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2. HDS Pulmonary > Protein Synthesis Inhibitors > Flashcards

Protein Synthesis Inhibitors Flashcards

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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

Study These Flashcards
A

GI upset and N/V ⇒ 30% of pts

22
Q

Tigecycline

Activity

Study These Flashcards
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

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

Macrolides

MOA

Study These Flashcards
A

Binds to 23s rRNA of 50s ribosomal subunit

⊗ translocation and transpeptidase

Bacteriostatic

25
Macrolides Pharmacodynamics
* **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
Macrolides Adverse Effects
* **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
Macrolides Drug Interactions
* _Erythromycin & Clarithromycin_ ⇒ **⊗ CYP-450** * Possible interactions w/ drugs that use the same pathway * Ex. Theophylline, warfarin, some statins * _Azithromycin_ ⇒ lower interaction potential
28
Macrolides Activity
* **Streptococcus spp.** * **Atypical pathogens** * Some **GNR** including: * **H. influenzae** * **M. catarrhalis** * _Clarithromycin_ ⇒ **H. pylori**
29
Macrolides Resistance
Efflux pump & Altered target site
30
Macrolides Clinical Uses
* **URTIs** * **Mild CAP** ⇒ due to resistance by S. pneumonia * **Mycobacterium avium-intracellulare (MAC or MAI) infections** * **PUD** ⇒ Clarithromycin in combo * **Chlamydia** * Promotility ⇒ Erythromycin
31
Macrolides Drugs
32
Chloramphenicol MOA
Binds 23s rRNA of 50s ribosomal subunit **⊗ Peptidyl transferase** _Bacteriostatic_
33
Chloramphenicol Pharmacodynamics
* **High bioavailability** ⇒ PO = IV * Very lipophilic ⇒ **good CNS penetration** * **Hepatically metabolized** through _conjugation by glucuronidation_ * Conjugate & parent drug **renally excreted**
34
Chloramphenicol Adverse Effects
* **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
Chloramphenicol Activity
* **Strep** * **Staph** ⇒ MSSA only * **Enterococci** including **VRE** * **Anaerobes** * **Some GNR**
36
Chloramphenicol Resistance
Due to enzymatic inactivation.
37
Chloramphenicol Clinical Uses
* **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
Clindamycin MOA
Binds 50s ribosomal subunit. **⊗ Translocation** _Bacteriostatic_
39
Clindamycin Pharmacodynamics
* Given PO, IV, or topically * ~90% bioavailability
40
Clindamycin Activity
* **Many anaerobes** * _But not C. difficile_ * **Staph including some MRSA** * **Strep including invasive group A strep**
41
Clindamycin Adverse Effects
* _Higher rate of GI superinfections_ ⇒ C. difficile * **Pseudomembranous colitis** * **Severe diarrhea** * Abdominal pain * Nausea * Fever * Rash
42
Clindamycin Resistance
**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
Clindamycin Clinical Uses
**Can be used orally, parentally, or topically.** * Aspiration PNA * SSTIs * Anaerobic intra-abdominal infections * Acne (topical)
44
Linezolid MOA
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
Linezolid Pharmacodynamics
* High bioavailability (PO = IV) * Dual **hepatic metabolism** (70%) & **renal elimination** * Not via CYP450
46
Linezolid Adverse Effects
* **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
Linezolid Activity
* Gram ⊕ aerobes * **Staph including MRSA** * **Strep** including **PCN-resistant strains** * **Enterococci** including **VRE**
48
Linezolid Resistance
Due to altered target site.
49
Linezolid Clinical Uses
**MRSA or VRE infections** * PNA caused by MRSA and PCN-resistant strep * Skin and soft tissue infections w/ MSSA and MRSA
50
Protein Synthesis Inhibitors Spectrum Summary

2. HDS Pulmonary (28 decks)

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