Gulsevin Exam 2 Materials Flashcards
Aminoglycosides
Are aminoglycosides acidic or basic?
basic, postively charged
especially at low pH, readily water soluble, poor absorption in GI tract
Aminoglycosides
How do Aminoglycosides enter the cell of the target organism?
- passive infusion through porins
- passage through membrane disruption
outer membrane, (-) charge interacts with drug, (+) charge
Aminoglycosides
How do Aminoglycosides enter the cytoplasm of the target organism?
- Proton motive force drives drug entry into the cytoplasm (H+ pumped out, drug (+ charged) pumped in)
- Oxygen-dependent process involving protein pumps
highly acidic enviroment or lack of oxygen= interfers with drug entry
Aminoglycosides
What is the mechanism of action of Aminoglycosides?
- blocks initiation of protein synthesis
- blocks further translation and elicits premature termination of protein synthesis
- incorporation of incorrect amino acid of protein synthesis
bacterialcidal, because bacteria cannot make essential proteins
Aminoglycosides
What is the binding site of aminoglycosides?
A-site of the ribosomal subunit
Aminoglycosides
What are the metabolism mechanisms of resistance to aminoglycosides?
- aminoglycoside acetylases (AAC)
- aminoglycoside phosphorylases (APH)
- aminoglycoside nucleotide transferases (ANT)
sites on the structure can be modified to avoid resistance
overall, resistance mechanisms include: metabolism, prevention of drug entry, mutation of drug target site
Aminoglycosides
What are the entry preventions mechanisms of resistance to aminoglycosides?
- mutations of the porin genes or lower porin expression may prevent drug entry into cells
- changes to membrane chemistry (change in charge) and composition can prevent effective contacts between aminoglycosides and the membrane surface
- changes that affect the proton motive force can decrease the aminoglycoside intake
- efflux pump overexpression can result in increased removal of aminoglycoside from the cell
overall, resistance mechanisms include: metabolism, prevention of drug entry, mutation of drug target site
Aminoglycosides
What are the drug target site mechanisms of resistance to aminoglycosides?
- single nucleotide mutations near the A site of the 16S rRNA can result in diminished binding
- methylation of the 16S rRNA mediated by methyltransferases can modify specific nucleotides preventing binding
- mutations in ribosomal proteins may prevent binding
Aminoglycosides
What is the use of replacing one of the sugar molecules of the aminoglycoside structure with a 5-membered ring?
extended spectrum to gram (+)
BUT it is more susceptible to degradation
Aminoglycosides
What aminoglycoside is used for the treatment of hepatic encephalopathy?
Neomycin B
MOA: supress bacteria in gut that produce urease (urea -> CO2 + NH4+)
Aminoglycosides
What are the adverse effects of Aminoglycosides?
- OTOTOXICITY, damage to the structures of the inner ear can lead to hearing loss, tinnitus, and/or balance disturbances. typically IRREVERSIBLE and can occur at therapeutic doses
- NEPHROTOXICITY, high quanities excreted in the urine, therefor kidney disfunction may require a reduced dose to prevent accumulation to toxic levels. increase risk of ototoxicity
- NEUROMUSCULAR JUNCTION BLOCKADE (less common) and may exaggerate muscle weakness in patients with myasthenia gravis or parkinsonism
Aminoglycosides
What drug class cannot be given with aminoglycosides in the same solution of at the same administration site?
beta-lactams
Macrolides
What is the binding site of Macrolides?
23S of ribosomal subunit
Macrolides
What is the mechanism of action of macrolides?
binds 23S rRNA to prevent further elongation of protein chains
bacteriostatic
Macrolides
How is Erythromycin formulated for IV delievery?
salf formation with acids (increased H2O solubility)
erythromycin is not very water soluble as free base
Macrolides
What is the half-life of Erythromycin?
1.5-2 hours, requires 4x/day dosing
Macrolides
What can be done with the formulation of Erythromycin to assist with it’s unpleasant taste?
prodrug formulation
- erthromycin ethylsuccinate (oral tablet and granules for oral suspension)
- stearate salt
- enteric coated
Macrolides
What is the route of metabolism of Erythromycin?
extensive metabolism via CYP3A4 in the liver, 80% is inactivated through demethylation, ~60% is excreted in the bile
Macrolides
How can Erythromycin be degradated after administration?
- gastric acidic enviroment
- self- degradation
Macrolides
What is the importance of structural changes in Clarithromycin and Azithromycin compared to Erythromycin?
- acid stability
- circumvent ketal formation (self-degradation)
overall, increased oral absorption and improved half life
also have a broader spectrum of action
Macrolides
What are the indications of Clarithromycin?
- Mycobacterium avium complex (MAC) in patient with AIDS
- H. pylori associated with duodenal ulcers
- Community-acquired pneumonia
- Sinusitis
- Acute exacerbations of chronic bronchitis
penetrates lung tissue and macrophages better than erythromycin
Macrolides
What is the dosing regimen of Clarithromycin?
2x/day dosing
Macrolides
What is the dosing of Azithromycin?
once daily dosing
Macrolides
What are the indications of Azithromycin?
- Mycobacterium avium complex (MAC) in patient with AIDS
- Otitis media
- Community-acquired pneumonia
- Sinusitis
Macrolides
What are the adverse effects of Macrolides?
GI upset (severe with erythromycin, mild with other macrolides)
Macrolides
What macrolid inhibits CYP3A4?
-erythromycin
-clarithromycin
Macrolides
What are the mechanisms of resistance to macrolides?
- N6 dimethylation
- mutations which change nucleotide identity
Tetracyclines
Are tetracyclines acidic or basic?
basic
typically protonated (+) under physiological conditions
Tetracyclines
What is the mechanism of action of tetracyclines?
bind to the 30S subunit= block tRNA binding to A site= inhibition of protein synthesis
Tetracyclines
What are the uses of tetracyclines?
ATYPICAL infections, GRAM (+), and GRAM (-)
- tick borne illnesses (Babesiosis, Lyme Disease, Anaplasmosis, Tularemia, Ehrlichiosis, Rocky Mountian Spotted Fever)
- Rickettsial infections
- STIs (chlamydia, gonorrhea, syphilis)
- Malaria
- Bacillius anthracis (Anthrax)
- doxycycline & minocycline= acne vulgaris and rosacea
Tetracyclines
What are the adverse drug interactions of tetracyclines?
METALS
avoid metal supplements including iron, magnesium, calcium, zinc, and antacids
tetracyclines chelates metal ions= decreased absorption
Tetracyclines
What structural modification leads to tetracyclines to be unstable in acidic and basic conditions?
hydroxyl group at C6
Tetracyclines
What are the adverse effects of tetracyclines?
Fanconi syndrome
due to metabolite, epianhydrotetracycline
Tetracyclines
What are the mechanisms of resistance to tetracyclines?
- mutations of efflux pumps (tetracycline resistance genes tetA, tetB, tetC)
- ribosomes protection proteins (Tet(M), Tet(O))
- enzymatic degradation of tetracycline through the tetX protein
Fluroroquinolones
Are fluroquinolones bactericidal or bacteristatic?
bactericidal
Fluoroquinolones
Why are fluoroquinoles a preferred treatment?
high bioavaliability and wide spectrum of action
Fluroquinolones
What is the spectrum of action of Nalixidic acid?
most gram negative
Fluoroquinolones
What is the mechanism of gyrase?
- DNA gyrase binds to 2 segments of DNA, creating a node of positive superhelix
- The enzyme then introduces a double strand break in the DNA and passes the front segment through the break
- The break is then resealed creating a negative supercoil
Fluroquinolones
What is the mechanism of action of Fluroquinolones?
stabilizes DNA to prevent the step necessary to supercoiling
variations in fluro structures leads to variation in DNA intercalation
Fluroquinolones
What are the interactions of Ciprofloxacin at the binding site, S. aureus gyrase?
- pi-pi binding
- hydrophobic interactions
- hydrogen bonding
Fluroquinolones
What is the purpose of modifying fluroquinolone drug structure?
- increase the drug potency
- altering the selectivity profile
- reduce drug metabolism
- increase the drug bioavaliability
modification made @ N-1, C-7, and some C-3
Fluroquinolones
What is the optimized modification at N-1 on Fluroquinolones?
4>5 carbon chain off of N-1 capped with an amine
effects are length dependent, not too short or too long
Fluroquinolones
What are the possible modifications at the C-3 position?
ester groups instead of acid may be utilized because they have better cell penetration and can be prodrugs
Fluroquinolones
What is the purpose of modifying the C-7 site on fluroquinolones?
changes to the C-7 site can change the drugs selectivity
large, extended, bulky groups have diminished activity
Fluroquinolones
What is the therapeutic effects of substituting a piperazine ring analogue at C-7?
more effective against gram (-) and pseudomonas
Fluroquinolones
What is the therapeutic effects of substituting a pyrrolidine ring analogue at C-7?
more effective against gram (+), atypical organisms, respiratory organisms, and streptococcus pneumoniae
Fluroquinolones
What are the adverse drug interactions of fluroquinolones?
METAL
avoid metal supplements like iron, calcium, zinc
fluroquinolones chelates metal ions= decreased solubility
Fluroquinolones
What Fluroquinolones are redily found in the urine making them good UTI drugs?
Ciprofloxacin (45% recovered in urine) and Levofloxacin (87% recovered in urine)
Moxifloxacin 20% in urine and Gemifloxacin ~36% in urine
Fluroquinolones
What are the adverse effects of Fluroquinolones?
- tendinitis and tendon rupture
- CNS effects
- phototoxicity/photosensitivity
- arthropathy (joint diseases)
- QT prolongation
- retinal detachment
- peripheral neuropathy
- GI effects
- hyper/hypoglycemia
Fluroquinolone
What Fluroquinolone has the highest risk of QT prolongation?
Moxifloxacin
Fluroquinolones
What are the mechanisms of resistance to Fluroquinolones?
- mutations of gyrase can prevent binding
- increase expression of efflux pumps
- if fluroquinolone has a piperazine ring at C-7 then it can be acetylated via mutant aminoglycoside-modifying enzyme
ciprofloxacin contains piperazine ring and can be metabolized
Fluroquinolones
Why do Fluroquinolones have an enviromental impact?
since they are renally excreted mostly unchanged they can enter the sewer system
Bacitracin
What organisms is Bacitracin effective against?
gram (+)
Bacitracin
What is the main use of Bacitracin?
topical treatment of minor skin injuries
Bacitracin
What are the adverse effects of Bacitracin?
allergic reaction (fever, hives, itching, swelling of lips and face, difficulty breathing, nausea, vomiting)
Bacitracin
What is the pregnancy risk category of Bacitracin?
C
no evidence of risk of fetal harm with use of topical bacitracin
Polymyxins
What is the use of Polymyxins?
- systemic infections caused by multi-drug resistant gram (-) bacteria, including: Enterobacteriaceae, Pseudomonas, Acinetobacter
- topically for otitis externa and bacterial conjunctivitis
- may be used IM or IV in sulfate salt formulation to treat serious UTI, meningitis, or septicemia
not first line
Polymyxin
What is the mechanism of action of Polymyxin?
polymyxin binds to the bacterial membrane with the lipids (LPS and Lipid A) which results in the displacement of Ca2+ and Mg2+ ions= disruption in the membrane structure, increased permeability, and subsequent rupture
Polymixins
What are the adverse effects Polymyxins?
- nephrotoxicity (hemauria, oliguria, and acute renal failure)
- neurotoxicity
- neuromuscular blockade
side effects limit use to multidrug-resistant infections-not first line
Vancomycin
What are the uses of Vancomycin?
GRAM POSITIVE ONLY
- methicillin-resistant staphlocococcus aureus (MRSA)
- C. difficile
- Enterocolitis caused by S. aureus
Vancomycin
Why must Vancomycin be given via IV?
poor oral bioavaliability
oral form is for C. diff only
Vancomycin
What is the mechanism of action of Vancomycin?
glycoprotein
inhibits PGT preventing synthesis of peptidoglycan
gram positive only
Vancomycin
What is the primary binding site of Vancomycin?
C-terminal D-Ala dipeptide of growing cell wall
multiple residues play a role in interaction with target site
Vancomycin
What are the adverse reactions of Vancomycin?
- thrombophlebitis (minimize by using diluted solution and rotate infusion site)
- flushing due to histamine release
- ototoxicity and nephrotoxicity (especially when administered with other toxic drugs at these sites)
Vancomycin
What can patients being treated with Vancomycin be pre-treated with to prevent flushing?
diphenhydramine
other histamine antagonists
Vancomycin
What drugs are second generation glycoproteins?
- telavancin
- dalbavancin
- oritavancin
semi-synthetic glycopeptides
Vancomycin
What is the spectrum of action of Daptomycin?
gram (+)
typically for soft tissue infection or endocarditis
Vancomycin
Why can Daptomycin not be used for lung infections?
deactivated by lung surfactants
Vancomycin
What are the adverse effects of Daptomycin?
myopathy
little to no ototoxicty or nephrotoxicity
Vancomycin
What is the mechanism of action of Daptomycin?
daptomycin binds to cytoplasmic membrane then forms complexes in a calcium-dependent manner. complex formation causes rapid loss of cellular potassium resulting in arrest of DNA, RNA, and protein synthesis= cell death
Antimycobacterial
What are the difference of mycolic acid in the membrane of mycobacteria versus regular fatty acids?
- decreased membrane permeability
- stabilizes the membrane
- less flexibility of the membrane
- increased survival in harsh conditions
Antimycobacterial
What drugs are Rifamycins?
- rifampin
- rifabutin
- rifapentine
combo product: isoniazid + rifampin
Antimycobacterial
What is the mechanism of action of Rifamycins?
inhibits bacterial DNA-dependent RNA polymerase (DDRP) aka RNA polymerase (RNAP) ultimately leading to the termination of RNA elongation
binds “rifampicin binding pocket”
Antimycobacterials
What is the use of Rifampin?
treatment of mycobacterial infections
Antimycobacterial
What are the adverse effects of Rifampin?
- orange discoloration of body fluids like tears, sweat, saliva, urine, and feces
- constipation
- hepatotoxicity
Antimycobacterial
What antimycobacterial drug induces CYP3A4?
Rifamycins
can increase the metabolism of other drugs metabolized by this enzyme
Antimycobacterial
Which Rifamycin is the preferred treatment in HIV patients?
Rifabutin
milder inducer of CYP3A4
Antimycobacterial
What is the use of Fidoxamicin?
C. diff infections
low absorption, lower stress on gut microbiome
Antimycobacterial
What is the use of Isoniazid?
tuberculosis, combo treatment in active cases or preventative treatment in high risk populations (HIV + patients)
WHO list of essential medications
Antimycobacterial
What antimycobacterial drug is a CYP450 inhibitor?
Isoniazid
Antimycobacterial
What is the mechanism of action of Isoniazid?
inhibitor of InhA (mycobacterium tuberculosis enoyl reductase)
irreversible
Antimycobacterial
What vitamin may become depleted during Isoniazid therapy?
vitamin B6
supplementation, severe depletion possible= seizures, acidosis, death
Antimycobacterial
What population may be at risk of hepatotoxicity on Isoniazid therapy?
slow acetylators
Antimycobacterial
What is the half life of Isoniazid?
30 mins-5 hours, dependent on NAT2 gene
Antimycobacterial
What is the use of Bedaquiline?
multi-drug resistant tuberculosis
resistant to isoniazid and rifampicin
Antimycobacterial
What is the half life of Bedaquiline?
4-5 months
Antimycobacterial
What is the mechanism of action of Bedaquiline?
binds ATP synthase
Antimycobacterial
What is the main route of metabolism of Bedaquiline?
CYP3A4
Antimycobacterial
What is the mechanism of action of Pyrazinamide?
lowers the pH of within the bacterium and macrophages which may interfer with the activity of FAS I, but may directly bind to FAS I to inhibit its activity. also, the acidification of the cell can disrupt the proton motive force which can inhibit ATP production
active compound pyrazinoic acid
Antimycobacterial
What is the use of Pyrazinamide?
particularly active against dormant or semi-dormant M. tuberculosis in macrophages
Antimycobacterial
What is the mechanism of resistance to Pyrazinamide?
mutation of pncA gene in mycobacterium
Antimycobacterial
What are the side effects of Pyrazinamide?
increase in uric acid may cause gout
Antimycobacterial
What is the use of Ethambutol?
primarly M. tuberculosis, but some activity against mycobacterium avium complex (MAC)
Antimycobacterial
How is Ethambutol metabolized?
some by the liver, but mostly excreted unchanged so renal dysfunction may lead to increased risk of toxicity
Antimycobacterial
What is the adverse effect of Ethambutol?
optic neuritis (decreased visual acuity and color blindness)
reversible
Antimycobacterial
What is the use of Pretomanid?
extensively drug resistant (XDR) or multi-drug resistant M. tuberculosis
typically in combo with bedaquiline and linezolid
Antimycobacterial
What is the mechanism of action of Pretomanid?
M. Tuberculosis is found in hypoxic enviroments which enhances reduction of pretomanid’s nitro group by nitroreductases= reactive N species cause damage to bacterial proteins, lipids, and DNA
inhibit mycolic acid synthesis via inhib hydroxy-mycolate to ketomycolat
Antimycobacterial
What are the second line treatment of tuberculosis?
- levofloxacin
- carpreomycin
- moxifloxacin
- linezolid
- aminosalicyclic acid
- cycloserine
- ethionamide
Antimycobacterial
What tuberculosis drug is PABA-like?
aminosalicylic acid
folic acid synthesis precursor
Antimycobacterial
What is the connection between tuberculosis and vitamin D?
patients with TB have lower serum vitamin D levels and may be given in adjunct
no difference in treatment outcomes
Antimycobacterial
What are the drugs used for the treatment of Leprosy?
- clofazimine
- dapsone
- rifampin
- thalidomide
Antimycobacterial
What is the mechanism of action of Clofazimine?
- binds to guanine-rich sequence of mycobacterium DNA= stops mycobacterial DNA replication
- activates mycobacterial phospholipase A2= increased accumulation of lysophospholipids
Antimycobacterial
What is the mechanism of action of Dapsone?
Antimycobacterial
What is the mechanism of action of Thalidomide?
thalidomide -> (arene oxide intermediate) is susceptible to neutophilic attacks and can bind DNA
Antimycobacterial
What is the use of Thalidomide?
Erthema Nodosum Leprosum(ENL), inflammation of the skin associated with leprosy
Antimycobacterial
In what population should Thalidomide be avoided?
pregnant patients
Oxazolidinone
What is the mechanism of action of Linezolid?
Binds specific sites on 23S rRNA within the 50S subunit- prevent complex formation with 70S
Oxazolidinone
What is the spectrum of action of Linezolid?
-gram positive, including vancomycin resistant Enterococcus faecium (VRE)and MRSA
-nosocomial (hospital) pneumonia and community acquired pneumonia
-skin infections
Oxazolidinone
What is the spectrum of action of Tedizolid?
-skin infections caused by S aureus (including MRSA and MSSA)
-streptococcus spp.
-Enterococcus spp.
Oxazolidinone
Which Oxazolidonone is most likely to cause serotonin syndrome?
Linezolid
non-selective MAO inhibitor, Tedizolid less likely
Oxazolidinone
Which Oxazolidinone can cause myelosuppression?
Linezolid
Tedizolid may also cause it but less likely
Oxazolidinone
What is the mechanism of resistance of Oxazolidinone?
methylation of adenosine sterically hinders binding to the 23S rRNA
mutation, Linezolid most susceptible to resistance
Oxazolidinone
What are the drug interactions of Linezolid/Tedizolid?
- serotonergic agent (risk of serotonin syndrome)
- foods high in tyramine
Plueromutilins
What is the mechanism of action of Retapamulin?
binds to bacterial ribosome with high affinity to inhibits ribosomal peptidyl transferase activity and partially inhibit the binding of the initiator tRNA substrate to the ribosome P-site
Pleuromutilins
What is the spectrum of action of Retapamulin?
-gram positive aerobic bacteria
-impetigo caused by Staph aureus (MSSA) and Streptococcus spp.
Pleuromutilins
What is the spectrum of action of Lefamulin?
- gram positive
- gram negative
- atypical organism
- community acquired bacterial pneumonia (CABP)
What is the mechanism of action of Mupirocin?
reversible inhibitor of bacterial isoleucyl-tRNA synthase= inhibits bacterial protein synthesis
What is the spectrum of action of Mupirocin?
- gram positive (including MSSA, MRSA, and Strept. pyogenes)
- skin infections due to Staph. and Strept.
What is the mechanism of action of Clindamycin?
prevents peptide bond formation thereby inhibiting protein synthesis by reversibly binding 50S subunit
What is the spectrum of action of Clindamycin?
aerobic or anaerobic gram positive cocci
more active than erythromycin against anaerobic bacteria
