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[MT 6314] Pharmacology & Toxicology > [3S] Protein Synthesis Inhibitors PPT > Flashcards

[3S] Protein Synthesis Inhibitors PPT Flashcards

1
Q

Selectively inhibit bacterial protein synthesis

A

Protein Synthesis Inhibitors

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2
Q

___ ribosomes in bacteria
___ ribosomes in mammalians

A

70S
80S

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3
Q

Basis for selective toxicity against microorganisms without causing major effects on mammalian cells
• Differences
• Ribosomal subunits
• Chemical composition
• Functional specificities of component nucleic acids and proteins

A

Protein Synthesis Inhibitors

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4
Q

Protein Synthesis Inhibitors MOA

A

• Bacteriostatic
• Bactericidal – Oxazolidinones and Pleuromutilins

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5
Q

• Simple and distinctive structure
• Effective orally as well as parenterally

A

Chloramphenicol

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6
Q

MOA
Inhibits microbial protein synthesis and is bacteriostatic against most susceptible organisms.

It binds reversibly to the 50S subunit of the bacterial ribosome and inhibits peptide bond formation

A

Chloramphenicol

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7
Q

ANTIMICROBIAL ACTIVITY

Active against both aerobic and anaerobic gram-positive and gram-negative organisms.

A

Chloramphenicol

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8
Q

ANTIMICROBIAL ACTIVITY

• Bacteriostatic
• Bactericidal - strains of H, influenzae, N. meningitidis, and some strains of Bacteroides

A

Chloramphenicol

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9
Q

ANTIMICROBIAL ACTIVITY

Not active against Chlamydia species.

A

Chloramphenicol

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10
Q

ANTIMICROBIAL ACTIVITY

Resistance is plasmid-mediated
• formation of chloramphenicol acetyltransferases

A

Chloramphenicol

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11
Q

CLINICAL USES

Rickettsial infections: typhus and Rocky Mountain spotted fever

A

Chloramphenicol

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12
Q

CLINICAL USES

Alternative to a β-lactam antibiotic for treatment of bacterial meningitis occurring in patients who have major hypersensitivity reactions to penicillin

A

Chloramphenicol

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13
Q

PKINETICS: CHLORAMPHENICOL

___ formulation: chloramphenicol succinate (prodrug) -> hydrolyzed to yield free chloramphenicol

A

IV

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14
Q

PKINETICS

Widely distributed to virtually all tissues and body fluids, including the central nervous system and cerebrospinal fluid
✔ Concentration in the brain tissue may be equal to that in serum

A

Chloramphenicol

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15
Q

PKINETICS

Penetrates cell membranes readily; readily cross the placental and blood-brain barriers

A

Chloramphenicol

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16
Q

PKINETICS

Inactived by:
(1) conjugation with glucuronic acid or
(2) reduction to inactive aryl amines

A

Chloramphenicol

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17
Q

Chloramphenicol excretion

A

Urine, small amount into bile & feces

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18
Q

TOXICITY

  1. Gastrointestinal disturbances
    • Nausea, vomiting, diarrhea
  2. Oral or vaginal candidiasis due to alteration of normal microbial flora
A

Chloramphenicol

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19
Q

TOXICITY

  1. Bone marrow
    • Inhibition of red cell maturation
    • dose-dependent and reversible
    • Aplastic anemia rare idiosyncratic reaction
    • usually irreversible
    • may be fatal
A

Chloramphenicol

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20
Q

TOXICITY: CHLORAMPHENICOL

• Lacks effective glucuronic acid conjugation mechanism for the degradation and detoxification
• Vomiting, flaccidity, hypothermia, gray color, shock, and vascular collapse

A

Gray Baby Syndrome

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21
Q

DRUG INTERACTIONS

• Inhibits hepatic drug-metabolizing enzymes
• Increasing the elimination half-lives of drugs
• Phenytoin
• Tolbutamide
• Chlorpropamide
• Warfarin

A

Chloramphenicol

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22
Q

Tetracyclines = Bacteriostatic or Bactericidal?

A

Bacteriostatic

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23
Q

MOA

Bind reversibly to the 30S subunit of the bacterial ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA-ribosome complex and prevents addition of amino acids to the growing peptide

A

Tetracyclines

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24
Q

PKINETICS

Absorption:
• _____% for tetracycline and demeclocycline
• _____% for doxycycline and minocycline

A

60–70
95–100

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25
Q

Tigecycline & Eravacycline ROA

A

IV

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26
Q

Tetracycline excretion

A

Feces (?)

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27
Q

PKINETICS

Absorption impaired by: by multivalent cations (Ca2+, Mg2+, Fe2+, Al3+); dairy products and antacids, and by alkaline pH.

A

Tetracyclines

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28
Q

PKINETICS

• Wide tissue distribution except CSF
• Cross the placental barrier and excreted in breast milk
• Excreted mainly in bile and urine
• Except : Doxycycline and tigecycline

A

Tetracyclines

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29
Q

PKINETICS

Doxycycline & Tigecycline elimination

A

Nonrenal mechanisms

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30
Q

PKINETICS

Short-acting

A

tetracycline (oral)

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31
Q

PKINETICS

Intermediate-acting

A

demeclocycline (oral)

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32
Q

PKINETICS

Long-acting (Oral & IV)

A

doxycycline and minocycline

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33
Q

PKINETICS

Long half-lives

A

Tigecycline (IV), Eravacycline (IV), Omadacycline (oral and IV)

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34
Q

ANTIBACTERIAL ACTIVITY

Active against gram-positive and gram-negative bacteria
• certain anaerobes, rickettsiae, chlamydiae, and mycoplasmas

A

Tetracyclines

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35
Q

RESISTANCE MECHANISMS

(1) impaired influx or increased efflux by an active transport protein pump
(2) ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome
(3) enzymatic inactivation

A

Tetracylcines

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36
Q

CLINICAL USES

Primary uses:
Mycoplasma pneumoniae (in adults) Chlamydiae
Rickettsiae*
Borrelia sp.*
Vibrios
some spirochetes
Anaplasma phagocytophilum
Ehrlichia sp

A

Tetracyclines

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37
Q

CLINICAL USES

Secondary uses
• community-acquired pneumonia (CAP)
• syphilis

A

Tetracyclines

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38
Q

CLINICAL USES

• Chronic bronchitis
• Leptospirosis
• Acne

A

Tetracyclines

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39
Q

CLINICAL USES

gastrointestinal ulcers caused by H. pylori

A

tetracycline

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40
Q

CLINICAL USES

Lyme disease
Malaria prophylaxis
Treat ameobiasis

A

doxycycline

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41
Q

CLINICAL USES

meningococcal carrier state

A

minocycline

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42
Q

CLINICAL USES

• inhibits the renal actions of antidiuretic hormone
(ADH)
• ADH-secreting tumors

A

Demeclocycline

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43
Q

CLINICAL USES

CONS, gram-positive cocci resistant to methicillin (MRSA strains) and vancomycin (VRE strains)

A

Tigecycline, eravacycline and omadacycline

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44
Q

CLINICAL USES

Streptococci, enterococci, gram-positive rods, Enterobacteriaceae, Acinetobacter sp, anaerobes, rickettsiae, Chlamydia sp, and L. pneumophila; and rapidly growing mycobacteria

A

Tigecycline, eravacycline and omadacycline

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45
Q

TOXICITY

  1. Gastrointestinal disturbances
    • Nausea, vomiting, and diarrhea
    • Esophageal ulceration
    • Life-threatening enterocolitis
    • Candidiasis (oral and vaginal)
    • bacterial superinfections S. aureus or C. difficile.
A

Tetracyclines

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46
Q

TOXICITY

  1. Bony structures and teeth
    • Fetal exposure
    • tooth enamel dysplasia
    • irregularities in bone growth
    • Younger children
    • enamel dysplasia
    • crown deformation (permanent teeth)
A

Tetracylcines

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47
Q

TOXICITY

  1. Hepatic toxicity
    • high doses
    • pregnant patients
    • preexisting hepatic disease
A

Tetracylcines

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48
Q

TOXICITY

Renal Toxicity: Fanconi Syndrome

A

outdated tetracyclines

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49
Q

TOXICITY

Renal Toxicity: Nephrotoxicity

A

tetracycline + diuretic

50
Q

TOXICITY

Renal Toxicity: exacerbate preexisting renal dysfunction

A

Tetracylcines

51
Q

TOXICITY

Photosensitivity

A

Demeclocycline

52
Q

TOXICITY

Vestibular Toxicity
• Dose-dependent reversible dizziness and vertigo

A

Doxycycline and minocycline

53
Q

Macrocyclic lactone ring with attached sugars

A

Macrolides

54
Q

Semisynthetic derivatives of erythromycin

A

Clarithromycin and azithromycin

55
Q

Macrolides prototype

A

Erythromycin

56
Q

MOA

Inhibition of protein synthesis occurs via binding to the 50S ribosomal RNA

A

Macrolides

57
Q

Macrolide antibiotics prolong the electrocardiographic QT interval due to an effect on potassium channels: _____________________________

A

torsades de pointes arrhythmia

58
Q

MACROLIDES

Absorption impeded by food

A

Azithromycin

59
Q

MACROLIDES

tissues and phagocytes > plasma

A

Azithromycin

60
Q

Good oral bioavailability
Distribute to most body tissues
Primarily hepatic metabolism

A

Macrolides

61
Q

Half-life shortest to longest

Azithromycin, Erythromycin, Clarithromycin

A

E > C > A

62
Q

ANTIMICROBIAL ACTIVITY

Gram-positive organisms:
pneumococci, streptococci, staphylococci, and corynebacteria
Mycoplasma pneumoniae, L pneumophila, Chlamydia trachomatis, Chlamydophila
psittaci, Chlamydophila pneumoniae, H pylori, Listeria monocytogenes, and certain mycobacteria (Mycobacterium kansasii, Mycobacterium scrofulaceum)

A

Erythromycin

63
Q

ANTIMICROBIAL ACTIVITY

Gram-negative organisms:
Neisseria sp, Bordetella
pertussis, Bartonella henselae, and Bartonella quintana as well as some Rickettsia species, Treponema pallidum, and Campylobacter species

A

Erythromycin

64
Q

RESISTANCE MECHANISMS

(1) Reduced permeability of the cell membrane or active efflux
(2) Production (by Enterobacteriaceae) of esterases that hydrolyze macrolides
(3) Modification of the ribosomal binding site (so-called ribosomal protection) by chromosomal mutation or by a macrolide-inducible or constitutive methylase.

A

Erythromycin

65
Q

T/F: Cross-resistance occurs between erythromycin and the other macrolides

A

T

66
Q

PKINETICS

Erythromycin excretion

A

Bile

67
Q

PKINETICS

• Absorbed drug is distributed widely except to the brain and cerebrospinal fluid.
• Taken up by polymorphonuclear leukocytes and macrophages
• Traverses the placenta and reaches the fetus

A

Erythromycin

68
Q

CLINICAL USES

Corynebacterial and chlamydial infections, M pneumoniae, and L pneumophila, useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci and streptococci

A

Erythromycin

69
Q

ADVERSE REACTIONS

Anorexia, nausea, vomiting, and diarrhea; acute cholestatic hepatitis

A

Erythromycin

70
Q

DRUG INTERACTIONS

theophylline, warfarin, cyclosporine, methylprednisolone, and digoxin

A

Erythromycin

71
Q

More active against Mycobacterium avium complex; also has activity against M leprae, T gondii, and H influenzae.

A

Clarithromycin

72
Q

PKINETICS

Clarithromycin metabolism & excretion

A

Liver and partially eliminated in the urine

73
Q

PKINETICS

14-hydroxyclarithromycin (major metabolite) with antibacterial activity and eliminated in the urine

A

Clarithromycin

74
Q

ADVERSE REACTION

• Lower incidence of gastrointestinal intolerance
• Similar drug interactions with Erythromycin

A

Clarithromycin

75
Q

ANTIMICROBIAL ACTIVITY

Active against M avium complex, T gondii, H influenzae, Chlamydia sp

A

Azithromycin

76
Q

MOA

Penetrates into most tissues (except cerebrospinal fluid) and phagocytic cells extremely well, with tissue concentrations exceeding serum concentrations by 10- to 100-fold

A

Azithromycin

77
Q

PKINETICS

No drug interactions

A

Azithromycin

78
Q

Chlorine-substituted derivative of lincomycin
(Streptomyces lincolnensis)

A

Clindamycin

79
Q

MOA

MOA similar to macrolides but are not chemically
related

A

Clindamycin

80
Q

ANTIMICROBIAL ACTIVITY

• Streptococci, staphylococci, and pneumococci
• Bacteroides sp and other anaerobes

A

Clindamycin

81
Q

Gram-negative aerobes are intrinsically resistant
• poor penetration through the outer membrane.

A

Clindamycin

82
Q

MECHANISM OF RESISTANCE

(1) mutation of the ribosomal receptor site
(2) modification of the receptor by a constitutively expressed methylase
(3) enzymatic inactivation

A

Clindamycin

83
Q

T/F: Cross-resistance between clindamycin and macrolides is common.

A

T

84
Q

Clindamycin ROA

A

Oral & IV

85
Q

Clindamycin metabolism & excretion

A

Hepatic metabolism, renal and biliary excretion

86
Q

CLINICAL USE

• Treatment of severe anaerobic infections: Bacteroides, Fusobacterium, and Prevotella
• Backup drug against gram-positive cocci: Community-acquired strains of MRSA

A

Clindamycin

87
Q

CLINICAL USE

• Toxic shock syndrome (with penicillin G) or necrotizing fasciitis
• Penetrating wounds of the abdomen and gut (combined with aminoglycoside or cephalosporin)

A

Clindamycin

88
Q

CLINICAL USE

• Septic abortion, pelvic abscesses, or pelvic inflammatory disease; and lung and periodontal abscesses
• Prophylaxis of endocarditis in valvular disease (patients allergic to penicillin)

A

Clindamycin

89
Q

CLINDAMYCIN

• In combination with __________ alternative vs P. jiroveci pneumonia in AIDS patients
• In combination with __________ for AIDS-related toxoplasmosis

A

primaquine
pyrimethamine

90
Q

TOXICITY

• Gastrointestinal irritation
• Skin rashes
• Neutropenia
• Hepatic dysfunction
• Superinfections C. difficile - pseudomembranous colitis

A

Clindamycin

91
Q

ANTIMICROBIAL ACTIVITY

Bactericidal except Enterococcus faecium

A

Quinupristin-dalfopristin

92
Q

ANTIMICROBIAL ACTIVITY

Active against gram-positive cocci, including multidrug-resistant strains of streptococci, penicillin-resistant strains of S pneumoniae, methicillin-susceptible and resistant strains of staphylococci, and E faecium

A

Quinupristin-dalfopristin

93
Q

MECHANISM OF RESISTANCE

• Modification of the quinupristin binding site (MLS-B type resistance)
• Enzymatic inactivation of dalfopristin
• Efflux

A

Quinupristin-dalfopristin

94
Q

Quinupristin-dalfopristin ROA & elimination

A

IV & Fecal route

95
Q

T/F: Quinupristin-dalfopristin

Dose adjustment is necessary for renal failure, peritoneal dialysis, or hemodialysis

A

F; not necessary

96
Q

Drug interactions due to inhibition of
CYP3A4: warfarin, diazepam, quetiapine, simvastatin, and cyclosporine

A

Quinupristin-dalfopristin

97
Q

CLINICAL USES

Infections caused by staphylococci or by vancomycin-resistant strains of E faecium

A

Quinupristin-dalfopristin

98
Q

ADVERSE EFFECTS

Pain at infusion site and arthralgia-myalgia syndrome

A

Quinupristin-dalfopristin

99
Q

ANTIMICROBIAL ACTIVITY

Active against gram-positive organisms including staphylococci, streptococci, enterococci, gram-positive anaerobic cocci, and gram-positive rods such as corynebacteria, Nocardia sp, and L monocytogenes, and Mycobacterium tuberculosis

A

Linezolid

100
Q

Bacteriostatic but bactericidal against streptococci

A

Linezolid

101
Q

MOA

Inhibits protein synthesis by preventing formation of the ribosome complex that initiates protein synthesis.
• Binding site: 23S ribosomal RNA of the 50S subunit

A

Linezolid

102
Q

T/F: Resistance: mutation of the linezolid binding site on 23S ribosomal RNA

A

T

103
Q

Linexolid ROA & metabolism

A

PO & IV; oxidative metabolism -> (2) inactive metabolites

104
Q

CLINICAL USES

vancomycin-resistant E faecium infections, HCAP, CAP, skin and soft tissue infections (gram-positive bacteria)

A

Linezolid

105
Q

CLINICAL USE

Off-label uses: treatment of MDR-TB and Nocardia infections

A

Linezolid

106
Q

ADVERSE EFFECTS

thrombocytopenia, anemia, neutropenia; optic and
peripheral neuropathy and lactic acidosis; serotonin syndrome

A

Linezolid

107
Q

Active moiety of the prodrug tedizolid phosphate

A

Tedizolid

108
Q

ANTIMICROBIAL ACTIVITY

High potency against gram-positive bacteria (MRSA, VRE, streptococci, gram-positive anaerobes)

A

Tedizolid

109
Q

PKINETICS

• 91% bioavailability; t1/2: 12 hours
• Higher protein-binding (70–90%) than linezolid (31%)
• Penetrates well into muscle, adipose, and pulmonary tissues
• No dose adjustment for renal or hepatic impairment

A

Tedizolid

110
Q

CLINICAL USE

skin and soft tissue infection

A

Tedizolid

111
Q

ADVERSE EFFECT

Lower risk of bone marrow suppression, lower risk of serotonergic toxicity

A

Tedizolid

112
Q

MOA

binding the 50S ribosome and inhibits bacterial protein synthesis; binding pocket closes around the drug molecule, preventing bacterial transfer RNA from binding appropriately

A

Lefamulin

113
Q

ANTIMICROBIAL ACTIVITY

Bactericidal: lower respiratory tract infections such as S. pneumoniae, H. influenzae, and atypical pathogens such as L. pneumophila, M. pneumoniae, and C. pneumoniae

A

Lefamulin

114
Q

ANTIMICROBIAL ACTIVITY

Most aerobic gram-positive organisms, including S. pyogenes, S. aureus, and E. faecium. It may also have activity against certain organisms causing STIs, such as M. genitalium, N. gonorrhoeae, and C. trachomatis

A

Lefamulin

115
Q

ANTIMICROBIAL ACTIVITY

Lacks activity: E. faecalis, P. aeruginosa, A. baumannii, and the Enterobacteriaceae group of gram-negative organisms

A

Lefamulin

116
Q

MECHANISM OF RESISTANCE

ribosomal target site alteration and active efflux from the site of action

A

Lefamulin

117
Q

CLINICAL USE

CAP

A

Lefamulin

118
Q

Lefamulin ROA & metabolism

A

PO/IV & hepatic metabolism (CYP3A4)

119
Q

T/F: Lefamulin = Dose adjustment for severe hepatic impairment

A

T

120
Q

ADVERSE EFFECTS

infusion-site reactions, GI disturbances, congenital malformations

A

Lefamulin

[MT 6314] Pharmacology & Toxicology (20 decks)

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