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Pharmacology > Protein synthesis inhibitors > Flashcards

Protein synthesis inhibitors Flashcards

1
Q

Protein synthesis inhibitors

MOA

A
  • MOA: Bind to and interfere w/ ribosomes
  • Mostly bacteriostatic
  • Bacterial ribosome (70S) differs form mammalian (80S) but closely resembles mammalian mitochondrial ribosome
Tetracyclines
Glycylcyclines
Aminoglycosides
Macrolides
Chloramphenical 
Clindamycin
Streptogramins
Linezolid
Mupirocin
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2
Q

Tetracyclines

MOA

A

Doxycycline, Minocycline, Tetracycline
- Broad spectrum
- bacteriostatic
- activity against manyaerobic and anaerobic Gram +ve and Gram -ve organisms
MOA:
Binds reversibly to 30S subunit of ribosome, preventing binding of amioacyl tRNA

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3
Q

Tetracyclines resistance

clinical applications

A
  • Widespread resistance (usually plasmid mediated)
  • Most common use= severe acne and rosacea
  • Used in empiric therapy of community-acquired pneumonia (outpatients)
  • Can be used for infections of respiratory tract, sinuses, middle ear, urinary tract and intestines
  • syphilis (patients allergic to penicillin)
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4
Q

Tetracyclines

clinical applications DOC

A 
DOC for:
Chlamydia
Mycoplasma pneumoniae
Lyme disease
Cholera
Anthrax prophylaxis
Rickettsia (Rocky Mountain Spotted Fever, typhus)
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5
Q

Tetracyclines
clinical applications
- used in combination for

A

H. pylori eradication
Malaria prophylaxis and treatment
Treatment of plague, tularemia, brucellosis

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6
Q

tetracyclines PK

Excretion?

A
  • Variable oral absorption (decreased by divalent and trivalent cat ions e.g Ca+2, Mg+2, Fe+2)
  • Doxycycline (lipid soluble)= preferred for parenteral admin. and good choice for STD’s and prostatitis
  • Minocycline = reaches high concentrations in all secretions (useful for eradication of meningococcal carrier state)
  • Concentrate in liver, kidney, spleen and skin

Excreted primarily in urine except doxycycline (primarily via bile)

TERATOGENIC-all cross placenta and are excreted into breast milk (FDA category D)

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7
Q

tetracyclines AE/CI

A
  • Discoloration and hypoplasia of teeth, stunting of growth (generally avoided in pregnancy and not given in children under 8y)
  • Fatal hepatotoxicity (in pregnancy, with high doses patients with hepatic insufficiency)
  • PHOTOSENSITIZATION
  • dizziness vertigo (esp. doxycyline and minocycline)
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8
Q

Glycylcyclines

A

Tigecycline
- structurally similar to tetracyclines

Antibacterial spectrum
- Broad-spectrum against multidrug-resistant Gram positive, some gram-negative and anaerobic organisms

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9
Q

Glycylcyclines clinical applications

BLACK BOX WARNING

A

Treatment of complicated skin, sorft tissue and intra abdominal infections.

BB warning: Increased risk of mortality has been observed with tigecycline compared with other abs when used to treat serious infections.

FDA recommends considering the use of alternative antimicrobials when treating patients w/ serious infections.

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10
Q

Gycylcyclines PK/AE

A

IV only
primarily bilary/fecal elimination
well tolerated
AE similar tetracyclines

CI: pregnancy and children

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11
Q

Aminoglycosides

Drugs used?

A 
"TANGS"
Amikacin, 
gentamicin,
Tobramycin, 
Streptomycin, 
Neomycin
- Bactericidal 
- associated with serious toxicities
- Largely replaced by safer abs
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12
Q

Aminoglycosides MOA

A

Actively transported (O2-dependent) across cytoplasmic membrane

bind 30S ribosomal subunit prior to ribosome formation leading to:
- misreading of mRNA and inhibition of translocation

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13
Q

Aminoglycoside resistance:

A

3 principal mechanisms:

  • plasmid associated synthesis of enzymes that modify and inactivate drug
  • decreased accumulation of drug
  • Receptor protein on 30S ribosomal subunit may be deleted or altered due to mutation
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14
Q

Aminoglycosides Pharmacodynamics

A

Postantibiotic effect + concentration Killing = Once daily dosing

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15
Q

which drug are concentration dependent?

what drugs are time dependent?

A
  1. aminoglycosides

2. Penicilins, cephalosporins

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16
Q

Aminoglycosides are most active against?
clinical applications?
DOC?

A
  1. Aerobic gram -ve bacteria
    - anaerobes lack O2 dependent transport
  2. Used mostly as combination
    - Empiric therapy of serious infections eg, septicemia, nocosomial respiratory tract infections, complicated UTI’s, endocarditis etc
    - once organism is indentified aminoglycosides are discontinued in favor of less toxic drugs.

DOC for: Infective Endocarditis incombination with either penicillin or (more commonly) vancomycin.

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17
Q

DOC for plague (Y. Pestis)

A

Streptomycin

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18
Q

Oral Neomycin used for?

A

used as adjunct in treatment for hepatic encephalopathy

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19
Q

Alternative to treatment options for hepatic encephalopathy?

A

Lactulose
Oral Vancomycin
Oral Metronidazole
Rifaximin

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20
Q

Lactulose
MOA
AE

A 
Nonabsorbable disaccharide
MOA:
degraded by intestinal bacteria--> lactic acid + other organic acids
-->acidification of gut lumen
--> favors formation NH4+ from NH3
--> NH4+ is trapped in colon effectively reducing plasma ammonia concentrations.
AE:
- osmotic diarrhea
- flatulence
- abdominal cramping
21
Q

Aminoglycosides PK

A
  • Parenteral admin. only (except neomycin-topical)
  • Once daily admin
  • well distributed (excluding CSF, bronchial secretions)
  • High level in renal cortex and inner ear*
  • 99% excreted in urine (reduce dose in renal insufficiency)
22
Q

Aminoglycosides AE

A

Both time- and concentration- dependent

  • Ototoxicity
  • Nephrotoxicity
  • Neuromuscular blockade (myasthenia gravis=Contraindicated)
  • Pregnancy unless outweighs risk- FDA category D
23
Q

Macrolides

MOA

A 
TACE
Erythromycin
Clarithromycin
Azithromycin
Telithromycin

MOA: Reversibly bind to 50S subunit inhibiting translocation.
- bind site is identical to clindamycin and chloramphenicol

  • Mainly used for Gram +ve infections
  • Bacteriostatic (bactericidal at high concentration)
24
Q

DOC for mycoplasma pneumoniae

A

DOC: Macrolides

25
Q

DOC for whooping cough disease (B. pertussis)

A

DOC: Erythromycin

26
Q

Common substitue for patients with penicillin allergyy

A

Macrolides are common substitute for patients with penicillin allergies

27
Q

Macrolides are CYP450 inhibitors except?

A

Azithromycin

28
Q

Macrolides
AE?
CI?

A

GI irritation
Hepatic abnormalities (erythromycin and azithromycin)
QT prolongation (Torsade de pointes)
Severe reactions are rare (anaphylaxis, colitis)

CI: STATINs (due to cyp450 inhibiton)

Telithromycin - fatal hepatotoxicity, exacerbations of myasthenia gravies and visual disturbances –> don’t use for minor illnesses.

29
Q

what macrolide can lead to fatal hepatotoxicity, exacerbations of myasthenia gravies and visual disturbances which should not used for minor illnesses.

A

Telithromycin

30
Q

Choramphenicol:

“developing world, treats meningitis.”

A
  • Potent inhibitor of protein synthesis
  • BROAD-SPECTRUM (aerobic and anerobic Gram +ve and -ve organisms.
  • Bacteriostatic (usually)
  • Toxicity limits use to life-threating infections w/ no alternatives
31
Q

Chloramphenicol MOA

Resistance?

A
  • Entry via active transport
  • Reversibly binds 50s ribosomes (site adjacent to site of action of macrolides and clindamycin)
  • Can inhibit protein synthesis in mitochondrial ribosomes –> bone marrow suppression

Resistance: chloramphenicol tranferase (inactivates drug)
- Changes in membrane permeability

32
Q

Chloramphenicol - Antibacterial spectrum

A 
Very broad
activity against:
- Gram + and -
- Rickettsiae
- Anaerobes

Never given systemically for minor infections (due to adverse effects)

33
Q

Chloramphenicol clinical applications (3rd world)
PK?
AE?

A
  • Meningitis
  • serious infections resistant to toxic drugs
  • active against VRE
  • Topical treatment of eye infections (mainly outside US)
  • when it’s penetrations to sights is more superior to other drugs.

PK: Oral, IV or topical

  • wide spread distribution (readily enters CSF)
  • Inhibits hepatic oxidases (3A4 and 2C9)
AE:
GRAY BABY SYNDROME (cyanosis), due to drug accumulation
Bone marrow depression:
- dose related reversible depression
- APLASTIC ANEMIA
34
Q

Clindamycin
PK?
MOA?

A
  • Oral or IV
  • MOA = same as macrolides (binds 50S subunit)
  • Bacteriostatic
  • Primarily used against Gram positive anaerobic bacteria.
  • Also active against Bacteriodes and gram +ve aerobes
35
Q

Clindamycin has cross resistance with ?

Clinical applications?

A
  1. Macrolides (bacteroides infections, abscesses, abdominal infections)
  2. Anaerobic infections
    - skin and soft tissue infections (streptococci and staphylococci, and some MRSA)
    - in combo with primaquine as an alternative in PCP
    - In combo with pyrimethamine as an alternative for toxoplasmosis of brain.
    - Prophylaxis of endocarditis in valvular patients allergic to penicillin.
36
Q

Clindamycin AE:

A
  • Pseudomembranous Colitis (superinfection of c. difficile)*
  • GI irritation
  • Skin rashes
  • Neutropenia and impaired liver function
37
Q

Streptogramins

- USE

A

Quinupristin, Dalfopristin (queen and dwarf of the Priest)

  • Given as a combination (act synergistically to have bactericidal action!)
  • Long postantibiotic effect***
  • GRAM +VE COCCI (drug resistant Staph or VRE)***
  • Multidrug resistant bacteria (streptococci, PRSP, MRSA, E. faecium)
38
Q

Streptogramins

  • admin?
  • MOA?
A

Quinupristin, Dalfopristin

IV only
Penetrates macs and PMNs
Inhibits CYP3A4
MOA:
- 50S bacterial ribosome 
- resistance is uncommon
39
Q

Streptogramins AE

A

Quinupristin, Dalfopristin

Infusion related (venous irritation, arthralgia and myalgi)
GI effects
CNS effects (headache, pain)
40
Q

Linezolid

A

Bacteriostatic (cidal against streptococci and clostridium perfringes)

  • Most Gram positive organisms
  • Tx of mulidrug resistant infections

MOA
- Binds to unique site on 23S ribosomal RNA of 50S subunit inibiting 70S initiation complex

No cross resistance

41
Q

Linezolid PK

A
  • Oral (100% bioavailable) and IV
  • Widely dietributed (including CSF)
  • weak reversible inhibitor of MAO
42
Q

Linezolide AE

A

Well tolerated for short admin. ( GI, nausea, diarrhea, headaches, rash)

Long-term admin. can cause:
Reversible myelosuppression
Optic and periperal neuropathy and lactic acidosis.

43
Q

Linezolide CI

A

reversible, nonselective inhibitor of MAO–> potential to interact with adrenergic and serotonergic drugs.

44
Q

Fidaxomicin

MOA

A
  • Narrow spectrum macrocyclic ab
  • Activity against gram-positive aerobes and anaerobes especially Clostridia
  • No activity against Gram-negative bacteria!

MOA:
Inhibits bacterial protein synthesis by binding to RNA polymerase.

45
Q

Fidaxomicin clinical applications:

A

Treatment of C. difficile colitis (in adults)

“C. difficile takes the VAN to the METRO”

46
Q

Fidaxomicin PK.

A

When administered orally, systemic absorption is negligible but fecal concentrations are high.

47
Q

Mupirocin

A
  • Antibiotic belonging to monoxycarbolic acid class
  • Activitiy again most gram +ve cocci, including MRSA and most streptococci (but not enterococci)
  • only topical/intranasal agent with activity against MRSA!!
  • tx impetigo or secondary infected traumatic skin lesions due to S. aureus or S. pyogenes.
48
Q

Mupirocin MOA

AE

A

Binds to bacterial Isoleucyl tranfer RNA synthetase–>inhibits protein synthesis
AE:
- resistance after prolonged use
- Mainly local and dermatologic effects (eg, burning, edema, tenderness, dry skin, pruritis).

Pharmacology (27 decks)

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