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Protein Synthesis lnhibitors
Ján Mojžiš
Department of Pharmacology
LF UPJŠ Košice
PROTEIN SYNTHESIS INHIBITORS
TETRACYCLINES
Tetracycline, Doxycycline, Minocycline
AMINOGLYCOSIDES
Amikacin, Gentamicin, Neomycin, Netilmicin
Streptomycin, Tobramycin
MACROLIDES
Erythromycin, Azithromycin, Clarithromycin
CHLORAMPHENICOL
CLINDAMYCIN
LINEZOLID
TETRACYCLINES
CHLORTETRACYCLINE, OXYTETRACYCLINE, TETRACYCLINE,
DEMECLOCYCLINE, METHACYCLINE, DOXYCYCLINE,
MINOCYCLINE
Mechanism of action
They bind reversibly to the 30S subunit of the bacterial ribosome,
thereby blocking access of the amino acyl-tRNA to the mRNAribosome complex at the acceptor site. Thus, bacterial protein
synthesis is inhibited.
Bacteriostatic
Antibacterial spectrum
Pharmacology
1. Absorption:
- adequately but incompletely absorbed after p.o.
- dairy foods in the diet decrease absorption because of
the formation of nonabsorbable chelates of the
tetracyclines with calcium ions.
2. Distribution:
- concentration in the liver, kidney, spleen, and skin
- bind to tissues undergoing calcification (e.g.,teeth,
bones), or to tumors that have a high calcium content
(e.g. gastric carcinoma). - penetration into body fluids is
adequate.
-CSF – only MINOCYCLINE enters the brain in the
absence of inflammation
-all TTCs cross the placental barrier and concentrate in
fetal bones
E. Adverse effects
gastric discomfort: Epigastric distress commonly results from
irritation of the gastric mucosa. This can be controlled if the drug
is taken with foods oher than dairy products.
effects on calcified tissues: Deposition in the bone and primary
teeth occurs in growing children
»»» discoloration and hypoplasia of the teeth
Use in pregnancy and in children younger than 8 years
(or before the second dentition) should be avoided !!!
hepatotoxicity
superinfections: these infections may occur with candida
(e.g. in the vagina) or with resistant staphylococci in the intestine.
Pseudomembranous colitis due to an overgrowth of Clostridium
difficile was also reported.
dysmicrobia, hypovitaminosis B and K
AMINOGLYCOSIDES
- mainstays of treatment of serious infections due to
gram-negative bacilli.
-use is limited by the occurrence of serious toxicities
A. Mode of action
- inhibit bacterial protein synthesis - they irreversibly
bind to the 30S ribosomal subunit + misread the genetic
code – production of „bad“ proteins .
-they synergize with beta-Iactam ATBs (enhance
diffusion of aminoglycosides into the cell).
-all AMG are bactericidal
Antibacterial spectrum
Bactericidal, effective only against aerobic organisms
Commonly used aminoglycosides:
AMIKACIN, GENTAMICIN, TOBRAMYCIN and
STREPTOMYCIN
Further aminoglycosides: NEOMYCIN, NETILMICIN,
KANAMYCIN
D. Pharmacology
Administration - parenterally
AMG penetrate most body fluids well except for the
CSF - may be administered intrathecally
accumulation in the renal cortex and in the endolymph
and perilymph of the inner ear »»» nephrotoxicity and
ototoxicity
Adverse effects
The elderly are more
susceptible to
nephrotoxicity and
ototoxicity !!
Patients with
myasthenia
gravis are
particularly at
risk.
MACROLIDE ANTIBIOTIC
ERYTHROMYCIN, AZITHROMYCIN, CLARITHROMYCIN
ERYTHROMYCIN - few indications where it is a drug of first choice,
mostly as an alternative to penicillin in allergy to beta-lactam ATBs.
Mechanism of action
- inhibits protein synthesis by reversibly binding to the 50S
ribosomal subunit
- generally bacteriostatic (may be –cidal - depending on the
concentration and on the type of microorganisms).
Antibacterial spectrum
D. Pharmacology
ERY inhibits CYP-450 system
Adverse effects
LlNEZOLID
New ATB; against resistant G+ organisms (e.g., methicillin- and
vancomycin-resistant S. aureus, vancomycin-resistant
Enterococcus faecium and Enterococcus faecalis, and PNCresistant streptococci).
A. Mechanism of action
Inhibition of bacterial protein synthesis by inhibiting the
formation of the 70S initiation complex. It binds to a site on the
50S subunit near the interface with the 30S subunit.
C. Antibacterial spectrum
- primarily against G+ organisms (e.g., staphylococci,
streptococci, and enterococci, as well as Corynebacterium
species and Listeria monocytogenes) - its main clinical use.
- moderately active against Mycobacterium tuberculosis.
- bacteriostatic (cidal against the streptococci and C. perfringens).
D. Pharmacokinetics
Completely absorbed after oral administration; . I.v. is also
available.
- widely distributed in the body.
-two metabolites -- one has antimicrobial activity.
- excretion - renal and nonrenal routes.
E. Adverse effects
Well-tolerated.
- GIT upset, nausea, and diarrhea
- headache and rash
-thrombocytopenia in cca 2 % (when longer than 2 weeks) reversible.
- considered as a choice of last resort where every
other antibiotic therapy has failed
CHLORAMPHENICOL
Adverse effects
Anemia: Hemolytic anemia in patients with low
levels of G6-PD
Other types of anemia - include reversible anemia
(is dose-related and occurs concomitantly with
therapy) and
aplastic anemia, which is idiosyncratic and
usually fatal !!!
Bone marow supression
Potential teratogenic effects
Gray baby syndrome
LINCOSAMIDES
CLINDAMYCIN
Action - as that of erythromycin.
Spectrum - Treatment of infections caused by
anaerobic bacteria (e.g. Bacteroides fragilis). Also
active against non-enterococcal, gram-positive cocci.
Pharmacology
Given orally (well absorbed) or parenterally; Distributes
well into all body fluids except the CSF
Adverse effects
- skin rashes, GIT disturbances, impaired liver function
- the most serious adverse effect is potentially fatal
pseudomembranous colitis
QUINOLONES
FIRST GENERATION
Nalidixic acid
FLUOROQUINOLONES
SECOND GENERATION
Ciprofloxacin, Norfloxacin
Ofloxacin
THIRD GENERATION
Gatifloxacin, Levofloxacin
Moxifloxacin, Sparfloxacin
FOURTH GENERATION
Trovafloxacin
FLUOROQUINOLONES
Old drug, NALIDIXIC ACID and NORFLOXACIN - used mainly for
recurrent urinary tract infections (UTIs).
Newer fluorinated quinolones - greater potency, broader spectrum
of antimicrobial activity, systemic effects.
New compounds - more active against G+ organisms, yet retain
favorable activity against G- microorganisms.
A. Mechanism of action
- they enter the bacterium by passive diffusion via water channels.
- inhibit bacterial topoisomerases which are necessary for DNA
synthesis
DNA gyrase (TOPO II) – primary target for GTopoisomerase IV - primary target for G+
Since DNA gyrase is a bacteriospecific target for antimicrobial
therapy, cross-resistance with other antimicrobial drugs is rare, but
this is increasing in the case of multidrug-resistant organisms.
Bactericidal
Antimicrobial spectrum
C. Examples of clinically useful fluoroquinolones
Ciprofloxacin - frequently used.
F. Adverse reactions - well tolerated
Connective tissue problems: They
should be avoided in pregnancy, in
nursing mothers, and in children
under 18 years - because articular
cartilage erosion (arthropathy)
SULFONAMIDES (SA)
Structurally related to p-aminobenzoic acid (PABA).
Seldom use alone. The introduction of trimethoprim in
combination with sulfamethoxazole led to a renewed interest in
sulfonamides.
The SA inhibit the synthesis of folic acid.
A. Mechanism of action
Folic acid - synthesized from PABA, pteridine, and glutamate.
- SA - analogs of PABA
- SA compete with PABA for the bacterial enzyme, dihydropteroate
synthetase – inhibition of the synthesis of bacterial FA.
All sulfa drugs are bacteriostatic.
B. Antibacterial spectrum
-selected enterobacteriaceae, chlamydia, and nocardia.
- SULFADIAZINE + pyrimethamine (dihydrofolate reductase
inhibitor) is the preferred form of treatment for toxoplasmosis and
chloroquine-resistant malaria.
Individual sulfonamides:
1) Well absorbed orally, short-acting: Sulfadiazine,
Sulfadimidine, Sulfisoxazole, Sulfamethoxazole
2) Well absorbed orally, long-acting:
Sulfamethopyrazine
3) Poorly absorbed in GIT: Sulfasalazine
4) Used topically: Silver sulfadiazine
E. Adverse effects
Adequate hydration and
alkalization of urine is
necessary and prevent the
crystalluria.
Note: It is contraindicated to
use acidic drugs (salicylates)
or food (oranges etc.) which
may lead to acidic pH of urine
during therapy with
sulfonamides !!!
TRIMETHOPRIM
inhibitor of bacterial dihydrofolate reductase; antibacterial
spectrum similar to SA. Mostly compounded with
sulfamethoxazole = co-trimoxazole.
A. Mechanism of action
The active form of folate - tetrahydroderivative (formed by
reduction of dihydrofolate by dihydrofolate reductase). This
enzymatic reaction is inhibited by trimethoprim - decreased
availability of the tetrahydrofolate coenzymes required for purine,
pyrimidine, and amino acid synthesis.
Action of trimethoprim - much stronger for the bacterial reductase
than for the mammalian enzyme
CO-TRIMOXAZOLE
Trimethoprim – mostly compounded with sulfamethoxazole.
Sequential Blockade
dTMP
E. Adverse effects
Dermatological: Reactions involving the skin are very common and
may be severe in the elderly.
GIT: Nausea, vomiting, glossitis, stomatitis - not unusual.
Hematological: Megaloblastic anemia, leukopenia,
thrombocytopenia - may be reserved by administration of FA.
Hemolytic anemia - in patients with G6-PD
Immunocompromised patients with pneumocystis pneumonia frequently drug-induced fever, rashes, diarrhea, and/or
pancytopenia.
Antibiotic use in orofacial dental infection
MICROBIOLOGY
• Most oral infections are mixed in origin
consisting of aerobic and anaerobic gram
positive and gram negative organisms
• Anaerobes predominant (75%)
Common Pathogens
Necrotic pulp and apical abscesses
Obligate anaerobic bacteria
Gram negative rods
Prevotella & porphyomonas spp.
Fusobacterium spp.
Campylobacter rectus
Gram positive rods
Eubacterium spp.
Actinomycetes spp.
Gram positive cocci
Peptostreptococcus spp.
Facultative anaerobic bacteria
Gram positive cocci
Strep and Entercoccus spp.
Common Pathogens
• Periodontal Diseases
Gingivitis
Fuso, strep, & actinomycetes
Adult peritonitis
Bacteroides, porphyomonas,
peptostreptococcus & prevotella
Acute necrotizing ulcerative gingivitis
Spirochetes, prevotella, fuso
Localized juvenile periodontitis
Actinobacillus
Common Pathogens
• Fungal Infections
Candida spp.
Mucorales spp.
COMMONLY USED ATB
Penicillins
• First choice for odontogenic infection
• G+ cocci and rod, spirochetes, anaerobes
• 0.7~10% hypersensitivity
• Nature: penicillin G (IV), penicillin V (PO)
• Penicillinase-resistant: oxacillin, dicloxacillin
• Extended spectrum: ampicillin, amoxicillin
• Combine β-lactamase inhibitor: augmentin
Cephalosporins
• More resistance to penicillinase
• G+ cocci, many G- rods
• Third generation: P. aeruginosa
Clindamycin
• G+ cocci
• Bacteriostatic (bactericidal)
• Second-line drug: should be held in
reserve to treat those infections caused
by anaerobes resistant to other antibiotics
Aminoglycosides
• G- aerobes, some G+ aerobes eg S. aureus
• Poorly absorbed from GI tract
• Adjustment of dosage in renal dysfunction
• Drugs: Gentamicin, Amikacin
• Combined with penicillin or cephalosporin
Metronidazole
• Only for obligate anaerobes
• Can cross blood-brain barrier
• To treat serious infections caused by
anaerobic bacteria, combined with β-lactam
ATB
• Effective against Bacteroides species, esp. in
periodontal infections
• Avoid pregnant women
Vancomycin
• G+, most anaerobes, some G- cocci
(Neisseria)
• Given i.v. - BP should be monitored
• Adjustment of dosage in renal dysfunction
Erythromycin
• G+ cocci, oral anaerobes
• Bacteriostatic
• Second choice for odontogenic infections
• Indication for out-patients with mild
infection
• Drug resistence: 50% of S. aureus, Strep.
viridans,
Tetracycline
• Only against anaerobes
• Contraindications: pregnant women,
children <12
• Limited usefulness in orofacial infection
• Use as adjunctive therapy for refractory
periodontitis
• Most likely to cause superinfection
Chloramphenicol
• Wide spectrum, highly active against
anaerobes
• Limited to severe odontogenic infection
threatening to the eye or brain
• Severe toxicity
• Empiric antibiotics in oral and maxillofacial
infection
■
First-line
Penicillin 3MU IV q6h -> Cefazolin 1000mg q6h
Gentamycin 60-80mg IV q8h-q12h
■
Second line
Amoxicillin + clavulanic a.1200mg q8h + amikacin
375mg q12h + metronidazole
■
Mild infection
Amoxicillin 250mg PO q8h
Clindamycin 300mg PO q6h
Antifungals
• Nystatin
– MOA: inhibit cell wall synthesis
– P.o.; topical
– GI upset
Antifungals
• ketoconazole, fluconazole
– MOA: inhibit cell wall synthesis
– Drug interactions: major p-450 enzyme
inhibitor, interactions with many drugs
• ketoconazole - rare GI problems, skin
intolerance