Tetra and Chloro and Aminoglyco

Question 1

what is the mechanism of tetracylines and what is it derived from

Answer 1

1. Tetracycline binds to a site on the 30S subunit and therefore interferes with the access of the aminoacyl tRNA. The antibiotic is derived from the bacteria Streptomyces aureofaciens.

Question 2

what is the structure of the tetracycline

Answer 2

composed of 4 fused six-membered unsaturated rings

Question 3

what is unique in the mechanism of action for tetracyclines

Answer 3

Organisms that are susceptible to tetracycline actually have an active uptake mechanism and that’s partly the explanation for tetracycline’s selective toxicity

also has greater affinity to the non-host ribosomes which adds to its selective toxicity and this is demonstrated by the fact that intracellular rickettsiae and chlamydiae can be treated

Question 4

what are the different infections that tetracylcine can cover

Answer 4

1. Chlamydial infections
2. Mycoplasma pneumonia
3. Lyme Disease
4. Rocky mountain spotted fever
5. Cholera

Question 5

Tetracycline is also

Answer 5

bacteriostatic

Question 6

1. How do bacteria become resistant to tetracycline?

Answer 6

because it exists in multi-drug resistance gene cassettes. Bacteria that have these multi-drug resistance gene cassettes are resistant to tetracyclines as well as other antibiotics

PUMP most important mechanism of resistance against tetracycline is the development of pumps that allow bacteria to increase efflux of the antibiotic.

bugs can inactivate tetracycline enzymatically

bacteria alter the target of tetracycline so that the drug won’t bind well due to decreased affinity

Question 7

for treatment of acne vulgaris and rosacea we use

Answer 7

tetracycline

Question 8

name two pharmacokinetics about tetracycline

Answer 8

it is orally active and it forms chelates with dairy products Mg, Ca, and Al to produce a non-absorbable complex

Question 9

the most orally active tetracylcine is

Answer 9

doxycycline

Question 10

tetracyclines bind to

Answer 10

tissues undergoing calcification (teeth and bone)

Question 11

tetracylines penetrates well in

Answer 11

tissues such as liver and kidneys

Question 12

tetracylclines is able to cross the

Answer 12

placenta

Question 13

what is used to treat someone in a meningococcal carrier state and why

Answer 13

Minocycline has high concentrations in the tears and saliva and therefore has been used on occasion to treat someone who is in the meningococcal carrier state. This is when the person doesn’t have an active infection but the meningococci are present and can be shed in nasal secretions, saliva, and tears

Question 14

a graph explaining the effect of milk on tetracylcine absorption

Answer 14

Question 15

how is tetracylcine eliminated

Answer 15

all undergo enterohepatic circulation except for doxycycline glucuronide

renal excretion is important for all except doxycycline which is excreted in feces

Question 16

tetracylcine is metabolized to varying extents by

Answer 16

glucuronide formation

Question 17

What types of ADRs are associated with the tetracyclines

Answer 17

GI distress

Deposition in bone an dprimary dentition during calcification (contraindicated in children less than 8 years)

discoloration of teeth

Hepatotoxicity in pregnant women

phototoxicity

vestibular disturbance with minocycline

Azotemia, Fanconi-like syndrome with outdated preparations

Question 18

drug interactions occur with tetracycline and what

Answer 18

Antacids

Warfarin-due in part to decreased intestinal flora which produce vitamin K

Digoxin

1. So if you give people on digoxin tetracycline because of an infection, the normal flora will be lowered in number.
2. Therefore now there’s less of the oral dose of digoxin being metabolized by normal flora.
3. This will increase the amount of digoxin that’s absorbed and thus increase blood levels of digoxin.

Question 19

Chloramphenical mechanism is similar to

Answer 19

macrolides and clindamycin

Question 20

how does resistance play a role against chloramphenicol

Answer 20

1. Enzymatic conversion to an inactive product by bacteria (acetyl coA transferase)
2. Decreased affinity

Question 21

what is the spectrum and structure

Answer 21

Spectrum:

H. influenzae

Acute typhoid fever

Ricketsial infections

Anaerobic infections

Question 22

how is chloramphenicol taken

Answer 22

can be orally active and parenteral preparations also

Question 23

what are the pharmacokinetics of chloramphenicol

Answer 23

well distributed; even enters CNS in absence of inflammation

Crosses placenta

extensive metabolism by host.

Question 24

what is the excretion and metabolism of chloramphenicol

Answer 24

extensive metabolism by host. Ultimate product is a glucuronide and it is excretd in urine

Question 25

what are the adverse effects of chloramphenicol

Answer 25

Hematological

• Hemolytic anemia in G6PDH deficiency
• Reversible anemia, lekopenia and thrombocytopenia- dose related; occurs during therapy
• idiosyncratic aplastic anemia-probably allergic in origin

Gray baby syndrome

Drug interactions because of CYP 450 inhibtion: caution in patients on warfarin, phenytoin

Question 26

Chloramphenicol and aplastic anemia

Answer 26

The only thing that has correlation with the idiosyncratic aplastic anemia is the number of times you’ve taken chloramphenicol. So if you’ve had chloramphenicol two times for two different diseases, or three times for three different diseases, as you increase the exposure to the drug, you increase the risk of the aplastic anemia

the idiosyncratic aplastic anemia is not dose dependent. It doesn’t matter how much chloramphenicol you give the patient because the aplastic anemia can occur at any dose

Question 27

what is gray baby syndrome

Answer 27

In the neonate, bilirubin(in excess in babys) and chloramphenicol will compete with eachother for the glucuronic acid. So if the neonate is put on chloramphenicol, its capacity to glucuronidate is so impaired that you wind up with elevated levels of chloramphenicol. Therefore unlike sulfonamide-induced kernicterus, the damage isn’t coming from excess bilirubin in gray baby syndrome but it’s due to the direct toxic effects of chloramphenicol. So you can look at a graph to demonstrate gray baby syndrome where the concentration of chloramphenicol and its metabolites in whole blood is on the y-axis while time after dose is on the x-axis

Question 28

explain this graph

Answer 28

1. In neonates 8 days or younger, the rate at which chloramphenicol levels decline in blood is slow. So neonates cannot get rid of the chloramphenicol fast enough which causes it to accumulate and cause toxic effects. The toxic effects of chloramphenicol are on the mitochondria and unfortunately some neonates can succumb to this condition.
   
   1. So one toxic effect of chloramphenicol is failure of the baby to thrive.
   2. The neonate will also have respiratory distress due to chloramphenicol toxicity because the mitochondria cannot utilize oxygen.
   3. Chloramphenicol toxicity will also cause bluish-gray skin in the baby.
2. In contrast, in children 2 years or older, chloramphenicol levels in the blood decline relatively faster after the drug is given.

Question 29

what are the therapeutic uses

Answer 29

anaerobic infections due to Bacteroides fragilis

Typhoid fever and H. influenzae meningitis when first line therapy fails or cannot be employed

Pneumococcal or meningococcal meningitis in penicillin-allergic patients

Rickettsial diseases as a substitute for tetracycline in those that are sensitive, ESRD, pregnancy,

Question 30

what is the mechanism of Aminoglycosides

4 things

Answer 30

they are bacteriocidal

1. Aminoglycosides binds to the 30S subunit at a site completely different from the site used by the tetracyclines. The binding of the aminoglycoside to the 30S subunit inhibits formation of the initiation complex. If you can’t initiate translation, protein will not be made
2. block further translation so that amino acids cannot be added to growing peptide chain and the antibiotic also causes premature termination of the growing chain

3. have an unusual property in that they actually cause misreading of the mRNA codon. This occurs because aminoglycosides sit on a site on the 30S subunit where the 3 nucleotides of the mRNA codon come together to be read

4. Entry across the bacterial cell membrane by aminoglycosides requires an active transport mechanism that needs oxygen. This limits the spectrum of organisms that are sensitive to aminoglycosides. So anaerobes won’t be affected by the aminoglycosides

Question 31

what is the mechanism of resistance of aminoglycosides?

Answer 31

Absence of the oxygen-dependent transport system

Decreased affinity at the 30s subunit binding site

plasmid associated inactivating enzymes that can acetylate, adenylate or phosphorylate the aminoglyoside

Question 32

what are the five aminoglycosides that were discussed

Answer 32

kanamycin, amikacin, streptomycin, gentamycin, and tobracin

Question 33

aminoglycosides have a unique way of averting the resistant bacteria can you explain it

Answer 33

Some bacteria have more than one of these inactivating enzymes while others only have one of the inactivating enzymes.

1. Kanamycin can be acted upon by 3 different types of acetylation enzymes which will acetylate an amine on the drug to inactivate it. Kanamycin can also be inactivated by enzymes that will phosphorylate or adenylate various sites on the molecule. One of the acetylation enzymes, AC_I, doesn’t work very well but all of the other inactivating enzymes are very good at inactivating kanamycin.
2. In the case of amikacin, none of the acetylation enzymes, phosphorylation enzymes, or adenylation enzymes are very good at inactivating the antibiotic. So bacteria are less likely to become resistant to amikacin. Amikacin can thus attack organisms that are resistant to kanamycin because the inactivation enzymes are good at inactivating kanamycin but not amikacin. So this is one of the few situations where you can use another aminoglycoside to treat a patient who seems to have developed bacteria that are resistant to the first aminoglycoside you gave.

Question 34

gentamycin, tobramycin and amikacin are effective against but not effective against

Answer 34

Gentamycin and amikacin and tobramycin are another set of aminoglycosides and they are both effective against Gram negative aerobic bacteria like Pseudomonas aeruginosa. They are not effective against Gram positive organisms

Question 35

streptomycin is used to treat

Answer 35

mycobacterium tuberculosis

Question 36

aminoglycosides are also effective agains

Answer 36

tularemia and enterococci

Question 37

list some combinations between Aminoglycosides and other drugs

Answer 37

Aminoglycoside are often used in combination either with a β-lactam or vancomycin as a means to get maximum killing. Aminoglycosides, β-lactams, and vancomycin are all bactericidal. So this is a place where it’s appropriate to give these drugs together. If you’re giving an aminoglycoside and a β-lactam (or vancomycin) to a patient, you’re probably going to give them intravenously since this combinatorial therapy is usually used to treat serious infections and you don’t want to rely on oral absorption. You don’t want to give an aminoglycoside in the same area and at the same time that you’re giving the β-lactam (or vancomycin) because they actually precipitate eachother by forming a salt. So you might have to have two IV lines in the patient and separate them far apart from eachother. But once the β-lactam (or vancomycin) and the aminoglycoside get into the blood, there’s enough buffering and dilution effects that precipitation won’t occur. You only worry about precipitation when the two sets of drugs are outside of the patient’s body and therefore you don’t want them mixing with eachother at that point

Question 38

what are the pharmacokinetics of Aminoglycosides

Answer 38

Parenterally

once a day dosing because it exhibits dose dependent killing

Distribution-extracellular fluid, it does not enter CSF

Cross the placenta

Concentrated in renal cortex and endolymph

Question 39

excretion of aminoglycosides are dependent on

Answer 39

glomerular filtration and must be therapeutically monitored

Question 40

explain this graph

Answer 40

1. So if you’re giving gentamycin 3 times a day, each dose is going to cause the blood concentration of the drug to go up to 10 μg/mL which is above the minimum threshold concentration. The blood concentration of the dug will then slowly go down as time passes on and will go below the minimum threshold concentration at about 6 hours after the dose was given. Therefore if you’re giving a dose of gentamycin every 8 hours, you still have 2 more hours to go until you give the next dose of gentamycin and thus 2 out of 8 hours after each dose is given will be spent below the threshold. This effect is seen each of the 3 times you give the dose of gentamycin throughout the 24 hours in a day. So if you’re giving gentamycin 3 times a day, how much of that time is spent above the threshold? You spend 18 hours of the day (i.e. 75% of the day) above the threshold concentration if you’re giving gentamycin 3 times a day.

You can instead give gentamycin in a single dose which is 3 times the single dose that would be given 3 times a day. So now the blood concentrations of gentamycin start off at 30 μg/mL at the beginning of the day. The blood levels of gentamycin will still lower over the course of the day and they will cross the threshold at the 12 hour mark. So if you give one dose, you’re spending 50% of the time in a day above the threshold. So even though you give a higher dose of gentamycin initially in comparison to giving the drug 3 times a day, you only spend 50% of the day (as opposed to 75%) above the threshold which means that you’ve lowered the risk of the adverse events associated with aminoglycosides. So these days you are likely to only give aminoglycosides once a day since the clinical outcomes in terms of getting rid of the infection are the same and the adverse effects in many cases are actually lessened

Question 41

aminoglycosides have what special effect

Answer 41

Aminoglycosides have a post-antibiotic effect where they can still exhibit bactericidal effects even after the antibiotic has been stopped

Question 42

what are some toxicity associated with aminoglycosides

Answer 42

• Aminoglycosides cause vestibulocochlear nerve (CN VIII) damage which means they’re ototoxic.
• You don’t want to give aminoglycosides during pregnancy because auditory toxicity can occur in the fetus as well
• Like vancomycin, aminoglycosides can cause nephrotoxicity although the risk for nephrotoxicity with vancomycin use is less. So not only are aminoglycosides dependent on renal function, but they can impair it as well
• Like clindamycin, aminoglycosides also cause some interference with neuromuscular function
• You don’t give aminoglycosides to people with impaired muscle function.

Question 43

what are the patient factors affecting dosing of aminoglycosides

Answer 43

age

obesity

renal function

pregnancy

DONT LOOK:hepatic function(THERE ARE NONE)