Immunopharm: Glucocorticoids, Calcineurn inhibitors, Proliferation Signal Inhibitors, inhibitors of Angiogenesis Flashcards
What are immunosupressive drugs used for?
Dampen the immune response in organ transplantation and auto-immune disease
The first immunosupressive agent are Glucocorticoids. What is their MOA?
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
The overall effect of glucocorticoid administration is anti-inflammatory and immunosupressive. What is the MOA for this?
Down regulate the expression of
–cytokines: TNFalpha, IL-1 and IL-4
Suppress eicosanoid biosynthesis
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
Induce synthesis of annexin I
–anti-inflammatory protein that inhibits cytosolic phospholipase A2 (blocks the release of arachidonic acid)
The second mechanism for glucocorticoids is induction of MAPK phosphatase 1, explain
Induce MAPK phosphatase I
–dephosphorylates and inactivates MAPKs therefore inhibiting proinflammatory signaling pathways
The third mechanism for glucocorticoids is repression of transcription of cyclooxygenase 2, explain
NF-kB is a transcription fact that stimulates transcription of cytokines and chemokines as well as COX2
–glucocorticoids inhibit NF-kB therefore reducing COX2
What are adverse effects of glucocorticoids?
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
What are the uses of glucocorticoids?
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
Next set of drugs are the calcineurin inhibitors. The first drug is cyclosporine. What is the primary use?
Organ transplant
Uveitis
RA
Psoriasis
What is the MOA of cyclosporine?
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
What are the adverse effects of cyclosporine?
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)
Tacrolimus is the other calcineurin inhibitor. What is the MOA?
Binds to FK-binding protein (FKBP)
–this complex inhibits calcineurin which is needed for activation of T cell specific transcription factor NF-AT
What are adverse effects and uses of Tacrolimus?
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
Next set of drugs are the proliferation signal inhibitors, first is Sirolimus, what is the MOA?
Binds to FK-BP
- -complex then binds to and inhibits serine-threonine kinase mTOR
- -blockage of mTOR blocks IL-2 driven T cell proliferation
What are adverse effects and uses of Sirolimus?
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
Next set of drugs are the inhibitors of Angiogenesis. First drug is Thalidomide, what is the MOA?
Unclear
—does inhibit synthesis of TNF-alpha and this inhibits angiogenesis
What are the adverse effects and uses of Thalidomide?
Adverse effects:
–teratogenesis, peripheral neuropathy, constipation, rash, fatigue, hypothyroidism, increased risk of DVT
Uses:
–tx of patients with erythema nodosum leprosum and multiple myeloma
Moving on to cytotoxic agents. The first are the antimetabolites and the first drug in this category is Azathioprine, what is the MOA?
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)
What are the adverse effects, drug interaction and uses of azathioprine?
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
Next cytotoxic agent that is under the antimetabolites is methotrexate, what is the MOA?
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)
What is the MOA of adenosine in regards to inflammation?
Acts on A2b receptors
–suppress NF-kB activation induced by TNF
inflammation is suppressed
What are the adverse effects of methotrexate?
- Nausea and mucosal ulcers
- Leukopenia, anemia
- Dose related hepatotoxicity
- Hypersensitivity in pneumonitis
- Eliminated by renal excretion
- Do not give in pregnancy
What are the uses of methotrexate?
RA Psoriasis Psoriatic arthritis Graft vs host disease Vasculitis SLE
The third cytotoxic agent that is under the antimetabolites is mycophenolate mofetil, what is the MOA?
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
What are the adverse effects and uses?
Adverse Effects Nausea/Vomiting/Diarrhea HA, HTN and reversible myelosuppression Uses: Prophylaxis of transplant rejection
The last cytotoxic agent that is under the antimetabolites is Leflunomide. What is the MOA?
Prodrug of an Inhibitor of Pyrimidine Synthesis, teriflunomide
–inhibits dihydroorotate dehydrogenase – decrease levels of UMP (need this for synthesis of pyrimidines)
What are the adverse effects and uses of Leflunomide?
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
The only cytotoxic agent that is an alkylating agent is Cyclophosphamide. What is the MOA?
Destroys proliferating lymphoid cells
–but also appears to alkylate DNA and other molecules in resting cells
What are the adverse effects and uses of Cyclophosphamide?
Adverse Effects:
–infertility in men and women, bone marrow suppression, hemorrhagic cystitis and bladder carcinoma
Uses:
-treat SLE and other autoimmune diseases
The last two cytotoxic agents are listed as other agents. The first is Hydroxychloroquine, what is the MOA?
Unclear
–anti-inflammatory due to T lymphocyte suppression
What are the adverse effects of hydroxychloroquine?
Hemolysis in patients with G6PD deficiency Retinal damage (avoided if dosage is low): monitor vision Can be used during pregnancy
Uses of hydroxychloroquine?
Mild RA and is well tolerated
3-6 months for effectiveness
The last cytotoxic agent listed as other is Sulfasalazine. What is the MOA?
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
What are the adverse effects and uses for sulfasalazine?
Adverse effects: -N/V -neutropenia -thrombocytopenia -hemolysis in ppl with G6PD deficiency Uses: tx of UC , RA, Crohns and Ankylosing Spondylitis
