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2. HDS Pulmonary > Protein Synthesis Inhibitors > Flashcards

Protein Synthesis Inhibitors Flashcards

1
Q

Bacterial Protein Synthesis

A

Prokaryotic ribosomes: 30s & 50s

  • Transcription: DNA ⇒ RNA
  • Translation:
    • Aminoacyl-tRNA binds to 30s subunit
    • Peptide bond formation and translocation on 50s subunit
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2
Q

Protein Synthesis Inhibitors

Sites of Action

A
  • 30s ribosomal subunit
    • Tetracyclines ⇒ ⊗ A-site
    • Aminoglycosides ⇒ misreading of genetic code ⇒ insertion of incorrect AA
  • 50s ribosomal subunit
    • Macrolides & chloramphenicol ⇒ ⊗ peptidyl transferase
    • Macrolides & clindamycin ⇒ ⊗ translocation of peptide from A-site to P-site
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3
Q

Resistance Mechanisms

A
  • Drug inactivation by bacterial enzymes
    • Ex. ⊗ aminoglycosides or chloramphenicol
  • ↓ Drug binding
    • Ex. Aminoglycosides to 30s subunit
  • Active removal of drug by membrane proteins
    • Ex. Macrolides
  • ↓ Drug uptake
    • Ex. Aminoglycosides via porins in bacterial membranes
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4
Q

Aminoglycosides

MOA

A

Binds 30s ribosomal subunit.

Causes irreversible misreading of the genetic code ⇒ insertion of incorrect AA

  • Bactericidal
  • Requires oxygen for uptake
    • Ineffective against anaerobes
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5
Q

Aminoglycosides

Pharmacokinetics

A

Concentration-dependent

  • Effectiveness determined by ratio of peak concentration to MIC
  • Given as a single large daily dose
    • Higher peak
    • Lower trough (zero)
    • Less monitoring
  • Remains effective for 24 hrs even though serum concentration drops below MIC ⇒ Post-antibiotic effect
  • Pharmacokinetic monitoring d/t potential for toxicity
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6
Q

Aminoglycosides

Pharmacodynamics

A
  • Very low bioavailability
  • Charged molecules ⇒ poor penetration into lung/sputum, bone, CNS, abscesses
  • Do not penetrate tissues well ⇒ volume of distribution close to extracellular volumes
  • Short half-lives
  • Eliminated unchanged primarily renally
    • Dose adjustment for renal function
  • Plasma concentrations monitored to minimize toxicity
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7
Q

Aminoglycosides

Adverse Effects

A
  • Dose-dependent nephrotoxicity
    • Manifests as acute tubular necrosis or glomerular toxicity
    • ↓ Renal function ⇒ ↑ [drug] ⇒ ↑ renal failure & ototoxicity
    • Effect enhanced when given with other nephrotoxic agents
    • Risk factors: age, hypovolemia, pre-existing renal dysfunction
    • Important to monitor renal function and peak/trough serum drug conc.
  • Dose-related cochlear and vestibular toxicity
    • Vestibular sx ⇒ dizziness, impaired vision, nystagmus, vertigo, N/V, poor postural balance, ataxia
    • Cochlear sx ⇒ tinnitus, hearing impairment, irreversible deafness
    • Often a delay in sx onset
  • Neuromuscular blockade
    • Esp. in pts taking neuromuscular blockers or have myasthenia gravis
  • Teratogenic
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8
Q

Aminoglycosides

Activity

A
  • Excellent activity
    • Enterobacteriaceae
    • Acinetobacter
    • Pseudomonas
    • Other GNR
  • Good activity when used in combo w/ cell-wall active agent
    • Many GPC
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9
Q

Aminoglycosides

Clinical Uses

A
  • Combo w/ beta-lactam abx ⇒ serious gram-⊖ infections
    • Febrile neutropenia
    • Sepsis
    • CF exacerbations
    • Ventilator-associated PNA
  • Combo w/ beta-latam abx or vancomycin ⇒ serious gram-⊕ infections
    • Endocarditis
      • Risk of renal issues without the benefit of cure
    • Osteomyelitis
    • Sepsis
  • Streptomycin ⇒ resistant TB
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10
Q

Aminoglycosides

Drugs

A
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11
Q

Tetracyclines

MOA

A

Binds to 16s rRNA of 30s ribosomal subunit.

Competitively blocks binding of tRNA to A-site.

Reversible ⇒ bacteriostatic activity

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12
Q

Tetracyclines

Pharmacodynamics

A
  • High oral bioavailability
  • Binds divalent and trivalent cations (Ca2+, Mg2+)
    • ↓ absorption if ingested w/ milk or antacids
  • Does not penetrate the CNS
  • Primarily eliminated renally
    • Dose adjustment for renal insufficiency
  • Doxycycline ⇒ fecally eliminated
    • No dose adjustments
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13
Q

Tetracyclines

Adverse Effects

A
  • Discoloration of developing teeth
    • Contraindicated in pregnant women and children < 8 y/o
  • Esophageal irritation & GI upset
    • N/V, borborygmus
    • Should take drug with water while standing
  • Photosensitivity
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14
Q

Tetracyclines

Drug Interactions

A
  • Multivalent cations ⇒ chelation ⇒ ↓ absorption
  • Cell-wall synthesis inhibitors ⇒ disruption of bactericial activity
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15
Q

Tetracyclines

Activity

A
  • Atypicals
  • Some MRSA
  • Strep. pneumoniae
    • Resistance in many other Strep
  • Some GNR and GPC
    • Limited by resistance
  • B. burgdorferi
  • H. pyloria
  • Rickettsia
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16
Q

Tetracyclines

Resistance

A

Due mostly to efflux pump.

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17
Q

Tetracyclines

Clinical Uses

A
  • Acne
  • Uncomplicated CAP ⇒ doxycycline
  • Tick-borne diseases ⇒ drug of choice
  • PUD
  • STI
  • Malaria prophylaxis and treatment
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18
Q

Tetracyclines

Drugs

A
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19
Q

Tigecycline

MOA

A

Tetracycline derivative w/ expanded spectrum ⇒ same MOA

Binds 16s of 30s ribosomal subunit.

Competitively blocks binding of tRNA to A-site.

Reversible ⇒ bacteriostatic activity

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20
Q

Tigecycline

Pharmacodynamics

A
  • Poor absorption
  • Very large volume of distribution (Vd) ⇒ low plasma concentrations
  • Long T½ but dosed q12h
  • Hepatic elimination
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21
Q

Tigecycline

Adverse Effects

A

GI upset and N/V ⇒ 30% of pts

22
Q

Tigecycline

Activity

A

Expanded spectrum vs Tetracyclines.

  • Many GNR and GPC
    • Covers VRE and MRSA
  • Good anaerobic coverage
  • Does not cover Pseudomonas or Proteus species
23
Q

Tigecycline

Clinical Uses

A
  • Complicated polymicrobial infections
  • Skin and soft tissue infections (SSTIs)
  • Intraabdominal infections
  • Not adequate coverage for HAP
24
Q

Macrolides

MOA

A

Binds to 23s rRNA of 50s ribosomal subunit

⊗ translocation and transpeptidase

Bacteriostatic

25
Q

Macrolides

Pharmacodynamics

A
  • Administered PO
    • Azithromycin
      • PO w/ long T½ ⇒ qDay dosing
      • IV for Legionnaires disease
    • Erythromycin
      • Short T½ ⇒ given 2-4x per day
      • Administered topically for acne
  • High bioavailability
  • Achieves high intracellular concentrations
  • Excellent lung penetration
  • Poor CNS penetration
  • Elimination:
    • Hepatic metabolism
    • Biliary or renal excretion
26
Q

Macrolides

Adverse Effects

A
  • Significant GI disturbances ⇒ N/V/D
    • Erythromycin sometimes used as a prokinetic for impaired GI motility
  • Cholestatic hepatitis
    • Rare but serious
  • Prolongation of QT interval
    • Issues if taken w/ antiarrhythmics
27
Q

Macrolides

Drug Interactions

A
  • Erythromycin & Clarithromycin ⇒ ⊗ CYP-450
    • Possible interactions w/ drugs that use the same pathway
    • Ex. Theophylline, warfarin, some statins
  • Azithromycin ⇒ lower interaction potential
28
Q

Macrolides

Activity

A
  • Streptococcus spp.
  • Atypical pathogens
  • Some GNR including:
    • H. influenzae
    • M. catarrhalis
  • Clarithromycin ⇒ H. pylori
29
Q

Macrolides

Resistance

A

Efflux pump

&

Altered target site

30
Q

Macrolides

Clinical Uses

A
  • URTIs
  • Mild CAP ⇒ due to resistance by S. pneumonia
  • Mycobacterium avium-intracellulare (MAC or MAI) infections
  • PUD ⇒ Clarithromycin in combo
  • Chlamydia
  • Promotility ⇒ Erythromycin
31
Q

Macrolides

Drugs

A
32
Q

Chloramphenicol

MOA

A

Binds 23s rRNA of 50s ribosomal subunit

⊗ Peptidyl transferase

Bacteriostatic

33
Q

Chloramphenicol

Pharmacodynamics

A
  • High bioavailability ⇒ PO = IV
  • Very lipophilic ⇒ good CNS penetration
  • Hepatically metabolized through conjugation by glucuronidation
  • Conjugate & parent drug renally excreted
34
Q

Chloramphenicol

Adverse Effects

A
  • Gray baby syndrome
    • Due to neonatal impairment of conjugation
    • See cyanosis, metabolic acidosis, weakness, respiratory depression, shock
  • Bone marrow suppression (2 types)
    • Reversible ⇒ dose-related
      • ⊗ Iron incorporation into heme
    • Irreversible ⇒ idopathic
35
Q

Chloramphenicol

Activity

A
  • Strep
  • Staph ⇒ MSSA only
  • Enterococci including VRE
  • Anaerobes
  • Some GNR
36
Q

Chloramphenicol

Resistance

A

Due to enzymatic inactivation.

37
Q

Chloramphenicol

Clinical Uses

A
  • Uncommonly used in the US
    • Only used to treat infections resistant to other drugs
    • Active against bacteria that cause meningitis
  • May be used more in some developing countries
38
Q

Clindamycin

MOA

A

Binds 50s ribosomal subunit.

⊗ Translocation

Bacteriostatic

39
Q

Clindamycin

Pharmacodynamics

A
  • Given PO, IV, or topically
  • ~90% bioavailability
40
Q

Clindamycin

Activity

A
  • Many anaerobes
    • But not C. difficile
  • Staph including some MRSA
  • Strep including invasive group A strep
41
Q

Clindamycin

Adverse Effects

A
  • Higher rate of GI superinfections ⇒ C. difficile
    • Pseudomembranous colitis
    • Severe diarrhea
    • Abdominal pain
    • Nausea
    • Fever
  • Rash
42
Q

Clindamycin

Resistance

A

Due to altered target sites.

  • In gram ⊕, often cross-resistant with macrolides
  • Inducible resistance
    • Erythromycin resistant but clindamycin sensitive ⇒ resistance to clindamycin can develop over time
      • Erythromycin resistance d/t induction of methylation of 50s subunit
      • Clindamycin also induces methylation but much slower
    • Can be measured with D-test
      • ⊕ results indicate bacteria will become resistant
43
Q

Clindamycin

Clinical Uses

A

Can be used orally, parentally, or topically.

  • Aspiration PNA
  • SSTIs
  • Anaerobic intra-abdominal infections
  • Acne (topical)
44
Q

Linezolid

MOA

A

Binds 23s rRNA of 50s subunit

Prevents binding of fMet-tRNA to 70s

⊗ Formation of 70s initiation complex

Binding site distinct from other protein synthesis inhibitors.

Bacteriostatic & Bactericidal depending on bacteria

45
Q

Linezolid

Pharmacodynamics

A
  • High bioavailability (PO = IV)
  • Dual hepatic metabolism (70%) & renal elimination
    • Not via CYP450
46
Q

Linezolid

Adverse Effects

A
  • Monoamine oxidase inhibition (weak, reversible)
    • Serotonin syndrome
      • If given w/ SSRIs, TCAs
    • Hypertensive crisis
      • ↑ Tyramine ⇒ ↑ NE ⇒ ↑ BP
      • Avoid tyramine-containing foods
    • Avoid other MAOIs
  • Thrombocytopenia
  • Peripheral and optic neuropathy
47
Q

Linezolid

Activity

A
  • Gram ⊕ aerobes
    • Staph including MRSA
  • Strep including PCN-resistant strains
  • Enterococci including VRE
48
Q

Linezolid

Resistance

A

Due to altered target site.

49
Q

Linezolid

Clinical Uses

A

MRSA or VRE infections

  • PNA caused by MRSA and PCN-resistant strep
  • Skin and soft tissue infections w/ MSSA and MRSA
50
Q

Protein Synthesis Inhibitors

Spectrum Summary

A

2. HDS Pulmonary (28 decks)

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