What is the absorption, distribution, and elimination of aminoglycosides?
Absorption: Very polar, not absorbed in GI tract. Given IV/IM, or topically, unless they're meant to only act on GI tract Distribution: Primarily Distributed within EC fluid. Doesn't reach CNS well (only with inflamed meninges). Elimination: Kidney is king. Glomerular filtration accounts for 99% of elimination (can have kidney toxicity). Short half-lives (2-3 hours) depending on kidney function.
What is aminoglycosides mechanism of action?
They are bactericidal. They bind to the 30 S ribosomal subunit and thus block initiation of translation (protein synth), which causes some misplacement of AAs in the chain. Freeze the 30S initiation complex. The Davis theory (not completely supported): tries to explain how they can be bactericidal. Says that small amts of aminoglycoside can enter the inner membrane of a bacteria then bind to 30S causing miscoding of proteins. The miscoded proteins form pores in the membrane which allow many more aminoglycosides to enter and damages the membrane.
What are 3 general types of resistance to aminoglycosides?
Enzymes that modify aminoglycoside
Altered ribosome binding site
altered aminoglycoside uptake
How do aminoglycosides causes ototoxicity? What are some forms in which the toxicity takes place? What are some risk factors for ototoxicity when taking aminoglycosides?
The outer hair cells in the ear are first destroyed (permanent loss of hearing high tones) and then the inner ones (eventually losing low tones and then complete deafness). Some people also are affected vestibularly (balance). Risk factors include dose, duration of therapy, hypovolemia, use of loop diuretics, use of vancomycin, repeated exposure, age, liver disfunction
How do aminoglycosides cause nephrotoxicity? What are some risk factors?
They bind to proximal tubule cells, enter inside of them and damage the brush border which allows cellular contents to leak out. This leads to decreased kidney function. It is reversible damage. Risk factors include, age, pre-existing renal disease, use of cisplatin, amphotericin, other nephrotoxic medications, NSAIDS, ACE inhibitors, or diuretics.
How do aminoglycosides cause neuromuscular blockade? What are the results?
They block the presynaptic release of Ach and the postsynaptic sensitivity to Ach. This causes acute muscle paralysis which could cause apnea.
What are some common clinical uses of aminoglycosides?
Serious, life-threatening gram-negative infection
Complicated skin, bone or soft tissue infection
Complicated urinary tract infection
Septicemia Peritonitis and other severe intra-abdominal infections
Severe pelvic inflammatory disease
Ocular infections (topical)
Otitis externa (topical)
Where are some places in the body in which aminoglycosides are effective at killing gram negative bacteria?
Lower respiratory infections (only 30-50% penetration)
Urinary tract (Aminoglycosides concentrate in urine & kidney)
Skin and soft tissue infections Bacteremia/sepsis
What are some gram + cocci that aminoglycosides are used to treat? What diseases do they cause? Which drug is used?
endocarditis, bacteremia, septicemia, meningitis, urinary tract
penicillin + aminoglycoside
What are some gram - bacillii that aminoglycosides are used to treat? What diseases do they cause? Which drug is used?
E. Coli, enterobacter, proteus, pseudomonas, klebsiella, serratia
bacteremia, urinary tract, pneumonia
What are some possible clinical uses for streptomycin? Why isn't it used much today? What are some unique toxicities?
• Tuberculosis (2nd line drug), Bubonic plague, Tularemia, Pseudomonas, Streptococcal endocarditis
It isn't used much b/c bacteria quickly gained resistance to it.
Optic nerve drainage
What is gentomycin used for? What is it sometimes used with? What are its drawbacks/side effects? What organisms are resistant to it?
It is the workhorse, the most commonly used.
For serious system infections, it is used with beta-lactams.
It is the most nephrotoxic drug that we use.
It also causes major ototoxicity (usually vestibular)
•Resistant organisms are streptococci, pneumococci, anaerobic bacteria and fungi
How does tobramycin compare to gentomycin?
• Properties similar to gentamicin (used as a backup basically)
• Costs more than gentamicin
• Has greater effect than gentamicin against pseudomonas aerugmisa
• Attacked by 7 enzymes
• Less nephrotoxic than gentamicin
What infection is amakacin used to treat? What are 4 of its benefits? Where is it most used and to treat what type of infections is it used there?
• Used to treat streptomycin resistant M. tuberculosis
• Effective against many organisms resistant to gentamicin and tobramycin
• Broadest spectrum
• Subject to attack at only 2 of 9 enzymes that can attack gentamicin
• Most used in hospital setting for treating gram- bacillary infections
What is the general structure of the tetracyclines? How do the different R groups affect function?
They are 4 rings bound together in a line. The different R groups affects their mechanism of action and their clearance.
How are tetracyclines absorbed? What factors affect their absorption?
They are absorbed well when taken orally. They should be taken on an empty stomach. Absorption is impaired by food, divalent cations, dairy products and antacids (multivalent cations) and by alkaline pH.
What is the main factor that affects distribution of tetracyclines? How is distribution?
It readily binds to plasma proteins making the Vd large. It distributes well, to brain, bone/teeth, etc.
Where are tetracyclines primarily excreted? In 24 hours, how much of the major tetracyclies will be excreted in the urine?
In the kidneys. Tetracycline (20-55%), oxytetracycline (10-35), chlortetracycline (10-15), Minocycline (~5).
What is the mechanism of action of tetracyclines? What are the two ways in which they enter the cell? What is the result of tetracylines on bacteria?
It can enter the cell passively or actively through porins. Once inside, it binds to the 30S subunit of the ribosome and prevents the initiation of translation. It is bacteriostatic. inhibits binding of aminoacyl tRNA ribosome complex
How do bacteria develop resistance to tetracylines?
They develop a transporter that binds tetracycline and pumps them out of the cell.
What are the side effects of tetracyclines?
• Hypersensitivity Reactions
• Gastrointestinal • Phototoxicity (deoxytetra, purplish skin in sun)
- • Liver toxicity
- • Kidney toxicity
- • Brown discoloration of teeth (pregnant women, children before permanent teeth)
- • Suprainfections by resistant microorganisms
what diseases are tetracyclines used for?
First Choice Drugs:
• Rickettsial infections
• Mycloplasma infections
• Chlamydial infections
• Lyme disease
Second Choice Drugs:
• Clostridium (tetanus, gangrene)
• Campylobacter (diarrhea)
• Leptospira (Weil’s disease)
• Actinomyces (abscesses)
Also used in mixed infections of the respiratory tract and in acne
Which drugs stay in the body longest and are thus the most used? What are they affective against? What unique side effects?
MInocycline: gram +, gram -, chlamydias, some phototoxicity
doxycycline: gram+, gram -, chlamydias, M. Pneumoniae, similiar S/E.
Which is a drug with an intermediate clearance/effectivity? What is it effective against? Side effects?
Demeclocycline: gram-, gram +, M. pneumoniae, chlamydia, strong phototoxicity
What are 3 other tetracyclines?
chlortetracycline, oxytetracycline, tetracycline
What is the mechanism of action of chloramphenicol? What effect does it have on most bacteria? On H. influenza?
It binds to the 50S subunit of ribosomes-->can't translate proteins (inhibits binding of aminoacyl tRNA) . It is bacteriostatic with most microbes but bacteriocidal with H. influenza.
Why is chloramphenicol rarely used? What is its toxicity? When is it used? What is its spectrum? distribution? elimination?
Rarely used due to toxicity. Causes BM suppression (can be serious-can be irreversible (aplastic anemia)), hypersensitivity, toxic to neonates (they can't glucoronidate it)-->grey baby sydrome.
Used with typhoid fever, bacterial menengitis, rickettsia, abscesses, brucella, only when nothing else works.
Broad specturm (gram +'s gram -'s chlamydia, ricketssia) .
Well distributed (including CNS). Some protein binding.
eliminated in liver biotransformation (inducible-P450).
What Aminoglycosides are there? What is its spectrum like?
Streptomycin, gentamycin, tobramycin, amikacin, nitilmicin, kanamycin, neomycin
Broad, many gram neg. bacilli, some gram + bacilli, aerobic, no anaerobic