DR. M.

OWAIS ISMAIL
DEPARTMENT OF PHARMACOLOGY & THERAPEUTICS

ZIAUDDIN UNIVERSITY
 ANTIMCROBIALS
Protein Synthesis inhibitors in Bacteria

Target is bacterial ribosome

Attached to 30s or 50s unit
Interferes with translation
Bacteriostatic except aminoglycosides
PROTEIN
SYNTHESIS
PROTEIN SYNTHESIS
Protein Synthesis

√ Blockade of initiation.
√ Blockade of further Translation
√ Incorporation of incorrect amino acids
 Inhibitors
of
Protein Synthesis in Bacteria

Aminoglycosides (30S)
Tetracyclines (30S)

Chloramphenicol (50S)
Macrolides (50S)
Clindamycin (50S)
Streptogramins (50S)
 ANTIMCROBIALS
Protein Synthesis inhibitors in Bacteria

Target is bacterial ribosome

Attached to 30s unit
Interferes with translation
Bacteriostatic
antibiotics with similar structure and activity.

1948, Chlortetracycline ------ Streptomyces aureofasciens

1950 Oxytetracycline ----------- Stretomyceus rimosus.

Chlortetracycline is
Dehalogenated to give Tetracycline
Demethylated to give demeclocycline.

OTHER SYNTHETIC TETRACYCLINES

Doxycycline,
Minocycline
Methacyclines.
 CLASS. Half life

Short acting.
Chlortetracycline 6-8 hrs
Tetracycline, Oxytetracycline

Intermediate acting 12 hrs

Demeclocycline, Methacycline

Long Acting
Doxycycline, Minocycline 16-18 hrs
MOA

Bind to 30s ribosomal subunit, blocking binding

of aminoacyl tRNA to the acceptor site

Addition of amino acids to the growing

peptide is prevented.
Properties

Bacteriostatic
Crystalline amphoteric
Low water solubility

Transport
passive diffusion
Oxygen dependent process
RESISTANCE
Natural
Transport system crucial Oxygen dependent

Induced
Acquired resistance Plasmid borne  I/C
concentration due to  influx or ↑ efflux.

Enzymatic inactivation

Impaired entry
Alteration in the porins

proteins production
interfere with the binding of drugs to target site.
PK profile Chlortetracycline
30%

Tetracycline, Oxy, 60-70%

ORAL ABSORPTION. Demeclocycline and
A portion remains in the gut Methacycline
modifying the gut flora.
95-
Doxycycline 100%
Absorption is impaired by Minocycline

-Food, - Dairy products and Antacids

-Divalent ions Ca++, Mg++,

Fe++ and Al+++.

-Alkaline pH.
PK profile

Protein binding is 40-80%

Distributed to all tissues and body fluids except CSF

Cross placenta and excreted in Milk

Minocycline secreted in saliva and tears.

Excreted in Bile (Recycled) and Urine 10-50%.

Upto 40% excreted in feces.

Doxycyline is not renally eliminated. No dosage

adjustment is necessary in renal failure.
Narrow MARGIN OF SAFETY

Effects
Bones and teeth
Liver
Kidney
Ear

Not used as first line drug usually

SPECTRUM

Broad spectrum bacteriostatic

g +ve, g-ve
Mycoplasma,
Chlymidiae,
Ricketsia.
Helicobacter Pylori.
Vibrio cholera.
Brucella
Entamoeba,
Plasmodium falciparum.
 THERAPEUTIC USES
Infections commonly indicated
Skin and soft tissue (Acne, wound infections),
GIT (AGE)
RTI (Pneumonia)
UTI
Non tuberculous M.B infections
STD
Plague, Tuleremia
 Malaria
Amebiasis
ADVERSE REACTIONS (NUMEROUS)

HYPERSENSITY REACTIONS.
G.I.T.
 NVD,
 Modify flora: anal pruritis, candidiases,
 Pseudomembranous enteroclitis with
shock and death
 Discolor teeth in children,
 Phototoxicity,
 Vestibular toxicity (minocycline)
 Renal toxicity
 Hepatic toxicity
 MACROLIDES
Target is bacterial ribosome

Attached to 50s unit

Interferes with translation

Bacteriostatic usually

Bactericidal at high conc.

Erythromycin
Clarithromycin
Ezithromycin
Roxithromycin
Telithromycin (ketolide)

Clarithro and Ezithro are synthetic

derivative of Erythromycin
MACROLIDES
So named because they contain a many-membered lactone
ring to which are attached one or more deoxy sugars
MOA
Bind to 50s ribosomal subunit, blocking
transfer of amino acid from incoming
charged tRNA to the acceptor site
inhibiting translocation of peptidyl-
tRNA

Block of initiation complex

Properties
Bacteriostatic, Have lactone ring

Poor water solubility

More active in alkaline pH

good absorbed from small intestine;

well distribute to body tissues

poor penetration in CNS

can cross the placenta

Destroyed by gastric acid

First-pass metabolism reduces bioavailability

Drug food interactions Food delays

absorption.

Oral and IV

small amount excreted in urine

Ezithromycin better absorption on empty

stomach
RESISTANCE

• Reduced cellular permeability or enhancement of

efflux

2. Production of enzymes that hydrolyze macrolides

(Estrases) Enterobacteriaceae

3. Change in ribosomal binding site properties.

PK profile

ABSORPTION small intestine;

Inactivated by gastric acids

Food delays absorption.

Oral or I/V.

Clarithromycin is absorbed rapidly from the GIT

First-pass metabolism reduces bioavailability to 50% - 55%.

Distributes widely to body tissues, except CSF.

PK profile

Distributes widely to all tissues, except CSF and ear

Significant concentrations in breast milk(50% of serum).

Cross the placental barrier, ( 5% to 20%).

Protein binding is approximately 70% to 90%.

ELIMINATION.

ORAL: 2% to 5% excreted in active form in the urine;

I/V : 12% to 15% _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _

Concentrated in the liver and appears in active form in bile.

The plasma elimination half-life of erythromycin is 1.6 hours

Clarithromycin also is eliminated by renal and nonrenal

mechanisms, metabolized in the liver to several metabolites,
the 14-hydroxy metabolite being the most significant because
of the amount produced and its important biological activity.

The exact biodisposition of azithromycin still is under study.

EXCRETION

Erythromycin
Hepatic metabolism (CYP3A)
Some biliary secretion

Azithromycin
Feces as unchanged drug
Prolonged half-life (68 hrs)
Given for only 5 days

Clarithromycin
Unchanged in urine (30%) and feces
SPECTRUM & CLINICAL
USES:
Mycoplasma pneumoniae.
Legionnaires' Disease. G +ve
Chlamydia Infections G -ve
Diphtheria.
Pertussis.
Streptococcal Infections.
Staphylococcal Infections.
Campylobacter Infections.
Tetanus.
Syphilis.
Gonorrhea.
Atypical Mycobacterial Infections.
Toxoplasmosis
H. pylori infection
UNTOWARD EFFECTS.
1.ALLERGIC REACTIONS
Fever,
Eosinophilia,
Skin eruptions,
Cholestatic hepatitis (hypersensitivity to
estolate)
2.G.I.T
Epigastric distress
Abdominal cramps,
Nausea, vomiting, and diarrhea.

3. Intravenous infusion may result on thrombophlebitis

4. C.V.S:
Cardiac arrythmias,
5.Transient auditory impairment.
DRUG INTERACTIONS.
Inhibits cytochrome P450-mediated metabolism
Potentiates the effect of following drugs

ASTEMIZOLE,
CARBAMAZAPINE,
CORTICOSTEROIDS,
CYCLOSPORINE,
DIGOXIN,
ERGOT ALKALOIDS,
TERFENADINE,
THEOPHYLLINE,
TRIAZOLAM,
VALPROATE,
WARFARIN,
Rx
Erythromycin 500 mg * PO * TID ( 5 days)
Simvaststin 10 mg * PO * OD
Rx
Clarithromycin 250 mg * PO * BID ( 7 days)
Theophylline 225 mg * PO * OD
 ANTIMCROBIALS
Protein Synthesis inhibitors in Bacteria

Target is bacterial ribosome

Attached to 50s unit
Interferes with translation
Bacteriostatic
MOA (same as erythro)

Bind to 50s ribosomal subunit,

blocking transfer of amino acid from
incoming charged tRNA to the
acceptor site

Block of initiation complex

Chlorine substitutive derivative of licomycin
Obtained from streptomyces
Lincomycin--- toxic --- no longer used
 RESISTANCE

Mutation of ribosomal receptor site

Enzymatic inactivation

Altered structure of ribosome

PK profile

Dose = 10 - 20mg/kg/d
90% protein bound
½ life = 2.5 hrs
Widely distributed to all body tissues
given oral or IV
Less absorption from GIT
Dosage = TID
Level achieved in most tissues are high
Metabolized in liver
Accumulated in liver and kidney
excreted via urine and bile
Can cross placenta
SPECTRUM

BROAD SPECTRUM
BACTERIOSTATIC
AEORBIC AND ANAEROBIC ORGANISMS
Strepto
Staph
Enterococci
Bacteroide fragilis
Cl. defficile
ADVERSE EFFECTS

NVD
Skin rash
Nephrotoxicity
Hepatotoxicity
Neutropenia
Psoudomembranous colitis