TETRACYCLINES

Dr. Johan PandianAssistant professor, Department of Pharmacology, MGMCRI

• Tetracyclines are broad spectrum bacteriostatic

antibiotics that inhibit protein

synthesis.• They are active against many gram-positive and gram negative bacteria

including anaerobes, Rickettsiae, Chlamydiae,

Mycoplasmas and L forms.

Mechanism of action:

Tetracyclines enter cells in part by passive diffusion and in part by active transport.

They bind irreversibly to 30S subunit of bacterial ribosome,

blocking the binding of aminoacyl tRNA to the acceptor site on mRNA

Prevents addition of amino acids. Thus protein synthesis

is inhibited.

Tetracyclines

Short acting (half life 6-8 hrs)

*Tetracycline*Chlortetracycline*Oxytetracycline

Intermediate acting (12 hrs)

*Demeclocycline*Methacycline

Long acting (16 hrs or more)

*Doxycycline*Minocycline*Tigecycline

Classification

Pharmacokinetics:

O Absorption after oral administration is approximately

O 30% for ChlortetracyclineO 60% for tetracycline, oxytetracycline,

demeclocycline and Methocycline.O 95-100% for doxycycline and minocycline.

O Absorption is impaired by food, dairy products and antacids.

O Tetracyclines are 40-80% bound by serum proteins.

O They can cross the placental barrier and are also excreted in milk.

O Carbamazepine, phenytoin, barbiturates and chronic alcohol ingestion shorten the half life.

O Tetracyclines are mainly excreted in bile and urine.

O Some of the drug excreted in bile is reabsorbed from the intestine and may contribute to the maintenance of serum levels.

O 10-50% is excreted in urine by glomerular filtration.

O 10-40% is excreted in feces.O The almost complete absorption and slow

excretion of doxycycline and minocycline alow for single daily dosage.

Clinical uses:O Tetracyclines are the drug of choice in infections

with,O Mycoplasma pneumoniaeO ChlamydiaeO Rickettsiae

O Used in combination regimens to treat gastric and duodenal ulcers caused by H.pylori.

O They are used in combination with aminoglycosides to treat plague, tularemia and brucellosis.

O Other uses include in the treatment of acne, exacerbations of bronchitis, community acquired pneumonia, Lyme disease, relapsing fever, leptospirosis and some atypical mycobacterial infections (eg. Mycobacterium marinum)

O Minocycline: 200mg orally for 5 days, can eradicate the meningococcal carrier state. In resistant cases Rifampin is preferred

O Demeclocycline: Inhibits action of anti diuretic hormone in renal tubules and has been used in the treatment of excess secretion of ADH.

O Tigecycline: Very broad spectrum. Formulated for IV administration only. Given as 100mg loading dose, then 50 mg every 12 hours. Active against S.aureus including methicillin resistant, vancomycin-intermediate and vancomycin-resistant strains, streptococci, Enterobacteriae, rickettsiae, chlamydia and legionella.

Adverse Reactions:O Gastrointestinal effects: Nausea, vomiting,

anorexia and diarrhea. They modify normal flora, with suppression of susceptible coliform organisms and overgrowth of pseudomonas, proteus, staphylococci, clostridia and candida. This can result in pruritis, vaginal or oral candidiasis, enterocolitis and in certain cases shock and death.

O Bony structures and teeth: Readily bind to calcium in newly formed bone or teeth in young children leadin to discolouration, enamel dysplasia and fluoresence.

O Liver toxicity: Hepatic necrosis has been reported with daily doses of 4g or more intravenously.

O Kidney toxicity: Renal tubular acidosis and other injury resulting in nitrogen retention.

O Local tissue toxicity: Intravenous injections can lead to venous thrombosis. Intramuscular injections produces painful local irritation.

O Photosensitization: Particularly in fair skinned persons.

O Vestibular reactions: Dizziness, nausea, vomiting.

THANK YOU

CHLORAMPHENICOL

INTRODUCTION

Chloramphenicol was initially obtained from streptomyces venezuelae.

It is a yellowish white crystalline solid,aqueous solution is quite stable,stands boiling,but needs protection from light.

It has a nitrobenzene substitution which is probably responsible for the antibacterial activity and its intensely bitter taste

Mechanism of action• Chloramphenicol inhibits bacterial protien

synthesis by interferring with transfer of elongating peptide chain

• It attaches to the 50s ribosome & hinder the access of aminoacyl-tRNA to the acceptor site for amino acid incorporation

• By acting as peptide analogue it prevents the formation of peptide bonds

• At high doses it can inhibit mammalian mitochondrial protein synthesis

Antimicrobial spectrum• Chloramphenicol is highly active against

salmonella including s.typhi • It is more active than tetracyclines against gram –

ve organisms-H.influenza, B.pertussis, klebsiella, N.meningitidis and anaerobes including Bact.fragilis

• It is less active against gram positive cocci- spirochetes, enterobacteria and chlamydia. Entamoeba and plasmodia are not inhibited.

• It is ineffective against mycobacteria, pseudomonas, viruses and fungi.

PHARMACOKINETICS

• Chloramphenicol is rapidly and completely absorbed after oral ingestion

• It is 50%-60% bound.• Metabolized by glucoronide conjugation.• It freely penetrates serous cavities and blood brain

barrier.• It crosses placenta and is secreted in bile and milk.• Excreted through urine.

PREPARATION

• The commonest route of administration of chloramphenicol is oral-as capsules:250-500mg 6 hourly,children25-50mg/kg/day.

• It is available for application to ear/ eye, but topical use at other sites is not recommended.

ADVERSE EFFECTS

• Bone marrow depression- anemia, leukemia, thrombocytopenia.

• Idiosyncratic aplastic anemia.• Hypersensitivity reactions• Irritative effects • Super infections• Gray baby syndrome

INTERACTIONS

Chloramphenicol inhibits metabolism of tolbutamide, chlorpropamide,warfarin, cyclophosphamide and phenytoin

Toxicity can occur if dose adjustments are not done.

Phenobarbitone,phenytoin,rifampin,enhance chloramphenicol metabolism.

USES & INDICATIONS • Never use chloramphenicol for minor infection• Avoid repeated courses • Daily dose not to exceed 2-3g;duration of therapy to

be <2weeks,total dose in a course <28g• Regular blood counts may detect dose-related bone

marrow toxicity• Combined formulation of chloramphenical with any

drug for internal use is banned in India

• Enteric fever

• Pyogenic meningitis

• Anaerobic infections (pelvic infections, brain abscess)

• Intraocular infections (endophthalmitis)

• Urinary tract infections