Immunopharmacology

Question 1

Prednisone

Answer 1

• prodrug of prednisolone, metabolized in vivo, represses COX-2 expression, decrases cytokine production, decreased production of endogenous inflammatory mediators, causes apoptois of eosinophils

Question 2

Cyclosporine

Answer 2

• calcineurin inhibitor- binds to cyclophilin and the complex binds to and inhibits phosphatase activity of calcineurin, preventing dephosphorylation and transolcation of NF-AT (a transcription factor that stimulates cytokine gene expression)
• Inhibition of T cell activation; decrased IL-2, IL-3, IL-4, TNF-a, IFN-y. Restasis formulation used to increase tear production that has decreased due to inflammation. Used to prevent organ rejection; TX for RA, psoriasis, IBD
• metabolized by CYP3A4, many drug interactions; narrow therapeutic window- therapeutic drug monitoring
• gingival hyperplasia is a specific adverse effect; others include nephrotoxicity, hypertension, hirsutism, hyperglycemia (rare)

Question 3

Tacrolimus

Answer 3

• forms complex with FK binding protein that binds to and inhibits phosphatase activity of calcineurin; prevents the dephosphorylation and translocation of NF-AT which stimulates cytokine gene expression–> inhibition of T cell activation and decreased release of IL-2, IL-3, IL-4, TNF-a, IFN-y;
• 50-100X more potent than cyclosporine; used to prevent organ rejection and as TX for psoriasis, atopic dermatitis
• mebabolized by CYP3A4 so many drug interactions; metabolites excreted in bile; concentrates in pancreas so may inhibit pancreatic insulin secretion (hyperglycemia more common than cyclosporine)
• therapeutic drug monitoring

Question 4

Sirolimus

Answer 4

• Binds to FK binding protein, complex then binds to and inhibits mTOR, a key kinase involved in upstream regulation of protein synthesis, cell growth, proliferation; inhibits progression from G1 to S phase of the cell cycle. Cytostatic- T cells still produce cytokines but fail to proliferate
• used to prevent rejection after renal transplant but not liver or lung transplant
• metabolized by CYP3A4
• pulmonary, heme, GI, metabolic, nephroxotic and may potentiate calcineurin inhibitor induced nephrotoxicity. use therapeutic drug monitoring

Question 5

Azathioprine

Answer 5

• Purine synthesis inhibitor
• Azathioprine → 6-MP → 6-thioguanine → 6-thioguanine nucleotides, which are incorporated into DNA and RNA → impaired function
• used in kidney transplant to prevent rejection as ell as TX for RA, Crohn’s; 6-MP is antileukemia agent
• shows good oral absorption; 6-MP is inactivated by oxidation by xanthine oxidase and methylation by thiopurine-S-methyltransferase; excretion is mostly renal

Question 6

Mycophenolate mofetil

Answer 6

Purine synthesis inhibitor

• reversible inhibitor of inosine monophosphate dehydrogenase, inhibits the de novo pathway of guanosine biosynthesis that is critical to lymphocyte proliferation and activation, resulting in blunted T and B cell responses; Selective for lymphocytes- other cells are able to recover purines via salvage pathway so can escape the effect
• Used with or as an alternative to cyclosporine/ tacrolimus to prevent organ rejection after renal, cardiac, or liver transplants. Less bone marrow suppression than azathioprine

Question 7

Muromonab-CD3

Answer 7

Immunosuppressive Antibody
- Murine monoclonal antibody that binds to T cell receptor associated CD3 complex, causing initial activation and cytokine release followed by blockade, apoptosis, and depletion of T cells
Triggers cytokine release syndrome: fever, chills, headache, tremor, dyspnea, chest pain, NVD. Subsides after about a day and can be avoided w/ glucocorticoid treatment. Seizures, rarely anaphylaxis

Question 8

Basiliximab

Answer 8

Immunosuppressive antibody (recombinant human mouse, IgG vs IL-2)

• IL-2 receptor antagonist; binds with high affinity to CD-25 (the IL-2 receptor a chain) on activated T cells, preventing activation by IL-2. CD25 is expressed only on activated T cells so does not cause depletion of all T cells
• Anti-CD25 antibody, recombinant human-mouse IgG vs IL-2 receptor-CD25 complex. Used for prophylaxis of acute rejection following kidney transplant, combined with cyclosporine and glucocorticoid

Question 9

Adalimumab

Answer 9

Fully humanized monoclonal immunosuppressive antibody

• Binds to TNF-a preventing its interactions with p55 an dp75 on cell surface. Decreased pro-inflammatory cytokines IL-1 and IL-6, decreased leukocyte migration, activation of neutrophils and eosinophils, decrased fibroblast proliferation, synthesis of prostaglandins, matrix metalloproteinases
• TX for RA, Crohn’s, ankylosing spondylitis, psoriasis
• given by sc injection every two weeks
• do not use if chronic or recurrent infection, TB, travel to area with endemic TB or mycoses