TETRACYCLINES Broad spectrum antibiotics

SOURCE Streptomyces aureofaciens (Chlortetracycline) Streptomyces rimosus (Oxytetracycline) Tetracycline . . . . . . . . . . . . . Semisynthetic derivative of chlortetracycline Semi synthetic derivatives (All others)

STRUCTURE Tetracycline Consist of four fused rings with a system of double bonds arranged cyclically. Different members differ in substitutions at these rings. They are close congeners of polycyclic Naphthacenecarboxamide.

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Glycyclines New group of tetracycline derivatives. Synthetic analog of tetracyclines Tigecycline

CLASSIFICATION Natural I. Based upon source Chlortetracycline Demeclocycline a mutant strain of Streptomyces aureofaciens Oxytetracycline

b. Semi-synthetic Tetracycline Clomocycline Methacycline Lymecycline Doxycycline Minocycline

Based on Duration of Action. A. Short-acting 6-8 hrs Chlortetracycline Oxytetracycline Tetracycline Clomocycline

B. Intermediate-acting ( 10 – 14 hrs ) Methacycline Demeclocycline Lymecycline C. Long-acting (16 – 18 hrs) Doxycycline Minocycline

PHARMACOKINETICS Oral absorption 30% for chlortetracycline 70% for tetracycline, oxytetracycline, demeclocycline 95-100% for doxycycline and minocycline Absorption is more in fasting state

Tigecycline is administered intravenously no oral absorption. Absorption of drug occurs mainly in upper small intestine and is impaired with Food Divalent cations Ca++, Mg++, Fe++ , Zn++ or Al+++ Dairy products Antacids (Al+++ and Mg++) Multivalent cations Alkaline pH

40-80% bound by serum proteins Distributed widely to tissues (urine and prostate) and body fluids except for cerebrospinal fluid. Minocycline reaches very high concentration in tears and saliva----useful for eradication of meningococcal carrier state Cross the placenta to reach fetus Excreted in breast milk----damage growing bones and teeth.

Undergo enterohepatic circulation

Mechanism of Action Broad-spectrum bacteriostatic antibiotics that inhibit protein synthesis Enter microorganisms in part by passive diffusion through the hydrophilic channels and in part by an energy dependent process of active transport

MOA

MECHANISM OF ACTION I. Tetracyclines inhibit bacterial protein synthesis at ribosomal level as follows:- Bind reversibly to 30 S subunit of the bacterial ribosome . Block binding of aminoacyl tRNA to the acceptor site on mRNA- ribosomal complex. Addition of AA to growing peptide is prevented. Protein synthesis is inhibited. II. Also interfere with oxidative phosphorylation, glucose oxidation, bacterial respiration and cell permeability

MECHANISM OF BACTERIAL RESISTANCE TO TETRACYCLINES Decreased intracellular accumulation of tetracyclines due to either impaired influx or Increased efflux by an active transport protein pump. Interfere with tetracyclines binding to the ribosome by bacterial proteins covering 30 S ribosomal subunits.

Note:- The most important of these is 3. Enzymatic inactivation of tetracyclines. Note:- The most important of these is presence of Bacterial Efflux Pump.

Spectrum of Activity Broad spectrum antibiotic 1. Rickettsiae 2. Chlamydia spp 3. Mycoplasma pneumoniae 4. Ureaplasma 5. Vibrio cholerae 6. Spirochetes 7. Helicobacter pylori Brucella 9. Actinomycetes 10. Streptococci 11. Staphylococci 12. Gonococcus 13. H. influenzae 14. Plasmodium falciparum 15. Meningococci 16. E.histolytica 17. Mycobacterium marinum 18. Coxiella burneti 19. Leptospira 20. Pseudomonas pseudomalii

THERAPEUTIC USES Respiratory Tract Infections: S. pneumoniae, H THERAPEUTIC USES Respiratory Tract Infections: S.pneumoniae, H.influenzae Mycoplasmal infections Primary atypical pneumonia. Skin and soft tissue infections: Methicillin resistant S.aureus Acne Act by inhibiting propionibacteria, reside in sebaceous follicles and metabolize lipids into irritating free fatty acids .

Intra-abdominal infections: Tigecycline has activity against Enterobacteriaceae and gram negative anerobes. GI Infections: Traveler's diarrhea Sexually Transmitted diseases: C. trachomatis, gonococcal urethritis, pelvic inflammatory diseases: endometritis, salpingitis, parametritis or peritonitis. Acute epididymitis in men.

b. Plague, Brucellosis, Tularemia, with Aminoglycosides. 4. Bacillary infections a. Cholera b. Plague, Brucellosis, Tularemia, with Aminoglycosides. Rickettsial Infections: Rocky Mountain spotted fever, recrudescent epidemic typhus , murine typhus and Q-fever. Spirochetal infections Lyme’s disease, Relapsing fever. Protozoal infections Amoebic Dysentery, Falciparum Malaria.

Eradication of Meningococci (Minocycline) From Menigococcal carriers Eradication of Meningococci (Minocycline) From Menigococcal carriers. Eradication of H-pylori in duodenal & Gastric Ulcers along with specific ulcer therapy. Community acquired pneumonia

Inappropriate secretion of ADH. causing ch hyponatraemia Inappropriate secretion of ADH. causing ch hyponatraemia. Demeclocycline produces unresponsiveness to ADH thus correcting hyponatraemia Anthrax : Doxycycline is indicated for prevention or treatment of anthrax. Atypical Mycobacterial infections caused by Mycobacterium marinum.

Acute treatment and for prophylaxis of leptosporiasis, relapsing fever (B.recurrentis) and Lyme disease (B. burgdorferi)

ADVERSE EFFECTS Effect on Bony structures & teeth (calcified tissues) Deposition in growing / newly formed bones or teeth, when given in pregnancy ,lactation or children below 8 yrs. Fluorescence, Discoloration of teeth (yellowish changing into permanent brownish discoloration & Enamel dysplasia, inhibition of primary dentition, pitting, caries and malformation of cusps / crowns. Deformity / Growth inhibition of Bones

2. GIT adverse effects a. Due to irritation: Epigastric burning and distress, Nausea ,vomiting , Anorexia & Diarrhea. b. Due to Superinfection (by proteus, pseudomonas, enterrococci, candida spp, C. difficle) C. difficle Pseudomembranous enterocolitis leading to malabsorption and vitamins deficiency; treated by Vancomycin 250mg 6 hourly orally or Metronidazole 200-400mg TDS

Hepatic toxicity With large doses or small doses during pregnancy given I/V Oxytetracycline and tetracycline are least hepatotoxic Renal toxicity Tetracyclines may aggravate azotemia in patients with renal disease.

Local tissue toxicity. Photosensitivity with Demeclocycline Vestibular reactions with Minocycline (dizzziness, ataxia, nausea and vomitting) Pseudotumor cerebri (increase intracranial pressure in young infants) Thrombophlebitis. Decreased protein synthesis with high doses (anti-anabolic effect) resulting in renal damage.

Disturbance of bone marrow with long – term therapy, causing leucocytosis, atypical lymphocytes and thrombocytopenic purpura Fanconi-like syndrome (nausea, vomiting, polyuria, polydipsia, proteinuria, acidosis, glycosuria and aminoaciduria).