Immunopharmacology Flashcards
What are glucocorticoids?
Broad anti-inflammatory effect where they bind cytosolic glucocorticoid receptors translocates to the nucleus and binds GREs (glucocorticoid response elements) in the promoter region of specific genes leading to up or down regulation of gene expression [mRNA alterations].
As anti-inflammatory drugs - they down-regulate expression of inflammatory mediators adding to their anti-inflammatory and immunosuppressive effect.
The main effect of glucocorticoids is that they inhibit prostaglandin synthesis via inhibiting PLA2 and reduce transcription of COX-2 enzyme. [This is different from what NSAIDs do as they inhibit activity NOT transcription of COX-2]
Uses…
- prevent and treat transplant rejection
- Treat autoimmune disorders (RA, SLE, psoriasis, asthma, IBD)
- palliative care to alleviate pain, nausea and fatigue [also improves appetite in people who are losing weight]
- Treat pain (incl. neuropathic and bone)
AE - [short term] HTN, hyperglycemia, immunosupression, psychotic reactions, cognitive impairment, [long term] myopathy, Cushing’s syndrome, osteoporosis
*useful drugs but adverse effects are difficult to tolerate
What is Cyclosporine?
Cyclosporine is a calcineurin inhibitor that revolutionized the prevention of organ transplant rejection.
Calcineurin is a phosphatase that activates NFAT (removes phosphate which activates it). NFAT can then move into the nucleus and induce cytokine genes (esp IL-2).
Cyclosporine forms complex with cyclophilin (an immunophilin) and the complex inhibits calcineurin preventing an upregulation of interleukins.
Uses…
- organ transplant
- Uveitis
- Rheumatoid arthritis
- Psoriasis
Metabolized by CYP3A4 therefore involved in many drug interactions.
AE - NEPHROTOXICITY (dose limiting happening in most people), tremor, HTN, hyperglycemia, hyperlipidemia, osteoporosis, hirsuitism, gum hyperplasia, little bone marrow toxicity
*nephrotoxicity is why most people stop therapy
What is Tacrolimus?
Tacrolimus is a calcineurin inhibitor. It binds to another immunophilin (FKBP = FK-binding protein).
Tacrolimus binds FKBP binding calcineurin, inhibiting calcineurin preventing interleukin transcription.
Uses..
- prevention of kidney, liver and heart transplant rejection
- topical formation used for atopic dermatitis and psoriasis
AE - nephrotoxicity, neurotoxicity, hyperglycemia, HTN, hyperkalemia, GI complaints
What is Sirolimus?
Sirolimus is a proliferation signal inhibitor that functions as an immunosuppressant. It is structurally similar to tacrolimus where it binds FKBP BUT, sirolimus-FKBP complex does not inhibit calcineurin rather inhibits a serine-threonine kinase mTOR which blocks IL-2 driven T cell proliferation.
[IL-2 receptor activated that activates mTOR and increases transcription – this drug blocks the mTOR]
**signal transduction of the cytokine signaling is prevented
Uses..
- renal transplant
- sirolimus-eluting (releasing) coronary stents are used to inhibit restenosis of the blood vessels in pts with severe CAD by reducing cell proliferation
AE - BONE MARROW SUPPRESSION (myelosuppression is of the bigges concern), hepatotoxicity, diarrhea, hypertriglyceridemia, penumonitis, headache
*nephrotoxicity is less common than with calcineurin inhibitors
What is Thalidomide?
Thalidomide is an inhibitor of angiogenesis used with immunosuppresion treatment. Its mechanism of action is unclear, but it inhibits TNF-a synthesis as well as angiogenesis. It is indicated in pts with erythema nodosum leprosum and multiple myeloma.
Thalidomide = immunomodulatory drug [may be put under immunostimulant or immunosuppressant]
What is Azathioprine?
This is a purine antimetabolite cytotoxic agent used in the treatment of cancer. It is given as a prodrug 6-mercaptopurine and converted to 6-MP then converted to metabolites which ultimately inhibits de novo purine nucleotide synthesis. By inhibiting synthesis this leads to suppression of B and T cell function, of immunoglobulin production (no antibodies made) and IL-2 secretion.
Drug inactivation depends on xanthine oxidase, so pts receiving allopurinol for hyperuricemia should have the dose of azathioprine reduced. [uric acid is dead end of purine metabolism when cells die. The two last steps of the pathway are xanthine oxidase, so azathioprine imitates a real purine nucleotide therefore is metabolized by xanthine oxidase causing it to be excreted in the urine. By giving the pt allopurinol, you block xanthine oxidase therefore increasing concentration of azathioprine - pt has gout and cancer at the same time]
Uses..
- prevent organ transplant rejection
- severe RA tx
AE - bone marrow suppression, GI disturbance, increase in infections and malignancies
What is Methotrexate?
This is an antimetabolite cytotoxic agent used in the treatment of cancer. Methotrexate at low doses tx rheumatic disease by inhibiting AICAR (aminoimidazolecarboxyamide ribonucleotide) transformylase. AICAR transformylase catalyzes the de novo synthesis of purine nucleotides (IMP). Methotrexate blocks the pathway causing increase in intermediates (esp AMP). Outside the cells AMP is released and converted to adenosine which is a potent inhibitor of inflammation.
Uses... 1. RA 2. Psoriasis 3. Psoriatic arthritis 4. Ankylosing spondylitis 5. SLE [only for inflammatory autoimmune disorders, not really transplant rejection]
AE - nausea, mucosal ulcers, leukopenia, anemia, GI ulcerations, hepatotoxicity, cirrhosis (rare), hypersensitivity pneumonitis
Giving leucovorin (folic acid derivative) or direct folic acid can reduce Methotrexate toxicity.
*do not use in pregnant women
What is Mycophenolate mofetik?
This is an antimetabolite cytotoxic agent that is convereted to mycophenolic acid. Mycophenolic acid inhibits inosine monophosphate dehydrogenase - enzyme in the de novo pathway of GTP synthesis. This action suppresses both B- and T- lymphocyte activation. [Lymphocytes are particularly susceptible to inhibitors of the de novo pathway b/c they lack the enzymes necessary for the salvage pathway - they divide extremely fast, so they are the most commonly affected first]
Uses..
- prophylaxis of transplant rejection
- SLE
AE - nausea, vomiting, diarrhea, abdominal pain, headache, HTN, reversible myelosuppression
What is Leflunomide?
This is an antimetabolite cytotoxic agent that is given as a prodrug and is converted to teriflunomide. Teriflunomide inhibits dihydroorotate dehydrogenase thus decreasing levels of UMP [pyrimidine synthesis affected]. UMP is essential for the synthesis of pyrimidines.
Uses…
- RA
- SLE
- Myasthenia gravis
AE - diarrhea, reversible alopecia, rash, myelosuppression, increases in aminotransferase activity, CBC and LFT tests should be monitored, carcinogenic/teratogenic in animals, contraindicated in pregnancy [these are all typical AE of chemo drugs]
What is cyclophosphamide?
This is an alkylating agent that acts as one of the most effective immunosuppressive drug out there. It destroys proliferating lymphoid cells and alkylates DNA and other molecules in resting cells. [causes massive cell death]
Uses… SLE and other autoimmune disorders
AE - infertility, bone marrow suppression, hemorrhagic cystitis, bladder carcinoma (rare), acroleine (metabolite that is responsible for urinary toxicities b/c it is irritating to the bladder), increased risk of infection and malignancy (with long-term use)
What is hydroxychloroquine?
Weak immunosuppressant that was originally developed for malaria. It is an oxidizing drug which is what leads to the hemolytic anemia.
Uses…
- mild RA [not drug of choice, bt has good AE profile - commonly used with methotrexate and sulfasalazine)
- Lupus erythematosus
* *may require 3-6 months to show clinical benefit
AE (rare!) - hemolysis in pts with G6PD deficiency, retinal damage (therefore vision should be monitored)
What is sulfasalazine?
Weak immunosuppressant that consists of sulfapyridine and 5-aminosalicylic (5-ASA) connected by a diazo bond. Sulfasalazine is metabolized by the bacteria in the colon in to its separate moieties: 5-ASA and sulfapyridine. It is though that 5-ASA is important for Ulcerative colitis and sulfapyridine is the active moiety in tx of RA.
Uses…
- UC (5-ASA)
- RA (sulfapryridine)
- Crohn’s disease
- Ankylosing spondylitis
AE - nausea, vomiting, headache, rash, neutropenia, thrombocytopenia (rare), drug-induced lupus (rare), hemolysis in pts with G6PD deficiency
What are antilymphocyte and antithymocyte antibodies?
Antilymphocyte globulin (ALG) Antithymocyte globulin (ATG)
Both are produced in horses or sheep by immunization against human thymus cells. The antibodies bind to T cells involved in antigen recognition and initiate their destruction by serum COMPLEMENT.
Uses…
- before stem cell transplant to prevent graft v host reaction
- before solid organ transplant to prevent rejection
What is Rho(D) immune globulin?
Rho(D) immune globulin is a preparation of human IgG containing antibodies against the Rho9D) antigen of the RBC. This is usually give at time of birth when Rh negative mother gives birth to Rh positive child – this is to prevent a primary immune response from the mother to make antibodies against the Rh antigen for future pregnancies. If Rho(D) is not given, then it leads to hemolytic disease of the newborn.
What is Infliximab?
TNF-a inhibitors
Chimeric monoclonal antibody that binds with high affinity and specificity to human TNF-a itself and not the receptor [constant part is human, variable part is from mouse].
Used in the tx of RA, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and UC
