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Chapter 5, Drug Toxicity Learning Objectives “All substances are poison; there is none which is not poison The right dose differentiates a poison and a remedy” –Paracelsus 1. Diphenhydramine is a first generation H1 receptor antagonist that has the side effect of somnolence? What do you call this effect? This is an “on target” adverse effect in an unintended tissue (the brain) 2. How does haloperidol cause its adverse effects? D2 receptor blockade causes increase in prolactin secretion => amenorrhea, galactorrhea 3. 4. What is a rare side effect of -statin therapy? Rhabdomyolyisis and myositis occurs in -statin therapy due to the geranyl-geranylation of muslce proteins i. Muscle disorders also occur in corticosteroid therapy What kind of compound that inhibits the hERG channel is safe for the heart? hERG (IKr potassium channel) inhibitors that have an IC50 (half-maximal inhibitory concentration ) more than 30 times the Cmax (maximum plasma conc. at therapeutic dose) pose a low risk of torsades de pointes i. Ex) fexofenadine 5. Which enantiomer of thalidomide is teratogenic? (S)-thalidomide [S is closer to T, for Teratogenic] 6. How can the effectiveness of penicillin be extended? probenecid can lengthen the half life of penicillin by inhibition of renal tubular transport 7. How does the combination of sildenafil and nitroglycerin cause dangerous hypotension? Sildenafil inhibits PDE5,which prolongs the action of cGMP nitroglycerin stimulates guanylyl cyclase to increase cGMP 8. Drug-herb interactions: Ginko biloba Echinacea St. John’s wort 9. + NSAIDS = bleeding [Said the gecko drinking blood] + acetominophen = hepatotoxicity [echidna liver] + SSRIs = serotonergic syndrome [st John trippin] What is a hapten? Small molecule drugs can act as haptens, which can bind to proteins in the body and trigger an immune response 10. What are immediate and delyaed hypersensitivity reactions? Give examples of drugs causing hypersensitivity reaction types I-IV: I (immediate ~30 min): IgE, wheal and flare i. penicillin II: IgG and CD8+ T cells on cell surfaces (usually RBCs), hemolysis i. Quinidine [planes/surfaces are II dimensional] III: IgG or IgM deposition, serum sickness, antivenins help i. bupropion IV (delayed 2-3 days): Th1 and CD8+ T cells, contact dermatitis, eventual cytokine storm i. Ciprofloxacin, latex, mantoux test 11. Where does red man syndrome show on the body? What drugs can cause red man syndrome? Red man syndrome is caused when mast cells are stimulated, and presents as cutaneous wheals and urticaria localized to the neck, arms, and upper trunk Vancomycin is the main causative agent, but ciprofloxacin, amphotericin B, rifampin, cremophor, and teicoplanin can also cause red man syndrome 12. What drugs cause the skin rashes known as Stevens-Johnson sydrome and toxic epidermal necrolysis? Phenytoin, carbamazepine, ibuprofen, celecoxib, and allopurinol cause Stevens-Johnson syndrome (anti-epileptics, painkillers, and anti-gout) 13. What drug in the text causes a resurgence in dormant JC virus and hepatitis B, leading to progressive multifocal leukoencephalopathy? Rituximab (B cell NHL) causes this syndrome because it inhibits CD20+ B cells (immunosuppression) i. Natalizumab can also unleash PML 14. What is the antiobiotic gentamicin’s negative effect? What is the bad effect of the antifungal Amphotericin B? Gentamycin causes renal phospholipidosis, which leads to lysozomal rupture and acute tubular necrosis Amphotericin-B reacts with cholesterol to form pores, which causes kidney injury 15. What kinds of compounds cause peripheral neuropathy? Vinca alkaloids (vincristine), paclitaxel, and platinum compounds (cisplatin) cause peripheral neuropathy by disrupting microtubules 16. What drug is toxic to cardiac myocytes? What drug is toxic to heart valves? Doxorubicin binds to iron and disrupts cardiac myocytes Fenfluramine increases serotonin, which is a mitogen for heart valve myofibroblasts 17. What drugs in the text are contraindicated in patients with pulmonary disease? Bleomycin (chemotherapeutic) and amidarone (antiarrhythmic) cause chronic injury in the form of fibrosis to the lungs 18. Which drug acts as an antagonist of estrogen receptors in the breast, but a partial agonist in the uterus and other tissues? Tamoxifen can often cause endometrial cancer when it is used to treat breast cancer i. Use raloxifene instead 19. What does Pregnancy Category B mean? Animal studies have shown no risk, and there are no adequate studies in humans 20. Category D? There is positive evidence of human fetal risk, but potential benefits may warrant use 21. How do you treat benzodiazepine overdose? Use the GABAA receptor antagonist flumazenil to treat benzodiazepine overdose