

Answer 9

Immunosuppressant cytotoxic agent
Mechanism of action–> IMP dehydrogenase inhibitor so effect on denovo purine synthesis pathways NOT salvage pathway
Selective toxicity for lymphocytes and inhibit proliferation and expression of cells surface adhesion molecules
More selective than Azathioprine or methotrexate but equally effective
Orally active
Used with cyclosporine and corticosteroids to prevent allograft rejection
Use to treat autoimmune diseases
Should be used with caution in patients with active GI disease and reduced renal function and infections
Side effect: infection, leukopenia, anemia
Should not be used in pregnancy

Question 10

Cyclosporine

Answer 10

Immunosuppressant cyclosporine like drugs
A lipophilic peptide antibiotic
Mechanism of action–> binds to cellular receptor (cyclophilin) and inhibits Ca dependent phosphatase (calcineurin) and blocks activation of transcription factor NFAT for IL-2 production so blocks T cell helper function and T cell proliferation band cytotoxicity
Does not alter T cell response to IL-2
Not lymphotoxic so more selective in action
Orally active
Prevent rejection of transplanted organs and more effective with fewer side effects and used in some autoimmune diseases
Side effects: Nephrotoxicity but reduction with dosage change or discontinuation and hepato toxicity may occur

Question 11

Tacrolimus

Answer 11

Cyclosporine like immunosuppressant
Binds the FK binding protein, a cyclophilin related protein and same mechanism of action as cyclosporine
Spectrum of action is same as cyclosporine but 50-100 times more potent
Less nephro and hepato toxicity

Question 12

Sirolimus

Answer 12

Cyclosporine like Immunosuppressant
Inhibits T cell activation and proliferation downstream of IL-2
Binds FKBP12 and this complex does not bind calcineurin or affect the activity but rather binds and inhibits mTOR, a kinase involved in cell cycle progression so blocks the G1–> S phase transition
Same use as cyclosporine and coating of cardiac stents
Side effects: GI disturbance, leukopenia, infection

Question 13

Steroid Drugs

Answer 13

Cortisol 
Dexamethasone 
Prednisolone 
Fludrocortisone
Aldosterone - high mineralocorticoid activity

Question 14

Steroid drugs uses

Answer 14

Adrenal insufficiency 
Rheumatoid arthritis 
Osteoarthritis 
Allergic disease 
Inflammatory disease of eye, ear, skin
Cerebral edema
Shock

Question 15

Metyrapone

Answer 15

Adrenal steroid synthesis inhibitors
Blocks 11-beta hydroxylation so synthesis stopped at 11-desoxycortisol
This does not inhibit ACTH release so plasma ACTH levels increase
ACTH stimulates synthesis and excretion of 17-hydroxycorticoids as 11-desoxycortisol
Diagnostic test but not for pituitary problems