Week 4 Drugs Flashcards
What antibiotic binds bacterial RNA polymerase at the active center, blocking the elongation of mRNA?
Spectrum: Myobacterium tuberculosis, extended
What are two methods of bacteria resistance to this?
What are the adverse effects?
Rifampin
Intrinsic resistance- some strains, the drug is unable to bind the beta subunit of RNA polymerase
Acquired resistance- the strain acquires a mutation in the rpoB gene (codes for beta subunit)
turns body fluid ORANGE-RED, GI side effects
induction of cytochrome P450 enzyme CYP3A4 can induce the metabolism of other medication leading to organ rejection and loss of seizure control
impairment of liver function leads to higher blood serum levels
excreted in feces
What bactericidal abx inhibits RNA polymerase?
Spectrum: NARROW, sparing many gut flora, Gram + anaerobes (C diff)
How are bacteria resistant?
Fidaxomicin
resistance has occured via point mutation in RNA pol in vitro
What group of abx is bactericidal by inhibiting DNA replication by binding bacterial DNA topoisomerase II (gyrase) and IV?
name three drugs in this group:
Spectrum: broad spectrum Gram +, Gram -, and atypical organisms like Mycoplasma (no cell wall), HAP, UTIs
How is resistance formed?
Flouroquinolones
Ciprofloxacin, levofloxacin, moxifloxacin
Resistance is formed by overprescribing for UTI, respiratory, and acute GI infections:
- active efflux - mutations in topoisomerases
What is the difference between topoisomerase II (gyrase) and IV?
Which is associated with flouroquinolones mechanism of action in Gram + and Gram -.
topoisomerase II (gyrase)- when inhibited it can’t relax the positively supercoiled DNA required for normal transcription and replication
GRAM -
topoisomerase IV interferes with separation of replicated chromosomal DNA (decatenation) into the respective daughter cells during division
GRAM +
Which drugs can cause double-stranded DNA breaks and cell death along with their main action on topoisomerases?
flouroquinilones
What generally happens with upregulation of transporter capable of effluxing?
multidrug resistance
What are the adverse effects of flouroquinolones?
GI probs
confusion and photosensitivity
C diff colitis
Candida vaginitis
Contraindicated in pregnant and breastfeeding women and children due to arthropathy
Formation of Chelate cations if taken with Ca, Fe, Al, Zn (avoid dairy products and Ca-fortified juice)
Adjust for renal dysfunction
Name two Folate antagonists that indirectly inhibit DNA synthesis:
Are these drugs bateriostatic or bactericidal?
Sulfonamides and Trimethoprim
bacteriostatic
What drug is a para-aminobenzoic acid (PABA) analog and acts as a competitive inhibitor to PABA?
What organisms is it effective against?
Why?
Sulfamethoxazole
Bacteria and fungi that synthesize their own folate.
Because PABA is a substrate that comes before dihydrofolic acid in tetrahydrofolic acid synthesis. This is also why bacteria that uptake dihydrofolic acid are resistant to sulfonamides if there is enough present in their environment.
How can bacteria that need to synthesize dihydrofolte resist sulfamethoxazole? (3 ways)
- change in dihydropteroate synthetase
- increased efflux
- increased production of PABA
What are the adverse effects of Sulfonamides?
Hypersensitivity-rash, Steven-Johnson syndrome
cross reaction to drugs containing sulfonamide moieties
crystalluria–>acute renal failure
Hemolysis if glucose 6-phosphate dehydrogenase is deficient
Kernicterus- neurologic condition occuring is severely jaundiced newborns
What drugs compete for binding to albumin leading to free bilirubin?
Why is this bad?
Sulfonamides
free bilirubin causes complications with other drugs like warfarin
What drug inhibits DHFR in bacteria that uptake folate from their environment but has low affinity for that enzyme in humans?
How are bacteria resistant?
What are the adverse effects?
Trimethoprim
Altered DHFR, increased amounts of DHFR, alternative metabolic pathways
GI probs
Name and describe the bactericidal “sequential blockade” of trimethoprim and sulfamethoxazole.
Spectrum: broad treatment of UTIs, Pneumocystis
Bactrin
Mechanism: sequential blockade of the folate synthesis pathway but if sulfa-allergy can use trimethaprim alone
Name the two drugs that, when reduced, create an “electron sink” generating free radical leading to DNA strand breaks and cell death (bactericidal)
Spectrum: Anaerobic bacteria including C diff, protozoa
Resistance: rare
What are it’s adverse effects?
Metronidazole and Tinidazole
Adverse effects: nausea, diarrhea, headache, metallic taste
avoid during pregnancy
Disulfiram-like reaction with EtOH
This drug is only metabolized to its active form in anaerobes:
Metronidazole
Describe the disulfiram-ethanol reaction caused by mixing booze and Metronidazole:
Metronidazole blocks aldehyde dehydrogenase, inhibiting oxidation of acetaldehyde and therefore increasing its concentration ofter EtOH consumption
HANGOVER sx: headache, nausea, vomitting, sweating, hypotension, confusion
What drug is reduced by bacterial flavoproteins to REACTIVE INTERMEDIATES?
What does that cause?
Spectrum: broad, rapidly excreted in the urine in active form, used for UTIs
No resistance, YAY
But what are the adverse effects?
Nitrofurantoin
Inactivates or alters bacterial ribosomal proteins to inhibit the synthesis of DNA, RNA, cell wall, and protein.
Adverse effects: vomiting, rash
What is the drug to chose for Mycobacteria tuberculosis (along with 3 other drugs due to high rate of resistance)?
Rifampin
What is an expensive new drug for Gram + anaerobes like C diff that has a narrow spectrum and saves many of the gut flora?
Fidaxomicin
What class of drugs would you chose for broad spectrum coverage of Gram + and - and atypical organisms like Mycoplasma, HAP, and UTIs?
Fluoroquinolones
What combo of drugs could be used for broad spectrum treatment of UTIs and pneumocystis?
TMP-SMX (Bactrin)
Two drugs you could use for anaerobic bacteria including C diff, and protozoa…but don’t add EtOH:
Metronidazole and tinidazole
What is the mechanism of action, what is the binding site, and what are the resistances for oxazolidinones?
Name drugs in this class:
bacteriostatic- binds to the 23s rRNA on 50s subunit and prevents formation of initiation subunit
resistance: modifications in the 23s rRNA
* **unique binding site prevents cross resistance with other drug classes
linezolid
What is the mechanism of action, what is the binding site, and what are the resistances for aminoglycosides?
Name drugs in this class:
bactericidal- prevents formation of initiation complex causing misreading and inducing early termination
Intrinsic resistance: failure of drug to enter cell (anaerobic)–> cotreat with cell wall inhibitor
Acquired resistance: acquisition of enzyme which inactivates the drug through acetylation, phosphorylation, or adenylation
Gentimicin, Amikacin, Tobramycin, Neomycin, Streptomycin
What is the mechanism of action, what is the binding site, and what are the resistances for tetracyclines?
Name drugs in this class:
bacteriostatic- binds 30s subunit of ribosome preventing attachment of aminoacyl-tRNA
Intrinsic resistance: decreased uptake
Acquired resistance:
- increased efflux - alteration of ribosomal target - rarely enzymatic inactivation of drug (acetyl)
Tetracycline, Doxycycline, Minocycline
What is the mechanism of action, what is the binding site, and what are the resistances for chloramphenicol?
bacteriostatic- binds 50s ribosomal subunit preventing peptide bond formation; peptidyltransferase can’t associate with amino acid substrate
Resistance: acetyltransferase modifies drug to prevent binding to ribosome
What is the mechanism of action, what is the binding site, and what are the resistances for macrolides?
Name drugs in this class:
bacteriostatic- inhibits translocation by binding to 23s of 50s subunit
Resistance: methylation of 23s binding site (also asoociated with clindamycin and quinupristin/dalfopristin resistance)
- increased efflux
- hydrolysis of macrolide by esterases
Erythromycin, Azithromycin, Clarithromycin
What is the mechanism of action, what is the binding site, and what are the resistances for lincosamides?
Name a drug in this class:
bacteriostatic- blocks translocation at 50s subunit
Resistance: mutation of ribosome
- methylation of rRNA (D test)
- cross resistance with macrolides and streptogramins
- inactivation of drugs by adenylation
Clindamycin
What is the mechanism of action, what is the binding site, and what are the resistances for streptogramins?
Name drugs in this class:
combined action bactericidal for some organisms, binds to 50s to inhibit translocation
Resistance: ribosomal methylase prevents binding of drugs to its target
- enzymes inactivate drugs
- efflux proteins pump drugs out of cell
- cross resistance with macrolides and clindamycin
Quinupristin, Dalfopristin
Four drug classes susceptible to decreased uptake resistance:
Tetracyclines
Sulfonamides
Aminoglycosides
Chloramphenicol
Seven drug classes susceptible to increased efflux:
cephalosporins
aztreonam
tetracyclines ***MOST IMPORTANT, with the exception of minocycline
macrolides
quinupristin/dalfopristin
fluoroquinolones
sulfonamides
Ten drug classes inhibited by target alteration:
Describe each:
beta lactams- altered penicillin binding protein (MRSA)
vancomycin- altered target
rifampin- ddRNA polymerase
fluoroquinolones- DNA topoisomerases II or IV
sulfonamides- dihydropteroate synthetase
trimethoprim- DHFR
linezolid- altered ribisome (50s)
aminoglycosides- altered ribosome (30s), uncommon
erythromycin, clindamycin, quinupristin/dalfopristin
-methyltransferase modified ribosome (50s)
tetracylines- production of proteins that interfere with ribosomal binding
Drug class inhibited by upregulation of substrate:
What is the substrate?
sulfonamides
PABA
Nine drug classes inactivated by enzymes:
What are the enzymes or mechanisms of inactivation?
penicillins- beta lactamases
cephalosporins- beta lactamases
aminoglycosides- acetyl group, Amikacin most resistant
chloramphenicol- acetyltransferase action
tetracyclines- minor acetylation
macrolides- bacterial esterases
clindamycin- adenylation
quinupristin/dalfopristin
metronidazole- decreased drug activation
Bactericidal inhibitors of protein synthesis that act on 303 ribosome (5 of them):
Aminoglycosides
- streptomycin
- neomycin
- amikacin
- gentamicin
- tobramycin
Bacteriostatic inhibitors of protein synthesis that act on 30s ribosome (4 of them):
Tetracyclines
- Doxycycline
- minocycline
- demecocycline
- tetracycline
Bacteriostatic inhibitors of protein synthesis that act on 50s ribosome (7 of them):
Macrolides:
- erythromycin
- azithromycin
- clarithromycin
- clindamycin
- chloramphenicol
- linezolid
- quinupristin/dalfopristin
Two drugs not safe for use in newborns:
Why?
Chloramphenicol, sulfonamides
they can’t glucuronidate
Two drug classes not safe for use in children:
fluoroquinolones, tetracyclines
Six drugs/classes not safe for use during pregnancy:
- tetracyclines
- aminoglycosides
- clarithromycin
- fluoroquinolones
- chloramphenicol
- sulfonamides
Three drug classes need adjusting for reduced renal function (usually in the elderly; increased half life):
beta lactams
aminoglycosides
fluoroquinolones
Toxicity associated with seizures:
beta lactams, particularly carbapenams
Toxicity associated with hepatotoxicity:
rifampin
Toxicity associated with neprotoxicity:
sulfonamides
aminoglycosides
vancomycin
Toxicity associated with ototoxicity:
aminoglycosides, vancomycin
Toxicity associated with QTc interval prolongation:
macrolides, fluoroquinolones
Toxicity associated with anemia:
chloramphenicol, trimethoprim
Toxicity associated with arthralgia:
quinupristin/dalfopristin, fluoroquinolones
Toxicity associated with disulfiram reaction when taken with EtOH:
metronidazole
2nd gen cephalosporins with methylthiotetrazole groups
Toxicity associated with superinfection:
clindamycin
fluoroquinolones
3rd gen cephalosporins
ampicillin
Which drug induces cytochrome p450 drug metabolizing enzymes creating the possibility of drug-drug interactions?
rifampin
Two drugs that inhibit hepatic metabolism:
clarithromycin and erythromycin (2 macrolides)
