Clindamycin and Tetracycline Flashcards
Which abx bind to 30S?
- AMGs
- Tetracycline
- What is the mechanism of clindamycin?
- How does it compare to erythromycin?
- Clindamycin inhibits protein synthesis by binding to the bacterial 50S ribosome.
- This is the same site erythromycin binds to.
- clindamycin inhibits peptide bond formation and elongation
- erythromycin blocks the ribosomal exit tunnel which also inhibits elongation
What are the main clinical uses of clindamycin?
- aerobic gram-positive cocci
- anerobic gram-negative bacilli
- bone infections
- severe acne
- bacterial vaginosis
What is the main side effects of clindamycin that limits clinical use?
- pseudomembranous colitis
(and diarrhea)
potentially lethal condition
How is clindamycin metabolized?
- Clindamycin is extensively metabolized by CYP 450 enzymes in the liver
- Clindamycin gets metabolized to the sulfoxide and the N-demethylated derivative.
- These metabolites are pharmacologically inactive
What is the absorption for clindamycin like?
- 90% of the administered dose is absorbed from the GI tract
- widely distributed
- penetrates CNS in high concentrations
How is clindamycin excreted?
- excreted in urine and bile
- half-life 1.5-5 hours
Accumulation of clindamycin can occur in patients with hepatic failure –> dose adjustments may be required
What is the significance of pseudomembranous colitis?
- potentially lethal
- overgrowth of C. diff results in production of toxins
- diarrhea, colitis, toxic megacolon
How do tetracyclines bind to heavy metals?
Ca, Al, Cu, Mg
Tetracyclines form stable chelates with metal ions via their hydroxyl and carbonyl groups.
Why should tetracyclines not be administered with meds/food containing metals?
calcium especially
Insoluble calcium chelates that form are not absorbed from the GI tract. The drug won’t work at all.
When unavoidable, the metals should be administered 1 hour before or 2 hours after the tetracycline.
What is the preferred route of administration for tetracyclines?
oral
Why shouldn’t children under the age of 8 years not take tetracyclines?
Tetracyclines chelate calcium during the formation of teeth. This results in permanently brown or grey teeth.
Why do tetracyclines undergo epimerization?
- The hydrogen on the amine-bearing carbon atoms is acidic.
- Epimerization is slow in the solid state and most rapid in solution at pH 4.
What is the effect of epimerization on tetracyclines?
The product is pharmacologically inactive.
What structural feature enables a tetracycline to undergo dehydration and what is the result?
- benzylic hydroxyl group at C6
- 4-epianhydrotetracycline
What are the toxicities associated with epianhydrotetracycline?
product of dehydration
- toxic to kidneys
- produce Fanconi-like syndrome
failure of the reabsorption mechanism in the proximal convoluted tubules which can be fatal
Why do minocycline and doxycycline lack the renal toxicity of tetracycline?
Minocycline and doxycycline lack a C-6 hydroxyl group, so they don’t undergo the dehydration that leads to toxicity
How do tetracyclines cleave in basic conditions?
Base-catalyzed cleavage starting at C12 leads to ring opening and loss of activity.
Undergo cleavage in base at pH values of 8.5 or above. The product is inactive
What is the mechanism of action of tetracyclines?
- Tetracyclines bind to the 30S ribosomal subunit
- This inhibits bacterial protein synthesis by blocking the attachment of aminoacyl-tRNA to the A site of the ribosome.
- This leads to termination of peptide chain growth.
- Inhibitors of the codon-anticodon interaction
Tetracyclines can inhibit protein synthesis in the host. How is come this it is not toxic to the host but it is toxic to bacteria?
- Eukaryotic cells do not have a tetracycline uptake mechanism
- This prevents tetracycline from reaching a high enough concentration for toxicity
What are the main therapeutic uses for tetracyclines?
- broad-specrum abx
- treatment of acne
- chlamydia
- Rickettsia
- brucellosis
What are the advantages to using tetracycline instead of one of the other abx in the tetracycline class?
- generic and inexpensive
How do food and milk impact oral absorption of tetracycline or demeclocycline?
Lower oral absorption by about 50%
Why is demeclocycline more stable to dehydration that tetracycline?
Demeclocycline has a secondary hydroxyl group at C6 instead of a tertiary hydroxyl group.
How is the absorption of minocycline or doxycycline impacted by food or milk?
The absorption of minocycline or doxycycline is decreased by 20%
What are the unique toxicities associated with minocycline?
- vestibular toxicities:
- vertigo
- ataxia
- nausea
Why is doxycycline considered the tetracycline of choice?
- no potential for dehydration rxn toxicities
- fewer GI symptoms
- 18-22 hour half life permits once a day dosing
What are the toxic effects of tigecycline?
- hepatotoxicity
- pancreatitis
- anaphylactoid
What are the main therapeutic uses for sarecycline and omadacycline?
- moderate to severe acne
- penumonia
- skin infections
Why should sarecycline and omadacycline not be administered to pregnant women?
- They cross the placenta and could cause fetal harm (teeth/bone malformations)
- excreted in breast milk
