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8/3/2019 Protein Synthesis Inhibitors 2ND 11
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Dr. Inas Darwish &
By Dr. Manal Hamza
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Protein synthesis inhibitors
How do protein synthesis
inhibitors work?
Target bacterial ribosomes
Ribosomes
Protein
synthesis
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Why dont protein synthesis inhibitors
work on mammalian cells?Mammalian ribosomes differ from bacterial ribosomes
Bacteria70S ribosomes
Mammalian cells80S ribosomes
Differ in ribosomal subunits
Bacterial ribosomes50S and 30S Mammalian ribosomes60S and 40S
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Which antibiotics work onthe bacterial 30S
ribosomal subunit?
AminoglycosidesTetracyclines
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Which antibiotics work onthe bacterial 50S
ribosomal subunit?
Chloramphenicol
MacrolidesClindamycin
Linezolid
streptogramins
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Classification
Broad spectrumChloramphenicol
Tetracyclines
Moderate spectrumMacrolides
Narrow spectrum Aminoglycosides
Clindamycin
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Aminoglycosides
AMINOGLYCOSIDES
AmikacinStreptomycin
Gentamicin Neomycin Tobramycin
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What is the mechanism of action?
50S 50S
30S 30S
Outer membrane
Inhibit bacterial protein synthesis
Porin Channels
Cell wall
Cell membrane
O2dependent active transport
Aminoglycosides transport enhanced by cell wall synthesis inhibitors
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Are aminoglycosides bacteristatic
or bactericidal?
Bactericidal
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What is the antibacterial
spectrum of aminoglycosides?Aerobic Gramve bacteriaE.coliEnterobacterKlebsiellaProteusPseudomonasSerratia
Effective against enterococci when combinedwith beta lactams
Synergism with beta lactams
Ineffective against anaerobes dueto lack of oxygen dependent active
transport
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What are the mechanisms of
resistance ?
Production of inactivating enzymes
Individual aminoglycosideshave varying susceptibilities
to inactivating enzymes
Amikacin is the least susceptible
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What are the pharmacokinetics
of aminoglycosidesPolar compounds : not absorbed when given orally
Given IV for systemic effectsGiven orally for local effect in the GIT
Eliminated by renal excretion throughglomerular filtration
Dose should be adjusted in renalinsufficiency to avoid toxic accumulation
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What are the clinical uses
of aminoglycosidesDrug Application
Gentamicin ,Amikacin ,tobramycin
Serious infection withaerobic
gram-ve bacteria
Streptomycin Tuberculosis
Neomycin
Kanamycin
Topical: skin infections
Oral : Bowel sterilization
Spectinomycin Single IM dose for Gonorrhea
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What are the adverse effects
of aminoglycosides?Ototoxicity Auditory Damage
More common :With renal impairment : if the dose in not adjustedIn the presence of other ototoxic drugs :Loop Diuretics
Ototoxicity may follow fetal exposure
Aminoglycosides contra-indicated in pregnancy
Vestibular damageMay be irreversible
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What are the adverse effects
of aminoglycosides?Nephrotoxicity
More common :Elderly Pt.In the presence of other Nephrotoxic drugs:cephalosporines ,Amphotericin B or
Vancomycin
Reversible
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What are the adverse effects of
aminoglycosides?Neuromuscular blockade: Skeletal muscle weakness
Large doses of aminoglycosides
May result in respiratory paralysis
Reversed with calcium and Neostigmine
Rare
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Chloramphenicol
Describe chloramphenicol?
It is a bacteristaticbroad spectrum antibiotic
It binds reversibly to 50S ribosomal subunitInhibits bacterial protein synthesis
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How does resistance to this drug
develop?
Bacterial cell
Synthesis
acetyltransferaseChloramphenicol
Inactivation
Drug penetration
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Describe the pharmacokinetics of
this drug?Very Good penetration in the CSF
Brain
Metabolized in the liver
by conjugation
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What is chloramphenicol
effective against ?Both gram +ve and gramve organismsRickettsia
Despite its wide range Limited use
Because of its serious adverse effects &increase incidence ofbacterial resistance
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What are the clinical uses of
chloramphenicolMeningitis
Pneumococci H. influenzae
Bacterial Brain abscess
Meningococci
In beta lactam sensitive patients
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What are the other clinical
uses of this drug?
Salmonella infection
Typhoid fever Salmonella septicemia
Alternative :Ciprofloxacin &3rd generation cephalosporines
Rickettsial infection in children
Topical antimicrobial agent
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Are there adverse reaction ?
Yes
GiT disturbances Direct irritationSuper-infection
BMS
Anemia
Dose dependent
Reversible
Aplastic anemiaRare
Idiosyncratic reactionIrreversible
fatal
Gray Baby syndromeCyanosis
CV collapse
Premature neonatesLess
glucuronyltransferase
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Tetracyclines
Give two examples of
tetracyclines
TetracyclineDoxycycline
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Mechanism of action of
tetracyclines
Bind to 30S ribosomal subunit
Inhibit bacterial proteinsynthesis
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What is the the antibiotic
spectrum of the tetracycline ?
Broad spectrum antibiotic
Gram +ve bacteriaGram-ve bacteria
Chlamydia
MycoplasmaRickettsia
Some protozoa
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How resistance to tetracycline develop?
EffluxActive transport
Tet A
Decrease Entry
Bacterial cell
drug accumulation
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Describe the Absorption of
tetracyclinesThey are adequately absorbed after oral administration
Absorption is impaired bymultivalent cations:1. Ca+2 present in dairy products
2. Iron containing preparation3. Mg +2 and Al+3 containing antacids
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What is the distribution of
tetracyclines?
Can be deposited in growing bone
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Are tetracyclines cross the placenta?
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Describe the clinical uses oftetracyclines?
Chlaymdia infection
Mycoplasma
Pneumonia
Cholera
Rickettsia infection: Rocky mountain spotted fever
What are the other uses of
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What are the other uses oftetracyclines?
Eradication of H.Pylori Antimicrobial therapypeptic ulcer
Prevent of malaria
Treatment of amebiasis Doxycycline
Doxycycline
Treatment of acne Topical or oral
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List the adverse effects of
tetracyclines administration?
Heart burnNausea
Vomiting
NO milk or antacid to relieve heart burn
Alteration in the normal Flora
Oral candidacolitis
C. difficile
Oral
Nystatin OralVancomycin
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List the adverse effects of tetracyclinesadministration
BoneTeeth
Tooth Enemals hypoplasiaIrregularity in the bone growth
Contraindicated in pregnancy
Young children
Discoloration and hypoplasia of the teeth
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List the adverse effects oftetracyclines administration
Hepatoxicity
Pregnant patients
With prexisting hepatic disease
Phototoxicity
Increase skin sensitivity to ultraviolet light
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List the adverse effects of
tetracyclines administration
Dizziness and vertigo
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MacrolidesWhat drugs are included in this
category?
Erythromycin:prototypeAzithromycinClarithromycinTelithromycin
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How do macrolides work?
Inhibit ribosomal protein synthesis
Bind to50S ribosome subunit
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How does resistance to macrolides
develop?Decrease Entry
Bacterial cell
drug accumulationProduction of inactivating E
Pharmacokinetics of macrolides
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AzithromycinClarithromycinErthromycinKinetics
Good( affected by food)
Good
Estolate salt
Good( affected byfood)
Oral absorption
Wide (except CSF)
Highly concentrated
inside macrophages (10-
100times plasmaconcentration)
Wide (except CSF)
Concentrated inside
macrophages
Wide ( except CSF)
Concentrated inside
macrophages
Distribution
Unchanged drug in the
urine
t 1/2=2-4daysOnce daily dosing
Short period of
treatment
Partly metabolized in
the liver & partly
excreted in the urine
> t1/2Twice daily dosing
Metabolized in the
liver & excreted in the
bile
Short t1/2
Elimination
NoInhibit metabolism of theophylline, warfarin
& cyclosprine toxic accumulation
Hepatic
cytochromeP450 inhibition
Pharmacokinetics of macrolides
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Describe the antibacterial
spectrum of macrolides.
Mycoplasma pneumoniae
Chlamydia Species.
Gram +ve cocci Gram +ve bacilli
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What are the clinical indications
of macrolides ?
CorynobacteriumInfection
Mycoplasmapneumonia
Beta lactamase producingstaph.infection in penicillin
allergic patients
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Specific clinical indication for
clarithromycin
A component of drug regimens for ulcers
due to H.pylori
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Specific clinical indication of
azithromycin
A single dose for urogenital infectiondue to Chlamydia
5 days course in
community acquired pneumonia
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Specific indication telithromycin
Used mainly in respiratory tract infection Metabolized in the liver
Given as a single daily dose
It is a Hepatic cytochrome P450 inhibitor
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What are the adverse effects
associated with the macrolides?
Nausea , vomiting and diarrhea
Cholestatic hepatitis
Epigastric distress
Erythromycin estolate
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Clindamycin
How does clindamycin work?
binds to 50S ribosomal subunits
Inhibits bacterial protein synthesis
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What is the antibacterial
spectrum of clindamycin?
Anaerobic bacteria: bacteroids fragilis
Gram positive cocci
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What is the route of
administration for clindamycin ?
Oral
absorption
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What are the pharmacokinetics of
clindamycin
Good penetration into bone
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What are the clinical uses of
clindamycin ?
Severe infection due to anaerobic organisms
Peritonitis :& gentamicin
Staphylococcal bone and joint infections
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What are the side effects ?
Pseudomembranous colitis
Diarrhea
Neutropenia
Skin rashes
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Streptogramins & Linezolid ?
What is their clinical use ?Streptogramins
Used as combination of two drug
Bactericidal
Linezolid
Treatment of infections caused by
VRSA
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Nucleic acid synthesis inhibitors
Rifampin inhibits Bacterial RNA
synthesis
Fluroquinolones inhibits Bacterial
DNA synthesis
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Fluoroquinolones
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What is the mechanism of action of
the fluoroquinolones ?
Inhibiting DNA gyrase & topoisomeraseIV inhibition of replication of Bacterial
DNA
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Antibacterial spectrum & clinical
uses of the fluoroquinolones ?1St generation: NorfloxacinEffective against Gram-ve bacteria used for urinary tract infection
2nd generation: e.g.CiprofloxacinExtended spectrum against Gram-ve bacteria + activity against some
Gram+ve bacteria used for GIT infection
3rd generation: GatifloxacinExtended spectrum against Gram-ve bacteria +Greater activity against
Gram+ve bacteria: used for respiratory tract infection4th generation: Moxifloxacin
Extended spectrum against Gram-ve bacteria + Greater activity againstGram+vebacteria+activity against anaerobes-used for respiratory tract infection
What are the major uses of
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j
fluoroquinolones ?
UTIs
Gram-ve bacteriaE.Coli, Klebisella ,P.aeruginosa
GIT
infections
Gram-ve bacteria
Salmonella, Shigella, campylobacter,E.Coli
Respiratory
tractinfections
Gram+ve &
Gram-ve organisms
Sexually transmittedDiseases
GonorrheaChlamydia infections
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What are the adverse effects of
fluoroquinolones ?
CNSHeadache ,dizziness ,insomania
Seizures
GITNausea ,diarrhea,
abnormal liver functions
Skin Rashes ,photosensitivity
Musculoskeletal TendonitisTendon rupture
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Can fluoroquinolones be used inchildren ?
They cause cartilage erosions
They must not also be used inPregnancy or Nursing mothers
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Metabolic inhibitors
Antifolate Drugs
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What is the biologic role of folic
acid ?
It is essential cofactor in purine , pyramidine,
and amino acid synthesis
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What are the antifolate drugs?
Sulfonamides
Trimethoprim
They are antimetabolites
They have chemical similarity to
endogenous compoundsInterfere with
cellular metabolism
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Sulfonamides
Describe the structure of sulfonamides compound.
Weakly acidic compounds
They have a chemical nucleus resembling PABA
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How do sulfonamides work?
SO2-NHRH2NCOOHH2
N
PteridineDihydropteroate
synthetase
PABA
Dihydrofolic acidDihydrofolate
Reductase
Tetrahydrofolic acid
Purines DNA
Sulphonamides
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How do sulfonamides act ?
Competitive inhibitor
of dihydropteroate synthase
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How does trimethoprim work?
COOHH2N
PteridineDihydropteroate
synthetase
PABA
Dihydrofolic acidDihydrofolate
Reductase
Tetrahydrofolic acid
Purines DNA
Trimethoprim
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Trimethoprim
Describe the structure of trimethoprim.
It resembles dihydrofolic acid
It is a weak base
What is meant by sequential
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What is meant by sequential
blockade ?
COOHH2N
PteridineDihydropteroate
synthetase
PABA
Dihydrofolic acidDihydrofolate
Reductase
Tetrahydrofolic acid
Purines DNA
Sulfonamide
Trimethoprim
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What is co-trimoxazole?
Trimethoprim is most often combined with
sulfmethoxazole to
cause a sequential blockade
of folic acid synthesis
Result in bactericidal and synergistic action
Trimethoprim/sulphamethoxazole ratio is 1/5
What can the trimethoprim
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What can the trimethoprim
/sulfamethoxazole combination drug is
used for ?1. Bacterial prostate infection
2. Complicated UTIs
3. GIT infections : shigellosis and typhoidfever
4. Respiratory tract infection due toH.influenzae and Moraxella catarrhalis
5. Prevention and treatment of pneumocystis carniipneumonia(parasitic infection)
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What toxicities should you watch for
when sulfonamides are prescribed ?
Hypersensitivity reactions
Fever & Skin rashes
Exfoliative dermatitis
Stevens- Jonson syndrome
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What toxicities should you watch for
when sulfonamides are prescribed ?
GIT effects
Nausea ,vomiting and diarrhea
Hematotoxicity
Granulocytopenia
Thrombocytopenia
Aplastic anemia
Acute hemolysis : G-6-P dehydrogenase deficiency
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What toxicities should you watch for
when sulfonamides are prescribed ?
In newborn ,sulfonamides will displace bilirubin fromalbumin
Excess bilirubin penetrates the CNS
Kernicterus
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