Z1. Pharmacology p288
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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
- Michael Shino
- 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
- Ampicillin and amoxicillin
- p. 291
- 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
- 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)
- 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?
- MTB, meningococcal prophylaxis
- 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?
- inhibits DNA-dependent RNA polymerase
- 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
- When do you use it?
- Anaerobic infections (e.g. Bacteroides fragilis and C.perfringens)
- Toxicities?
- Minor hepatotoxicity and increases P-450
- Sulfonamides
- p. 295
- Name some sulfonamides
- Sulfamethoxazole (SMX), sulfisoxazole, triple sulfa and sulfadiazine
- What are its uses?
- anti-protozoal: Giardia, Entamoeba, Trichomonas, Gardnerella vaginalis, anaerobes (bacteroides, clostridium)
- Trimethoprim
- p. 295
- Fluoroquinolones
- p. 295
- What the most famous floroquinolone?
- Ciprfloxacin (treatment for Anthrax)
- 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
- 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
- Isoniazid
- p. 296
- 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 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
- 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.