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

1. TETRACYCLINES &TETRACYCLINES &
CHLORAMPHENICOLCHLORAMPHENICOL
Dr.Arun Sharma
Dept. of Pharmacology
SLIMS, Puducherry
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2. TETRACYCLINESTETRACYCLINES
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 Introduction
 Classification
 Mechanism of action (MOA)
 Spectrum of Action
 Resistance
 Clinical Pharmacokinetics
 Administration
 Drug Interactions
 Adverse effects
 Uses
 Contraindications & Precautions

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).
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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.
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5. ClassificationClassification
TETRACYCLINES
SHORT ACTING:
•Tetracycline
•Oxytetracycline
INTERMEDIATE
ACTING:
•Demeclocycline
•Lymecycline
LONG ACTING:
•Doxycycline
•Minocycline
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t1/2: 6-10 hr t1/2: 12-13 hr t1/2: 18-20 hr

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.
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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
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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
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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.
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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
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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.
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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. 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. 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.
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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
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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.
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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)
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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
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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
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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.
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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.
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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)
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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
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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
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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.
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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.
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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!).
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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 .
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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.
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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
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31. CHLORAMPHENICOLCHLORAMPHENICOL
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 Introduction
 Mechanism of action (MOA)
 Spectrum of Action
 Resistance
 Clinical Pharmacokinetics
 Adverse effects
 Uses
 Drug Interactions

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.
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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
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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.
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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)
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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.
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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.
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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.
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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.
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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)
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48. THANK YOU !!THANK YOU !!
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