Lecture 11: Clindamycin, Tetracycline, Quinolones Flashcards
Cushman's Section
What is the Mechanism of action for clindamycin and compare it to erythromycin?
- Similar to Erythromycin; Inhibits protein synthesis by binding to 50s - preventing movement to the A-site
What is the main clinical use of Clindamycin?
- Gram (+): Strep & Staph
- Gram (-): Bcteroides & Fusobacterium
- TREATS bone infections with SA, Severe ance, vaginosis
- IV Clinda with pyrimethamine Treats AIDS by Toxoplama gondii
What is the Main Side Effect that limits the its clinical use of Clindamycin?
- Pseudomembranous Colitis and Diarrhea
What is the metabolic pathway of clindamycin and state the effects of metabolism on biological activity?
- By CYP450 in the liver to Sulfoxide & N-demethylated Derivative
What is the absorption, distribution, and elimination of clindamycin?
- Absorption: GI tract
- Distribution: widely even in CNS
- Elimination: Urine & Bile
Half Life of 1.5-5 h
May need to dose adjust
What are some of the adverse effects of clindamycin?
- Diarrheaa, C. Diff, Nausea, Vomiting, Stomach Cramps, Rash
What is Psudomembranous Colitis and its signifiances?
- Potentially Lethal Condition
- An overgrowth of C. Diff in the colon that SHOULD be treated with Metro or Vanco
What is the reason that Tetracyclines SHOULD NOT be given with food that are rich in Calcium, or with other drugs that are rich in Calcium, or other heavy metals?
- Tetracyclines WONT be absorbed with Calcium products
- Should be given 1 hour before or 2 hours after
What is the preferred route of administration of the Tetracyclines?
- ORAL
What is the reason that Children SHOULD NOT take Tetracycline during the period of permanent teeth formation?
- Stain the Teeth –> Brown or Grey
What is Epimerization and what effect does it have on bioloigcal activity?
- There is an elongation [amide group] that makes it inactive
- Slow in steady state & rapid at pH4
What is the pH that tetracycline epimerization is most rapid and the relative rate of epmierizatin in the sild state vs in solution?
- pH 4 = most rapid
- SLOW in solid state [capsules]
What is Tetracycline Dehydration?
- C-6 Group is antiperiplaner so a H- at C-5a kicks it off making a Methyl
What is the toxicity of Epianhydrotetracycline?
- Toxic to kidneys
- Produces Fanconi syndrome [failure of reabsorption in kidneys = malabsorption] which is FATAL
What is the why that there is selective toxicity of tetracyclines to bacteria BUT not the host?
- Eukaryotic cells DONT have uptake mechanisms
What is the reason that Minocycline and Doxycycline lack the renal toxicity of Tetracycline?
- Lack C-6 hydroxyl group
What is the way that the Tetracycline are cleaved under basic conditions?
- Cleave at pH <8.5; lactone is inactive
What is the mechanism of action for the Tetracyclines?
- Bind to 30s and inhibit synthesis by blocking tRNA to A-site = termination of chain growth
What is the Main Theraputic Use for Tetracyclines?
- ACNE
- Chlamydia, Rickettsia, Brucellosis
- Anthrax, Plague, Tularemia, Leginonnarries
What is the main advantage of using tetracycline itself rather than on of the other antibiotics in the tetracycline class?
- Generic and Inexpensive
What is the way that Demeclocycloine is more stable to dehydration than tetracycline?
- Hydroxyl group at C-6 instead of tertiary hydroxyl group
- Dehydrates slow because of secondary cation
What is the reason that Minocycline and Doxycyline do not undergo dehydration?
- Lacks C-6 hydroxyl group
What is a unique toxicity for Minocycline in comparsion to the other Tetracyclines?
- Vistibular Toxicities [Vertigo, Axtaxia, Nausea]
What is the reason that Doxycycline is widely considered the Tetracycline of Choice?
- NO 4 -epianhydrotetracycline toxicity AND fewer GI issues
What is the reason that Tigecycline has no potential for 4-epianhydrotetracycline-mediated toxicity?
- NO C-6 hydroxyl group
What is the main theraputic use of Sarecycline and Omadacycline?
- Mod to severe Acne
Why sarecycline and omadacycline should not be given to pregnant woman and are not recommended during breast feeding?
- Fetal harm
What is the mechanism of action for Chlorapmhenicol?
- Binds to 50s that is near for erythromycin and clindamycin
- Inhibits the peptidyl transferase activity - blocking the action between P-site & A-site
What is the relationship between Chlorampheicol sodium succinate and chloramphenicol?
- Cholrampheicol sodium succinate is a PRODRUG for IV or IM that becomes Chloramphicol
What is the main therpautic use of Cholrampheicol sodium succinate?
- Meningitis, typhoid fever, rickettsial infections…
What is the metabolism of chooramphenicol sodium succinate?
- Hydrolyed in the liver??
What is the solubility characteristics and ditribution of chlorapmphenicol?
- Lipid soluble; remain unbound
- Penetrates all tissues of the body even the brain
What are the mechanism of resistance for chloramphenicol?
- Reduced permeability
- Mutation of 50s
- Increase of Chloramphenicol Asetyltransferase
What are some of the more serious toxicities of chloramphenicol and how it limits the use of it?
- Aplastic Anemia; can be fatal
- High risk with oral and low risk with eye drops
How does the risk factor of Aplastic Anemia compare between Chloramphenicol Eye drop vs oral?
- HIGHEST RISK orally and LOWEST RISK eye droply
Is Chloramphenicol Bone Marrow Suppression a predictor for Aplastic Anemia?
- NO
What is the relationship between Chloramphenicol bone marrow suppression and cumulative dose?
- Predictable once the cumulative does of 20g is given
What is the relationship of Chloramphenicol-induced childhood leukemia and length of treatment with chloramphenicol?
- Increased risk and Increased Length
What are the drug interactions with Chloramphenicol?
- Inhibits CYP450
What is the effect that inflammation of the meninges has on the brain concentrations of Chloramphenicol?
- Conc. are about 30-50% when NOT inflammed AND about 89% WHEN inflammed
What is the core structure of the Quinolones?
- Two 6 membered rings connected with a N at C-1
What are some general characteristics of the 1st, 2nd, and 3rd generation Quinolones?
- 1st: Good Gram (-); UTI [D/Cd]
- 2nd: F at C-6 & Piperazine at C-7; Good Gram (+)
- 3rd: Good Gram (+), even S. Pneumoniae
What is the function of the Gyrases and Topoisomerases?
- Untangling DNA by cutting ONE or TWO strands; passing them through
What are the differences between topoisomerase I and II?
- Topo I: Cuts ONE strand
- Topo II: Cuts TWO strands
What is the common mechanism for DNA Gyrase, Bacterial Topoisomerase IV and Mammalian Topoisomerase II?
- G-segment binds to CAP region; T-segment comes into OPEN ATPase domain; ATP will CLOSE domain BREAKING the G-segment; passing T-segment through; Reconnecting G-segment; repeat
What is the unwinding by the strand passage mechanism by DNA Gyrase, Bacterial Topoisomerase IV and Mammalian Topoisomerase II?
- Basically grab open part and twist it 360 degress
What is the theraputics uses of the Quinolones?
- UTI [Cipro], Prostatitis [Cipro & Oflox], STI, GI infections [Cipro], Respiratory Tract…
What is the main bacterial resistance mechansim to the Quinolones?
- Decreased Permeability
- Efflux pumps
- Mutation of target enzymes
What are the main features of Quinolones absorption, distribution and elimination?
- Absorption: Readly absorb orally
- Distribution: Widely
- Elimination: Renally and Hepatically
How is Ciprofloxacin metabolized?
- Glucuronide at the 3-carboxyl position in the urine
What are the main adverse effects of the Quinolones?
- Nausea, Vomiting, Diarrhea
- Headache, Dizziness
- Rash