-have broad anti-inflammatory effects + immunosuppressive effects
-glucocorticoids act by binding to the cytosolic glucocorticoid receptor
-The glucocorticoid-glucocorticoid receptor complex translocates to the nucleus and binds to glucocorticoid response elements (GREs) in the promoter region of specific genes, either up- regulating or down-regulating gene expression.
ANTI-INFLAMMATORY MECHANISM OF ACTION OF GLUCOCORTICOIDS
Glucocorticoids relieve pain due to the modulation of inflammatory responses. Glucocorticoids suppress several inflammatory pathways. They can inhibit prostaglandin synthesis through three independent mechanisms:
1. INDUCTION of annexin I
Glucocorticoids induce synthesis of annexin I. Annexin I is an antiinflammatory protein that inhibits cytosolic phospholipase A2α (cPLA2α), thus blocking the release of arachidonic acid and its subsequent conversion to eicosanoids.
2. INDUCTION of MAPK phosphatase 1
Glucocorticoid-induced MAPK phosphatase 1 dephosphorylates and inactivates MAPKs, thus inhibiting proinflammatory signaling pathways. MAPK phosphatase 1 may also inhibit cPLA2α activity by blocking its phosphorylation by MAPKs
3. Repression of transcription of cyclooxygenase 2.
NF-kB is a transcription factor that stimulates transcription of cytokines and chemokines. NF-kB also induces the transcription of cyclooxygenase 2. Glucocorticoids inhibit NF-kB, thus reducing the expression of COX2
1) they RELIEVE PAIN d/t the modulation of infammatory responses, and suppress several inflammatory pathways
2) Used to TREAT AUTOIMMUNE DISORDERS such as RA, SLE, psoriasis, asthma, IBD
3) to PREVENT + TREAT TRANSPLANT REJECTION
4) In palliative care GLUCOCORTICOIDS are used to ALLEVIATE PAIN, NAUSEA, + FATIGUE
SHORT-TERM USE: hypertension, hyperglycemia, immunosuppression, psychotic reactoins, and cognitive impairment
LONG-TERM USE: MYOPATHY, CUSHINGS SYNDROME, + OSTEOPOROSIS
-increased CORTISOL = CUSHING SYNDROME: Hypertension, weight gain, moon facies, truncal obesity A , buffalo hump, skin changes (thinning, striae), osteoporosis, hyperglycemia (insulin resistance), amenorrhea, immunosuppression.
Note: don't confuse with cycloPHOSPHAMIDE
CALCINEURIN INHIBITOR = T CELL INHIBITOR
CYCLOSPORIN --> CYCLOPHILLIN (must fill up before you go) --> then CALCINEURIN (N UR IN!!!) is in with a chick. Sporin, Phill up, then Ur in! Inhibits NFAT (no fat chicks) --> inhibits IL-2,3, and gamma
Cyclosporine is a peptide antibiotic. Cyclosporine binds to CYCLOPHILLIN, a member of a class of intracellular proteins called immunophilins. Cyclosporine and cyclophilin form a COMPLEX --> inhibits the cytoplasmic phosphatase, CALCINEURIN, which is necessary for the activation of a T- cell-specific transcription factor. This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-2) by activated T cells. Cyclosporine inhibits the gene transcription of IL-2, IL-3, IFN-γ, and other factors produced by antigen-stimulated T cells.
1) ORGAN TRANSPLANTATION
CYCLOSPORIN --> causes NEPHROTOXICITY (cyclo b/c your kidneys cycle your blood). Also, adverse effects of having a good date is you make her smile and you realise the GUM HYPERPLASIA. Although, she does have BIG TITTIES (hirstuism). She's a bit of a hoar she b/c she interacts with CYP3A4 --> many drug interactions
Toxicities are numerous and include: nephrotoxicity, tremor, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, **hirsutism, gum hyperplasia.**
***Nephrotoxicity is limiting and occurs in the majority of patients treated. ****
It is the major indication for cessation or modification of therapy.
Cyclosporine causes very little bone marrow toxicity.
Cyclosporine is primarily metabolized by CYP3A4; therefore it is involved in many drug interactions.
CALCINEURIN INHIBITOR = T CELL INHIBITOR
TACROLIMUS --> like getting a TAC in your skin then squeezing a LIME on top ---> is used to treat atopic dermatitis + psoriasis. When you squeeze the lime on, it makes you scream FK!!!!! Lime had vitamin C --> make you think of calcineurin
--> can also think T for TOPICAL and T cell inhibitor and affects the TOP (neurotoxicity is an AE)
• Tacrolimus binds to FK-binding protein (FKBP).
• FKBP is an IMMUNOPHILIN
• The tacrolimus-FKBP complex inhibits calcineurin.
1) Prevention of rejection of transplanted kidney/liver/heart
2) topical formulation is used for ATOPIC DERMATITIS + PSORIASIS
ADVERSE EFFECTS: nephrotoxicity, neurotoxicity, hyperglycemia, hypertension, HYPERkalemia, GI complaints
PROLIFERATION SIGNAL INHIB = T CELL INHIBITOR
SIR, LIME US please. Note is not the TACrolimus, so is not used for skin. Think of a surgeon saying "SIR-LIME-US" --> used for CORONARY STENT for a RESTENOSIS --> does this all by inhibiting the SERINE-threonine kinase mTOR (SURGEON WORKS IN TORONTO)
-Structurally similar to tacrolimus.
-Sirolimus binds to FKBP .
-But the sirolimus-FKBP complex does not inhibit calcineurin.
Instead, it inhibits the serine-threonine kinase ***mTOR.****
Blockade of mTOR blocks IL-2-driven T-cell proliferation.
1) RENAL TRANSPLANTATION
2) SIROLIMUS-ELUTING CORONARY STENTS are used to inhibit REstenosis of the blood vessels in patients with severe CAD by decreasing cell proliferation
ADVERSE EFFECTS: hypertriglyceridemia, pneumonitis, headache
INHIBITOR OF ANGIOGENESIS
T-HAL --> can think of TOM HALL --> is huge, so angiogenesis, but you want to inhibit that behavior. This drug also inhibits TNF-alpha which is for wasting, and his mother has breast cancer, so this makes sense. Thinking of mother from T hall, you can double the M for mom and get MM. Also used for Leprosy because his mom's eyes kind of look like a leapord.
- Its mechanism of action is unclear.
Inhibits synthesis of TNF-α AND inhibits ANGIOGENESIS
Thalidomide is now called an immunomodulatory drug.
--> indicated for the treatment of patients with
- 1) ERYTHEMA NODOSUM LEPROSUM +
- 2) MULTIPLE MYELOMA*****
ANTIMETABOLITE (CYTOTOXIC AGENT)
AZ-"PRINE" = purine w/o the U --> is a PRODRUG b/c goes from A-->Z
--> gets conerted to 6-MP (purine is 6 letters long) --> suppresses B AND T function because does from A --> Z
--> Prodrug of 6-mercaptopurine that gets converted to 6-MP
--> 6-MP is converted to metabolites that inhibit de novo PURINE nucleotide synthesis
This leads to suppression of B AND T cell function, of immunoglobulin production and of IL-2 secretion.
1) prevention of organ transplant rejection
2) severe rheumatoid arthritis
ADVERSE EFFECTS: bone marrow suppressoin, GI distrubances, increase in infectious + malignancies
DRUG INTERACTIONS** ON EXAM:
ALLOPURINOL --> XANTHINE (almost full alphabet) --> can help you remember the AZATHIOPRINE
much of the drug's inactivatoin depends on XANTHINE OXIDASE --> patients who are also receiving allopurinol for control of hyperuricemia should have the dose of azothiprine reduced
--> allopurinol increases concentration by inhibiting xanthine oxidase
ANTIMETABOLITE (A CYTOTOXIC DRUG)
MethoTrex --> she's on her Trex to go get her meth. so she screams out AI, CAR!!!
--> she usually gets that PURE stuff from her pimp, but she is on the steets now, and is yelling, so she is AMP'd UP!!! --> ADENOSINE --> then is a potent inhibitor of inflammation (when she's amp'd up, not attractive, is anti-inflammatory)
Methotrexate’s main mechanism of action at the low doses used in rheumatic diseases is inhibition of (AICAR) transformylase. (aminoimidazolecarboxamide ribonucleotide transformylase)
• AICAR transformylase normally catalyzes the final steps in de novo PURINE BIOSYNTHESIS which lead to synthesis of IMP.
-Inhibition of AICAR transformylase **leads to accumulation of AMP.**
AMP is released and converted extracellularly to adenosine
- ADENOSINE is a POTENT INHIBITOR OF INFLAMMATION
ANTIMETABOLITE (A CYTOTOXIC DRUG)
METH-TREX --> she's a heavy drinker too --> hepatotoxicity --> also is contraindicated in pregnancy (obviously)
AE: nausea, mucosal ulcers, leukopenia, anemia, GI ulcerations, hepatotoxicity, cirrhosis is rare, hypersensitivity pneumonitis
-toxicity can be reduced with LEUCOVORIN or FOLIC ACID
NOTE: METHOTRAXATE is CONTRAINDICATED in pregnancy
3) PSORIATIC ARTHRITIS
4) ANKYLOSING SPONDYLITIS
5) SYSTEMIC LUPUS ERYTHEMATOSUS
ANTIMETABOLITE (CYTOTOXIC DRUG)
Double M --> inhibits BOTH B + T lymphocyte activation. Inhibits IMP DEHYDROGENASE, the de novo pathway of PURINE synthesis (pure b/c is MM) and inhibits iMp Dehydrogenase. Aderse effect is MYELOsuppression
-mycophenolate mofetil is converted into MYCOPHENOLIC ACID
--> mycophenolic acid INHIBITS IMP DEHYDROGENASE, an enzyme in the DE NOVO pathway of GTP synthesis (PURINE SYNTHESIS)
-suppreses BOTH B+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
USES: 1) Prophylaxis of TRANSPLANT REJECTION, 2) SLE
AE: nausea, vomiting, diarrhea, abdominal pain, headache, HTN, REVERISBLE MYELOSUPPRESION
PRODRUG of teriflunomide.
--> decreases levels of UMP by saying NOOOOOO using dihydroOOROTATE
--> must check LFT!!! (looks like LeFlunomide) --> is TERATOGENIC in animals
Teriflunomide inhibits dihydroorotate dehydrogenase.
This decreases levels of UMP. (UMP is essential for the synthesis of PYRIMIDINES)
USES: 1) RA 2) SLE 3) MYASTHENIA GRAVIS
AE: diarrhea, reversible alopecia (immune system attacking hair), rash, myelosuppression, increases in aminotransferase activity
--> CBC and LIVER FUNCTION TESTS should be MONITORED
--> is CARCINOGENIC + TERATOGENIC in animals
--> is CONTRAINDICATED IN PREGNANCY
ALKYLATING AGENT (don't confuse with Cyclosporin!!!)
CYCLE of P!!! --> destorys the Proliferating Lymphoid cells, and alkylates the resting DNA cells --> uses is P(enis) so much that he becomes INFERTILE, and even gets HEMORRHAGIC CYSTITIS, maybe even BLADDER CARCINOMA!!!
--> NOTE: ACROWlein is responsible for these toxic penis effects
-is one of the most effective immunosuppressive drugs available
--> it 1) DESTROYS PROLIFERATING LYMPHOID CELLS
--> it also 2) ALKYLATES DNA and other molecules in RESTING CELLS
USES: to treat SLE + other autoimmune diseases
AE: INFERTILITY, bone marrow suppression, HEMORRHAGIC CYSTITIS, rarely BLADDER CARCINOMA
--> ACROLEIN = a metabolite, is responsible for the URINARY toxicities
--> long-term use increaes the risk of infection/malignancy
HYDROXYCHLOROQUINE --> she's a QUEEN so it takes 3-6 months for her to like you, but can BREAK YOUR EYES (retinal damage) if you stare at her too long. Can also cause HEMOLYSIS
mechanism of anti-inflammatory action is UNCLEAR
1) moderately effective for MILD RHEUMATOID ARTHRITIS, and is usually tolerated quite well.
-often used with other drugs, particularly METHOTREXATE/SULFASALAZINE
Note: the drugs effectiveness may require 3-6 months to become apparent
AE: serious adverse effects are RARE
--> can get HEMOLYSIS**** in patients with G6PD deficiency
--> RETINAL DAMAGE******: vision should be monitored
SULFASALAZINE --> SULFA SAL (2 S's means it has 2 diff mechs)
--> SulfaPyridine --> RA
--> 5-ASA --> Ulcerative Colitis (b/c it's near your ASSa)
-consists of SULFAPYRIDINE and 5-aminosalicylic (5-ASA) connected by a diazo bond
-is metabolized by bacteria of the colon to the constituent moieties
--> the sulfapyridine is probably the active moiety in the treatment of RA
-the 5-ASA moiety is thought to be important in ULCERATIVE COLITIS
USES: 1) UC 2) RA 3) Crohns 4) Ankylosing Spondylitis
AE: nausea, vomiting, headache, rash, NEUTROPENIA, but thrombocytopenia is very rare. Drug-induced lupus is rare, hemolysis in patients with G6PD
ANTILYMPHOCYTE + ANTITHYMOCYTE ANTIBODIES
When are they used?
-2 types of antisera directed against lymphocytes are available
- Anti LYMPHOCYTE globulin (ALG)
- Anti THYMOCYTE globulin (ATG)
-both are produced in horses or sheep by immunization against human thymus cells
-antibodies in these preps bind to T cells involving in antigen recogntiion and initiate their destruction by SERUM COMPLEMENT
1) before STEM CELL TRANSPLANTATION to prevent graft-vs-host reaction
2) SOLID ORGAN TRANSPLANTATION
RHo(D) IMMUNE GLOBULIN
-Rho(D) immune globulin is a preparation of human IgG containing antibodies against the Rho(D) antigen of the red cell.
-Rh-negative women may be sensitized to the Rh antigen, usually at the time of birth of an Rho(D)- positive infant, when fetal red cells leak into the mother’s bloodstream.
If the women have a primary immune response, they will make antibodies to Rh antigen.
In subsequent pregnancies, maternal antibody against Rh-positive cells is transferred to the fetus during the third trimester.
This leads to hemolytic disease of the newborn, a life-threatening syndrome.
1) to PREVENT hemolytic disease of the newborn
Administration of Rho(D) immune globulin to Rho(D) negative mothers at time of antigen exposure blocks the primary immune response to the foreign cells.
Therefore, maternal antibodies to Rh-positive cells are not produced in subsequent pregnancies, and hemolytic disease of the neonate is prevented.
TNF-α INHIBITOR (MONOCLONAL ANTIBODY)
IN-FLIX --> b/c want to prevent wasting away by going to the outside world, so by preventing wasting, you inhibit TNF-alpha
Blocking TNF-α action results in suppression of downstream inflammatory cytokines and adhesion molecules involved in leukocyte activation and migration.
TNF NORMAL ACTION ON:
MACROPHAGES --> release cytokines --> increased inflammation
ENDOTHELIUM --> adhesion molecules --> increased cell infilatration
HEPATOCYTES --> increased CRP
SYNOVIOCYTES --> metalloproteinase synthesis --> cartilage degredation
Adverse Effects of the ANTI-TNF DRUGS
1) CYTOPENIAS --> CBC should be monitored regularly
2) SERIOUS INFECTIONS --> are the most important potential AEs
-these drugs should NOT be given to patients with an active infection
-patients should be screened for LATENT TB INFECTION before and during treatemnt with a TNF inhibitor
-patients may be at inreased risk for malignancies
TNF-α INHIBITOR (CHIMERIC MONOCLONAL ANTIBODY)
-Chimeric monoclonal antibody.
-Binds with high affinity and specificity to human TNF-α
Used in the treatment of
1) rheumatoid arthritis,
2) psoriatic arthritis,
3) ankylosing spondylitis,
4) Crohn’s disease, and
5) ulcerative colitis.
TNF-α INHIBITOR (CHIMERIC MONOCLONAL ANTIBODY)
ADAL = ADELLE --> she's the numer on GIRL IgG1 anti-TNF (b/c is imab)
-fully human IgG1 anti-TNF monoclonal antibody.
-Binds to soluble TNF-α and prevents its interaction with TNF receptors.
Used in the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis.
TNF-α INHIBITOR (MONOCLONAL ANTIBODY)
E-TANER --> not a true tanner therefore not a true Mab, but still does inhibit TNF-alpha
Not a true Mab.
Contains the ligand-binding portion of a human TNF-α receptor fused to the Fc portion of human IgG1.
Binds to TNF-α and prevents it from interacting with its receptors.
Approved for rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis, and psoriatic arthritis.
OMAL --> think of OMAR --> is from EGYPT --> therefore the OMAL is the anti-IgE recombinant that prevents the IgE from binding to mast cells/basophils
-Anti-IgE recombinant humanized monoclonal antibody.
Binds to IgE and prevents IgE from binding to mast cells and basophils, thereby preventing release of inflammatory mediators after allergen exposure.
1) ASTHMA REFRACTORY to inhaled corticoids and evidence of allergic sensitization.
2) CHRONIC URTICARIA
BASIL --> 2nd letter in alphabit --> IL-2 receptor antagonist
-IL-2 receptor antagonist.
Chimeric human-mouse IgG.
Binds to the IL-2 receptor.
Used in combination with other immunosuppressants to prevent renal transplant rejection.
RUTU --> think of RUUTU on the devils --> most he's ever scored is 20 goals!!! (CD20) --> used for NON-hodgkins, CLL
Chimeric murine-human monoclonal antibody that binds to the CD20 molecule on B lymphocytes.
Causes depletion of circulating Bcells.
1) treatment of non-Hodgkin’s lymphoma and
2) chronic lymphocytic leukemia.
3) rheumatoid arthritis.
ANAKINRA --> ANNA KORNIKOVA = first letter of alphabet/1ST/hottest player in tennis --> IL-1 receptor antagonist
IL-1 receptor antagonist.
Recombinant version of the naturally occurring human IL-1RA that prevents IL-1 from binding to its receptor.
Approved for moderate to severe rheumatoid arthritis.
ABETACEPT --> A beta = a tester = trys to turn on your computer, but it interferes with the activation (interferes with T cell activation)
-Fusion protein that interferes with T-cell activation.
• Used for moderate to severe rheumatoid arthritis. .
• Used for moderate to severe polyarticular juvenile idiopathic arthritis.
ALDESLEUKIN --> All Dis Leukin!!! --> is just adding IL-2 in to the body!!! promotes production of cytotoxic T cells and activates NK cells --> used for RENAL CC (b/c have 2 kidneys, is IL-2), and MALIGNANT MELANOMA (2m's) (note it is not multiple myeloma)
-Recombinant interleukin-2 (IL-2).
-IL-2 is a lymphokine that promotes the production of cytotoxic T lymphocytes and activates NK cells.
1) adjunctive treatment of RENAL CELL CARCINOMA
2) MALIGNANT MELANOMA