Immunopharm: Glucocorticoids, Calcineurn inhibitors, Proliferation Signal Inhibitors, inhibitors of Angiogenesis

Question 1

What are immunosupressive drugs used for?

Answer 1

Dampen the immune response in organ transplantation and auto-immune disease

Question 2

The first immunosupressive agent are Glucocorticoids. What is their MOA?

Answer 2

Steroid Hormones

• -act by binding to the cytosolic glucocorticoid receptor
• -the glucocorticoid-glucocorticoid receptor complex translocates to the nucleus and binds to the glucocorticoid response elements in the promoter region of specific genes

Question 3

The overall effect of glucocorticoid administration is anti-inflammatory and immunosupressive. What is the MOA for this?

Answer 3

Down regulate the expression of
–cytokines: TNFalpha, IL-1 and IL-4
Suppress eicosanoid biosynthesis

Question 4

Glucocorticoids inhibit prostaglandin synthesis and therefore suppress inflammatory pathways. There are three mechanisms, each card will go through one. The first is induction of annexin I, explain this

Answer 4

Induce synthesis of annexin I

–anti-inflammatory protein that inhibits cytosolic phospholipase A2 (blocks the release of arachidonic acid)

Question 5

The second mechanism for glucocorticoids is induction of MAPK phosphatase 1, explain

Answer 5

Induce MAPK phosphatase I

–dephosphorylates and inactivates MAPKs therefore inhibiting proinflammatory signaling pathways

Question 6

The third mechanism for glucocorticoids is repression of transcription of cyclooxygenase 2, explain

Answer 6

NF-kB is a transcription fact that stimulates transcription of cytokines and chemokines as well as COX2
–glucocorticoids inhibit NF-kB therefore reducing COX2

Question 7

What are adverse effects of glucocorticoids?

Answer 7

Short term administration: HTN, hyperglycemia, immunosuppression, psychotic reactions and cognitive impairment
Long term administration: osteoporosis, weight gain, fluid retention, cataracts, poor wound healing, gastric ulcers, GI bleeding, hyperglycemia, HTN, adrenal suppression and increased risk of infection

Question 8

What are the uses of glucocorticoids?

Answer 8

Prevent and treat transplant rejection
–most commonly used are prednisone and methylprednisolone
Treat Autoimmune Disorders (RA, SLE and so on)
–prednisone and prednisolone
Alleviate symptoms such as pain, nausea, anorexia, and malaise and improve quality of life (palliative care)
Can be used for pain
–dexamethasone is preferred for cancer pain due to long half life

Question 9

Next set of drugs are the calcineurin inhibitors. The first drug is cyclosporine. What is the primary use?

Answer 9

Organ transplant
Uveitis
RA
Psoriasis

Question 10

What is the MOA of cyclosporine?

Answer 10

Binds to cyclophilin
–cyclosporine + cyclophilin complex that inhibits cytoplasmic phosphatase, calcineurin, which is needed to activate T cell specific transcription factor (NF-AT)
–NF-AT is involved in the synthesis of interleukins by activated T cells
Cyclosporines inhibit gene transcription of IL-2,IL-3, IFN-gamma and other factors produced by T cells

Question 11

What are the adverse effects of cyclosporine?

Answer 11

Toxicities: nephro, tremor, HTN, hyperglycemia, hyperlipidemia, osteoporosis, hirsutism, gum hyperplasia
Nephrotoxicity is limiting and occurs in majority of patients treated
Little bone marrow toxicity
Metabolized by CYP3A4 (drug interactions)

Question 12

Tacrolimus is the other calcineurin inhibitor. What is the MOA?

Answer 12

Binds to FK-binding protein (FKBP)

–this complex inhibits calcineurin which is needed for activation of T cell specific transcription factor NF-AT

Question 13

What are adverse effects and uses of Tacrolimus?

Answer 13

Adverse effects:
—similar to that of cyclosporine: nephrotoxicity, neurotoxicity, hyperglycemia, HTN, hyperkalemia and GI complaints
Uses:
–prevention of rejection of transplanted kidneys, liver or heart

Question 14

Next set of drugs are the proliferation signal inhibitors, first is Sirolimus, what is the MOA?

Answer 14

Binds to FK-BP

• -complex then binds to and inhibits serine-threonine kinase mTOR
• -blockage of mTOR blocks IL-2 driven T cell proliferation

Question 15

What are adverse effects and uses of Sirolimus?

Answer 15

Adverse Effects:
–myelosuppression, hepatotoxicity, diarrhea, hypertrigylceridemia, pneumonitis, and headache
Uses:
—approved for use in renal transplantation
–used to inhibit restenosis of the blood vessels in patients with severe coronary artery disease by reducing cell proliferation

Question 16

Next set of drugs are the inhibitors of Angiogenesis. First drug is Thalidomide, what is the MOA?

Answer 16

Unclear

—does inhibit synthesis of TNF-alpha and this inhibits angiogenesis

Question 17

What are the adverse effects and uses of Thalidomide?

Answer 17

Adverse effects:
–teratogenesis, peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, increased risk of DVT
Uses:
–tx of patients with erythema nodosum leprosum and multiple myeloma

Question 18

Moving on to cytotoxic agents. The first are the antimetabolites and the first drug in this category is Azathioprine, what is the MOA?

Answer 18

Converted to 6-mercaptopurine
–this is converted to additional metabolites, which then inhibit de novo purine synthesis
(this leads to suppression of B and T cell function and therefore suppression of IL-2 secretion)

Question 19

What are the adverse effects, drug interaction and uses of azathioprine?

Answer 19

Adverse Effects:
—bone marrow suppression, GI disturbances
Drug Interaction:
–xanthine oxidase (Therefore patients taking allopurinol for hyperuricemia should have the dose of azathioprine reduced to prevent excessive toxicity)
Use:
–prevention of organ transplant rejection

Question 20

Next cytotoxic agent that is under the antimetabolites is methotrexate, what is the MOA?

Answer 20

Inhibition of Aminoimidazolecarboxamide Ribonucleotide (AICAR) transformylase
–AICAR will accumulates and this inhibits AMP deaminase leading to accumulation of AMP
AMP is then converted to adenosine (this is an inhibitor of inflammation)

Question 21

What is the MOA of adenosine in regards to inflammation?

Answer 21

Acts on A2b receptors
–suppress NF-kB activation induced by TNF
inflammation is suppressed

Question 22

What are the adverse effects of methotrexate?

Answer 22

1. Nausea and mucosal ulcers
2. Leukopenia, anemia
3. Dose related hepatotoxicity
4. Hypersensitivity in pneumonitis
5. Eliminated by renal excretion
6. Do not give in pregnancy

Question 23

What are the uses of methotrexate?

Answer 23

RA
Psoriasis
Psoriatic arthritis 
Graft vs host disease 
Vasculitis 
SLE

Question 24

The third cytotoxic agent that is under the antimetabolites is mycophenolate mofetil, what is the MOA?

Answer 24

Converted to mycophenolic acid
–inhibits inosine monophosphate dehydrogenase (Enzyme in the de novo pathway of guanosine triphosphate synthesis)
This action suppresses both B and T lymphocyte activation
–lymphocytes use de novo because they lack enzymes for the salvage pathway in GTP synthesis

Question 25

What are the adverse effects and uses?

Answer 25

Adverse Effects 
Nausea/Vomiting/Diarrhea 
HA, HTN and reversible myelosuppression 
Uses:
Prophylaxis of transplant rejection

Question 26

The last cytotoxic agent that is under the antimetabolites is Leflunomide. What is the MOA?

Answer 26

Prodrug of an Inhibitor of Pyrimidine Synthesis, teriflunomide
–inhibits dihydroorotate dehydrogenase – decrease levels of UMP (need this for synthesis of pyrimidines)

Question 27

What are the adverse effects and uses of Leflunomide?

Answer 27

Adverse Effects:
Diarrhea, reversible alopecia, rash, myelosuppression and increase in aminotransferase activity
CBC and liver function need to be monitored
No pregos
Uses:
RA and other auto immune diseases SLE and Myasthenia gravis

Question 28

The only cytotoxic agent that is an alkylating agent is Cyclophosphamide. What is the MOA?

Answer 28

Destroys proliferating lymphoid cells

–but also appears to alkylate DNA and other molecules in resting cells

Question 29

What are the adverse effects and uses of Cyclophosphamide?

Answer 29

Adverse Effects:
–infertility in men and women, bone marrow suppression, hemorrhagic cystitis and bladder carcinoma
Uses:
-treat SLE and other autoimmune diseases

Question 30

The last two cytotoxic agents are listed as other agents. The first is Hydroxychloroquine, what is the MOA?

Answer 30

Unclear

–anti-inflammatory due to T lymphocyte suppression

Question 31

What are the adverse effects of hydroxychloroquine?

Answer 31

Hemolysis in patients with G6PD deficiency 
Retinal damage (avoided if dosage is low): monitor vision 
Can be used during pregnancy

Question 32

Uses of hydroxychloroquine?

Answer 32

Mild RA and is well tolerated

3-6 months for effectiveness

Question 33

The last cytotoxic agent listed as other is Sulfasalazine. What is the MOA?

Answer 33

Consists of sulfapyridine and 5-aminosalicyclic (5-ASA) connected by a diazo bond
–metabolized by bacteria in the colon to the constituent moieties
Sulfapyridine is the active moiety for RA
5-ASA is for UC

Question 34

What are the adverse effects and uses for sulfasalazine?

Answer 34

Adverse effects: 
-N/V
-neutropenia
-thrombocytopenia 
-hemolysis in ppl with G6PD deficiency 
Uses: 
tx of UC , RA, Crohns and Ankylosing Spondylitis