Miscellaneous Topics in Pharmacology
IMMUNOSUPPRESSIVE AGENTS
What are the main targets of immunosuppressive agents?
Inhibition of gene expression; inhibition of lymphocyte signaling and activation; depletion of proliferating lymphocytes; inhibition of cytokine action; depletion of specific immune cells; blockade of costimulation; blockade of cell adhesion and migration; inhibition of complement activation
Which agents are signaling inhibitors of B-/T-cell proliferation?
Cyclosporine A, tacrolimus, and sirolimus
What is the mechanism of action of cyclosporine A?
Complexes with cyclophilin to inhibit calcineurin, thereby decreasing interleukin (IL)-2, which is the main inducer for activation of T lymphocytes
What are the main therapeutic indications of cyclosporine A?
Prevention of organ rejection in heart, kidney, and liver transplants
What are the adverse effects of cyclosporine A?
Nephrotoxicity; hepatotoxicity; cytomegalovirus (CMV) infections; hypertension; hyperkalemia; hirsutism; glucose intolerance; gingival hyperplasia; tremor; upper respiratory infections; anemia; leukopenia; thrombocytopenia
Name three medications that can cause gingival hyperplasia:
- Cyclosporine
- Phenytoin
- Nifedipine
What major hepatic enzyme metabolizes cyclosporine A?
CYP 3A4
Cyclosporine A becomes more effective as an immunosuppressant when combined with what class of drugs?
Glucocorticoids
FK506 is also known as?
Tacrolimus
What are the main therapeutic indications of tacrolimus?
Prevention of organ rejection in liver and kidney transplants
What is the mechanism of action of tacrolimus?
It inhibits calcineurin by binding to FK binding protein (FKBP) rather than cyclophilin, cyclosporin’s target protein. It inhibits the signaling pathway coupling cell receptor activation of IL-2 gene transcription (IL-2 synthesis).
What is the mechanism of action of sirolimus?
It blocks IL-2 receptor signaling required for cell activation and proliferation. It forms a complex with the immunophilin FKBP, it does not affect calcineurin activity, but inhibits the kinase mTOR, which is necessary for cell growth and proliferation.
What are the adverse effects of tacrolimus?
Nephrotoxicity; neurotoxicity; hypertension; headache; tremor; rash; hyperglycemia; hyperkalemia; anemia; leukocytosis; thrombocytopenia
Which murine monoclonal antibody interferes with T-lymphocyte function by binding to CD3 glycoprotein?
Muromonab-CD3 (OKT3)
Give examples of cytotoxic agents used in immunosuppressive therapy:
Azathioprine, mycophenolate mofetil, methotrexate, leflunomide, hydroxychloroquine, cyclophosphamide
Which cytotoxic agents used in immunosuppressive therapy are pro-drugs?
Azathioprine, mycophenolate mofetil, leflunomide
Which cytotoxic immunosuppressant is an alkylating agent?
Cyclophosphamide
Which immunosuppressant is a derivative of 6-mercaptopurine, antagonizes purine metabolism, and is cytotoxic to lymphocytes?
Azathioprine
Which immunosuppressant inhibits inosine monophosphate dehydrogenase, thereby inhibiting de novo guanosine nucleotide synthesis?
Mycophenolate mofetil
Which immunosuppressive agents are cytokine inhibitors?
Etanercept, infliximab, adalimumab, certolizumab, thalidomide, anakinra
Which cytokine inhibitor is not a tumor necrosis alpha (TNF-α) inhibitor?
Anakinra (It is an interleukin-1 [IL-1] receptor antagonist.)
Give two examples of immunosuppressive agents that inhibit costimulation:
- Abatacept
- Belatacept
Give two examples of immunosuppressive agents that block cell adhesion:
- Natalizumab
- Efalizumab
Give an example of an immunosuppressive agent that blocks complement action:
Eculizumab
AGENTS FOR OBESITY
What anorexiant works by increasing dopamine and norepinephrine levels in the brain?
Phentermine
What anorexiant works by blocking reuptake of serotonin, norepinephrine, and dopamine into presynaptic nerve terminals in the brain?
Sibutramine
What are the adverse effects of phentermine and sibutramine?
Tachycardia; hypertension; headache; insomnia; dry mouth; constipation
What drugs should be avoided in patients taking sibutramine?
Monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); dextromethorphan
What popular name was given to the combination regimen fenfluramine and phentermine and why was it eventually pulled off of the market?
Fen-phen (combination of fenfluramine and phentermine); pulmonary hypertension and heart valve abnormalities. Fenfluramine was removed from the markets in 1997 in the United States because of these side effects.
What antiobesity agent inhibits gastric and pancreatic lipase, thereby inhibiting breakdown of dietary fat?
Orlistat
What are the adverse effects of orlistat?
Oily spotting; abdominal discomfort; flatus with discharge; fatty stools; fecal urgency; increased defecation
What vitamin supplementation is recommended in patients taking orlistat?
Fat-soluble vitamins
What are the fat-soluble vitamins?
A; D; E; K
AGENTS FOR OSTEOPOROSIS
Give examples of medications that belong to the bisphosphonate drug class:
Alendronate; risedronate; etidronate; pamidronate; ibandronate
What is the mechanism of action of the bisphosphonates?
Inhibition of osteoclast-mediated bone resorption
Which bisphosphonate can only be administered intravenously?
Pamidronate
What must patients be counseled on regarding oral bisphosphonate therapy?
Take medication with a full glass of water and stay in a sitting or standing position for 30 minutes following administration to prevent esophageal irritation.
Intravenous pamidronate can also be used to treat what conditions?
Hypercalcemia of malignancy; osteolytic bone lesions associated with multiple myeloma or metastatic breast cancer
What selective estrogen receptor modulator can increase bone density in women without increasing the risk for endometrial cancer?
Raloxifene
How is calcitonin administered?
Intranasally
What is the source of medically used intranasal calcitonin?
Salmon
How much calcium should a postmenopausal woman take daily?
Calcium should be taken with what other supplement to enhance its absorption?
Vitamin D
What recombinant N-terminal 34-amino-acid sequence of parathyroid hormone stimulates osteoblast function, increases gastrointestinal (GI) calcium absorption, and increases renal tubular reabsorption of calcium?
Teriparatide
AGENTS FOR ERECTILE DYSFUNCTION
What prostaglandin ET(PGE1) analog is injected into the corpus cavernosum and causes increased arterial inflow and decreased venous outflow to and from the penis, respectively?
Alprostadil
What is the mechanism of action of sildenafil?
Enhances the vasodilatory effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE-5) which allows for increased cyclic guanosine monophosphate (cGMP) levels (cGMP causes smooth muscle relaxation in the corpus cavernosum)
Name two other PDE-5 inhibitors used in the treatment of erectile dysfunction:
- Tadalafil
- Vardenafil
- Udenafil
- Avanafil
What are the adverse effects of sildenafil?
Headache; dizziness; color vision disturbances; hypotension
Sildenafil is contraindicated in patients taking what type of medications?
Nitrates (potentiates hypotension)
AGENTS FOR RHEUMATOID ARTHRITIS
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