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 Pharmacokinetics p. 288 amount of drug in body/_______ = Vd plasma drug concentration (note: Vd is Volume of Distribution) rate of elimination of drug/[plasma drug] = ? CL (Clearance) (.7)(Vd)/CL = ? T 1/2 A drug infused at a constant rate reaches about 94% of steady state after _______ t 1/2s. 4 Dosage Calculations p. 288 A loading dose is calculated using this formula. (Cp)(Vd)/F (note: Cp = target plasma concentration, and F = bioavailability) A maintenance dose is calculated using this formula. (Cp)(CL)/F Elimination of Drugs p. 288 Rate of elimination is proportional to _______ ______ in 1st order elimination. drug concentration In the case of EtOH, which is elimated by _____ order elimination, a constant amount of drug is eliminated per unit time. zero Phase I vs. Phase II metabolism p. 289 Phase ____ (I or II) reactions yield slightly polar metabolites that are often _____ (active or inactive) I, active Phase ____ (I or II) reactions yield very polar metabolites that are often _____ (active or inactive) and are excreted by the _______. II, inactive, kidney Phase II reactions are often of this type. conjugation Cytochrome P-450 is involved in _____ phase (I or II) reactions. I Drug Development p. 289 A patent lasts for _____ years after filing for application. 20 How many phases are there in drug development? 4 Drugs are first tested in patients in phase _____ of clinical testing, pharmacokinetic safety is determined in phase ______ of clinical testing, double blind tests are done in phase ____ and post-market surveillance is done in phase _____. 2,1,3,4 Pharmacodynamics p. 289 In a dose response curve, a competitive antagonist shifts the curve _____, while a non-competitive antagonist shifts the curve ______. right, down AUTHOR HiralShah Pharmacodynamics (continued) p. 290 What pharmacologic relationship would determine the existence of spare receptors? EC50 < Kd What does it mean if EC50 and Kd are equal? The system does not have spare receptors A partial agonist acts on the same receptor system as a full agonist? T/F TRUE What's the main difference between a partial agonist and a full agonist? A partial agonist has a lower maximal efficacy. Is a partial agonist less potent than a full agonist? Not necessarily. It can be less, more or equally potent as a full agonist. Antimicrobial Tx -- Mechanism of Action p. 291 The penicillin type drugs work by blocking ------ synthesis, specifically by inhibiting this molecule from cross-linking? blocks bacterial cell wall synthesis by inhibition of peptidoglycan synthesis. Which other drugs (aside from penicillin) have this same mechanism of action? Imipenem, aztreonam and cephalosporins Bacitracin, vancomycin and cycloserine block the synthesis of this molecule, preventing cell wall synthesis peptidoglycans These drugs block the 50s ribosomal subunit clindamycin, chloramphenicol, erythromycin, lincomycin, linezolid, streptogramins "Buy AT 30, CELL at 50" These drugs block the 30s ribosomal subunit Aminoglycosides and tetracyclines "Buy AT 30, CELL at 50" These drugs block nucleotide synthesis by interfering with the folate pathway Sulfonamides (e.g. Bactrim), trimethoprim These drugs block DNA topoisomerases Quinolones (e.g. Cipro) Which drug blocks mRNA synthesis rifampin Which are the bacteriacidal Abx Penicillin, cephalosporin, vancomycin, aminoglycosides, fluoroquinolones, metronidazole These drugs disrupt the bacterial/fungal cell membranes polymyxins These specific disrupt fungal cell membranes amphotericin B, nystatin, fluconazole/azoles (FAN the fungal cell membranes) What is the mechanism of action of Pentamidine Unknown Penicillin p. 291 Which is the IV form and which is the oral form G = IV, V=oral Which of these is not a mechanism of penicillin action: (1) binds penicillin-binding protein, (2) blocks peptidoglycan synthesis, (3) blocks transpeptidase catalyzed cross-linking of cell wall and (4) activates autolytic enzymes Penicillin does not block peptioglycan synthesis, bacitracin, vancomycin and cycloserine do that T or F: penicillin is effective against gram pos and gram neg rods False: penicillin is used to treat common streptococci (but not staph), meningococci, gram pos bacilli and spirochetes (i.e. syphilis, treponema). Not used to treat gram neg rods. What should you watch out for when giving penicillin? Hypersensitivity rxn (urticaria,severe pruritus) and hemolytic anemia Methicillin, nafcillin, dicloxacillin p. 291 These drugs are used mainly for what type of infection Staphlococcal infection (hence very narrow spectrum) T or F: these drugs have the same mechanism of action as penicillin TRUE Are these drugs penicillinase resistant? If so why? Bulkier R group makes these drugs resistant to penicillinase What should you watch out for when giving these drugs? Hypersensitivity rxn (urticaria,severe pruritus); methicillin can cuase interstitial nephritis Ampicillin and amoxicillin p. 291 T or F: these drugs have the same mechanism of action as penicillin TRUE Which has greater oral bioavailability? amOxicillin (O for Oral) What do you use these for? Ampicillin/amoxicillin HELPS to kill enterococci (H. influenzae, E. coli, Listeria monocytogenes, Proteus mirabilis, Salmonella) Can penicillinase effect these drugs efficacy? Yes, they are penicillinase sensitive Why not give these drugs with a penicillinase inhibitor. Name one. clavulanic acid What should you watch out for when giving these drugs? Hypersensitivity rxn (ampicillin rash), pseudomembranous colitis Carbenicillin, piperacillin, ticarcillin p. 292 Why are these considered to have an extended spectrum? Because they are effective against pseudomonas and other gram neg rods (enterobacter and some species of klebsiella) What should you watch out for when giving these drugs? Hypersensitivity rxn Why does concomitant administration with clavulanic acid increase the efficacy of these drugs? Because they are penicillinase sensitive. (only piperacillin and ticarcillin) Cephalosporins p. 292 What is the mechanism of action of Cephalosporins? inhibit cell wall synthesis How are they similar/different from penicillin? both have a beta-lactam ring structure but cephalosporins are less susceptible to penicillinases What are the main similarities/difference between 1st and 2nd generation cephalosporins? 2nd gen has extensive gram neg coverage but weaker gram pos coverage 1st gen covers what bugs? gram positives (staph and strep), Proteus mirabilis, E. coli, Klebsiella (PEcK) 2nd gen covers what bugs? gram positives (staph and strep) though less so, H. influenzae, Enterobacter aerogenes, Neisseria, Proteus mirabilis, E. coli, Klebsiella (HEN PEcK) What can 3rd generation drugs do that 1st and 2nd generation can't? Cross the blood brain barrier What are some other benefits of 3rd gen? better activity against gram neg bugs resistant to beta-lactam drugs. Ceftazidime for Pseudomonas and ceftriaxone for N. gonorrhea What are the benefits of 4th gen (e.g. Cefipime)? increased activity against Pseudomonas, gram pos organisms and more beta-lactamase resistant (i.e. 4th gen combines 1st gen and 3rd gen characteristics into super drug) What drugs should you avoid taking with cephalosporins? Aminoglycosides (increases nephrotoxicity) and ethanol (causes a disulfiram-like rxn -- headache, nausea, flushing, hypotension) Aztreonam p. 292 When would you use aztreonam? Only to treat Klebsiella, Pseudomonas and Serratia spp. Is it beta-lactamase resistant? Yes, this is one of the huge benefits of the drug, and it is not cross-reactive with PCN! Which population of pt. is this drug good for? The PCN-allergic patient that can't take aminoglycosides b/c of renal insufficiency Are there any toxicity issues with this drug? Not really. Generally well tolerated with occasional GI upset. Vertigo, Headache and rare hepatotoxicity have been reported. Imipenem/cilastatin p.293 What is imipenem? broad spectrum beta-lactamase-resistant abx What do you always administer it with and why? cilastatin -- it decreases inactivation of imipenem in renal tubules What do you use it for? Gram pos cocci, gram neg rods and anaerobes (broad spectrum) What bug is it the drug of choice for? Enterobacter What are its side-effects GI distress, skin rash, seizures at high conc. Vancomycin p. 293 Is it bactericidal or bacteriastatic and why? Bactericidal because it blocks cross linkage and elongation of peptidoglycan by binding D-ala D-ala protion of cell wall. How does resistance to Vanco occur? D-ala D-ala is replaced with D-ala D-lactate which vanco does not block What is it used for? Used for serious infection that is resistant to other drugs (e.g. gram pos multi-drug resistant organisms like S. aureus and C. difficile, methicillin resistant staph (MRSA)) What are the important toxicities of vanco? generally NOT many problems except, Nephrotoxicity, Ototoxicity and Thrombophlebitis What can happen with rapid infusion of vanco? Red man's syndrome. Diffuse flushing which can be controlled by pretreatment with anti-histamines and with slow infusion rate Protein Synthesis Inhibitors p. 293 Which drugs target bacterial protein synthesis by blocking the 30S unit vs 50S unit? Buy AT 30, CELL at 50 What does AT stand for? A = Aminoglycosides (streptomycin, gentamicin, tobramycin an damikacin. And T = Tetracyclines What does CELL stand for? C = Chloramphenicol, E= Erythromycin, L= Lincomycin and L= cLindamycin Which of the above are bactericidal? Only the aminoglycosides are, the rest are bacteriostatic Aminoglycosides p. 294 Name some aminoglycosides? Gentamicin, neomycin, amikacin, tobramycin and streptomycin How do these drugs work? They inhibit formation of the initiation complex in mRNA translation Why are they ineffective against anaerobes? They require oxygen for uptake into bacteria When would you use aminoglycosides? against severe gram-negative rod infections What drugs can you use aminoglycosides with for synergy? the drugs that inhibit cell wall synthesis (e.g. penicillin and cephalosporins -- the beta-lactam antibiotics). Presumably this allows the drug to get in with out reliance on oxygen transport What drug in this class is commonly used for bowel surgery? Neomycin What are the two major toxicities? Nephrotoxicity (esp. when used with cephalosporins) and Ototoxicity (esp. when used with loop diuretics). amiNOglycosides Tetracyclines p. 294 Name some tetracylcines Tetracycline, doxycycline, demeclocycline, minocycline How does it work? Blocks t-RNA attachment to 30S subunit Which tetracycline can you use in patients with renal failure and why? Can use doxycycline because its elimination is fecal Should you take these drugs with a glass of milk? NO, because it intereferes with absorption in the gut as does antacids and iron-containing preparations What are tetracyclines used for? VACUUM your Bed Room -- Vibrio cholerae, Acne, Chlamydia, Ureaplasma, Urealyticum, Mycoplasma pneumoniae, Borrelia burgdorferi, Rickettsia, tularemia What are the common toxicities GI distress, teeth discoloration, inhibition of bone growth in children, Fanconi's syndrome and photosensitivity Macrolides p. 294 Name some macrolides? Erythromycin, azithromycin, clarithromycin How do these drugs work?Macrolides inhibit protein synthesis What are Macrolides used for? URIs, pneumonias, STDs -- gram pos cocci in patients that are allergic to PNC --- Mycoplasm, Legionella, Chlamydia, Neisseria. Pneumonic for macrolide use? Eryc's Nipple is at his Mid Clavicular Line (Eryc is brand name for erythromycin). Mycoplasm, Legionella, Chlamydia, Neisseria. What are the major toxicities?Macrolides GI discomfort, acute cholestatic hepatitis, eosinophilia, skin rashes What is the most common cause for non-compliance to macrolides? GI discomfort Chloramphenicol p. 294 How does Chloramphenicol work? inhibits 50S peptidyltransferase Main use? Meningitis (H. influenzae, N. meningitides, S. pneumo). Used conservatively b/c of toxicity What are the main toxicities? Anemia and aplastic anemia (both dose dependent), gray baby syndrome (in premes b/c they lack UDP-glucoronyl transferase) Clindamycin p. 294 How does it work? blocks peptide bond formation at 50S When do you use it? Anaerobic infections (e.g. Bacteroides fragilis and C.perfringens) Toxicities? Pseudomembranous colitis, fever, diarrhea Sulfonamides p. 295 Name some sulfonamides Sulfamethoxazole (SMX), sulfisoxazole, triple sulfa and sulfadiazine How does it work? Inhibits bacterial folic acid synthesis from PABA by blocking dihydropteroate synthase. What are its uses? Gram-positive, gram-negative, Nocardia, Chlamydia. Triple sulfas and SMX for simple UTIs Toxicities? hypersensitivity rxn, hemolysis if G6PD deficient, nephorotoxicity (tubulointerstitial nephritis), kernicterus in infants, displace other drugs from albumin (e.g. warfarin) Trimethoprim p. 295 How does it work? inhibits folic acid pathway by blocking dihydrofolate reductase which humans have as well What are its uses? used in combo with Sulfamethoxazole (TMP-SMX) causing a sequential block of folate synthesis. Used for recurrent UTIs, Shigella, Salmonella, and prophylaxis for PCP in AIDS patients Toxicities? Megaloblastic anemia, pancytopenia (may be alleviated with supplemental folinic acid) Fluoroquinolones p. 295 What the most famous floroquinolone? Ciprfloxacin (treatment for Anthrax) How does it work? inhibits DNA gyrase (topoisomerase II) What are its uses? Gram neg rods or urinary and GI tract (incl. pseudomonas), Neisseria, some gram pos spp What population is contraindicated for use? pregnancy and children What are its toxicities? GI upset, superinfection, skin rashes, headache, dizziness and tendonitis and tendon rupture in adults. FluoroquinoLONES hurt attachment to BONES. Metronidazole p. 296 How does it work? forms toxic metabolites in the bacteria. Bactericidal. What are its uses? anti-protozoal: Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, anaerobes (bacteroides, clostridium) What is the role of Metronidazole in H. pylori infection? Used as part of triple therapy: bismuth, amoxicillin and metronidazole Main toxicity? disulfiram-like (antabuse) reaction to alcohol and headache Which drug do you use to treat anaerobic infections above the diaphram and below the diaphram anaerobes above diaphram: Clindamycin, and anaerobes below diaphram: metronidazole Polymyxins p. 296 How does it work? disrupts osmotic properties of bacteria, acts like a detergent What is it used for? resistant gram negative infections Toxicities? neurotoxicity, ATN Isoniazid p. 296 How does it work? decreases synthesis of mycolic acid What is it used for? MTB (mycobacterium tuberculosis). The only agent used as solo prophylaxis against TB Toxicities? Hemolysis if G6PD deficient, neurotoxicity, hepatotoxicitiy, drug induced SLE. INH, Injures Neurons and Hepatocytes What vitamin prevents neurotoxicity Vitamin B6 (pyridoxine) Why are toxicities particularly important to monitor in patients taking INH? INH half-lives are different in fast versus slow acetylators! Rifampin P. 296 How does it work? inhibits DNA-dependent RNA polymerase What is it used for? MTB, meningococcal prophylaxis Toxicities? Minor hepatotoxicity and increases P-450 How can it be used for leprosy? rifampin delays resistance to dapsone when used for leprosy What would happen if you used rifampin alone? get rapid resistance What does it do to bodily fluids? makes them red/orange in color What are the 4 R's of Rifampin RNA polymerase inhibitor, Revs up microsomal p-450, Red/Orange body fluids, Resistance is rapid Anti-TB Drugs p. 296 What are the anti-TB drugs? Rifampin, Ethambutol, Streptomycin, Pyrazinamide, Isoniazid (INH) -- RESPIre What do you use for TB prophylaxis? INH What toxicity is common to all? hepatotoxicity AUTHOR Michael Shino Resistance mechanisms for various antibiotics p297 Most common resistance mechanism for penicillins / cephalosporins. Beta-lactamase cleavage of beta-lactam ring. Most common resistance mechanism for aminoglycosides. Modification via acetylation, adenylation, or phosphorylation. Most common resistance mechanism for vancomycin. Terminal D-ala of cell wall component replaced with D-lac; decrease affinity. Most common resistance mechanism for Chlorampenicol. Modification via acetylation. Most common resistance mechanism for macrolides. Methylation of rRNA near erythromycin's ribosome-binding site. Most common resistance mechanism for tetracycline. Decrease uptake or increase transport out of cell. Most common resistance mechanism for sulfonamides. Altered enzyme (bacterial dihydropteroate synthetase), decrease uptake, or increase PABA synthesis. Nonsurgical antimicrobial prophylaxis p297 Drug of choice for meningococcal infection. Rifampin (drug of choice), minocycline. Drug of choice for gonorrhea. Cefriaxone. Drug of choice for syphilis. Benzathine penicillin G. Drug of choice for history of recurrent UTIs. TMP-SMX. Drug of choice for Pneumocystis carinii pneumonia. TMP-SMX (drug of choice), aerosolized pentamindine. Anti-fungal therapy p297 Mechanism of action of the anti-fungal therapy polyenes. Form artificial pores in the cytoplasmic membrane. Mechanism of action of the anti-fungal therapies terbinafine and azoles. Terbinafine blocks the conversion of squalene to lanosterol. Azoles block the conversion of lanosterol to ergosterol. Mechanism of action of the anti-fungal therapy flucytosine. Blocks the production of purines from the precurors. Mechanism of action of the anti-fungal therapy griseofulvin. Disrupts microtubles. Amphotericin B p298 Mechanism of action of Amphotericin B. Binds ergosterol (unique to fungi); forms membrane pores that allow leakage of electrolytes and disrupt homeostasis. "Amphotericin 'tears' holes in the fungal membrane by forming pores." Clinical uses of Amphotericin B. Used for a wide spectrum of sytemic mycoses. Cryptococcus, Blastomyces, Coccidioides, Aspergillus, Histoplasma, Candida, Mucor (systemic mycoses). Intrathecally for fungal meningitis; does not cross blood-brain barrier. Symptoms of Amphotericin B toxicity. Fever/chills ("shake and bake"), hypotension, nephrotoxicity, arrhythmias ("amphoterrible"). Nystatin p298 Mechanism of action of Nystatin. Binds to ergosterol, disrupting fungal membranes. Clinical use of Nystatin. Swish and swallow for oral candidiasis (thrush). Fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole. p298 Mechanism of action for fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole. Inhibits fungal steroid (ergosterol) synthesis. Clinical uses of fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole. Systemic mycoses. Fluconazole for cryptococcal meningitis in AIDS patients and candidal infections of all types (i.e., yeast infections). Ketoconazole for Blastomyces, coccidioides, Histoplasma, Candida albicans; hypercortisolism. Symptoms of fluconazole, ketoconazole, clotrimazole, miconazole, itraconazole, voriconazole toxicity. Hormone synthesis inhibition (gynecomastia), liver dysfunction (inhibits cytochrome P-450), fever, chills. Flucytosine p298 Mechanism of action of Flucytosine. Inhibits DNA synthesis byconversion to fluorouracil, which competes with uracil. Clinical uses of Flucytosine. Used in sytemic fungal infections (e.g. Candida, Cryptococcus). Symptoms of Flucytosine toxicity. Nausea, vomitting, diarrhea, bone marrow suppression. Caspofungin p298 Mechanism of action for Caspofungin. Inhibits cell wall synthesis. Clinical use of Caspofungin. Invasive aepergillosis. Symptoms of Caspofungin toxicity. GI upset, flushing. Terbinafine p298 Mechanism of action of Terbinafine. Inhibits the fungal enzyme squalene epoxidase. Clinical use of Terbinafinel. Used to treat dermatophytoses (especially onychomycosis). Griseofulvin p298 Mechanism of action of Griseofulvin. Interfers with microtubule function; disrupts mitosis. Deposits in keratin-contianing tissues (e.g. nails). Clinical use of Griseofulvin. Oral treatment of superficial infections; inhibits growth of dermatophytes (tinea, ringworm). Symptoms of Griseofulvin toxicity. Teratogenic, carcinogenic, confusion, headaches, increase warfarin metabolism. Antiviral chemotherapy p299 Viral adsorption and penetration into the cell is blocked by ---------. Gama-globulins (non-specific). Uncoating of the virus after its penetration into the cell is blocked by --------. Amantadine (influenza A). Early viral protein synthesis is blocked by --------. Fomivirsen (CMV). Viral nuclei acid synthesis is blocked by --------. Purine, pyrimidine analogs; reverse transcriptase inhibitors. Late viral protein synthesis and processing is blocked by --------. Methimazole (variola); protease inhibitors. Packaging and assembly of new viron is blocked by --------. Rifampin (vaccinia). Amantadine p299 Mechanism of action of Amantadine. Blocks viral penetration/uncoating; may buffer pH of endosome. Also causes the release of dopamine from intact nerve terminals. "Amantadine blocks influenza A and rubellA and causes problems with the cerebellA." Clinical uses of Amantadine. Prophylaxis for influenza A; Parkinson's disease. Symptoms of Amantadine toxicity. Ataxia, dizziness, slurred speech. (Rimantidine is a derivative with fewer CNS side effects.) Zanamivir p299 Mechanism of action of Zanamivir. Inhibits influenza neuraminidase. Clinical use of Zanamivir. Both influenza A and B. Ribavirin p299 Mechanism of action of Ribavirin. Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase. Clinical use of Ribavirin. RSV (respiratory syncytial virus). Symptoms of Ribavirin toxicity. Hemolytic anemia. Severe teratogen. Acyclovir p299 Mechanism of aciton of Acyclovir. Perferentially inhibits viral DNA polymerase when phosphorylated by viral thymidine kinase. Clinical use of Acyclovir. HSV, VZV, EBV. Mucocutaneous and genital herpes lesions. Prophylaxis in immunocompromised patients. Symptoms of Acyclovir toxicity. Delirium, tremor, nephrotoxicity.