BROAD SPECTRUM ANTIBIOTICS

TETRACYCLINE&

CHLORAMPHENICOL

DR. MOHAMMED ABDUL RAOFPHARMACOLOGY(D.C.M.S).

STRUCTURE OF TETRACYCLINE

STRUCTURE OF TETRACYCLINE

TETRACYCLINES have a ring structure:FOUR-CYCLIC-ANTHRACYCLIN

Different substitution on ring structure affecting their pharmacokinetics

TETRACYCLINEIt is a BROAD-SPECTRUM ANTIBIOTIC. Obtained from soil actinomycetes.Slightly bitter & weakly water soluble. Discovered by- DR.YELLAPRAGADA SUBBA RAO.TETRACYCLINES have a ring structure: FOUR-CYCLIC-ANTHRACYCLIN Different substitution on ring structure

affecting their pharmacokinetics. Consumption of out-dated Tetracycline –

Fanconi’s syndrome.

CLASSIFICATION OF TETRACYCLINE:

GROUP 1: Shorter Acting (t1/2 =6-10 hours) TETRACYCLINE, CHLORTETRACYCLINE OXYTETRACYCLINE GROUP 2: Intermediate Acting(t1/2=12-13 hours) DEMECLOCYCLINE METHACYCLINE GROUP 3: Long Acting(t1/2=18-20 hours) DOXYCYCLINE MINOCYCLINE

Pharmacodynamics:

Tetracycline's are bacteriostatic. The carrier involved in the active transport of

tetracycline's are absent in the mammalian 60S/40S cellular ribosomal units, hence they cannot damage host but selectively toxic to the microorganisms only.

In Gram positive bacteria's – tetracycline's enter the cytoplasm by an energy-dependent active transport system, once inside the bacterial cell, tetracycline's inhibit the bacterial protein synthesis by binding to their 30S ribosomal subunit and blocking the attachment of t-RNA & m-RNA resulting in the peptide chain growth failure.

In Gram negative bacteria's - tetracycline's enter the outer membrane by passive diffusion through their pore channels.

The tetracycline's (T) bind to the 30S subunit and prevent binding of the incoming charged tRNA unit. Step 1 in protein synthesis.

Pharmacokinetics:Tetracycline's are absorbed from GIT with variable

bioavailability Tetracycline's are widely distributed except C.S.F. cross placental barrier excreted in the milk.Tetracycline's are readily deposited in teeth, bones and

tumours.Dairy products, antacids & iron preparation's impair

tetracycline's absorption either by chelation/altering the gastric PH except doxycycline and minocycline.

Tetracycline induces the action of Phenytoin, Warfarin & Chlorpropamide

Metabolized in the liver, concentrated in bile and excreted in urine.

In renal impairment needs dose adjustment for long acting tetracycline's except Doxycycline.

Anti Microbial spectrum:HIGHLY ACTIVE Rickettsia,

Chlamydia Psittaci, Chlamydia Trachomatis ,Chlamydia Pneumoniae.

HIGHLY EFFICACIOUS

Spirochete's like - Borrelia burgdorferi, Borrelia recurrentis.

HIGHLY SENSITIVE

Atypical pathogen like -Mycoplasma pneumoniae, -Ureaplasma urealyticum. Gram-negative bacilli like – Vibrio Cholerae,Brucella abortus Helicobacter pylori, Yersinia pestis Actinomyces israeli,Francisella tularensis.

RESISTANCE :•Four mechanisms by which an organism develops resistance to tetracycline's-Decreased cell permeability of the drug.Increased drug efflux from bacteria by energy-

dependant process.Initiation of ribosomal protection which results

in decreased affinity for the drug by ribosomes binding sites.

Enzymatic inactivation of the drug.•Almost all gram-positive and gram-negative cocci and gram negative bacilli have become resistant. Some gram positive bacilli are inhibited without clinical benefit.

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CONTRA INDICATIONS:• Renal impairment • Hepatic insufficiency• Pregnancy• Lactation • in Children’s less than 10years of age.• Intraathecial injections should be avoided.

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CLINICAL USES & DOSES:TREATMENT DISEASE CONTROL USES/DOSES

FIRST CHOICE Rocky mountain fever, Typhus fever, Relapsing fever, Psittacosis, Lyme disease, Atypical pneumonia.

Group1:250mg QID oral/ivGroup 2:300mg BID oralGroup 3:100mg BID oral/iv

EFFECTIVE Brucellosis,H.Pylori, Tularaemia,Plague, Bacteraemia,Acne v, Abscesses,Trachoma,Non specific urethritis / cervicitis,Chronic Amoebiasis,Resistant malaria.

Tetracycline in combination with Streptomycin/Bactrim DS/Amoxicillin.

ERADICATION OF CARRIER STATE

Meningococcal, swimming pool granuloma, Anthrax.

Minocycline 100mg BID oral for 5days

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Precautions• During pregnancy and lactation• Avoided in patients on diuretics• Renal/hepatic insufficiency• Avoid preparation beyond expiry date• Do not mix injectable TC with penicillin-

inactivation occurs.• Do not inject tetracycline's Intra-thecally.

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ADVERSE EFFECTS: ROUTE OF ADMINISTRATION

ADVERSE EFFECTS

ORAL ADMINISTRATION Nausea, Vomiting, Epigastric burning, diarrhoea, Stomatitis, Chronic fungal Esophagitis, Inhibit intestinal flora.

I.V. ADMINISTRATION Thrombophlebitis.I.M. ADMINISTRATION Painful local irritationOINTMENTS Painful local irritation & sensitization.CHRONIC ADMINISTRATION

Super infections, Stomatitis, Chronic fungal esophagitis, temporary suppression of bone growth, Staining of teeth, Headache, Pseudotumour cerebri,Vestibular toxicity, Anti-anabolic effects, Minocycline photosensitivity, Hepatotoxicity in pregnancy, Cumulative renal toxicity in impaired renal functions,Demeclocycline induced nephrogenic diabetes insipidus.

CHLORAMPHENICOL

It is a NATURALLY OCCURING BROAD-SPECTRUM ANTIBIOTIC largely bacteriostatic isolated from STREPTOMYCES VENEZUELAE.

It is yellowish white crystalline light-sensitive & intense bitter in taste.

CHLOROMYECTIN posses a NITRO GROUP AS NITROBENZENE MOIETY which is responsible for its anti-bacterial property.

Chloramphenicol is active against a wide range of Gram-negative organisms, Gram positive organisms and serious anaerobic infection.

Chloramphenicol is used topically for treating conjunctivitis and external ear infections.

Chloramphenicol was earlier drug of choice for typhoid fever.

Pharmacodynamics:Chloramphenicol is bacteriostatic in low doses

and bactericidal in high doses. MOA: inhibits bacterial protein synthesis by

binding to the 50S ribosomal subunit. In Gram positive bacteria-enter the cytoplasm

by an energy-dependent active transport system, tetracycline's inhibit the bacterial protein synthesis by binding to 50S ribosomal subunit and blocking the attachment of t-RNA & m-RNA resulting in the peptide chain growth failure.

In Gram negative bacteria’s-enter the outer membrane by passive diffusion through pores.

Chloramphenicol (C) and macrolides (M) bind to the 50S ribosomal subunit and block transpeptidation Step 2 in the bacterial protein synthesis.

Pharmacokinetics :Chloramphenicol on oral administration rapidly

and completely absorbed from GIT. Chloramphenicol widely distributed

throughout the body tissues and fluids including C.S.F.

Crosses placental barriers & also present in breast milk.

Metabolized in the liver by Glucuronyl conjugation, concentrated in bile or excreted in urine.

Plasma half-life is 3-5 hours.Paracetamol increases the bioavailability.Chloramphenicol is a potent enzyme inhibitor,

inhibits the metabolism of morphine, warfarin,..

Anti Microbial spectrum:HIGHLY ACTIVE

Salmonella typhi, Haemophilus influenza, Neisseria meningitides,Streptococcus pneumonia, Penicillin-resistant Bacteroides fragilis.

SENSITIVE Spirochetes',Rickettsia,Mycoplasma,Klebsiella,Chlamydia.

RESISTANCE :Three mechanisms by which a bacteria develops resistance to Chloramphenicol-Decreased cell permeability of the drug.Initiation of ribosomal protection which results

in decreased affinity for the drug by ribosomes binding sites.

Production of R-plasmid as well as chromosomal mediated chloramphenicol acetyltransferase that metabolizes chloramphenicol to an inactive form.

•CONTRA INDICATIONS:•Renal impairment, Hepatic insufficiency, Pregnancy, Neonates, blood forming diseases.

ADVERSE EFFECTS:Chloramphenicol induces bone marrow depression and

aplasia, use is no longer .SEVERE / FATAL

Idiosyncratic Aplastic anaemia –It is unrelated to the dose has a genetic cause. Gray baby syndrome –neonates cannot conjugate chloramphenicol, slow GFR can lead to fatal neonatal toxicity.Super-infection.

REVERSIBLE Dose related bone marrow depression when daily doses exceeds 3-4gram/day for more than 1-2weeks.Recovery after 3-6weeks of Discontinuation of treatment.

IRRITABLE EFFECTS

Nausea, Vomiting, Diarrhoea, Pain on injection.

As an clinician our advice to the patients:

THANK YOU