These are a class of antibiotics having a nucleus of four cyclic rings. The tetracyclines are primarily bacteriostatic; inhibit protein synthesis by binding to 30S ribosomes in susceptible organism. Subsequent to such binding, attachment of aminoacyl-t-RNA to the acceptor (A) site of mRNA-ribosome complex. The carrier involved in active transport of tetracyclines is absent in the host cells. Moreover, protein synthesizing apparatus of host cells is less susceptible to tetracyclines. These two factors are responsible for the selective toxicity of tetracyclines for the microbes.

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.

30. Glycylcyclins
(TIGECYCLINE )

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.