Week 4 Flashcards
Talk about Rifampin
- Inhibits RNA Polymerase
- Bactericidal
- Used to treat TB (RIPES)
- Binds to bact. RNA Polymerase at active center, preventing elongation of the mRNA
- Causes GI side effects, turns fluids orange-red & stains contact lenses, can induce cytochrome p450 enzyme CYP3A4 which can induce metabolism of other medicines [leads to organ rejection and loss of seizure control]
Acquired Resist= strain acquires mutations in rpoB gene
Intrinsic Resist= drug is unable to bind beta-subunit of RNA polymerase
What are the two inhibitors of RNA Polymerase?
Rifampin and Fidoxamicin
Talk about Fidoxamicin
- Bactericidal
- Inhibits Bact. DNA Polymerase
- Narrow spectrum: gram + bacteria, anaerobic bacteria, especially C, difficle [spares gut flora]
- low absorption = few side effects
- Some bacteria are resistant due to a point mutation in RNA Polymerase
- New drug, only available for the past year
What three Fluoroquinolones do you need to know?
Levofloxacin, Ciprofloxacin, Moxifloxacin
Tell me about Fluoroquinolone potency, spectrum and mechanism:
- Bactericidal
- Very Broad Spectrum - Gram + and Gram -, along with atypical organisms (Mycoplasma)
- Frequently used for pneumonia & UTI
- Mech: Inhibits DNA replication (binary fission in bacteria) by binding bacterial DNA Topoisomerase II (gyrase) & IV
What is the different effects induced by Fluoroquinolones on Gram - and Gram + organisms?
Gram -: Inhibits Topoisomerase II (DNA gyrase) and prevents relaxation of pos. supercoiled DNA required for normal transcription and replication
Gram +: Inhibits Topoisomerase IV - interferes with the seperation of replicated chromosomal DNA (decatenation) into the daughter cells during cell division
What side effects can Fluoroquinolones induce?
GI side effects, Confusion, Photosensitivity, Inc. in C. difficle colitis, Inc. in candida vaginitis, tendon problems/joint disease in pregnant women, breastfeeding women and children
–Patients are supposed to avoid dairy & Calcium (Ca, Fe, Al, Zn) = drug has chelate cations
What resistance has developed against Fluoroquinolones?
- They have been overprescribed for UTI, resp. infections & acute GI infections –> causes resistance
- Resist: Active efflux of the drug, mutations in topoisomerase, activation of DNA stress response (SOS) & DNA repair - repair of dsDNA breaks
- Some bacteria upregulate many transporters that can efflux many different drugs = multidrug resistance!
What is unique about Ciprofloxacin?
Fluoroquinolone
-used to treat & prevent dangerous illnesses deliberately spread (ex: plague, tularemia & anthrax of skin or mouth)
What are the folate agonists?
Sulfonamides & Trimethoprim
Mech: Work by indirect inhibition of DNA synthesis
Spectrum: Bacteria & fungi that synthesize their own dihydrofolic acid
Tell me about Trimethoprim.
-Bacteriostatic
Mech: Inhibits bacterial dihydrofolate reductase (drug has dec. affinity for mammalian version of the enzyme)
Side effect: GI upset
Resistance: Altered dihydrofolate reductase, Inc. amouts of dihydrofolate reductase & alternative metabolic pathways
Tell me about Sulfamethoxazole.
-Bacteriostatic
Mech: Para aminobenzoic acid (PARA) analog & acts as competitive inhibitor of dihydropteroate synthetase
Resist: Through change in dihydropepteroate synthetase (first enzyme in folate synthesis pathway) which causes an increase in efflux of the drug & increase in production of PABA
Side Effects: Hypersensitivity, Steven-Johnson syndrome, cross reaction with drugs, Crystalluria –> renal failure, hemolysis & kerniterus
TMP-SMX
Also called Bacitrin
Combination of 2 drugs that sequentially block the folate synthesis pathway
-bactericidal together
Spectrum: broad UTI treatment & pneumocystis
–People with sulfa allergies use TMP alone
–If patient has a glucose 6-phosphate dehydrogenase deficiency, they should not be given SMX!!! – So treat their UTI with Nitrofurantoin/
How do sulfonamides cause Kernicterus?
Kernicterus = neurological condition that occurs in severely jaundiced newborns
–SMX compete for binding to albumin leading to free bilirubin & complications with drugs like warfarin –> this leads to kernicterus due to a build up of bilirubin in the pathway
Tell me about Metronidazole.
Bactericidal
Targets: C. difficle & protozoans (anaerobes)
Mech: Indirect inhibitor of DNA, when reduced & active it will generate free radicals leading to DNA strand breaks and cell death
Drug resist: Rare
Side effects: nausea, diarrhea, headache & metallic taste
-Avoid during pregnancy & avoid alcohol use [drug undergoes a disulfram like reaction]
-Only metabolized into its active form in anaerobes
Tell me about Nitrofurantoin.
Bactericidal
-Broad spectrum
Mech: Bact. flavoproteins reduce it to reactive intermediates that inactivate bacterial ribosome proteins –> inhibit synthesis of DNA, RNA, cell wall & proteins
Side effects: Vomiting & Rash
–Bacteria hasn’t yet developed resistance
It’s rapidly excreted in the urine in its active form so its only good for UTI infections!!
Tell me about Linezolid.
Oxazolidinone
-Bacteriostatic
Targets: gram (+), MRSA, Vanco. resistant Enterococci
Mech: Inhibits protein synthesis by binding 23s ribosomal RNA on the 50s subunit & preventing formation of the intiation complex [binds to P site on the 50s]
Side effects: Bone marrow suppression, serotonin syndrome [if taken with SSRI]
Resist: Alterations of modifications in 23S ribosomal RNA
What are the aminoglycosides?
Gentamicin, Amikacin, Tobramycin, Neomycin, Streptomycin
Aminoglycoside: Spectrum, Mech, Class, Admin.
Bactericidal
- Target: gram (-) aerobic, usually used in combination with other drugs
- Mech: prevents formation of the initiation complex, causes mRNA misreading, induces early termination
- Admin: poor gut adsorption, usually given IV, polar drug, excluded from CSF
- ->requires energy to enter the cell
Aminoglycosides: Side effects, Resistance
Side effects: Tubular necrosis: 1)nephrotoxicity 2)Ototoxicity (vestibular and auditory disfunction) 3) Pregnancy Class D -hearing loss in fetus
Resistance: Intrinsic: failure of drug to enter bact. cell - cotreat with cell wall inhibitor
Acquired: acquisition of enzymes that inactivate the drug through acetylation, phosphorylation or adenylation
What’s unique about the aminoglycoside Amikacin?
It’s broader spectrum [including pseudomonas] & less susceptible to enzyme inactivation
What are the four tetracyclines you need to know?
Tetracycline, Doxycycline, Minocycline, Demeclocycline
Tetracycline: Mech, Spectrum, Resistance
Mech: Bind to the 30s subunit, prevent attachment of amino-acyl-tRNA
Spectrum: Broad initially but now resist: H. burgdorferi, H. pylori, Mycoplasma pneumoniae
Resist: Intrinsic: decreased uptake
Acquired: Increased efflux and alteration of ribosomal target [rarely enzymatic inactivation]
Tetracyclines: Side effects
- Form stable chelates with metal ions (Ca, Mg, Fe, Al- decreases the gut absorption of the drug]
- GI irritation & photosensitivity (abnormal sunburn)
- teeth discoloration
- inhibits bone growth in children (sometimes)
- pregnancy class D
Chloramphenicol
Bacteriostatic
Spectrum: Extended but use is limited due to severe side effects
Mech: Binds 50s subunit, preventing peptide bond formation- peptidyltransferase can’t associated with the amino acid substrate
Resist: Acetyltransferase modifies drug target to prevent binding to ribosome
SE: TOXIC - bone marrow depression & aplastic anemia (bone marrow doesn’t make new RBCs), Gray baby syndrome- don’t use in pregnancy
What is gray baby syndrome?
Premature infants lack the enzyme UDP-glucuronyl transferase and have low renal function so high levels of the drug accumulate which can lead to cardiovascular and respiratory collapse
What are the Macrolides?
Erythromycin, Azithromycin & Clarithromycin
Tell me about Macrolides.
Bacteriostatic
Target: broad coverage of resp. pathogen - Chlamydia
Mech: Inhibits translocation by binding 23s rRNA of the 50s subunit, prolonged QT interval, inhibitors of cytochrome p450
Resist: Methylation of 23s rRNA binding site, increased efflux, hydrolysis of macrolide by esterases
Clarithromycin– not safe for pregnancy!!
Tell me about Clindamycin.
It’s a Lincosamide (class)
Bacteriostatic
Targets: gram(+), including anaerobic, treat acne
Mech: blocks translocation at 50s ribosomal subunit
Side effects: hypersensitivity (rash, fever), diarrhea, abdominal pain, mucus & blood in stool, super-infection with C. difficle
Resist: Mutation in ribosome, methylation of ribosomeal RNA, cross-resistant with macrolides & streptogramins, inactivation of drug by adenylation
Tell me about Quinupristin/Dalfopristin.
Class: Streptogramins
Bactericidal - for some organisms when combined
Targets: should be solved for infections caused by multiple drug resist. G (+) bacteria
Mech: Inhibits translocation by binding 50s subunit
SE: High incidence including arthralgias & myalgias are common, inhibits p450 & likely to have sign. drug interactions
Resist: Ribosomal methylase prevents binding of drug to target, enzymes inactivate drugs, efflux proteins pump drug out of the cell, X-resistance with Macrolides & Clindamycin
What’s unique about Mycoplasma pneumonia?
It’s an atypical pneumonia, beta-lactams are not effective against it.
-Can use: Doxycycline, Azithromycin, Levofloxacin
What agents may cause hemolysis in patients with glucose 6-phosphate dehydrogenase deficiency?
Sulfonamides (Trimethoprim/Sulfamethoxazole)
Css
Steady State Concentration
Kin (drug input) /Cl (drug clearance)
Vd
Volume of distribution
Total drug/C0 (plasma concentration of the drug)
t(1/2)
half life
0.693(Vd/Cl)
ke
Elimination Constant
Cl (drug clearance)/Vd (volume of distribution)
Loading Dose
(CssXVd)/f
Maintenance Dose
[Dosing rate (unit/time) that acheives desired level of effect X Dosing interval (hrs)]/f (bioavailability)
What are the basics of alcohol metabolism?
Ethanol – (ADH/ADH2 or MEOS) –> acetaldehyde – (ALDH/ALDH2) -> acetate - (acetyl CoA synthetase - ACS) –> Acetyl CoA –> liver (FA synthesis) or muscle (TCA cycle)
