Antibiotics 3 - Clindamycin and Tetracyclines

Question 1

Clindamycin is synthesized from ______

How? What does this do?

Answer 1

Lincomycin

Tretment with Chlorine and tri-phenyl-phosphine in acetonitrile.

(This reaction inverts the configuration)

Question 2

MOA of clindamycin

Answer 2

Inhibits protein synth.

Binds 23SrRNA of the 50S ribosomal subunit

Question 3

Clindamycin binds to the same subunit as ________

Answer 3

erythromycin

Question 4

Clindamycin is most effective against

Answer 4

Aerobic gram positive cocci (Staph/Strep)

Anaerobic gram negative bacilli (Bacteriodes/Fusobacerium)

Question 5

Forms of clindamycin admistration

Answer 5

Systemic (bone infctns)

Topical (acne)

Vaginal cream (bact. vaginosis)

Question 6

Clinda has replaced Pen for _______ and ________

Answer 6

Treatment of lung abscesses and anaweobic lung and pleural space infections

Question 7

How does clindamycin fit into treatment plan for Toxo encephalitis in AIDS patients?

Answer 7

Administered parenterally with pyrimethamine + leucovorin

Question 8

Metaboolism of Clindamycin:

• Enzyme
• Metabolites (and activity)
  *

Answer 8

• Metabolized by P450
• to the sulfoxide and N-methylated derivative

(both are inactive)

Question 9

Clinda IV form

Clinda Topical form

Answer 9

Clindamycin phosphate (IV)

Clindamycin phosphate or hydrochloride (Topical)

Question 10

Clinda absorption? (where, how much)

Answer 10

90% of administered dose absorbed by GIT

Question 11

Clindamycin excretion routes

Half life

Answer 11

Urine and bile

1.5 - 5 hours

Question 12

In what case would you need to adjust the dose of clindamycin?

Answer 12

In cases of hepatic failure where accumulation occurs

Question 13

Common sides of clinda

Answer 13

Diarrhea/pseudomembranous colitis, N/V, rash/dermatitis

Question 14

Treatment of pseudomembranous colitis (c.diff)

Answer 14

Mzole or Vm

Question 15

Tetracyclines have a base structure ring of ____

Answer 15

12 carbons

Question 16

Tetracycline forms stable chelates with…

Answer 16

polyvalent metal ions

Ca++, Al+++, Cu++, Mg++

Question 17

The chelates formed by Tetracyclines are _____

Answer 17

insoluble

Question 18

Tetracycline should not be given with…

Answer 18

Calcium-rich foods or supplements

Hematinics containing Iron

Question 19

Tetracycline chelates calcium…

Answer 19

during the formation of teeth

Question 20

Tooth discoloration by tetracycline is made worse as a result of…

Answer 20

photo-oxidation reaction

Question 21

Why is inected Tetracycline painful?

Answer 21

Formation of Calcium chelates

Injectable formulations can contain EDTA to prevent this (it will chelate the calcium instead)

Question 22

What is the reason for epimerization and enolization of Tetracycline?

Answer 22

because the H on the amine-bearing carbon is acidic

**the epiTetracycline product can be formed in solution OR in solid state

Question 23

EpiTetracycline product is…

Answer 23

pharmacologically inactive

formed most rapidly at pH 4.0 in solution

Question 24

Tetracycline dehydration

The tertiary benzylic OH group at C6 has a ____ relationship with ______. What does this do?

Answer 24

The tertiary, benzylic hydroxyl group at C-6 has an antiperiplanar relationship with the proton at C-5a,

So it is “set up” for elimination

Question 25

Why doesnt the C12 OH group get eliminated?

Answer 25

Its tertiary, but it is NOT next to an antiperiplanar H

(and it is also deactivated by being next to a carbonyl group –> stable)

Question 26

Why shouldnt old tetracycline be used?

Answer 26

It is less active, and the 4-epianhydrotetracycline metabolite is toxic to kidneys

can produce a fatal Falconi-like syndrome

Question 27

When does tetracycline undergo cleavage?

What does this form?

Answer 27

At pH 8.5 or above

an inactive lactone product

Question 28

Tetracycline MOA

Answer 28

Tetracyclines bind to the 30S ribosomal subunit

=block the attachment of the aminoacyl-tRNA to the A site of the ribosome

= chain termination

Question 29

Why doesnt tetracyline cause its effects in host cells?

Answer 29

eukaryotic cells do not have a tetracycline uptake mechanism

Question 30

Tet binds to the ___ ribosomal subunit in ___ locations

Answer 30

small, 6

Question 31

(tetracycline)

The site of highest occupancy

Answer 31

Tet1

located near where the aminoacyl tRNA binds to the A site

Question 32

Most common use for tetracycline

It is DOC for _____ (4)

Answer 32

acne

Chlamydia, rickettsia, brucella, spirochete

Question 33

Tet is also used to treat ____, ____, _____, and _____

Answer 33

anthrax

plague

tularemia

Legionnaires’ disease

Question 34

______ lowers tetracycline effetiveness by about 50%

Answer 34

food and milk

Question 35

Demeclocycline structural difference

Demeclocycline _____ more slowly than tetracycline. Why?

Answer 35

has a secondary hydroxyl group at C-6 instead of the tertiary hydroxyl group

dehydrates more slowly because it forms secondary alcohol rather than tertiary alcohol as with tetracycline

Question 36

Minocycline structural difference

What effect does this have?

Answer 36

Lacks the C6 hydroxyl group

Therefore does NOT undergo dehydration

= no potential for 4-epianhydrotetracycline-mediated toxicity

Question 37

Minocycline BA

Answer 37

oral BA = 90-100%

Question 38

Minocycline unique AE’s

Answer 38

Vestubular toxicity

Question 39

Most hydrophobic tetracycline

Answer 39

oxytetracycline

Question 40

Oral BA of oxytetracycline

Answer 40

60%

Question 41

Doxy contains what group at C6?

Answer 41

no group

No rxn = no 4-epianhydrotetracycline-mediated toxicity

Question 42

Doxy half life

Answer 42

18-20 hours

allows DAILY admin