IMMUNOPHARMACOLOGY Flashcards
List 7 different types of immunosuppressive drugs?
Glucocorticoids Calcineurin Inhibitors Proliferation Signal Inhibitors Inhibitors of Angiogenesis Cytotoxic Agents Other Agents Immunosuppressive Antibodies
Glucocorticoids effects and how does it modulate its effects?
• Glucocorticoids have broad anti-inflammatory
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 upregulating or down-regulating gene expression
• Glucocorticoids down-regulate the expression
of many inflammatory mediators.
• The overall effect of glucocorticoid administration
is profoundly anti-inflammatory and
immunosuppressive.
GLUCOCORTICOIDS:
ANTI-INFLAMMATORY MOA
• Glucocorticoids relieve pain due to the modulation
of inflammatory responses.
• Glucocorticoids suppress several inflammatory
pathways.
• Glucocorticoids inhibit prostaglandin synthesis
through independent mechanisms:
• Inhibition of PLA2
• Reduction of transcription of COX-2
GLUCOCORTICOIDS: ADVERSE EFFECTS?
• Short-term use: hypertension, hyperglycemia,
immunosuppression, psychotic reactions, and
cognitive impairment.
• Long-term use: myopathy, Cushing’s syndrome,
and osteoporosis.
GLUCOCORTICOIDS: USES?
• Used to prevent and treat transplant rejection.
• Used to treat autoimmune disorders such as
rheumatoid arthritis, SLE, psoriasis, asthma, and
IBD.
• In palliative care glucocorticoids are used to
alleviate pain, nausea, and fatigue.
• Used to treat pain, including neuropathic and bone pain. Dexamethasone is usually preferred because of its long half-life and low mineralocorticoid
effects.
List 2 Calcineurin inhibitors?
- Cyclosporine
* Tacrolimus
Cyclosporine moa?
• Calcineurin is a phosphatase necessary for activation of a Tcell-specific transcription factor: NFAT. • NFAT is required for the induction of cytokine genes. • Cyclosporine forms a complex with cyclophilin, an immunophilin. • This complex inhibits calcineurin
Cyclosporine AE?
• Main adverse reactions: Nephrotoxicity, tremor,
hypertension, hyperglycemia, hyperlipidemia,
osteoporosis, hirsutism, gum hyperplasia.
• Nephrotoxicity is limiting and occurs in the
majority of patients treated. Major indication
for cessation of therapy.
• Very little bone marrow toxicity.
Cyclosporine drug interactions and uses?
• Primarily metabolized by CYP3A4: involved in
many drug interactions.
uses: • Organ transplantation • Uveitis • Rheumatoid arthritis • Psoriasis
Tacrolimus moa?
- Tacrolimus binds to FK-binding protein (FKBP).
- FKBP is an immunophilin.
- The tacrolimus-FKBP complex inhibits calcineurin.
Tacrolimus AE?
- Nephrotoxicity
- Neurotoxicity
- Hyperglycemia
- Hypertension
- Hyperkalemia
- GI complaints
TACROLIMUS: USES?
• Prevention of rejection of transplanted kidneys,
liver or heart.
• Topical formulation is used for atopic dermatitis
and psoriasis.
SIROLIMUS category and moa?
PROLIFERATION SIGNAL INHIBITORS
• 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.
Sirolimus AE?
• Myelosuppression • Hepatotoxicity • Diarrhea • Hypertriglyceridemia • Pneumonitis • Headache. • Nephrotoxicity is less common than with calcineurin inhibitors.
Sirolimus uses?
• Renal transplantation.
• Sirolimus-eluting coronary stents are used to
inhibit restenosis of the blood vessels in patients
with severe CAD by reducing cell proliferation.
Thalidomide category, actions, and uses?
INHIBITORS OF ANGIOGENESIS
- Its mechanism of action is unclear.
- Inhibits synthesis of TNF-α.
- Inhibits angiogenesis.
- Thalidomide is now called an immunomodulatory drug.
- Indicated for the treatment of patients with erythema nodosum leprosum and multiple myeloma
Two categories falling under cytotoxic agents?
- ANTIMETABOLITES
* ALKYLATING AGENTS
Name 4 antimetabolites?
- Azathioprine
- Methotrexate
- Mycophenolate mofetil
- Leflunomide
AZATHIOPRINE: ADVERSE EFFECTS?
- Bone marrow suppression
- GI disturbances
- Increase in infections and malignancies
Azathioprine moa?
• Purine antimetabolite.
• Prodrug of 6-mercaptopurine.
• 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.
AZATHIOPRINE: DRUG INTERACTIONS?
• Much of the drug’s inactivation depends on
xanthine oxidase.
• Patients who are also receiving allopurinol for
control of hyperuricemia should have the dose of
azathioprine reduced.
AZATHIOPRINE: USES?
- Prevention of organ transplant rejection
* Severe rheumatoid arthritis
Methotrexate moa?
• Methotrexate’s main mechanism of action at the
low doses used in rheumatic diseases is inhibition of aminoimidazolecarboxamide
ribonucleotide (AICAR) transformylase
• AICAR transformylase catalyzes the penultimate
and 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.
METHOTREXATE: ADVERSE EFFECTS?
- Nausea
- Mucosal ulcers
- Leukopenia
- Anemia
- GI ulcerations
- Hepatotoxicity
- Cirrhosis is rare.
- Hypersensitivity pneumonitis
