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TETRACYCLINES &TETRACYCLINES &
CHLORAMPHENICOLCHLORAMPHENICOL
Dr.Arun Sharma
Dept. of Pharmacology
SLIMS, Puducherry
1
TETRACYCLINESTETRACYCLINES
2
 Introduction
 Classification
 Mechanism of action (MOA)
 Spectrum of Action
 Resistance...
IntroductionIntroduction
Tetracyclines : Class of antibiotics having a
nucleus of 4 cyclic rings.
Broad spectrum antibio...
All tetracyclines have practically the same
antimicrobial activity.
Different substitution on cyclic rings affects
indiv...
ClassificationClassification
TETRACYCLINES
SHORT ACTING:
•Tetracycline
•Oxytetracycline
INTERMEDIATE
ACTING:
•Demeclocycli...
Mechanism of ActionMechanism of Action
They are mainly bacteriostatic.
Act by binding to 30 S ribosome of
susceptible or...
Carrier involved in the active transport of
tetracyclines is absent in host mammalian
cells.
They also do not bind to ma...
Spectrum of ActionSpectrum of Action
They were originally designated “broad
spectrum” antibiotic.
Promiscuous use has li...
Atypical pathogens like M. pneumoniae and U.
urealyticum are also very sensitive.
Some selctive G –ve bacilli (V. Choler...
Entamoeba and Plasmodia inhibited at
higher concentrations(hence used as
adjuvant drugs).
Strep. pyogenes, S. aureus (in...
ResistanceResistance
Develops by 4 main mechanisms:
1. ↓ cell permeability of drug
2. ↑ drug efflux from bacterial cell (...
PharmacokineticsPharmacokinetics
Variably absorbed from the GIT .
Food ↓ absorption of all tetracyclines except
doxycycl...
Tetracyclines are widely distributed in
body tissue and fluids except CSF.
Concentrated in liver, spleen and
connective ...
Doxycycline and Minocycline are primarily
excreted through bile.
So, they can be given safely in renal
impairment withou...
AdministrationAdministration
Most commonly administered in oral
capsule form.
Should be taken1/2 hr before or 2 hr after...
Drug InteractionsDrug Interactions
Antacids and iron preparations decrease
absorption by chelation.
Enzyme inducers (bar...
Adverse effectsAdverse effects
Oral administration can cause N,V,D epigastric
burning, stomatitis. Chronic use can cause
...
Except doxycycline & minocycline, others
are occasionally nephrotoxic on long use.
Renal toxicity (Fanconi’s syndrome)
o...
Tetracyclines reduce protein synthesis
(antianabolic) and can increase blood urea.
Minocycline can cause vestibular toxi...
Tetracyclines frequently cause
superinfection due to suppression of
resident flora.
Intestinal Candida albicans infectio...
Uses of TetracyclinesUses of Tetracyclines
Should be used only in those cases where
more selective agent not available.
...
(B) As First Choice Drugs:
Venereal diseases like Chlamydial non-specific
urethritis, Lymphogranuloma venereum and
Granul...
(C) Second Choice Drugs:
To penincillin for anthrax, tetanus, Listeria
and Leptospirosis
Ceftriaxone/azithromycin for go...
(D) Miscellaneous Other Uses:
UTI where organism tests sensitive.
Community acquired pneumonia where a more
selective ag...
DOXYCYCLINE:
Has long t1/2 and lacks nephrotoxicity,
popular in pts. with pre-existing renal
disease.
It can also be giv...
DEMELOCYCLINE:
Has been used in treatment of SIADH.
MINOCYCLINE: (Most potent member)
Used to eradicate meningococcal ca...
Precautions and ContraindicationsPrecautions and Contraindications
CI in pregnancy, lactation, infants and
children < 10 ...
GLYCYLCYCLINES: TigecyclineGLYCYLCYCLINES: Tigecycline
Minocycline analogue approved in 2005.
Active against most bacter...
Active against MRSA, VRE, multidrug
resistant S. pneumoniae, most
Enterobateriaceae, N.gonorrhoeae and M.
catarrhalis.
A...
Eliminated through bile so dose
adjustments not needed in renal conditions
Not metabolized by Cytochrome P450 so
drug in...
CHLORAMPHENICOLCHLORAMPHENICOL
31
 Introduction
 Mechanism of action (MOA)
 Spectrum of Action
 Resistance
 Clinical ...
Chloramphenicol : IntroductionChloramphenicol : Introduction
Chloramphenicol / Chloromycetin is a
broad spectrum antibiot...
Mechanism of ActionMechanism of Action
Inhibits protein synthesis by binding to 50 S
ribosomal subunit of the microbe.
A...
Antimicrobial SpectrumAntimicrobial Spectrum
Broad spectrum antibiotic like tetracyclines.
Active against S. typhi, H. i...
ResistanceResistance
Resistance occurs due to indiscriminate use and
on a graded manner, like tetracyclines.
Resistance ...
ResistanceResistance
Partial cross resistance noted between
chloramphenicol and erythromycin/clindamycin
as all of them b...
Clinical PharmacokineticsClinical Pharmacokinetics
Rapidly & completely absorbed after oral
ingestion.
Crosses placenta ...
Adverse effectsAdverse effects
1) Dose related Bone marrow depression: Of all
drugs, chloramphenicol is m. imp. Cause of a...
Hepatic/ renal insufficiency predispose to this
type of toxicity. Periodic blood counts advised.
2) Idiosyncratic Aplasti...
3) Gray Baby Syndrome:
Neonates lack ability to conjugate
chloramphenicol via glucoronidation.
High levels of chloramphe...
4) Hypersensitivity reactions:
Rashes, fever, atrophic glossitis, angioedema
5) Irritation:
N,V,D & pain on injection
6)...
Uses of TetracyclinesUses of Tetracyclines
1) Since effective CSF levels are obtained, it
is preferred for meningitis due ...
2) Chloramphenicol was drug of choice for
typhoid (enteric fever) till 1980s until
resistant strains emerged globally.
• B...
3) Can be used in serious anaerobic
infections (wound infections, pelvic and
brain abscess) caused by penicillin resistant...
4) Also used topically for treating Ocular
(conjunctivitis, 0.5-5%) and external ear
infections.
• Systemically given, it ...
5) Miscellaneous uses as 2nd
choice drug:
 To tetracyclines in brucellosis and rickettsial
infections, especially in youn...
Drug InteractionsDrug Interactions
 Paracetamol enhances bioavailability of
Chloramphenicol by 28%.
 Chlorampenicol is a...
THANK YOU !!THANK YOU !!
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Tetracyclin and chloramphenicol: Pharmacology, Mechanism of Action & Uses

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Pharmacology of tetracyclines and chloramphenicol including mechanism of actions, uses and adverse effects.

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Tetracyclin and chloramphenicol: Pharmacology, Mechanism of Action & Uses

  1. 1. TETRACYCLINES &TETRACYCLINES & CHLORAMPHENICOLCHLORAMPHENICOL Dr.Arun Sharma Dept. of Pharmacology SLIMS, Puducherry 1
  2. 2. TETRACYCLINESTETRACYCLINES 2  Introduction  Classification  Mechanism of action (MOA)  Spectrum of Action  Resistance  Clinical Pharmacokinetics  Administration  Drug Interactions  Adverse effects  Uses  Contraindications & Precautions
  3. 3. IntroductionIntroduction Tetracyclines : Class of antibiotics having a nucleus of 4 cyclic rings. Broad spectrum antibiotics whose misuse has resulted in many resistant bacterial strains. Chlortetracycline: first member to be isolated from S. aureofaciens (1948). 3
  4. 4. All tetracyclines have practically the same antimicrobial activity. Different substitution on cyclic rings affects individual pharmacokinetics and variations in clinical usefulness. All tetracyclines are bitter solids and are slightly water soluble. They are yellow in colour and HCL salts are used for oral administration usually in capsule form to mask the bitter taste. 4
  5. 5. ClassificationClassification TETRACYCLINES SHORT ACTING: •Tetracycline •Oxytetracycline INTERMEDIATE ACTING: •Demeclocycline •Lymecycline LONG ACTING: •Doxycycline •Minocycline 5 t1/2: 6-10 hr t1/2: 12-13 hr t1/2: 18-20 hr
  6. 6. Mechanism of ActionMechanism of Action They are mainly bacteriostatic. Act by binding to 30 S ribosome of susceptible organism which interferes with attachment of t-RNA to acceptor site of mRNA. Due to this peptide chain fails to grow and thus protein synthesis is inhibited. 6
  7. 7. Carrier involved in the active transport of tetracyclines is absent in host mammalian cells. They also do not bind to mammalian 40 S or 60 S ribosomal units. Thus, the protein synthesizing apparatus of host cell is less susceptible to tetracyclines. Due to these, tetracyclines are selectively toxic to the microbes and not to the host 7
  8. 8. Spectrum of ActionSpectrum of Action They were originally designated “broad spectrum” antibiotic. Promiscuous use has limited and narrowed their usefulness. Currently, highly active against Rickettsiae, Chlaymdia psittaci, C. trrachomatis and C. pneumoniae. Highly effective against Spirochetes Borrelia burgdoerferi and B. recurrentis 8
  9. 9. Atypical pathogens like M. pneumoniae and U. urealyticum are also very sensitive. Some selctive G –ve bacilli (V. Cholerae, A. israelii, Y. pestis, H. pylori) are quite sensitive. Some G +ve bacilli like B. anthracis, C. perferingens and C. tetani are modestly inhibited. Almost all G –ve & G +ve cocci and notable G –ve bacilli (E. coli, Enterobacter, Proteus, Klebsiella, Shigella etc.) are now resistant. 9
  10. 10. Entamoeba and Plasmodia inhibited at higher concentrations(hence used as adjuvant drugs). Strep. pyogenes, S. aureus (including MRSA) and Enterobacter still show response. Active against few strains of N. gonorrhoeae and N. meningitidis presently. Not effective against viral infections 10
  11. 11. ResistanceResistance Develops by 4 main mechanisms: 1. ↓ cell permeability of drug 2. ↑ drug efflux from bacterial cell (**) 3. Ribosomal protection 4. Enzymatic inactivation of drug Incomplete cross resistance seen among different members of this group. Partial cross resistance exists between tetracyclines and chloramphenicol. 11
  12. 12. PharmacokineticsPharmacokinetics Variably absorbed from the GIT . Food ↓ absorption of all tetracyclines except doxycycline & minocycline. Tetracyclines have “chelating property”; form complexes with dairy products (milk, curd), Ca++, Mg++, Al+++(antacids), Fe++ (iron preparations) These decrease bioavailability of tetracyclines so co administration should be best avoided. 12
  13. 13. Tetracyclines are widely distributed in body tissue and fluids except CSF. Concentrated in liver, spleen and connective tissue in bone and teeth. Minocycline has tendency of fat deposition. All of them cross the placental barrier. Metabolised in liver and are concentrated in bile or excreted in urine. 13
  14. 14. Doxycycline and Minocycline are primarily excreted through bile. So, they can be given safely in renal impairment without any dose adjustments. Minocycline is also excreted through saliva and tears. All tetracyclines are secreted through breast milk. 14
  15. 15. AdministrationAdministration Most commonly administered in oral capsule form. Should be taken1/2 hr before or 2 hr after food intake. Not recommended via I.M. route as painful and poor absorption from the site. Topical application should be avoided due to risk of sensitization 15
  16. 16. Drug InteractionsDrug Interactions Antacids and iron preparations decrease absorption by chelation. Enzyme inducers (barbiturates, phenytoin etc.) reduce serum level of tetracyclines. Tetracyclines inhibit Vitamin K producing intestinal flora, thus can potentiate the anti coagulant effect of warfarin. 16
  17. 17. Adverse effectsAdverse effects Oral administration can cause N,V,D epigastric burning, stomatitis. Chronic use can cause fungal esophagitis. If given after first trimester of pregnancy or in children below 10 yrs, staining of both permanent and deciduous teeth & retardation of bone growth may occur. Hepatotoxicity may occur rarely, esp. in pregnant women (tetracycline is safer) 17
  18. 18. Except doxycycline & minocycline, others are occasionally nephrotoxic on long use. Renal toxicity (Fanconi’s syndrome) observed with use of post expiry date tetracyclines. Risk is present only in presence of an existing renal condition. Phototoxicity can occur in some (maximum seen with doxycycline and 18
  19. 19. Tetracyclines reduce protein synthesis (antianabolic) and can increase blood urea. Minocycline can cause vestibular toxicity which subsides with cessation. Demelocycline antagonizes ADH action and can cause nephrogenic diabetes insipidus. Pseudotumor cerebri & bulging fontanelles is complication of chronic use but resolves 19
  20. 20. Tetracyclines frequently cause superinfection due to suppression of resident flora. Intestinal Candida albicans infection is most common. A rare but serious superinfection is pseudomembrane enterocolitis. Tetracyclines should be discontinued asap. 20
  21. 21. Uses of TetracyclinesUses of Tetracyclines Should be used only in those cases where more selective agent not available. Use has declined due to availability of better and more efficacious agents. (A)Empirical Therapy: Used when nature and sensitivity of microbe is unknown or in case of a mixed infection. 21
  22. 22. (B) As First Choice Drugs: Venereal diseases like Chlamydial non-specific urethritis, Lymphogranuloma venereum and Granuloma Inguinale. Atypical pneumonia (Mycoplasmal and Chlamydial), Psittacosis, Relapsing fever. Cholera (limit stool volume), Brucellosis, Plague (bubonic & pneumonic), Lyme disease Rickettsial infections( typhus, Q fever etc) 22
  23. 23. (C) Second Choice Drugs: To penincillin for anthrax, tetanus, Listeria and Leptospirosis Ceftriaxone/azithromycin for gonorrhoea. To ceftriaxone in syphilis for penicillin allergic patients. To Streptomycin for Tularemia To ceftriaxone/azithromycin for chancroid 23
  24. 24. (D) Miscellaneous Other Uses: UTI where organism tests sensitive. Community acquired pneumonia where a more selective agent cant be used. Amoebiasis along with metronidazole. As adjuvant to quinine or artesunate in chloroquine resistant P. falciparum malaria. Acne (P. acnes is sensitive to tetracyclines). H. pylori induced peptic ulcer where these are used as adjuvants. Prophylaxis of traveller’s diarrhea 24
  25. 25. DOXYCYCLINE: Has long t1/2 and lacks nephrotoxicity, popular in pts. with pre-existing renal disease. It can also be given via i.v. route. Treatment of choice for early stage Lyme’s disease and prophylaxis of anthrax. 25
  26. 26. DEMELOCYCLINE: Has been used in treatment of SIADH. MINOCYCLINE: (Most potent member) Used to eradicate meningococcal carrier state from nasopharynx and treatment of swimming pool granuloma caused by Mycobacteria marinatum. 26
  27. 27. Precautions and ContraindicationsPrecautions and Contraindications CI in pregnancy, lactation, infants and children < 10 yrs. Avoid in patients on diuretics (urea may ↑). Use cautiously in renal/hepatic insufficiency. Don’t use beyond expiry date (risk of Fanconi’s syndrome!). 27
  28. 28. GLYCYLCYCLINES: TigecyclineGLYCYLCYCLINES: Tigecycline Minocycline analogue approved in 2005. Active against most bacteria that are resistant to traditional tetracyclines. Binds with higher affinity to 30 S ribosomal unit & is 20 times more potent. It does not show cross resistance as bacterial efflux pumps are unable to pump it out . 28
  29. 29. Active against MRSA, VRE, multidrug resistant S. pneumoniae, most Enterobateriaceae, N.gonorrhoeae and M. catarrhalis. Also useful in E.coli, Bacteroides, M. pneumoniae, H. influenzae Pseudomanas & Proteus are resistant. Given I.V. as 100 mg loading dose followed by 50 mg I.V. every 12 hrs. 29
  30. 30. Eliminated through bile so dose adjustments not needed in renal conditions Not metabolized by Cytochrome P450 so drug interactions are rare. Approved for use in: ◦ Complicated skin/soft tissue infections ◦ Intra abdominal infection due to Enterobacter and enterococci ◦ Severe hospitalized cases of CAP 30
  31. 31. CHLORAMPHENICOLCHLORAMPHENICOL 31  Introduction  Mechanism of action (MOA)  Spectrum of Action  Resistance  Clinical Pharmacokinetics  Adverse effects  Uses  Drug Interactions
  32. 32. Chloramphenicol : IntroductionChloramphenicol : Introduction Chloramphenicol / Chloromycetin is a broad spectrum antibiotic isolated from Streptomyces venezuelae. It has a nitrobenzene moiety that is responsible for antibacterial activity and the bitter taste. 32
  33. 33. Mechanism of ActionMechanism of Action Inhibits protein synthesis by binding to 50 S ribosomal subunit of the microbe. At high doses, it can inhibit host cell mitochondrial 70 S ribosome (toxicity). Bone marrow cells are most susceptible. Bacteriostatic to most organisms but bactericidal to H. influenzae & N. meningitidis 33
  34. 34. Antimicrobial SpectrumAntimicrobial Spectrum Broad spectrum antibiotic like tetracyclines. Active against S. typhi, H. influenzae, S. pneumoniae, B. fragilis and other microbes inhibited by tetracyclines. Less active against Chlamydia, Spirochetes while more against Klebsiella, B. pertussis. Ineffective against Proteus, viruses and Pseudomonas just like tetracyclines. 34
  35. 35. ResistanceResistance Resistance occurs due to indiscriminate use and on a graded manner, like tetracyclines. Resistance develops due to: ◦ Ribosomal protection leading to less affinity for drug binding. ◦ Decreased permeability to the drug. ◦ Plasmid / chromosomal mediated production of chloramphenicol acetyltransferase enzyme (metabolizes chloramphenicol to inactive form) 35
  36. 36. ResistanceResistance Partial cross resistance noted between chloramphenicol and erythromycin/clindamycin as all of them bind to 50 S subunits adjacently. Some cross resistance with tetracyclines also seen, although teracyclines bind to the 30 S subunit. Highly resistant strains of S. typhi have emerged due to transfer of R factor by conjugation. 36
  37. 37. Clinical PharmacokineticsClinical Pharmacokinetics Rapidly & completely absorbed after oral ingestion. Crosses placenta and secreted in milk and bile. Widely distributed in body compartment as well as in CSF (tetracyclines do not in CSF). It undergoes glucoronide conjugation in liver, so dose needs to be lowered in neonates and cirrhotics. 37
  38. 38. Adverse effectsAdverse effects 1) Dose related Bone marrow depression: Of all drugs, chloramphenicol is m. imp. Cause of aplastic anemia, agranulocytosis, thrombocytopenia or pancytopenia. Reversible on discontinuation of drug. Seen frequently when dose exceeds 3-4g/day for 1-2 weeks. Occurs due to inhibition of host mitochondrial 70 S ribosomes. 38
  39. 39. Hepatic/ renal insufficiency predispose to this type of toxicity. Periodic blood counts advised. 2) Idiosyncratic Aplastic Anemia: Rare, but serious and often fatal (1 in 40,000). Possibly has a genetic cause and occurs commonly after repeated courses or even after a single oral/ocular administration. Aplastic anemia: m/c manifestation. Many survivors tend to develop leukemias later. 39
  40. 40. 3) Gray Baby Syndrome: Neonates lack ability to conjugate chloramphenicol via glucoronidation. High levels of chloramphenicol (100mg/kg) may cause fatal neonatal toxicity. Abdominal distension, progressive cyanosis (gray body), hypothermia, vomitting, loss of hunger and CV collapse leading to death. 40
  41. 41. 4) Hypersensitivity reactions: Rashes, fever, atrophic glossitis, angioedema 5) Irritation: N,V,D & pain on injection 6) Superinfection: Same as tetracyclines, but are less common 41
  42. 42. Uses of TetracyclinesUses of Tetracyclines 1) Since effective CSF levels are obtained, it is preferred for meningitis due to H. influenzae, N. meningitidis & S. pneumoniae.  Use has declined due to III generation cephalosporins (ceftriaxone/cefotaxime)  Given in dose of 50-75 mg/kg/day in divided doses 6hrly fro 2 weeks duration. 42
  43. 43. 2) Chloramphenicol was drug of choice for typhoid (enteric fever) till 1980s until resistant strains emerged globally. • But as it is orally active and cheap, it can be used against sensitive strains. • A 500 mg QID dose subsides fever within 3- 4 days, after which 250 mg QID is given for 7 days for intestinal lesions. • Does not prevent/cure the carrier state. 43
  44. 44. 3) Can be used in serious anaerobic infections (wound infections, pelvic and brain abscess) caused by penicillin resistant B. fragilis. • Clindamycin & metronidazole are the preferred drugs nowadays. • Chloramphenicol may be given in addition to or as an alternative to these drugs. 44
  45. 45. 4) Also used topically for treating Ocular (conjunctivitis, 0.5-5%) and external ear infections. • Systemically given, it reaches high concentrations in ocular fluid thus preferred for endopthalmitis due to sensitive strains. • Topical use on skin not preferred due to risk of sensitization. 45
  46. 46. 5) Miscellaneous uses as 2nd choice drug:  To tetracyclines in brucellosis and rickettsial infections, especially in young children and pregnant women where tetracyclines are contraindicated.  To erythromycin for whooping cough.  In UTI when a sensitive strain is present or if kidney substance is involved. 46
  47. 47. Drug InteractionsDrug Interactions  Paracetamol enhances bioavailability of Chloramphenicol by 28%.  Chlorampenicol is a potent enzyme inhibitor and inhibits metabolism of: ◦ Morphine (respiratory depression) ◦ Chlorpropamide (aggravate hypoglycemia) ◦ Warfarin (may cause bleeding) 47
  48. 48. THANK YOU !!THANK YOU !! 48

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