Tetracycline chloramphenicol-vinay gupta
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The document provides a comprehensive overview of broad spectrum antibiotics, specifically tetracyclines and chloramphenicol, detailing their history, classification, pharmacokinetics, mechanism of action, and therapeutic uses. It discusses the antimicrobial spectrum and resistance mechanisms encountered, as well as therapeutic applications and adverse effects associated with these antibiotics. Additionally, the document highlights precautions for use and specifics about individual drugs within these classes.
Tetracycline chloramphenicol-vinay gupta
- 1. Vinay Gupta Deapartment of Pharmacology UP University of Medical Sciences Saifai, Etawah (UP) BROAD SPECTRUM ANTIBIOTICS TETRACYCLINES CHLORAMPHENICOL
- 2. 1) Introduction & history 2) Classification 3) Pharmacokinetics 4) MOA 5) Resistance TETRACYCLINES 6)Antimicrobial Spectrum 7) Therapeutic Uses 8)Adverse Effects 9)Individual Drugs 10) Precautions
- 3. 1) INTRODUCTION & HISTORY In the 1940’s soil actinomycetes were systematically screened for the elaboration of antimicrobial substances.
- 4. TETRACYCLINES A class of antibiotics named for their nucleus of four (“tetra-”) hydrocarbon rings. All are obtained from soil actinomycetes. Chlortetracycline (1948). Oxytetracycline (1950). Tetracycline (1953).
- 5. Tetracyclines divided into- a) Naturally : • Chlortetracycline • Oxytetracycline • Tetracycline • Demeclocycline b) Semisynthetic : • Doxycycline • Minocycline • Meclocycline • Methacycline
- 6. GROUP-I • Shorter duration (t1/2- 6-10 hr) • Less Potent • Mildly Absorbed • QID/TDS • Renal Excretion Short Acting 2) CLASSIFICATION GROUP-II • Intermediate duration (t1/2-12-16 hr) • Moderately Potent • Moderately Absorbed • BD • Partial Renal Intermediate Acting GROUP-III • Longer duration (t1/2- 18-24 hr) • Highly Potent • Completely Absorbed • OD • Excretion Liver Long Acting
- 7. GROUP I : (Short Acting) • Chlortetracycline • Oxytetracycline • Tetracycline GROUP II : (Intermediate Acting) • Demeclocycline • Methacycline GROUP III : ( Long Acting) • Doxycycline • Minocycline COT – DEME - DOMINO
- 8. 3) PHARMACOKINETICS GROUP-I GROUP-II GROUP-III Short Acting Intermediate Acting Long Acting Intestinal Absorption Moderate Moderate Complete Plasma Protein Binding Low Moderate High Elimination Rapid renal Partial Metabolism Slower Renal Bile & Faeces Alteration of Intestinal Flora High Moderate Least Incidence of Diarrhoea High Moderate Low
- 9. 3) PHARMACOKINETICS Cont. ABSORPTION : Incomplete Intestinal Absorption • Group I & II – Incomplete; Empty Stomach • Chlor TC (30%) • Oxy/ Deme/ Tetra Cycline (60%) • Group III – Complete • Doxy (90%) • Mino (100%)
- 10. • Chelating Property with dairy product & Al+++, Mg++, Ca++, Fe++ & bivalent, trivalent ions. • Food absorption of all TC except Doxy & Minocyclines.
- 11. DISTRIBUTION : • Widely distributed to various body tissues & accumulate in Liver, Spleen, Bone marrow & Teeth • Cross BBB,CSF, Placenta, breast milk. EXCRETION : • TC are partially metabolised & remaining amount is excreted unchanged in URINE (Minocyclines is exception, considerably metabolized in LIVER) Group I & II – Kidney (70-75%) Group III – Bile & Faeces - Enterohepatic Circulation (Doxy)
- 12. 4) Mechanism of Action BACTERIOSTATIC Drug enter in bacteria by - (Gm +Ve) - Active Transport (Cytoplasmic Memb) (Gm-Ve) - Porin channels – Passive diffusion (Cell Memb) Binds to 30s ribosome Inhibits attach of aminoacyl t RNA to “A”site Inhibition of protein synthesis
- 13. • Act by binding to 30 s ribosome of susceptible organism which interferes attachment of aminoacyl t-RNA to (A) acceptor site of m-RNA. • Due to this, the peptide chain fails to grow & thus protein synthesis is inhibited.
- 16. • Why they are not affecting to host ? • TC do not bind to mammalian 40 S or 60 S ribosomal sub unit. • Prokaryotic Ribosomes are 70S; –Large subunit: 50 S • 33 polypeptides, 5S RNA, 23 S RNA –Small subunit: 30 S • 21 polypeptides, 16S RNA • Eukaryotic are 80S Large subunit: 60 S • 50 polypeptides, 5S, 5.8S, and 28S RNA –Small subunit: 40 S • 33 polypeptides, 18S RNA
- 17. Differences in structure between prokaryotic and eukaryotic ribosomes makes antibiotics selectively toxic against bacteria. Carrier involved in Active transport of TCs is absent in host mammalian cells. Thus TCs are selectively toxic to microbes & not to the mammalian host.
- 18. 5) RESISTANCE Decreased AB Influx Increased Efflux by Active Transport (Pumping Out of Drug) Reduced access of drug to the ribosome (ribosome protection proteins) Inactivation of Drug by elaboration of enzymes Cross Resistance
- 20. 6) ANTIMICROBIAL SPECTRUM G +ve Bacilli : • Clostridia • Corynebacteria • B. Anthracis • P. acnes G –ve Bacilli : • V. Cholerae • Brucella • H. ducryi • H. pylori • Y. pestis • Y. enterocolitica G +ve Cocci : • Streptococci • Staphylococci G –ve Cocci : • N. gonococci • N. meningococci
- 21. ANTIMICROBIAL SPECTRUM Cont. Rickettsiae Chlamydiae Mycoplasma Actinomyces Spirochetes Entamoeba Plasmodia
- 22. 7) Therapeutic Uses • (A) As First Choice Drug- Rickettsial Infections (Rocky mountain spotted fever, typhus & Q fever. Chlamydial Infections Mycoplasma infection (M. pneumoniae – atypical pneumonia) Cholera Plague Relapsing fever
- 23. • (B) As Alternative Drug- STD (Gonorrhoea, Syphilis) – Doxy Streptococcal Infection (apart from resistance TC can be used if organism is sensitive) • (C) Resistant- Staphylococcal & meningococcal Salmonella & Shigella infection UTI
- 24. • (D) Other uses- Malaria (as adjuvant in chloroquine resistant P. falciparum - Doxy) Amoebiasis (TC by altering gut flora) Acne vulgaris Leprosy
- 25. 8) ADVERSE EFFECTS GI disturbances Effect on teeth & bones – chelating comp Superinfection: Disturbances in the normal flora Photosenstivity (Demeclo > Doxy > Others) Renal (Doxy is safe while Minocycline are moderately safer than other TCs) Hepatotoxicity – causes jaundice ( Least by Oxy & Tetra) Vestibular Increased intracranial tension Hypersensitivity reactions
- 26. 9) INDIVIDUAL TCs DOXYCYCLINE- (Most commonly used) • Good oral absorption (95 %) • Longer duration of Action (t1/2: 18-20 hr) – OD • Absorption not affected by Food • Can be used by I.V. • Less alteration of Gut flora – Less Diarrhoea • Eliminated in faeces through bile – Safe in Renal Dysfunction. • Dose: 100mg BD for Day-1, then 100 mg OD • Adverse Effect – More Photosensitivity
- 27. MINOCYCLINE Similar to DOXY • Good oral Absorption • Least alteration of Gut flora – Less Diahrroea • Food does not affect Absorption • Long duration of action (t1/2: 18-20 hr) – OD • Can be used I.V. Differ to DOXY • Incidence of Photosensitivity is Less • Attains high C/n in saliva, CSF & Tears • Marked Vestibular side effect (High c/n in CSF) • Can not be used in Renal Dysfunction. • Has additional activity against Leprosy.
- 28. DEMECLOCYCLINE (DEMETHYL CHLORTETRACYCLINE) • Similar to other TCs in uses • Its only TCs used for SIADH (Syndrome of Inappropriate secretion of ADH) • Highest incidence of Photosensitivity OXYTETRACYCLINE • Commonly used earlier • Absorption is incomplete- affected by food • Duration of action is shorter (t1/2: 6-8 hr)- QID/ TDS • Unsafe in both Hepatic & renal Dysfunction
- 29. 10) PRECAUTIONS • None of the TCs are active against – Myccobacterium tuberculosis, Proteus, Pseudomonas, Salmonella, Klebsiella, Viruses & Fungi • All TCs are avoided in children below age of 8 yrs • Avoided in Pregnancy • Phototoxicity is Highest (Demeclo > Doxy) • Vestibular Toxicity – Minocycline • Except Doxy, rest all are unsafe for Kidney • Chloro & Methacycline are no more used.
- 31. Glycylcyclins (TIGECYCLINE ) It is the first member of a new class of synthetic tetracycline analogues (glycyl- cyclines) which are active against most bacteria that have developed resistance to the classical tetracyclines. A derivative of minocycline, and was introduced in 2005 Poorly absorbed from g.i.t; the only route of administration is by slow i.v. infusion. Eliminated mainly in the bile; dose adjustment is not needed in renal insufficiency
- 32. The duration of action is long; elimination t½ is 37–67 hrs Not suitable for urinary tract infection, because only low concentrations are attained in urine. Dose: 100 mg loading dose, followed by 50 mg 12 hourly by i.v. infusion over 30–60 min, for 5– 14 days Not recommended for children and during pregnancy. The most common side effect is nausea and occasionally vomiting. Others are epigastric distress, diarrhoea, skin reactions, photosensitiviy
- 33. MOA is similar to TCs Active against various TCs resistant organism. Even active against Methicillin resistant S. aureus & S. epidermidis Penicillin resistant S. pneumoniae & Vancomycin resistant Enterococci Its not active against Proteus & Pseudomonas similar to other TCs. It should be reserved for the treatment of life threatening resistant infections where other TCs are not effective.
- 34. CHLORAMPHENICOL
- 35. CHLORAMPHENICOL • Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947. • It was soon synthesized chemically and the commercial product now is all synthetic.
- 36. MOA (Cholramphenicol) Attaches to the 50S ribosome near the acceptor (A) site and prevents peptide bond formation between the newly attached aminoacid and the nascent peptide chain. MOA (Tetracyclines) Attachment to the 30S ribosome of aminoacyl- t-RNA to the acceptor (A) site of mRNA- ribosome complex .
- 37. ANTIMICROBIAL SPECTRUM • Broad-spectrum antibiotic, active against nearly the same range of as TCs. • Primarily bacteriostatic, though high c/n exert cidal effect on some bacteria, e.g. H. influenzae and N. meningitidis. • It is more active than TCs against H. influenzae (though some have now developed resistance), B. pertussis, Klebsiella, N. meningitidis. • Like tetracyclines, it is ineffective against Mycobacteria, Pseudomonas, many Proteus, viruses and fungi.
- 38. PHARMACOKINETICS • Completely absorbed after oral ingestion. • 50–60% bound to plasma proteins. • Freely penetrates serous cavities and blood-brain barrier. • CSF concentration is nearly equal to that of unbound drug in plasma. • Crosses placenta and secreted in bile and milk. • Plasma t½ of is 3–5 hours in adults. • Primarily conjugated in Liver and little is excreted unchanged in urine.
- 39. ADVERSE EFFECTS Bone marrow depression Idiosyncratic reaction (rare):- (1: 30,000 to 40,000) Aplastic anaemia, agranulocytosis, thrombocytopenia or pancytopenia unpredictable, but serious, often fatal. Dose dependent- manifested as Anaemia, Leucopoenia, thrombocytopenia – reversible on stopping the drug. (Due to Inhibition of Mammalian Mitochondrial Protein Synthesis)
- 40. • Gray baby syndrome - occurred when high doses (~100 mg/kg) were given prophylactically to neonates, especially premature. • The baby stopped feeding, vomited, became hypotonic and hypothermic, abdomen distended, respiration became irregular • An ashen gray cyanosis developed in many, followed by cardiovascular collapse and death. • Chloramphenicol should be avoided in neonates, and even if given, dose should be - 25 mg/kg/day.
- 41. THERAPEUTIC USES • Clinical use for systemic infections is now highly restricted due to fear of fatal toxicity. • Combined formulation of chloramphenicol with any drug meant for internal use is banned in India. • Cephalosporins (± vancomycin) are presently the first line drugs for empirical therapy of bacterial meningitis. • Second line drug for H. influenzae.
- 42. • Intraocular infections - Given systemically attains high concentration in ocular fluid. It is the preferred drug for endophthalmitis caused by sensitive bacteria. • Topically In conjunctivitis, external ear infections 0.5–5.0% is highly effective. • Topical use on skin or other areas is not recommended because of risk of sensitization.