Lecture 9: Aminoglycosides Flashcards
What are the structural features that are common among the Aminoglycosides?
- 1,3 - Diaminocyclitol “core”
- Main core sturctures are Streptidine & 2-Deoxystrptamine
What is the Mechanism of Action for the Aminoglycodies?
- Inhibit protein buosynthesis by binding to 30s subunit
- Bind to the A-site further blocking synthesis
- Lead to leakage of ions = cell death
affects frame shifts
What is the Aminoglycoside uptake mechanism?
- AGs go through the outer membrane affecting the Mg & Ca salt bridges = more permeable to AGs
What are the Mechanisms of Resistance of the Aminoglycosides?
- Metabolism: Inactived by Acetylation, Adentylation, Phosphorylation
- Altered Ribosomes: 16s gets mutated
- Altered AG Uptake: Stops AGs
What are some of the toxicities of Aminogylcosides?
Risk Factors?
- Ototoxic (Tinnitus or Hearing Loss) [Irrevesible] & Nephrotoxic [Reversible]
- Risk Factors: Taking other ototoxic drugs, renal issues, genetics, old
What are some of the symptoms of Aminoglycoside Ototoxicity?
- Irreversible
- Tinnitus, High-Frequnecy Hearing Loss, Vestibular Damage = Vertigo, Loss of Balance, Ataxia
What Aminoglycoside toxicities are Reversible and which are Irreversible?
- Ototoxicity: Irreversible
- Nephrotoxicity: Reversible
What are the drugs that are able to cause Nephrotoxicity of the Aminoglycosides?
- Loop Diuretics [Ethacrynic Acid & Furosamide]
- Vancomycin or Amphotericin
What is the potential toxic effects that Aminoglycosides can have the Respiration, and how is it revered or treated?
- Respiratory Paralysis
- Reversed by Neostigmine or Ca Gluconate BUT Ventiation might be good
What are some of the Risk Factors that my manifest Aminoglycosides Toxicity?
- < 5d of Treatment, Old People, Renal Issues, High Doses
What is the main clinical use of the Aminoglycosides?
- Mainly Gram (-)
- Streptomycin treats TB
- Gentamicin treats UTI, Burns, Pneumonias, Bone Infections
- Amikacin good for Hospital infections
AG + Pen is good BUT DONT give at the same time
What is the reason that Aminoglycosides and Penicilins shouldnt be given together?
- Chemical Reaction that will inactive both
- Given in separate arms
What is the Aminoglycoside-induced fram shift and what are its consequences?
- AGs affect 30s that causes a Frame Shift
- Causes altered proteins
What is the main clinical use of Amikacin?
- L-hydroxyaminobuteryl amide inhibits bacterial metabolism by R-factor
- Good for TB, Pseudomonas Aeruginosa, Hospital Infections
What is the Main Clinical use of Tobramycin?
- Lacks 3’-hydroxyl so NO phosphorlytion
- Gentamicin-resistant Pseudomonas Aeruginosa
What is the Main Clinical Use for Gentamicin?
- Most Gram (+)
- UTI, Bone/Joint infections, Burns, Eye infections
What is the Main Clinical Use for Neomycin B & Paromomycin?
- NOT Abosrbed in GI
- Travelers Diarrhea, Prophylactically before GI Surgery
What is the Main Clinical Use for Streptomycin?
- CURE TB –> IM injection
- Bubonic & Tularemia
What is the Main Clinical Use for Plazomicin?
- UTI, Pyelonephritis, E. Coli, K. Pneumoniae, P. Mirabilis, E. Cloacae
What is the reason that Amikacin is less susceptible to bacterial metabolism than Kanamycin?
- L-hydroxyaminobuteryl Amide inhibits bacterail metabolism by R-factors = MORE POTENT
What Aminoglycosides are Orally active?
- Neomycin B, Paromycin, Streptomycin, Plazomicin
What is the Polyketide biosynthesis pathway for the Macrolides?
- Propionate groups being added to a chain = Methyls on alternate carbon atoms of the Ring
What are important to know about the sturctures within Macrolides?
- Desosamine: GOOD for activity
- Cladinose: BAD for activity
What is the reasoning that there are Methyl Groups on alternating Carbon Atoms in Macrolides?
- Because of the Polyketides; they are produced by sequentail addition of propinate groups to a growing chain
- Result: Methyl groups on alternate carbon atims in the ring
What is the way that Erythromycin’s solubilty is increased?
- Amine forms Salts??
Which will increase soluble
What is the Mechanism of action for the Macrolides?
- Inhibit synthesis by binding reversibly to the P-site of the ribsome; inhibiting RNA to go from A-site to P-Site
- Mainly invovle 23s
What are the Mechanism of Resistance for the Macrolides?
- Lactone Ester Hydrolase: degrades Macrolides
- Drug-induced production of RNA Methylase: A2058 on 23s of 50s
- Mutation of A to G at A2058
- Efflux Pump
A = Adenine
G = Guanine
What are some of the way that the incidence of macrolides resistance can be minimized
- Not using tem as much?
What is the reason that resistacne to Pseudomonas sp. and Enterbacter sp. CANNOT be avoided?
- They have intrinsic activity and cannot allow entry of the drug
What is the way that Acidic conditions can inactivate erythromycin and how is it overcome with some of the newer macrolides?
- 6-OH & 12-OH make a Ketal formation that inactives it [Erythro]
- Clarithro: 6-OCH instead of 6-OH blocks Ketal Formation
- Azithro: C-9 latcone replace blocks Ketal Formation
What is the metabolism of Erythromycin?>
- LIVER
- Half life = 1.5h
What is the basis for drug interactions with the Macrolides and which Macrolides are more likely to be involved in them?
- ALL except Azithro
- Bind and inhibit CYP3A and P450
What is the Spectrum of Activity for the Macrolides and there main uses?
- DOC: M. Pneumoniae, Leginella, Bordetella, Corynebacterium
- Syndromes: Bronchitis, Otitis, Sinusitis, Ance
- Prophylaxis: Endocarditis, Surgery
What are the main side effects of Macrolides?
- GI issues, Rashes, SJS, Jaundice
What is the reasont hat Erythromycin has an oral dosage form?>
- Inactivated by Gastric Acids = EC Caps or Tabs OR stable Salts [card 25]
What is the role that Phagocytes paly in the deliveray of eytheromycin to the site of action?
- Large concentrations are released
