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.
Human glucocorticoid system
- Affect the immune response
- Possess anti-inflammatory actions
- Restrain clonal proliferation through decreasing transcription of the gene for IL-2.
-Decrease the transcription of many other cytokine genes in both induction and effector phases. - effects mediated through inhibition of the action of transcription factors:
- activation protein-1 (AP-1)
- nuclear factor kB (NFkB)
Adrenal steroids
- adrenal cortex
-ACTH released from anterior pituitary gland in brain. - The adrenal glands above kidneys
–>medulla secretes catecholamines
–> cortex secretes adrenal steroids
Two types:
-mineralocorticoids –> water and electrolyte balance
-glucocorticoids –> actions on intermediate metabolism
Main features of glucocorticoids as anti-inflammatory and immunosuppressive drugs
-Clinical uses
-MOA
-Main effects
-Adverse effects
- Adrenal gland secretes a mixture of glucocorticoids.
-Main hormone in humans = hydrocortisone - Rodents = corticosterone
- anti-inflammatory and immunosuppressive properties, therefore all their metabolic and other actions are seen as unwanted side effects.
-essential hormones
-deficiency in corticosteroid production = Addison’s disease.
- excessive glucocorticoid = cushing’s syndrome.
–> hypersecretion from the adrenal glands
–> by prolonged therapeutic glucocorticoid regimens.
- possible = to separate, the glucocortiod from the mineralocortoid actions.
- Not possible = separate, anti-inflammatory actions from other actions
- intracellular glucocortiod receptors (GRs)
- nuclear receptor superfamily
- transactivation -
TM low level
positive glucocortiod response elements (GREs) and upregulates transcription - transrepression -
driven by TF
negative glucocorticoid esponse elements (nGRE) and expression falls.
-AP-1 and NFkB involved.
MAIN METABOLIC EFFECTS
- carbohydrate & protein metabolism
–> decrease the uptake and utilization of glucose = hyperglycaemia
–> increase in glycogen storage
-decrease protein synthesis
-Large doses over long period = Crushing’s syndrome
- Produce negative calcium balance = osteoporosis
- Both endogenous & exogenous have negative feedback.
Clinical use
- Replacement therapy (adrenal failure)
-Anti-inflammatory/immunosuppressive therapy:
-> asthma
->inflammatory conditions of skin/eye/ear/nose
->hypersensitivity states
-> autoimmune/inflammatory diseases
-In neoplastic disease:
–> in combination with cytotoxic drugs
-reduce cerebral edema
Pharmacokinetics:
- oral, topical or parenteral or also IV or intramuscularly
-Pharmacologic levels of systemic glucorticoids invariably = in severe adverse effects
UNWANTED EFFECTS
- suppression of the response to infection
–> opportunistic infection serious unless quickly treated with antimicrobial agents along with an increase in the dose of steroid.
- wound healing may be impaired
-peptic ulceration
-metabolic actions
-Suppression of endogenous glucocorticoid = Cushing’s syndrome .
Hydrocortisone < Prednisolone < Dexamethasone
Anti-cytokine therapies: current and future drugs
ADVANTAGE:
specific aspects of the inflammatory diseases
DISADVANTAGE:
-Biopharmaceuticals
-difficult to produce
-expensive
- Infliximab = monoclonal antibody against tumor necrosis factor (TNF)-a
- Etanercept = TNF receptor
- Adalimumab = monoclonal antibody against tumor necrosis factor (TNF)-a
- Those three bind TNF and inhibit its effects
- Basiliximab = IL-2 receptor (blocking this receptor on Th cells)
-can be given once a week
None of these drugs can be given orally as a protein.
- must be administered parenterally
- Orally active TNF-a inhibitor: thalidomide
-unwanted effects because they are inflammatories they may be precipitate latent disease or encourage opportunistic infections.
Stress-induced increase in cortisol limits the extent of the inflammatory responses.
CRH =?
ACTH=?
CRH = corticotropin-releasing hormone
ACTH = adrenocorticotrophic hormone
Actions of inflammatory cells:
- Decreased egress of neutrophils
- reduced activation of neutrophils and macrophages.
- Decreased activation of T helper cells (Th)
- Reduced clonal proliferation of T cells
- Decreased fibroblast function -> reduced healing and repair
- Decreased expression of COX-2
- Decreased gene transcription
- Reduction of complement components
- Decreased generation induced nitric oxide
- Decreased histamine
- Decreased lgG
- Inhibit the release of arachidonate
- Increased synthesis of anti-inflammatory factors.
