Exam 1- Cushman Lec 4- Clindamycin and Tetracycline

Question 1

What is the moa of clindamycin?

Answer 1

Similar to macrolides
-inhibits protein synthesis by binding to 50S ribosome

Question 2

What is the clinical use of clindamycin?

Answer 2

Aerobic Gram + cocci (staph and strept)

Anaerobic Gram - bacilli (bacterioides and fusobacterium)

-bone infections
-acne
-vaginosis
-lung abscesses
-anaerobic lung and pleural space infections
-MRSA
-AIDS patients with encephalitis caused by Toxoplasma gondii

Question 3

What are the drug limiting side effects of clindamycin?

Answer 3

Pseudomembranous Colitis
**potentially lethal
-involves overgrowth of Cdiff that produces toxins

Diarrhea

Question 4

How is clindamycin metabolized?

Answer 4

By cytochrome P450 enzymes in the liver
-metabolized to sulfoxide and the N-demethylated derivative

***metabolites are pharmacologically inactive

Question 5

Where is clindamycin absorbed?

Answer 5

90% from GI tract

Question 6

How does clindamycin distribute in the body?

Answer 6

Widely distributed
-penetrates the CNS

Question 7

How is clindamycin excreted?

Answer 7

Mainly in the urine and bile

*dosage adjustments required in hepatic failure, this can lead to accumulation of drug

Question 8

How do we treat Pseudomembranous colitis caused by clindamycin?

Answer 8

Metronidazole or Vancomycin

Question 9

What important chemical property do tetracyclines have?

Answer 9

Chelation

-able to form stable chelates with polyvalent metal ions

*note that these can form if drug is taken with calcium-containing food/products

Question 10

What are the consequences of tetracyclines forming chelates?

Answer 10

-Chelates formed with calcium are not absorbed from the GI tract

-Note that tetracyclines chelate with calcium during teeth formation and will cause brown/gray coloring
–do not give to kids 8 or younger, or pregnant women after month 4

Question 11

What is the preferred route of administration of tetracyclines?

Answer 11

Oral

Question 12

How does epimerization affect tetracycline activity?

Answer 12

The epitetracycline product formed is inactive

*This is how old preparatins can lose half of their potency

Question 13

At what pH is epimerization most active?

Answer 13

pH 4

Question 14

How does epimerization in the solid state compare to the solution state?

Answer 14

Epimerization is slow in the solid state and rapid in solutions of pH 4

Question 15

How does dehydration affect the activity of tetracyclines?

Answer 15

-Discolored, old tetracyclines should be thrown out
-The product of dehydration 4-epianhydrotetracycline is inactive as an antibiotic but toxic to the kidneys

-This can produce a Fanconi-like syndrome
(failure of the reabsorption mechanism in the proximal convoluted tubules) that can be fatal

Question 16

Which tetracyclines lack a C-6 hydroxyl group and therefore cannot be dehydrated or cause Fanconi-like syndromes?

Answer 16

Minocycline
Doxycycline
Tigecycline

Question 17

What is the MOA of tetracyclines?

Answer 17

Bind the 30S ribosomal subunit and inhibit bacterial protein synthesis
-done by blocking the attachment of the tRNA to the A site of the ribosome
-results in termination of peptide chain growth

(inhibit the codon-anticodon interaction)

Question 18

How are tetracyclines able to have selective toxicity for the bacteria and not the host?

Answer 18

-They can inhibit protein synthesis in the host but are less likely to reach the concentration needed for toxicity
–this is because eukaryotic cells do not have tetracycline uptake mechanisms

Question 19

What is the therapeutic use of tetracyclines?

Answer 19

Broad-spectrum

Most common use: acne
Treatment of choice for: chlamydia, Rickettsia, brucellosis, spirochetal infections (Lyme disease and syphilis)

Question 20

What is the main benefit to using tetracycline itself and not the other drugs in the class?

Answer 20

It is generic and inexpensive

Question 21

Food and milk lower the oral absorption of tetracycline by how much?

Answer 21

50%

Question 22

Why is demeclocycline more stable to hydration?

Answer 22

It has a secondary hydroxyl group at C-6 instead of the tertiary hydroxyl group
-this results in slower dehydration because the secondary cation intermediate from demeclocycline is less stable (higher energy) than the tertiary cation intermediate from tetracycline

Question 23

What unique toxicities does minocycline have?

Answer 23

Vestibular toxicities (vertigo, ataxia, nausea)

Question 24

Which tetracycline is considered the tetracycline of choice by many physicians and why?

Answer 24

Doxycycline

-does not undergo dehydration
-fewer GI symptoms
-absorption only lowered by 20% with food/milk
-long half life permits once daily dosing

Question 25

What two tetracyclines can cause fetal harm if given while breastfeeding/pregnant?

Answer 25

Sarecycline
Omadacycline