Antibiotic Tetracyclines history,classification,mechanism of action and adverse effect

Antibiotic Tetracyclines history,classification,mechanism of action and adverse effect

1. Tetracyclines AMIR SOHAIL

2. Tetracyclines History Chemistry Classification Mechanism of action Spectrum of activity Bacterial Resistance Pharmacokinetics Adverse Effects Clinical uses

3. History: Broad spectrum antibiotics Naturally from soil actinomycetes or prepared semi-synthetically In 1948, first member introduced was chlortetracycline derived from soil actinomycetes streptomyces aureofacens Followed by oxytetracycline .

4. Removal of chlorine atom from chlortetracycline produced semi-synthetic tetracycline introduced in 1952. Semisynthetic are methacycline, doxycycline, rolitetracycline etc. Doxycycline and minocycline are newer tetracyclines with high lipid solubility and longer duration of action.

5. Chemistry The basic tetracycline structure consists of four benzene rings with various constituents on each ring. ( Naphthacenecarboxamide Nucleus) The crystalline bases are faintly yellow, odorless, slightly bitter compounds. They are only slightly soluble in water at pH 7 but they can form soluble sodium and hydrochloride salts .

6. Other Properties: Acidic Hygroscopic In aqueous solution form salts with both acids and bases. Stable as powder, aqueous solutions are not stable Available in injections, bolus, capsules, powder, feed additives, ointments.

7. Classification: Short acting: t1/2= <8 hrs. Oxytetracycline , tetracycline, chlortetracycline Intermediate acting:t1/2= 8-16 hrs. Demeclocycline , methacycline Long acting:t1/2= >16 hrs. Doxycycline , minocycline

8. Mechanism of Action: Inhibit bacterial protein synthesis Two steps 1.Passage into bacterial cell 2. Interaction with bacterial ribosomes . Tetracycline bind to the 30 S ribosomal subunit and prevent the binding/access of aminoacyl t-RNA to acceptor (A) site on the mRNA-ribosome complex.This prevents addition of amino acids to the growing peptide chain resulting in inhibition of protein synthesis.

9. Tetracyclines binds to the 30S ribosomal subunit, thus preventing the binding of aminoacyl-tRNA to the ribosome. aa = amino acid.

10. Antimicrobial Spectrum: Bacteriostatic Broad spectrum Active against mycoplasma , rickettsia , chlamydia , and some protozoa like anaplasma , amoebae etc. Pseudomonas, aeruginosa , proteus , klebsiella , salmonella, staph., corynebacterium are resistant.

11. Typical therapeutic applications of tetracyclines .

12. Microbial resistance: Decrease penetration of drug Increased activity of efflux pumps Enzymatic inactivation of drug Production of proteins by bacteria that protect ribosomes by binding with tetracyclines

13. Pharmacokinetics: Absorption: Minocycline and doxycycline being 100% bio available. All produce varying degree of tissue irritation on parenteral administration.

14. All tetracyclines are adequately but incompletely absorbed from the G.I. tract. The % of an oral dose that is absorbed (when the stomach is empty) is lowest for chlortetracycline (30%) and highest for minocycline (~98-100%). Most absorption takes place from the stomach and upper small intestine (greater in a fasting state).

15. Absorption of tetracyclines is impaired by food in the stomach, milk products, aluminum OH gels, Na+ bicarbonate, Ca++ & Mg++, and Fe++ preparations . Thus milk,antacids or iron salts should be avoided 3 hrs before and after oral administration.

16. After a single oral dose peak plasma concentrations are achieved in 2-4 hours. The mechanisms responsible for decreased absorption appear to be chelation .

17. CSF levels are 10 -20% of the serum levels. Tetracyclines are stored in the reticuloendothelial cells  of liver, spleen, & bone marrow They can cross the placental barrier and can accumulate in fetal bones, thus delaying bone growth. They are also excreted in breast milk. Binding action with Ca++ is the result of dental enamel

18. Effect of antacids and milk on the absorption of tetracyclines .

19. Distribution: Widely distributed in kidneys, liver, lungs, bile, bones. With exception of lipid soluble members like doxycycline and minocycline, tetracyclines do not penetrate the brain and CSF. Cross placenta.

20. They are bound to plasma protein in varying degree. Penetration of these drugs into most tissues and body fluids is excellent. All tetracyclines are concentrated in the liver and excreted by way of the bile into the intestine from which they are partially reabsorbed ( enterohepatic circulation)  

21. Biotransformation: With exception of lipid soluble tetracycline, they are not metabolized to a significant extent in the body

22. Excretion: All the tetracyclines are excreted in the urine and the feaces , the primary route for most being the kidney. The mechanism of renal exertion is glomerular filtration. They will accumulate in the body in patients with depressed renal function; EXCEPT doxycycline -not eliminated via the same pathways as other tetracyclines . Intestinal excretion is the major route of elimination for doxycycline

23. The drug is excreted in the feces, largely as an inactive conjugate.

24. Administration and fate of tetracyclines .

25. Adverse Effects Have relatively low toxicity at normal dosage levels TET can produce a variety of adverse effects ranging from minor inconvenience to life-threatening. Gastrointestinal upsets: All produce GI irritation, mostly after oral administration

26. Anorexia, abdominal pain, diarrhoea , nausea and vomiting may occur

27. Effect on Bones: Deposited in growing teeth and bones due to chelating properties with calcium Form tetracycline-calcium orthophosphate complex which inhibits calcification So permanent discoloration of the teeth. Delay fracture healing

28. Children receiving long-or short term therapy with TET may develop brown discoloration of the teeth. The drug deposits in the teeth and bones probably due to its chelating property and the formation of a TET -calcium orthophosphate complex. Avoid giving to pregnant.

29. Hepato toxicity: Acute hepatic necrosis with fatty changes is common in patients receiving high doses. Nephrotoxicity : Potentially nephrotoxic particularly in renal insufficiency

30. Hypersensitivity reaction: Not common. Skin rashes, urticaria , pruritis , dermatitis etc. Cardio vascular effects: Rapid IV inj. results in hypotension, collapse and sudden death. Due to rapid chelation of blood calcium

31. Other Effects: Cause irritation on parenteral administration Swelling, necrosis, yellow discoloration at inj. site. Drug fever, photoallergic dermatitis etc. Prolong blood coagulation

32. Some adverse effects of tetracycline

33. Contra indications/Precautions : Contra indicated in hepatic insufficiency, renal diseases and in hypersensitive patients.

34. Drug Interactions: Antacids, iron preparations, saline purgatives, kaolin, pectin, sodium bi carbonate decrease absorption of tetracyclines from GI tract. May interfere with bactericidal activity of penicillins, cephalosporins and aminoglycosides.

35. Clinical Uses: Bronchopneumonia UTI Metritis Mastitis Prostatitis Cholangitis etc. Actinomycosis and actinobacillosis also respond to TET. Chlortetracycline used in food producing animals as growth promoters

36. Administration: Oral, Parenteral, Topical, Intramammary All can be given IV or IM