Clindamycin and Tetracyclines

Question 1

how is clindamycin synthesized?

Answer 1

from naturally occurring antibiotic Lincomycin

• treatment with chlorine and triphenylphosphine in acetonitrile
• inversion configuration

Question 2

MOA of clindamycin

Answer 2

same has erythromycin
inhibits protein synthesis by binding to bacterial 50S ribosome
-binds same site as erythromycin

Question 3

what is clindamycin most effective against?

Answer 3

1. aerobic G+ cocci, including most staph/strep

2. anaerobic G- bacilli, including bacteroids and fusobacterium genera

Question 4

what has clindamycin replaced that normally penicillin would be used for?

Answer 4

lung abscesses and anaerobic lung and pleural space infections
-can treat MRSA as well

Question 5

clindamycin can treat systemic ______ infections from _______?

Answer 5

bone infections with staph. aureus or topically to treat severe acne
-vaginal cream for vaginitis

Question 6

how is clindamycin administered to treat AIDS or toxo?

Answer 6

by IV with pyrimethamine and leucovorin to treat AIDS patients with encephalitis caused by toxoplasma gondii

Question 7

clindamycin dosage forms

Answer 7

capsules, oral suspensions, IV (clindamycin phosphate), topical forms

Question 8

metabolism of clindamycin

Answer 8

cytochrome P450 in liver

-metabolites: sulfoxide and N-demethylated derivative (both inactive)

Question 9

how much of clindamycin is absorbed in GI tract?

Answer 9

90%

-widely distributed

Question 10

does clindamycin penetrate CNS?

Answer 10

yes

-can be useful to treat cerebral toxoplasmosis in human immunodeficiency virus infected patients

Question 11

half life of clindamycin

Answer 11

1-1.5 hours

Question 12

elimination of clindamycin

Answer 12

clindamycin and metabolites excreted in urine abd bile

Question 13

side effects of clindamycin

Answer 13

diarrhea, pseudomembranous colitis, V&N, abdominal cramps, rash
-topical application can cause dermatitis

Question 14

lethal complication from clindamycin

Answer 14

pseudomembranous colitis

• overgrowth of C. difficile (resistant to clindamycin), results in production of a toxin that causes a range of adverse side effects like diarrhea to colitis and toxic megacolon
• treat with metronidazole or vancomycin

Question 15

what do tetracyclines form?

Answer 15

chelation, form stable chelates with polyvalent metal ions such as calcium, Al, Cu, Mg
-chelates are usually insoluble

Question 16

tetracyclines should NOT be administered with what kinds of food?

Answer 16

1. calcium rich b/c calcium chelates are not absorbed by GI tract,
2. antacids that contain multivalent metals
3. hematinics containing iron

Question 17

what if therapy with tetracyclines and multivalent metals cannot be avoided?

Answer 17

metals should be administered 1 hour before or 2 hours after tetracycline

Question 18

why shouldn’t tetracycline be give to children while forming their permanent teeth?

Answer 18

will chelate with calcium during formation of teeth and cause permanent teeth to turn brown or grey.

Question 19

why are injectable tetracycline formations contain EDTA?

Answer 19

pain on injection as been attributed to formation of insoluble calcium complexes, so EDTA is added to chelate calcium and they are buffered to acidic pH where chelation is suppressed

Question 20

what is epimerization

Answer 20

hydrogen on amine bearing carbon atom is acidic and can undergo enolization and epimerization
-epitetracycline is inactive, but can cause tetracycline to lose potency because can occur in solid state as well as in solution, but slow in solid state and most rapid at pH4

Question 21

how does dehydration occur with tetracycline?

Answer 21

teritary benzylic hydroxyl group at C6 has an antiperiplanar relationship with proton C5a, so set up for elimination

Question 22

why should discolored tetracyclines be thrown out?

Answer 22

4-epitetra. is toxic to kidney and can produce Fanconi-like syndrome (failure of reabsorption mechanism in proximal convoluted tubule)

Question 23

what pH do tetra. undergo cleavage?

Answer 23

pH8.5 or above-> inactive

Question 24

MOA of tetra.

Answer 24

bind 30S subunit and inhibit bacterial protein synthesis by blocking attachment of the aminoacyl-tRNA to A site of ribosome-> termination of peptide chain growth
-inhibits of codon anticodon interaction

Question 25

why is it less likely for tetra to inhibit host protein synthesis?

Answer 25

eukaryotic cells don't have an uptake mechanism for tetracycline

Question 26

most common use of tetracycline

Answer 26

``` acne -but also for: c hlamydia, rickettsia, brucellosis, spirochetal infections (lyme, borreliosis, syphilis) anthrax tularemia legionnaires disease ```

Question 27

what lowers tetracycline absorption?

Answer 27

milk and food, by 50%

Question 28

dehydration rate difference in tetracycline versus demeclocycline

Answer 28

dehydration in demeclocycline is slower because of hydroxyl and C6 position is secondary-> forms secondary intermediate

Question 29

what lowers demeclocycline absorption?

Answer 29

food and milk, by 50%

Question 30

does Minocycline undergo dehydration?

Answer 30

No, does NOT contain C-6 hydroxyl group | -NO potential for 4-epitetra. toxicity either

Question 31

what lowers minocycline absorption?

Answer 31

food and milk, by 20% | -also has 90-100% oral bioavailability

Question 32

what side effects does minocycline have that other tetracyclines don't?

Answer 32

vestibular toxicities: vertigo, ataxia, nausea

Question 33

oxytetracycline

Answer 33

bioavailability of 60% | -reduced by 50% when taken with food or milk

Question 34

doxycycline

Answer 34

doesn't undergo dehydration - 90-100% bioavailability - absorption lowered by 20% when taken with food or milk - half life 18-22 hours, permits one day dosing

Question 35

chloramphenicol

Answer 35

not as used because of toxicities

Question 36

MOA of chloramphenicol

Answer 36

binds reversibly to 50S ribosomal subunit at site that is near the site for erythromycin and clindamycin - competitive binding interactions - inhibits peptidyl transferase activity of ribosome and thus blocks peptide bond formation between P and A sites

Question 37

main therapeutic use of chloramphenicol

Answer 37

ointment or eye drops to treat bacterial conjunctivitis -chloramphenicol sodium succinate-> prodrug for IV and IM-> hydrolyzed in liver: treats typhoid fever, rickettsial, intraocular infections, etc.

Question 38

chloramphenicol characteristics

Answer 38

- lipid soluble - remains relatively unbound to plasma proteins - penetrates effectively into all tissues of the body, including brain

Question 39

what are the three ways resistance formed for chloramphenicol

Answer 39

1. mutation of 50S ribosomal subunit 2. reduced membrane permeability 3. elaboration of chloramphenicol acetyltransferase-> acetylates one or both hydroxy groups to form metabolites that do not bind to 50S ribosomal subunit

Question 40

toxicity with chloramphenicol

Answer 40

aplastic anemia - high risk orally, low risk with eye drops - recommended to monitor blood levels when taking chloramphenicol to keep it less than 25 micrograms/mL bone marrow suppression-> impairment of mitochondrial function from protein synthesis inhibition childhood leukemia N&V and diarrhea in adults but rarely children

Question 41

MOA of chloramphenicol

Answer 41

metabolized to glucuronide in liver-> inactive and excreted by kidneys - reaction is catalyzed by glucuronyl transferase and therefore chloramphenicol dosage should be reduced in those with hepatic function impairment - neonates cannot metabolize chloramphenicol