Week 4 Drugs Flashcards by Weston Tardy

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

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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

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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

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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 +

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Which drugs can cause double-stranded DNA breaks and cell death along with their main action on topoisomerases?

flouroquinilones

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What generally happens with upregulation of transporter capable of effluxing?

multidrug resistance

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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

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Name two Folate antagonists that indirectly inhibit DNA synthesis:

Are these drugs bateriostatic or bactericidal?

Sulfonamides and Trimethoprim

bacteriostatic

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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.

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How can bacteria that need to synthesize dihydrofolte resist sulfamethoxazole? (3 ways)

change in dihydropteroate synthetase
increased efflux
increased production of PABA

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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

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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

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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

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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

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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

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This drug is only metabolized to its active form in anaerobes:

Metronidazole

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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

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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

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What is the drug to chose for Mycobacteria tuberculosis (along with 3 other drugs due to high rate of resistance)?

Rifampin

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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

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What class of drugs would you chose for broad spectrum coverage of Gram + and - and atypical organisms like Mycoplasma, HAP, and UTIs?

Fluoroquinolones

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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 1. streptomycin 2. neomycin 3. amikacin 4. gentamicin 5. tobramycin

Bacteriostatic inhibitors of protein synthesis that act on 30s ribosome (4 of them):

Tetracyclines 1. Doxycycline 2. minocycline 3. demecocycline 4. tetracycline

Bacteriostatic inhibitors of protein synthesis that act on 50s ribosome (7 of them):

Macrolides: 1. erythromycin 2. azithromycin 3. clarithromycin 4. clindamycin 5. chloramphenicol 6. linezolid 7. 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:

1. tetracyclines 2. aminoglycosides 3. clarithromycin 4. fluoroquinolones 5. chloramphenicol 6. 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)