Immunoregulatory Drugs: Flashcards
(44 cards)
1
Q
What is the purpose of Immunoregulatory Drugs?
A
- To suppress the immune systems response in organ transplantation and autoimmune diseases.
- Suppress inflammatories diseases.
2
Q
What is the purpose of Immunostimulatory Drugs?
A
-Applicable to treatments of infection, immunodeficiency and cancer.
3
Q
What is innate immunity?
A
- Immediate response
- Receptors which recognize common molecules, microbes and viruses.
- -Includes macrophages, neutrophils, mast cells, natural killer cells, complement and interferon.
4
Q
What is acquired immunity?
A
- Takes days–> weeks
- Unique antigen specific receptors called B cells and T cells (lymphocytes)
- Includes antigen presenting cells, T- lymphocytes & B-lymphocytes.
–>Cell mediated responses and humeral responses.
5
Q
What is a cell mediated response in acquired immunity?
A
-Involves Th1 mediated activation of macrophages and generation of CD8+ cytotoxic T-1 lymphocytes (CTL’s)
6
Q
What is the humeral response in acquired immunity?
A
-Involves TH2 cells which secrete cytokines that stimulate proliferation and differentiation of B cells to antibodies- secreting plasma cells.
7
Q
What is released from cells that plays a role in inflammation of Rheumatoid Arthritis?
A
Cytokines: TNF-alpha, IL-2, IFNs, TGFs, CSF’s, etc.
Chemokines:
8
Q
What are Chemokines?
A
- A family of chemotaxis cytokines that are secreted or membrane bound, and are structurally related proteins of 67- 127 amino acid peptides. There are about 50 Chemokines in humans, which fall in 4 subfamilies:
- ->CXC (alpha), CC (Beta), C (gamma) and CX3C (delta)
- -Chemokines transmit the signals to the cells via binding chemokine receptors, which are 7 transmembrane G protein coupled receptors similar to the cell surface receptors for other chemoattractants.
*Over 40 chemokines within the 4 subclasses.
9
Q
What is the role of Chemokines in inducing Inflammation?
A
- -Chemokines are key players in inducing leukocyte- trans epithelial migration.
- Chemokines interact with endothelial cells and activate Integrins on tolling leukocytes to trigger firm adhesion to the endothelium– a prerequisite for leukocyte transmission.
–>Integrins respond to breached sub endothelial structures.
10
Q
What are the 2 cytokines detected in Rheumatoid Arthritis?
A
- TNF alpha (from monocytes/ macrophages)
- IL-1B (from monocytes/ macrophages)
*Both increase inflammation & tissue damaged which leads to the pain associated with rheumatoid arthritis.
11
Q
Overview of the Treatments for Rheumatoid Arthritis:
A
- Physical Therapy,
- Drugs for the relief of symptoms (NSAIDS, simple analgesia, corticosteroids)
- Surgery
- Disease- Modifying Anti-Rheumatic Drugs (DMARDS)
- Immunosuppressive Drugs
- Complementary medicine (Diet and Food supplements)
12
Q
Prednisone, Prednisolone, Methylprednisolone
A
- Glucocorticoid
- Has immunosuppressive effects on tissue
- Leads to regression of lymphoid tissue, enhances destruction of lymphocytes, interferes with the cell cycle of activated lymphoid cells, inhibit leukocyte actions including recruitment, migration, chemotaxis, phagocytosis and activation of CTLs, inhibits antibody formation as inhibit inflammatory mediators.
- ->Prednisone inhibits COX-2 and thus reduces it’s release of inflammatory mediators (PGs and IL’s)
- Blocks PLA2, therefore limiting the availability of AA.
13
Q
Clinical Uses of Glucocorticoids as well as Adverse Effects:
A
- Organ and Tissue Transplantation
- Auto immune diseases
- Inflammatory diseases (Allergy and bronchial diseases, RA, IBD, ect.)
Adverse Effects:
- Suppression of the Pituitary- Adrenal Axis
- Increased susceptibility to serious infections.
- Peptic ulcers
- Catabolic Effects (Hyperglycemia, bone catabolic effects, ect.)
14
Q
What are Cytokines and what are their key Adverse Effects?
A
- Cytokines are soluble, antigen- non specific signalling proteins that bind to the cell surface receptors on a variety of cells.
- Cytokines include Interleukins, interferons, TNFs, TGFs, CSFs and chemokines.
AEs:
- Nephrotoxicity
- Hepatotoxicity
- Predisposition to infections
- ->Lymphoma (cancer) may occur. Most immmunosuppresive drugs pose a threat to cancer.
Other adverse effects include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance and gum hyperplasia.
15
Q
•Cyclosporine (CsA):
A
- Type of cytokine
- Suppresses cell mediated immune reactions, whereas humoral immunity is affected to a far lesser extent.
- ->CsA binds to cyclophilin and the complex binds and inhibits calcineurin. NFAT remains inactive and can’t enter the nucleus to promote the synthesis of several cytokines, including IL-2.
AE: -Nephrotoxicity (always monitor kidney function)
- Hepatotoxicity
- Predisposition to infections
- Chance of lymphoma
- Other AE’s include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance and gum hyperplasia.
- ->CsA causes very little bone marrow toxicity.
16
Q
Tacrolimus (TAC,FK506):
A
- Is a more potent cytokine compared to Cyclosporine A, and allows for lower doses of glucocorticoid to be used in conjunction.
- Binds to a different immunophilin (FKBP-12)
17
Q
Sirolimus (Rapamycin):
A
- Also binds FKBP-12, which forming a complex called mTOR (Mammalian Target of Rapamycin)
- When Sirolimus binds to mTOR after IL-2 has bound it’s receptor, it blocks the progression of activated T cells from the G1 to the S phase of the cell cycle, consequently blocking the proliferation of these cells and reducing the response of IL-2s.
- Sirolimus does not owe it’s effects to lowering IL-2 production, but rather it inhibits the cellular response to IL-2.
18
Q
Cytotoxic Drugs- Immunosuppressive Anti- Metabolites:
A
- Includes Methotrexate and Leflunomide)
- Are generally used in combination with glucocorticoids and calcineurin inhibitors (Cyclosporin- CsA) and Tacrolimus.
- Cytotoxic drugs interfere with the availability of normal purine or pyrimidine nucleotide precursors either by inhibiting their synthesis, or by competing with them in DNA or RNA synthesis.
- Maximal effects in the S Phase.
19
Q
Methotrexate (MTX):
A
- Mainstay drug used to treat Rheumatoid Arthritis.
- Doses are much lower than needed in cancer chemotherapy.
- MTX acts as an antagonist of that folic acid and inhibits dihydrofolate reductase– reduces levels of folic acid.
- Dihydrofolate is responsible for converting folic acid to its active coenzyme form, tetra folic acid (FH4)
- -It decreases the biosynthesis of adenine, guanine, thymidine, methionine and serine– which leads to depressed DNA, RNA and protein synthesis and ultimately cell death.
*Antagonist of folic acid… explains why it’s also an abortifacient.
20
Q
Leflunomide:
A
- Leflunomide reversibly inhibits dihydroorotate dehydrogenase (DHODH) and therefore deprives the cells of the precursor for uridine monophosphate (UMP).
- It reduces pain and inflammation associated with the disease, and slows progression of structural damage.
21
Q
Immunosuppressive Alkylating Agents:
A
- Alkylation of DNA is lethal to cells.
- Includes Mechlorethamine & Cyclophosphamide
- Alkylating agents do not discriminate between cycling and resting (cell cycle non specific)
- They are mutagenic and carcinogenic, and can lead to a second malignancy such a acute leukemia.
22
Q
Mechlorethamine:
A
-Alkylates the N-7 nitrogen of a guanine residue in one or both strands of a DNA molecule, leading to cross linkage between guanine residues in the DNA chains.
–>It has been largely replaced by cyclophosphamide.
Mechanism of Action: (Alkylation of guanine bases in DNA is responsible for the cytotoxic effects of Mechlorethamine)
23
Q
Cyclophosphamide:
A
- Older and most commonly used alkylating agent.
- It is bio-transformed to the active compound, phosphoramide mustard, which alkylates DNA.
24
Q
Conventions for naming Antibodies:
A
Murine antibodies– MURO in their name (ex. muromonab)
Humanized antibodies- have ZU in their name (ex. Daclizumab)
Chimeric Antibodies- XI in their names (ex. Basiliximab)
25
Anti- thymocyte globulins:
-Purified polyclonal antibodies (gamma globulins) from a rabbit and used for the treatment of acute renal transplant rejection (in conjunction with immunosuppressive agents)
--Used for the depletion of T cells (lymphopenia), reducing impaired T cell responses. Humoral (B cell mediated) antibody mechanism remains active.
26
Muromonab:
- Murine antibody
- Used for the depletion of human T cells
- Used in autoimmune disorders and renal, cardiac and hepatic transplant patients, and for the depletion of T cells from the donor bone marrow.
27
Adverse Effects of Antibodies:
Adverse Effects:
-“Cytokine Release Syndrome” aka Cytokine Storm: release of TNF, IL-2, IL-6 and INF-alpha
*Using humanized anti-CD3 mAb can minimize this effect.
28
Intravenous Immunoglobulins:
-The IV use of polyclonal human antibodies (IgG) pooled from thousands of healthy human donors, for the treatment of IgG deficiencies, AIDS, autoimmune disorders and bone marrow transplants.
29
Hyperimmune Immunoglobulins:
IV IgG high titers of Ab against particular agents of interest, such as viruses and toxins.
--Various hyperimmune IV IgG's are available for respiratory syncytial virus (RSV), herpesvirus 3, HBV, rabies, tetanus and digoxin overdose.
30
Omalizumab:
-Anti-IgE recombinant humanized mAb which blocks the building of IgE to Fce receptor.
Used for the treatment of allergic asthma patients whose symptoms are refractory to inhaled corticosteroids.
31
Basiliximab & Daclizumab:
IL-2 receptor antagonists
- -Humanized mAbs
- Used with CsA and glucocorticoids
- Both are anti- CD25 mAbs (binds to the alpha chain of the IL-2 receptor on activated T cells)
-Used for the prophylaxis of acute organ rejection in adult patients.
32
Infliximab:
- TNF-alpha Antagonist
| - ->Chimeric Antibody (Ab)
33
Adalimumab:
- TNF-alpha Antagonist
| - ->Humanized Ab
34
Etanercept:
- TNF-alpha Antagonist
- ->Fusion protein which is comprised part of TNF p75 receptor and the Fc portion human IgG. It binds TNF-alpha and lymphotoxin (LT)
35
Certolizumab:
- TNF-alpha Antagonist
| - Pegylated Ab lacking an Fc region
36
Golimumab:
- TNF-alpha Antagonist
| - ->Humanized Ab
37
Efficacy of Anti- TNFalpha drugs in Rheumatoid Arthritis;
- All 3 anti-TNF drugs show similar results.
- Efficacy of anti- TNF therapy in key domains:
1. Rapid improvement in symptoms and signs
2. Radiographic inhibition of structural damage in majority (possible healing in a subgroup)
- -In early disease, it leads to infliximab- free control or remission in approx. 50% exceeding 3 years
Reduction in CV comorbidity and mortality.
*Co-therapy with methotrexate augments efficacy.
38
Adverse Effects of Anti- TNF alpha drugs:
- Injection site reactions
- Infections*- especially in people who had have TB, TBV, HCV and HIV
* All active infections must be treated prior to anti- TNF-alpha therapy
- Always take preventative measures
- -Tuberculin skin test
- -Chest X ray examination
*TNF-alpha antagonists have increased risk for malignancies and may exacerbate cardiac failure.
39
Anakinra:
- Is a recombinant form of IL-1 receptor antagonists (IL-1 Ra)
- Differs from the natural protein by a single methionine residue at its amino terminus.
- Clinical uses and AE effects are similar to INF- alpha antagonists.
- Asthma may be a co-morbid risk factor for serious infections.
- Concomitant use of ANAKINRA and ETANERCEPT increases the risk of neutropenia and serious infections (only in exceptional circumstances and extremely cautiously)
40
Other Antibodies:
* Tocilizumab: A humanized Ab specific for Il-6 receptor
* Rituximab: A chimeric mAb specific for CD20 (an antigen on mature B cells)
* Abatacept: A fusion protein comprising the extracellular domain of human cytotoxic T lymphocyte antigen 4 (CTLA4) and the Fc portion of human IgG.
--These drugs are used in patients who have failed to respond to both DMARDS and TNF antagonists.
41
Immunostimulatory Agents:
- Clinical Uses- to treat infections, immunodeficiency and cancer.
- Recombinant cytokines: Includes Interferons (IFN's), Interleukins (IL-2's) and CSF's
42
Which drugs are considered DMARDS ?
All but TNF-alpha antagonists
43
Recombinant Interleukin-2:
-Recombinant human IL-2 is produced by recombinant DNA technology in E. coli
- It's in vivo actions (STIMULATES an immune response)
- Enhances cellular immunity
- ->IL-2 promotes proliferation and differentiation of lymphocytes into CTL's and activation of NK cells.
- -Lymphocytosis, eosinophilia and thrombocytopenia
- Release of multiple cytokines (eg. TNF, IL-1 and IFN- gamma)
Clinical Uses:
-Treatment of breast cancer, metastatic renal cell carcinoma and AIDS (in combination)
AE: With severe CV toxicity, resulting from capillary leak syndrome (loss of vascular tone and leak from plasma proteins and fluids into extracellular space)
44
Granulocyte Colony Stimulating Factors (G-CSF's):
-Granulocyte- CSF stimulate the production of neutrophils.
Granulocyte- macrophage CSF- (GM-CSF) stimulates the production of granulocytes, platelets, erythrocytes, eosinophils and macrophages.
