Ch. 69: Immunosuppressants

Question 1

Calcineurin Inhibitors

Answer 1

• cyclosporine, tacrolimus, and pimecrolimus are most effective
• share same mechanism: inhibit calcineurin, suppressing production of IL-2 (T-cell proliferation)
• prevention of organ rejection in transplants

Question 2

Cyclosporine

Answer 2

• molecular target is a protein called cyclophilin
• does not cause bone marrow suppression
• therapeutic use: drug of choice to prevent organ rejection in recipients of an allogenic transplant; also used for psoriasis and rheumatoid arthritis
• pharmacokinetics: orally (preferred- GI tract is incomplete and erratic) or IV; protein bound; excreted via bile
• adverse effect: nephrotoxicity (75% of patients- renal failure is reversed after reduction) and increased risk of infection (74% of patients; latent infection with BK virus can result in kidney damage)
• drugs that decrease levels: induce CYP3A4 accelerates metabolism
• drugs that increase levels: inhibit CYP3A
• nephrotoxic drugs can intensify renal damage
• grapefruit inhibits metabolism
• repaglinide levels can increase (diabetes drug) causing hyperglycemia

Question 3

Tacrolimus

Answer 3

• preventing allograft rejection; transplant in liver, kidney, or heart
• more effective but more toxic than cyclosporine
• must first bind to intracellular protein called FKBP-12
• pharmacokinetics: orally (slow and incomplete) or IV; metabolized by CYP3A4; excreted via bile; half-life is 8-9 hours
• adverse effects: nephrotoxicity (33-40%), neurotoxicity, GI effects, hypertension, hyperkalemia, hyperglycemia, hirsutism and gum hyperplasia; increases risk of infection; anaphlyaxis with IV admin
• agents that inhibit CYP3A4 increased levels
• NSAIDS can injure kidneys

Question 4

mTOR Inhibitors

Answer 4

• inhibit mammalian target of rapamycin (mTOR), a protein kinase to regulate cell growth, proliferation, and survival
• suppress B and T cell proliferation

Question 5

Sirolimus

Answer 5

Actions: prevent rejection of renal transplant
- binds with FKBP-12 and inhibits mTOR making IL-2 unable to cause activation
Pharmacokinetics: rapidly but incompletely absorbed; food reduces the rate but increases the extent of absorption; metabolized by CYP3A4; excretion via bile and breast milk
Adverse Effects: increase risk of infection, raises levels of cholesterol and triglycerides, liver and problems
- reduce immune response to all vaccines

Question 6

Everolimus

Answer 6

Use: prevent rejection in 18 years and older following liver or kidney transplant
- treat advances renal cancer
Action: sae as sirolimus
Pharmacokinetics: oral and plasma peaks 1-2 hours after dosing; excreted by feces
Adverse: peripheral edema, constipation, hypertension, nausea, anemia, UTI, any hyperlipidemia

Question 7

Cytotoxic Drugs

Answer 7

• kill B and T lymphocytes undergoing proliferation
• nonspecific- cause bone marrow suppression, GI problems, reduced fertility, and alopecia
• for patients who have not responded to safer immunosuppressants