detailed note on protein synthesis inhibitors

1. Mechanism of Protein synthesis

2. Formation of the Initiation Complex

3. Joining of 50S Ribosomal Subunit

4. Protein Elongation

5. Termination of Translation

6. Aminoglycoside

7. AminoglycosidesAminoglycosides
• Streptomycin – 1944
• Actinomycetes – Streptomyces griseus
• Bactericidal antibiotics
• Interfere with protein synthesis
• Used to treat aerobic Gram –ve bacteria
• Resemble each other in MOA, pharmacokinetic
therapeutic and toxic properties
• Relatively low margin of safety
• Exhibit ototoxicity and nephrotoxicity

8. Aminoglycosides
• Systemic
– Streptomycin
– Gentamicin
– Kanamycin
– Amikacin
– Sisomicin
– Tobramycin
– Netilimicin
• Topical
– Neomycin
– Framycetin

9. Mechanism of action
• Initially they penetrate
bacterial cell wall, to reach
periplasmic space through
porin channels (passive
diffusion)
• Further transport across
cytoplasmic membrane takes
place by active transport by
proton pump; an oxygen-
dependent process

10. Mechanism of Action
• Bind 30S ribosomal
subunits and interfere
the initiation complex
• Induce misreading of
genetic code on mRNA
• Breakup of polysomes
into monosomes

11. Post antibiotic effect
• Aminoglycosides exhibit concentration
dependent killing.
• They also possess significant Post-antibiotic
effect.
• Single daily dosing at least as effective as and
no more toxic than multiple dosing.

12. Mechanism of resistance
• Synthesis of plasmid mediated bacterial
transferase enzyme: Inactivate
aminoglycosides
• ↓ transport into bacterial cytosol
• Deletion/alteration of receptor protein on 30 S
ribosomal unit by mutation: prevents
attachment

13. Antibacterial spectrum
• Primarily against Gm –ve aerobic bacilli
– Proteus, pseudomonas
– E.Coli,enterobacter
– Klebsiella
– Shigella
• Only few Gm +ve cocci:
– staph aureus, strepto viridans
• Not effective against Gm +ve bacilli, Gm-ve
cocci and anaerobes

14. Pharmacokinetics
• Highly polar basic drugs: poor oral BA
• Administered parenterally or applied locally
• Poorly distributed and poorly protein bound
• Do not undergo any significant metabolism
• Nearly all IV dose is excreted unchanged in
urine
• Dose adjustment is needed in renal
insufficiency

15. Pharmacokinetics

16. Clinical uses
• Gram –ve bacillary infection
– Septicaemia, pelvic & abdominal sepsis
• Bacterial endocarditis –
– enterococcal, streptococcal or staphylococcal infection of
heart valves
• Pneumonias, Tuberculosis
• Tularemia
• Plague, Brucellosis
• Topical – Neomycin, Framycetin.
• Infections of conjunctiva or external ear
• To sterilize the bowel of patients who receive
immunosuppressive therapy, before surgery & in
hepatic coma

17. Shared toxicities
• Ototoxicity
– Vestibular damage
– Cochlear damage
• Nephrotoxicity
• Neuromuscular blockade
• Skin rash

18. Ototoxicity
• Impairment of VIII cranial nerve function
• May be irreversible
• Cochlear damage
– Hearing loss and tinnitus
– More with neomycin , amikacin and kanamycin
• Vestibular damage
– Vertigo, ataxia, loss of balance
– More with Streptomycin, gentamycin
• Tobramycin has both types of toxicity
• Netilimycin claimed to have low ototoxicity

19. Nephrotoxicity
• Gentamicin, amikacin and tobramycin are
more toxic than streptomycin
• Responsible for 10-15% of all renal failure
cases
• Reversible if drug promptly discontinued
• ↓ GFR, ↑ sr creatinine
• ↓clearance of antibiotic → ↑ ototoxicity

20. Neuromuscular blockade
• Cause N-M junction blockade by
– Displacing Ca2+
from NM junction
– By blocking post synaptic NM receptors
– Inhibiting Ach release from motor nerve
• Neomycin & streptomycin: more propensity
• Tobramycin least likely to produce it
• Myasthenic weakness ↑by these drugs

21. Streptomycin
• Ribosomal resistance develops fast
• Limited usefulness as single agent
• Plague, tularemia and brucellosis
– In combination with tetracycline
• SABE: due to Streptococcus Viridans & faecalis
– With penicillin but gentamicin preferred
• Reserve first line drug for tuberculosis used
only in combination

22. Chloramphenicol
• An antibiotic produced by Streptomyces
venezuelae, an organism first isolated in
1947 from a soil sample collected in
Venezuela.

23. Mechanism of Action
• Chloramphenicol inhibits protein synthesis in bacteria and,
to a lesser extent, in eukaryotic cells. The drug readily
penetrates bacterial cells, probably by facilitated diffusion.
• Chloramphenicol acts primarily by binding reversibly to the
50 S ribosomal subunit. Although binding of tRNA at the
codon recognition site on the 30 S ribosomal subunit is thus
undisturbed, the drug appears to prevent the binding of the
amino-acid-containing end of the aminoacyl tRNA to the
acceptor site on the 50 S ribosomal subunit. The interaction
between peptidyltransferase and its amino acid substrate
cannot occur, and peptide bond formation is inhibited

25. • Chloramphenicol also can inhibit mitochondrial protein
synthesis in mammalian cells, perhaps because
mitochondrial ribosomes resemble bacterial ribosomes
(both are 70 S) more than they do the 80 S cytoplasmic
ribosomes of mammalian cells.

26. Pharmacokinetics:
• Chloramphenicol is available for oral administration
in two forms: the active drug itself and the inactive
prodrug, chloramphenicol palmitate (which is used to
prepare an oral suspension).
• Hydrolysis of the ester bond of chloramphenicol
palmitate is accomplished rapidly and almost
completely by pancreatic lipases in the duodenum
under normal physiologic conditions.

27. Absorption
• Chloramphenicol then is absorbed from the
gastrointestinal tract
• peak concentrations of 10 to 13 µg/ml occur within 2
to 3 hours after the administration of a 1-g dose.
• In patients with gastrointestinal disease or in
newborns, the bioavailability is greater for
chloramphenicol than for chloramphenicol palmitate,
probably because of the incomplete hydrolysis of the
latter

28. Absorption cont.
• The hydrolysis of chloramphenicol succinate
may be due to esterases of the liver, kidneys,
and lungs.

29. Absorption cont.
• Chloramphenicol succinate itself is rapidly cleared
from plasma by the kidneys.
• This renal clearance of the prodrug may affect the
overall bioavailability of chloramphenicol, because up
to 20% to 30% of the dose may be excreted prior to
hydrolysis.
• Poor renal function in the neonate and other states of
renal insufficiency result in increased plasma
concentrations of chloramphenicol succinate

30. Distribution
• Chloramphenicol is well distributed in all body fluids
and readily reaches therapeutic concentrations in
CSF, where values are approximately 60% of those in
plasma (range, 45% to 99%).
• Chloramphenicol is present in bile, is secreted into
milk, and readily traverses the placental barrier. It also
penetrates into the aqueous humor after
subconjunctival injection.

31. Fate and Excretion
• The half-life of chloramphenicol has been correlated
with plasma bilirubin concentrations.
• About 50% of chloramphenicol is bound to plasma
proteins.
• The half-life of the active drug (4 hours) is not
significantly changed in patients with renal failure
• The major route of elimination of chloramphenicol is
hepatic metabolism to the inactive glucuronide.
• Over a 24-hour period, 75% to 90% of an orally
administered dose is excreted; about 5% to 10% is in
the biologically active form.

32. Adverse effects cont.
Hematologic Toxicity
• The most important adverse effect of
chloramphenicol is on the bone marrow.
• Chloramphenicol affects the hematopoietic
system aplastic anemia, fatal pancytopenia,
• Leukopenia , thrombocytopenia.

33. Reversible bone marrow suppression
• A second, and dose-related, toxic hematologic
effect of chloramphenicol is a common and
predictable (but reversible) erythroid suppression
of the bone marrow.
• probably due to inhibitory action of the drug on
mitochondrial protein synthesis.
• It occurs regularly when plasma concentrations are
25 µg/ml or higher and is observed with the use of
large doses of chloramphenicol, prolonged
treatment, or both.

34. Gray baby syndrome
• Fatal chloramphenicol toxicity may develop in
neonates, especially premature babies, when they
are exposed to excessive doses of the drug.
• The manifestations in the first 24 hours are vomiting,
refusal to suck, irregular and rapid respiration,
abdominal distention, periods of cyanosis, and
passage of loose, green stools. Soon they become
flaccid, turn an ashen-gray color, and become
hypothermic

35. Hypersensitivity Reactions
• Although relatively uncommon, macular or vesicular
skin rashes occur as a result of hypersensitivity to
chloramphenicol.
• Angioedema is a rare complication. Jarisch-
Herxheimer reactions have been observed shortly
after institution of chloramphenicol therapy for
syphilis, brucellosis, and typhoid fever.

36. Therapeutic Uses
• Chloramphenicol has a wide range
activity that includes gram+, gram-,
aerobic and anaerobic bacteria
• Typhoid Fever
• Bacterial Meningitis
• Anaerobic Infections
• Rickettsial Diseases
• Brucellosis

37. Tetracycline

38. CONTENTS
• Introduction
• Classification and there structures
• Mechanism of action
• Structure Activity Relationship
• Spectrum of activity
• Toxicity and uses

39. INTRODUCTION
• Tetracyclines is a group of antibotic that include
tetracycline.
• Tetracyclines are obtained by fermentation from
Streptomyces spp. Or by chemical transformation of
natural products.
• They are derivatives of an octahydro- naphthacene,a
hydrocarbon system that comprises four annulated
six member rings.

40. CLASSIFICATION
TETRACYCLINES
SHORT ACTING:
•Tetracycline
•Oxytetracycline
INTERMEDIATE
ACTING:
•Demeclocycline
•Lymecycline
LONG ACTING:
•Doxycycline
•Minocycline

41. Mechanism of Action
• Tetracyclines are specific inhibitors of
bacterial protein synthesis. They bind to the
30S ribosomal subunit and thereby prevent
the binding of aminoacyl tRNA to the mRNA
ribosome complex.
• Tetracyclines also inhibit protein synthesis in the
host ,but are less likely to reach the concentration
required because eukaryotic cells do not have a
tetracycline uptake mechanism.

43. Spectrum of activity
• Tetracyclines are broad spectrum antibiotics,
active against wide range of Gram-positive
and Gram-negative bacteria, spirochetes,
mycoplasm, rickettsiae, and chalmydiae.

44. Toxicity of tetracycline
• Use of this medication for prolonged or repeated
periods may result in oral thrush or a new yeast
infection (oral or vaginal fungal infection).
• Nausea, vomiting, diarrhea, loss of appetite, mouth
sores, black hairy tongue, sore
throat, dizziness, headache, or rectal discomfort may
occur.
• This antibiotic treats only bacterial infections. It will
not work for viral infections (e.g.,common cold, flu).
Unnecessary use or overuse of any antibiotic can
lead to its decreased effectiveness.

45. Uses of tetracycline
• Tetracycline is used to treat a wide variety of
infections, including acne. It is an antibiotic
that works by stopping the growth of bacteria.
– Used in treatment of infections like septicemia,
endocarditis , meningitis.

46. Macrolides

48. • Belong to the Polypetide class of naturalBelong to the Polypetide class of natural
products.products.
• A group of antibiotics consisting of aA group of antibiotics consisting of a
macrolide ringmacrolide ring
• A large lactone ring to which one or more deoxy sugars,A large lactone ring to which one or more deoxy sugars,
are attached.are attached.
• The lactone ring can be either 14, 15 or 16 memberedThe lactone ring can be either 14, 15 or 16 membered.

49. • Naturally-occurring macrolide derived fromNaturally-occurring macrolide derived from
Streptomyces erythreusStreptomyces erythreus
• Problems with erythromycinProblems with erythromycin
• Acid labileAcid labile
• Narrow spectrumNarrow spectrum
• Poor GI tolerancePoor GI tolerance
• Short elimination half-lifeShort elimination half-life

50. Structural derivatives
Clarithromycin and AzithromycinClarithromycin and Azithromycin
• Broader spectrum of activityBroader spectrum of activity
• Improved PK properties –Improved PK properties –
» Better bioavailabilityBetter bioavailability
» Better tissue penetrationBetter tissue penetration
» Prolonged half-livesProlonged half-lives
• Improved tolerabilityImproved tolerability

51. • Inhibits protein synthesis by reversibly binding toInhibits protein synthesis by reversibly binding to
thethe 50S50S ribosomal subunitribosomal subunit
– Suppression of RNA-dependent protein synthesisSuppression of RNA-dependent protein synthesis
byby inhibition of translocation of mRNAinhibition of translocation of mRNA
• TypicallyTypically bacteriostaticbacteriostatic activityactivity
• BactericidalBactericidal at high concentrations against veryat high concentrations against very
susceptible organismssusceptible organisms

53. Gram-Positive AerobesGram-Positive Aerobes ::
Erythromycin & clarithromycin display the best activityErythromycin & clarithromycin display the best activity
(Clarithro>Erythro>Azithro)(Clarithro>Erythro>Azithro)
• Methicillin-susceptibleMethicillin-susceptible Staphylococcus aureusStaphylococcus aureus
• Streptococcus pneumoniaeStreptococcus pneumoniae –resistance is developing–resistance is developing
• Group and viridans streptococciGroup and viridans streptococci
• Bacillus spBacillus sp..
• Corynebacterium sp.Corynebacterium sp.

54. Gram-Negative AerobesGram-Negative Aerobes – Newer macrolides with– Newer macrolides with
enhanced activityenhanced activity
(Azithro>Clarithro>Erythro)(Azithro>Clarithro>Erythro)
• H. influenzae (not erythro),H. influenzae (not erythro),
• M. catarrhalis,M. catarrhalis,
• Neisseria sp.Neisseria sp.
• Do NOT have activity against anyDo NOT have activity against any EnterobacteriaceaeEnterobacteriaceae

55. Macrolide Spectrum of Activity
AnaerobesAnaerobes – Upper airway anaerobes– Upper airway anaerobes
Atypical BacteriaAtypical Bacteria – All have excellent activity– All have excellent activity
• Legionella pneumophila - DOCLegionella pneumophila - DOC
• Chlamydia sp.Chlamydia sp.
• Mycoplasma sp.Mycoplasma sp.
• UreaplasmaUreaplasma

56. Macrolide Spectrum of Activity
Other Bacteria –
• Mycobacterium aviumMycobacterium avium complexcomplex
(MAC – only A and C),(MAC – only A and C),
• Treponema pallidum,Treponema pallidum,
• CampylobacterCampylobacter
• Borrelia, BordetellaBorrelia, Bordetella
• BrucellaBrucella
• PasteurellaPasteurella

57. AbsorptionAbsorption
ErythromycinErythromycin – variable absorption, food may– variable absorption, food may
decrease the absorptiondecrease the absorption
– Base: destroyed by gastric acid; enteric coatedBase: destroyed by gastric acid; enteric coated
– Esters and ester salts: more acid stableEsters and ester salts: more acid stable
ClarithromycinClarithromycin – acid stable and well-absorbed– acid stable and well-absorbed
regardless of presence of foodregardless of presence of food
AzithromycinAzithromycin –acid stable; food decreases absorption–acid stable; food decreases absorption
of capsulesof capsules

58. DistributionDistribution
 Extensive tissue and cellular distributionExtensive tissue and cellular distribution
 clarithromycin and azithromycin withclarithromycin and azithromycin with
extensiveextensive penetrationpenetration
 Minimal CSF penetrationMinimal CSF penetration

60. – Gastrointestinal – up to 33 %
Nausea, vomiting, diarrhea, dyspepsia
Gastic pain, cramps
Most common with erythro; less with new agents
– Cholestatic hepatitis - rare
 > 1 to 2 weeks of erythromycin estolate
– Thrombophlebitis – IV Erythro and Azithro
Dilution of dose; slow administration
– Other: Ototoxicity (high dose erythro );
QTc prolongation;
Allergy

61. Erythromycin and Clarithromycin ONLY– are
inhibitors of cytochrome p450 system in the
liver; may increase concentrations of:
Theophylline Digoxin, Disopyramide
Carbamazepine Valproic acid
Cyclosporine Terfenadine, Astemizole
Phenytoin Cisapride
Warfarin Ergot alkaloids

62. • ENT infections , Tonsillitis, URTIENT infections , Tonsillitis, URTI
• Mycoplasma pneumonie infectionsMycoplasma pneumonie infections
• Legionnaires DiseaseLegionnaires Disease
• Chlamydial infections (any macrolides)Chlamydial infections (any macrolides)
• Diphtheria (erythromycin)Diphtheria (erythromycin)
• Pertussis (erythromycin)Pertussis (erythromycin)

63. • Strep/Staph Infections; alternatives in patientsStrep/Staph Infections; alternatives in patients
allergic to Penicillinallergic to Penicillin
• Prophylaxis against endocarditis in dentalProphylaxis against endocarditis in dental
proceduresprocedures
• Campylobacter/ Helicobacter Infections :Campylobacter/ Helicobacter Infections :clarithroclarithro
• Tetanus: in patients allergic to PenicillinTetanus: in patients allergic to Penicillin
• Mycobacterial Infections:Mycobacterial Infections: Clathri / AzithroClathri / Azithro Ist choiceIst choice

64. “Drug of Choice” for
 Mycoplasma pneumoniae
Legionella pneumophila
 Chlamydia pneumoniae, C. trachomatis
Bordetella pertussis (whooping cough)
C. diphtheriae
Esters of erythromycinEsters of erythromycin -sterate/estolate/ethylsuccinate are
resistant to inactivation.