Protein Synthesis Inhibitors 2ND 11

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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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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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


synthetase

PABA


Reductase


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


synthetase

PABA


Reductase


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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GIT effects

Nausea ,vomiting and diarrhea

Hematotoxicity

Granulocytopenia

Thrombocytopenia

Aplastic anemia

Acute hemolysis : G-6-P dehydrogenase deficiency


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In newborn ,sulfonamides will displace bilirubin fromalbumin

Excess bilirubin penetrates the CNS

Kernicterus


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Protein Synthesis Inhibitors 2ND 11