PROTEIN SYNTHESIS

INHIBITORS

Dr. Sadia Kazi

Associate Professor
Department of Pharmacology
Classification
Inhibit 50s Subunit Inhibit 30s Subunit
 Aminoglycosides (gentamicin)
 Macrolides
 Tetracyclines
 Chloramphenicol
 Glycylcyclines
 Clindamycin

 Linezolid

 Streptogramins
Aminoglycosides
 Local
 Systemic
 Streptomycin (for tuberculosis, brucellosis, plague & tularemia)  Neomycin
 Gentamicin
 Tobramycin
 Amikacin

 Natural and semi-synthetic

 Poor oral absorption; no Per Oral forms (highly polar)
 Limited utility
 Very potent antibiotics with serious toxicities
 Bactericidal
 Elimination= 90% in urine (unchanged)
 Crosses placental
 M.O.A
 Aminoglycoside Bind to 30S ribosomal unit irreversibly and interfere
with protein synthesis
 Block formation of initiation complex.

 Cause misreading of mRNA which causes incorporation of incorrect amino acids

into peptide and result in non functional proteins

 Breakup of polysomes into nonfunctional monosomes

 Enters the outer cell membrane via porins through passive diffusion

 They have Both properties are present bacteriostatic & bactericidal

 Bactericidal property is dose dependent

Resistance
1. Efflux pumps
2. Decreased uptake
3. Modification & inactivation by enzyme (Plasmid-mediated formation of inactivating
enzymes Transferases)

Antibacterial spectrum
 Aminoglycosides are effective for majority of aerobic Gram –ve bacilli including multidrug
resistant such as
 Gram-negative bacilli: Kliebsiella, Serratia, Proteus, Pseudomonas, Mycobacteria (TB), N.
gonorrhoeae, tularemia, plague, brucellosis

 Gram positive cocci: Staphylococcus, Group B Streptococcus, viridans

streptococci, Enterococcus

 Often combined with β lactum antibiotics specially for enterococcus faecalis & enterococcus
faecium infective endocarditis
Clinical Uses
 Tuberculosis
 Plague
 Gonorrhea
 Urinary tract infection
 Peritonitis
 Septicaemias
 Meningitis
 Complication of cystic fibrosis
 Visceral leishmaniasis
 Aminoglycosides are not recommended as monotherapy for severe infections, but must be
combined with another agent
 Not effective against anaerobes
 SIDE EFFECTS
Ototoxicity Auditory OR High concentration accumulates in
Vestibular damage endolymph & perilymph

Nephrotoxicity Retention by proximal tubular cells

disrupts calcium mediated transport
necrosis occur

Neuromuscular paralysis Associated with rapid increase in

concentration or concurrent use with
neuromuscular blockers
Allergic reaction Contact dermatitis due to neomycin
reaction
 Tetracyclines
 Tetracycline
 Doxycycline
 Minocycline
 Demeclocycline

Short acting (6- Intermediate acting Long acting (16-

8 hrs): (12hrs): 18 hrs):
 Tetracycline  Demeclocycline  Doxycycline
 Minocycline
 Tetracyclines
 The tetracycline antibiotics are bacteriostatic agents that have a
limited but important role in the armamentarium of antibacterial
agents

 The tetracycline class of antibiotics is a large family of broad spectrum

 The basic structure consists of four fused 6-carbon rings.

 Both Oral & IV routes used

 Distributed throughout (bile, liver, kidney, skin, body fluid)

 Elimination majorly via kidney urine unchanged (Minocycline goes

through hepatic metabolism)
 M.O.A
 Tetracyclines enter bacterial inner cytoplasmic membranes through passive diffusion and partly through
active transport (energy dependant)

 Binds reversibly to 30s sub unit of bacterial ribosome , this action prevents binding of tRNA to messenger
RNA-ribosome complex there by inhibiting bacterial protein synthesis .

Resistance
 Impaired influx or increased efflux by an active transport protein

 Production of proteins that interfere with tetracyclines binding to ribosome

 Enzymatic inactivation.
 Antibacterial spectrum
 They are rarely used because of resistance.
 They are also active against mycoplasma, rickettsia, legionella, spirochetes and chlamydia

Gram positive Gram negatives

 Pneumococcus  Enterobacteriaceae
 Streptococci  Neisseria
 Enterococci  Hemophilus
 Shigella
Clinical Uses
 Drug of choice (First choice)
 Lyme disease
 Rickettsia
 Mycoplasma pneumonia
 Cholera, bacterial gasteroenteritis
 Plague, tuleremia, brucellosis (tetracycline + Aminoglycosides)

 Other uses
 Prophylaxis of protozoal infection
 Gastric and duodenal ulcers due to H.pylori
 STDs except gonococcal infections(resistance)
 Entamoeba histolytica infection
 Plasmodium falciparum
 Acne
 Exacerbation of bronchitis
 Community acquired pneumonia
 Relapsing fever, leptospirosis, non-tuberculosis mycobacteria
 UTI
 Meningococcal infection
 SIDE EFFECTS
G.I.T SIDE EFFECTS
Nausea, vomiting, diarrhea Local irritation

Effect of calcified tissues Tetracyclines binds to calcium deposited

Bone, teeth ,etc in bones and teeth.
Hepatotoxivity Impairs hepatic function specially during
(I/V high doses) pregnancy or pre-existing hepatic failure

Pseudotumor cerebri Benign intracranial hypertension

characterized by headache & blurred
vision may occur

Photosensitization Sensitivity to sunlight to sunlight or UV

light
Vestibular Reaction Dizziness, vertigo, nausea and vomiting
Contraindicated
 Milk
 Antacids
 Ferrous sulfate
 Pregnant women
 Children younger than 8 year (bone+teeth discoloration)
 Renal & hepatic dysfunction
 Macrolides/Ketolides
 Erythromycin (Prototype)
 Clarithromycin
 Telithromycin (Semisynthetic derivatives of Erythromycin)
 Azithromycin (Semisynthetic derivatives of Erythromycin)

 The macrolides are a family of safe, bacteriostatic drugs that are generally used in the treatment of
community acquired infections

 Large 14-16 member lactone ring structure

 Erythromycin choice of drugs in patient with allergy to beta lactam drug

M.O.A
 Bind irreversibly binding to 50s sub unit of bacterial ribosome thus inhibiting
translocation step of protein synthesis Also interferes with other steps such as
transpeptidation

 It is a bacteriostatic drug but at higher doses it is bactericidal.

Resistance
 Reduced permeability of cell membrane
 Presence of efflux pump
 Production of estrases that hydrolyze macrolydes
 Modification of ribosomal binding site
 Antibacterial spectrum
 Macrolides are active against Gram positive bacteria
 Including
 Streptococci
 Pneumococci
 Methicillin sensitive staphylococci.

 The limited Gram negative spectrum includes

 Bordetella
 Campylobacter.

 The macrolides also have activity against

 Mycoplasma,
 Legionella,
 Chlamydia
 Treponemes
 Clinical Uses
 Ear, nose and throat infections
• Otitis media (infection of the middle ear), labyrinthitis (infection of the inner ear), sinusitis (infection of
the sinuses), tonsillitis (infection of the tonsils) and laryngitis (infection of the voice box).

 Chest infections
• Pneumonia (infection of the lining of the lung), bronchitis (infection of the airways of the lung) and
whooping cough.
 Skin infections
• Eczema, psoriasis or acne that has become infected

 Mouth and dental infections

• Gingivitis (infection of the gums) and a tooth abscess (infection in the root of a tooth)

 Sexually transmitted infections

• Chlamydia (Neonatal ocular infection)
Clinical Uses
 Corynaebacterium infection:
• Diphtheria, sepsis

 Community acquired pneumonia

• Pneumococcus, mycoplasma and legionella

 Substitute for penicillin allergy in streptococcal, staphylococcal or pneumococcal infection

 Prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease.

 Mycobacterium avium complex, m.laprae, toxoplasmosis

 Preparation of colonic surgery. Preoperative Erythromycin+neomycin+kanamycin.

 SIDE EFFECTS
GI side effects Smooth muscle contraction by
Anorexia, activating M receptors
nausea, vomiting, diarrhea

Liver toxicity Contraindicated

Acute cholestatic
hepatitis (fever jaundice, impaired
LFT)

Ototoxicity High does of erythromycin

QT prolongation
Contraindicated
They should also be avoided if you have:
 Inherited blood disorder (porphyria)
 Heart rhythm disorder
 Myasthenia gravis
 Should be used with caution if you have a kidney or liver problem
 Pregnancy and breastfeeding (Only erythromycin can be used)

Drug Interactions
 There are no known interactions between macrolide antibiotics and food.

 Macrolide can cause stomach irritation, so try to take them with (or just after) food
or milk. This reduces the likelihood of this side effect.

 There are no known interactions between macrolide antibiotics and alcohol

 Chloramphenicol
 Bacteriostatic as well as bactericidal
 Broad spectrum antibiotic
 It achieves high concentrations following oral administration including in the CSF
 It has activity against agents that cause meningitis including
 Pneumococcus
 Hemophilus
 Neisseria

M.O.A
 Reversibly binds with 50s ribosomal subunit and inhibits peptidyl transferase
reaction of protein synthesis
 Clinical Uses
Bactericidal Bacteriostatic
• Aerobic & anaerobic (G+ve and G-ve
• H.influenzae
organism) Rickettia
• N.meningitidis
• Bacteroids • Serious ricketsial infection:
• Typhus
• Meningococcal meningitis • Rocky mountain spotted fever
• Ocular infection because it penetrates
cornea (not for chlamydial infection)
Resistance
1. Production of acetyl transferase a plasmid-encoded enzyme that inactivates drug
2. Decreased ability to penetrate the organism
3. Ribosomal binding site alteration

SIDE EFFECT

GI disturbances Nausea vomiting & diarrhea

Secondary infection: Vaginal candidiasis

Bone marrow suppression Dose related suppression of

Aplastic anemia RBC production

Gray baby syndrome

Contraindications
 Hypersensitivity

 Do not use oral or topical; not for use in trivial infections or for prophylaxis

 Avoid during breastfeeding

 Serious and fatal blood dyscrasias, including aplastic anemia, hypo plastic anemia,
thrombocytopenia, and granulocytopenia, have occurred after short-term and prolonged therapy.
 Gray baby syndrome
 Gray syndrome has been reported in neonates, premature infants, and infants. It usually appears
after 3 to 4 days of chloramphenicol therapy and manifests as abdominal distension

 High chloramphenicol serum levels (greater than 90 mcg/mL) have been associated with gray
syndrome and large doses have been associated with a rapidly fatal course

 Chloramphenicol is inactivated through liver by conjugation with glucoronidation (addition of

glucorinic acid)

 Infants have lack of glucuronic acid due to immature liver. So the drug accumulates in body
resulting in,

 Poor feeding
 Depressed breathing
 Cardiovascular collapse(gray color)
 Cyanosis (Hence the term Gray baby)
 Death