L31- Protein Synthesis Inhibitors II Flashcards
list the protein synthesis inhibitors
- tetracyclines
- glycylcyclines
- aminoglycosides
- macrolides
- chloramphenicol
- clindamycin
- streptogramins
- linezolid
- mupirocin
Protein Synthesis Inhibitors:
- bacterio-(static/cidal)
- (2) MOA
- (3) MOA’s effects that are basis for AEs
1- bacteriostatic (mostly, aminoglycoside is only bacteriocidal)
2- binds bacterial ribosome (70S = 50S + 30S) —- differs from eukaryotic ribosome (80S = 60S + 40S)
3- binds mammilian mitochondrial ribosome (due to resemblance to bacterial ribosome) => AEs
______ is the only bacteriocidal protein synthesis inhibitor
aminoglycosides
Chloramphenicol:
- effective against (1) bacteria
- usually restricted use to (2) infections, explain
1- aerobic and anaerobic Gram+/- bacteria
2- life-threatening infections b/c highly toxic
Chloramphenicol MOA:
- (1) entry
- binds (ir-/reversibly) to (3) in order to inhibit (4)
- due to MOA, (5) is the main effect / toxicity in humans
1- active transport
2- reversibly
3- 50S ribosomal subunit
4- peptidyltransferase
5- inhibits mitochondrial ribosomal protein synthesis => BM suppression / toxicity
describe the mechanisms of Chloramphenicol resistance
- presence of chloramphenicol acetyltransferase => enzymatic inactivation
- change in membrane permeability (requires active transport)
Chloramphenicol Pharmacokinetics:
- (1) route of administration
- (2) describe distribution
- major inhibitor of (3)
1- oral, IV, topical
2- wide distribution- including CSF
3- CYP3A4, CYP2C9
Chloramphenicol AEs:
- (1) common minor AEs
- (2) serious AE, explain
- (3) neonate AE, explain
1- GI distress
2- BM suppression (reversible —> irreversible anaplastic anemia)
3- Gray Baby Syndrome / cyanosis in neonates <2wks old since they do not have metabolic enzyme yet –> crosses BBB and CNS accumulation
Clindamycin MOA:
- binds to (1) in order to block (2)– similar MOA to (3) agents
- mainly used / active against (4) bacteria and alternatively used against (5)
1- 50S ribosomal subunit
2- translocation
3- macrolides, chloramphenicol
4- Gram+ anaerobes
5- Gram+ aerobes, bacteroides
Clindamycin Resistance:
- (1) describe mechanisms
- (2) bacteria are intrinsically resistant
- cross-resistant with (3) agents
1:
- ribosomal receptor site mutation
- modification of receptor
- enzymatic inactivation
2- most Gram- aerobes, enterococci
3- macrolides
Clindamycin clinical applications:
- treats (1) and (2) infections alone
- treats (3) and (4) in combination, indicate other drug
- alternative to (5) in certain patients
1- anaerobic infections
2- skin / soft tissue infections
3- PCP Tx alternative with primaquine
4- Toxoplasmosis of brain Tx alternative with pyrimethamine
5- prophylaxis in Pts allergic to penicillin (eg. dental surgeries, animal bites)
Clindamycin Pharmacokinetics:
- (1) route of administration
- (2) describe distribution
1- IV, oral
2- good penetration –> includes bone and abscesses
Clindamycin AEs:
- (1) is the biggest and hallmark risk
- (2) are the common milder AEs
1- potentiall fatal pseudomembrane colitis via C.diff. superinfection
2- GI irritation (20% diarrhea), rash (10%), neutropenia, impaired liver function
Streptogramins:
- (1) agents, given in (2) fashion- explain
- long (3) effect (hint- affects dosage)
1- quinupristin, dalfopristin
2- always in combination, b/c bacteriocidal —- bacteriostatic if given alone
3- long postantibiotic effect
Streptogramins bind (1) in order to prevent (2). (3) is the key difference in comparson to other agents with similar MOA, therefore (4) is uncommon with streptogramins.
(quinupristin-dalfopristin combination) 1- 50S ribosomal subunit 2- protein synthesis 3- different site on 50S compared to other agents 4- resistance is rare
Streptogramins are effective against (1) and (2) bacteria, therefore are restricted clinically to be used for (3).
(quinupristin-dalfopristin combination)
1- gram+ cocci
2- MDR
3- MRSA + other resistance Strep. spp., VRE
Streptogramins Pharmacokinetics:
- (1) route of administration
- penetrates into (2) cells
- inhibitor of (3)
(quinupristin-dalfopristin combination)
1- IV
2- macrophages, PMNs
3- CYP3A4
list Streptogramin AEs
(quinupristin-dalfopristin combination)
-infusion related: venous irritation, arthralgia, myalgia
- GI effects
- CNS effects: HA, pain
Linezolid MOA:
-binds to unique site on (1) part of (2) in order to inhibit (3)
1- 23S rRNA
2- 50S ribosomal subunit
3- formation of 70S initiation complex
describe the mechanisms of Linezolid resistance, discuss cross-resistance (explain)
- dec binding to target site
- point mutation of rRNA
-NO cross-resistance with other agents with similar MOAs b/c it binds unique site on 23S rRNA
Linezolid is effective against (1) bacteria and is restricted to treating (2) infections
1- Gram+ bacteria
2- MDR infections (MRSA, VRE)
Linezolid Pharmacokinetics:
- (1) route of administration
- (2) describe distribution
- weak reversible inhibitor of (3)
1- oral (100% F), IV
2- wide distribution, includes CSF
3- MAOI
Linezolid AEs:
- (1) from short-term therapy
- (2) from long-term therapy
- (3) is the main contraindication
1- well-tolerated: GI- n/d, HA, rash
2- BM suppression (thrombocytopenia mainly), Optic/Peripheral neuropathy, lactic acidosis, Serotonin Syndrome
3- many drugs in relation to its weak reversible inhibition of MAOIs —> to avoid serotonin syndrome and hypertensive crisis
Fidaxomicin is effective against (1) bacteria only and is the drug of choice for (2). Its MOA involves binding and inhibition of (3).
1- gram+ aerobes / anaerobes (no activity vs Gram-)
2- C. difficile
3- RNA polymerase (like rifampin)
describe the pharmacokinetics and AEs of Fidaxomicin and how it relates to its functions
To Tx C. diff.:
- zero or minimal oral F —> very high fecal concentration
- good at treating GIT infections as it stays in the gut
- all AEs are GI related
Mupirocin MOA: it binds (1) in order to inhibit (2)
1- isoleucyl transfer-RNA synthetase
2- protein synthesis
Mupirocin:
- effective generally against (1) bacteria
- (2)/(3): give the route of administration and the related clinical use
1- Gram+ cocci (MRSA, Strep. spp.)
2- Intranasal: MRSA in nasal cavity (adults, healthcare workers)
3- Topical: impetigo (Staph. aureus, Strep. pyogenes) or secondary infected traumatic skin lesions
Mupirocin:
- (1) discuss resistance
- (2) list AEs
1- may develop with long-term use
2- local/dermatological: burning, edema, tenderness, dry skin, pruritus
