Lecture 12: Immunosuppressants, steroidal anti-inflammatory drugs & anti-cytokine drugs Flashcards
Major groups of anti-inflammatory drugs (not LOs)
- Drugs that inhibit the cyclo-oxygenase (COX) enzyme.
–> non-steroidal anti-inflammatory drugs (NSAIDs)
–> includes coxibs (COX-2 selective inhibitors) - Antirheumatoid drugs- the so-called disease-modifying antirheumatic drugs (DMARDs)
–> with some immunosuppressants - The glucocorticoids (steroidal anti-inflammatories)
- Anti-cytokines and other biopharmaceutical agents
- Antihistamines used for the treatment of allergic imflalmmation.
- Drugs specifically used to control gout.
Immunosuppressants (not LOs)
-Used in the therapy of autoimmune disease.
-Used to prevent an/or treat transplant rejection.
-They impair immune responses
–> response to infections is decreased
–> malignant cell lines may emerge
General features of autoimmune diseases
- characterized by presence of autoantibodies and autoreactive T cells against self-antigens.
Antibodies frequently detected:
- anti-DNA antibody in systemic lupus erythematosus (SLE)
- rheumatoif factor (autoantibody too lgG) in rheumatoid arthritis;
Immunosuppressants: Clinical use (not LOs)
- suppress rejection of transplanted organs
- suppress graft-versus-host disease (GVHD)
- to treat conditions with an autoimmune component.
Immunosuppressants: MOA (not LOs)
- Most act during the induction phase reducing lymphocyte proliferation.
- Other also inhibit the effector phase.
Clinical use and MOA of cyclosporine (ciclosporin)
(immunosuppressants)
- Discover as a specific inhibitor of T-cell-mediated immunity
- not cytotoxic
- inhibit IL-2 production/action
- main action is a selective inhibition of IL-2 gene transcription; similar effect on interferon (IFN)-y and IL-3
Clinical use and MOA of tacrolimus (immunosuppressants)
- acts by binding to FK-binding proteins (FKBP)
- inhibits IL-2, IL-3, IL-4, IFN-y, and TNF-a production; inhibits cell-mediated immunity without suppressing B cell or natural killer (NK) cell function.
- doesn’t look like the structure of cyclosporin but mechanisms are very similar
-more severe side effects than cyclosporine
Pharmacokinetics of CsA (not LOs)
-Poorly absorbed by mouth (IV)
- Plasma half-life ~24h
- metabolism occurs in liver
- Cyclosporine accumulates in most tissues @ concentrations three to four times that seen in the plasma.
Unwanted effects of CsA (small TI) (not LOs)
-Nephrotoxicity
-Hepatotoxicity
-Hypertension
—> anorexia, tremor….
- has no depressant effect on the bone marrow
- Interacts w a wide variety of other drugs & grapefruit juice
Cyclosporine vs tacrolimus
- cytophilin and FK-binding protein (FKBP) are immunophilins.
(CsA (unlike FK506) is antiapoptotic: prevents opening of mitochondrial permeability transition (PT) pore -> inhibits Cyt C (pro-apoptotic factor) release into cytoplasm.
Pharmacokinetics of tacrolimus
-Can be given orally by IV or as an ointment for topical use in inflammatory disease of the skin.
- 99% metabolized by the liver and has half-life of ~7h
Unwanted effects of tacrolimus
-Similar to CsA, but more severe
–> incidence of nephrotoxicity and neurotoxicity is higher.
clinical use and MOA of drug interactions with grapefruit juice
- GJ undergo cytochrome P450 oxidative metabolism in the intestinal wall or liver.
- contain various furanocoumarins affect CYP system –> CYP3A4
- bind to CYP3A4 as substrate and impair first-pass metabolism.
Effect: selective down-regulation of CYP3A4 in the small intestine.
-less drug metabolized prior to absorption, greater amounts reach the systemic circulation -> higher blood levels -> increases in therapeutic and/or toxic effects.
MOA of cytotoxic agents + their use as immunosuppressants:
Cyclophosphamide
- Used in combinations with gluccorticosteroids.
- alkylates DNA (interferes with DNA synthesis and cell division.
- prodrug -> activated by the cytochrome P450
- most active during the S phase of DNA synthesis.
- Also used for the chemotherapy of leukemias, lymphomas and other neoplasms.
- Immunosuppresent activity -> prevents the clonal expansion of both B and T cells, and induces lymphocytopenia.
–> inhibits B-cell antibody production
–> suppresses cytokine production of Tcells.
–> Inhibits inflammatory & immune activites of monocytes. - administered orally or IV
- unwanted effects –> permanent amenorrhea (absence of menstrual periods), azoospermia, increased risk of malignancy, bone marrow suppression.
MOA of cytotoxic agents + their use as immunosuppressants:
Azathioprine
- Used for immunosuppression and to prevent tissue rejection.
- metabolized to give mercaptopurine.
- Inhibits clonal proliferation (B and T cells)
-Main unwanted effect = depression of the bone marrow
-others: nausea & vomiting, skin eruption.
