Download 5TETRACYCLINES

TETRACYCLINES
HISTORY

Obtained from soil actinomyces.

Introduced in 1948- chlortetracycline under
the trade name of ‘aureomycin’ from
S.aureofaciens

Followed by oxytetracycline in 1950

Tetracycline in 1952
CHEMISTRY

The basic tetracycline structure consists of
four benzene rings with various constituents
on each ring.

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 salts and
hydrochloride.
R7
R6 R5
CLASSIFICATION
GROUP-I
SHORT ACTING
6-8 hr
TETRACYCLINE
OXYTETRACYCLINE
CHOLRTETRACYCLINE
GROUP-II
INTERMEDIATE ACTING
12 hr
DEMECLOCYCLINE
METHACYCLINE
LYMECYCLINE
GROUP- III
LONG ACTING
16-18 hr
DOXYCYCLINE
MINOCYCLINE
MECHANISM OF ACTION

Primarily bacterostatic

Inhibit protein synthesis by binding to
30S ribosome in susceptible organisms

It interferes with the attachment of
aminoacyl t-RNA to the m- RNA ribosome

As a result peptide chain fails to grow
MECHANISM OF ACTION
TETRACYCLINE
ANTIMICROBIAL SPECTRUM




All gram +ve and negative cocci except strept.pyogenes
,staphylococci aureus
Gram +ve bacilli such as clostridia,corynebacterium but not
mycobacterium
Sensitive gram –ve bacilli ,H.ducreyi,V.cholerae,
Other organisms spirochetes, ricketssiae . E.histolytica
actinomyces, mycoplasma
RESISTANCE
Tetracycline concentrating becomes less
efficient
Elaboration of tetracycline inactivating enzymes
Plasmid mediated synthesis of a
“protection proteins” which protects the
ribosomal binding site from tetracycline
Complete cross resistance is seen among tetracycline groups.
Partial cross resistance with chloramphenicol
PHARMACOKINETICS
 incompletely absorbed from GIT
 Absorbs faster taken on empty stomach
 Doxycycline and minocycline not interfered by food
 chelating property -not taken with milk, iron , antacids
 Higher concentration in liver ,spleen :bind to connective
tissue and of bone and teeth
 CSF – ¼ the plasma conc whether meninges inflammed or
not


Metabolised in liver, undergoes
enterohepatic circulation
Excretion mainly by glomerular
filteration. Dose has to be decreased in
renal failure except doxycycline
Administration





Tetracyclines to be taken ½ hr before
or 2 hr after food
Not by IM
Slow IV in severe cases
Topical preparations – high risk of
sensitization
But can be given for topical application
ADVERSE EFFECTS


Irritative effects on GI mucosa, esophageal
ulceration due to release of material from
capsules
Dose related toxicity
- liver damage –fatty infiltration of liver,
precipitates acute hepatic necrosis in
pregnant women
- kidney damage
- Reversible fancony syndrome-caused by
degraded by products – epitetracycline,
anhydrotetracycline, epianhydrotetracycline
ADVERSE EFFECTS


Photo toxicity-sun burn /severe skin
reaction , with demeclocycline,
doxycycline
Teeth and bones- brown discoloration of
teeth, susceptible to caries
TETRACYCLINE STAINING
ADVERSE EFFECTS
•
•
•
•
Antianabolic effect
Increased intracranial pressure in infants
Diabetes insipidus –demeclocycline
Vestibular toxicity- minocycline : ataxia,
vertigo, nystagmus
• Hypersensitivity
• Superinfection – less with doxycycline and
minocycline
PRECAUTION
Pregnancy, lactation and in children below 8
years
 patients on diuretics
 cautiously used in renal /hepatic diseases
 Do not mix it with penicillin – inactivation
occurs

CLINICAL USES
Drug of choice in
 Venereal diseases – LGV, G.inguinale
 Atypical pneumonia- mycoplasma
 Cholera
 Brucellosis
 Rickettsial infection
 Acne
 Plague
 H.pylori
CLINICAL USES








Amoebiasis- E. histolytica
Malaria-adjuvant to quinine/sulfodoxinepyrimethamine for chloroquine resistant
malaria
Bronchitis
Lymes disease
Leptospirosis
Community acquired pneumonia
Meningococcal carrier- minocycline 200mg/d
SIADH-demeclocycline
CHLORAMPHENICOL




Source: Streptomyces venezulae
Bacteriostatic
Spectrum: aerobic and anaerobic G+ve and G –ve
organisms
(S.typhi), ricketsiae, H. influenza, N. meningitidis
Mechanism of action




Binds to 50 s ribosome
Inhibits peptidyl transferase
Prevents attachment of peptide chain
from P site to A site
Prevents formation of peptide bond
Resistance




Production of chloramphenicol
acetyltransferase ( plasmid encoded)
Decreased permiability
Low affinity of ribosome for
chloramphenicol
Cross resistance with tetracyclines
Kinetics




Oral- well absorbed
Wide distribution to various tissues ,
body fluids, CNS
Conjugated with glucuronic acid
Excretion in urine, feces, bile
Uses







Enteric fever- 500mg 6 hrly
Rickettsial infection – rocky mountain spotted fever,
typhus fever
Meningococcal meningitis
Anaerobic infections in wounds, abcesses
Topical- eye, ear- endopthalmitis, conjunctivitis
Alternative to tetracyclines for brucellosis, cholera,
rickettsia
Alternative to erythromycin for whooping cough
Adverse effects

Gastrointestinal: Nausea, vomiting, diarrhoea
Aplastic anemia

Bone Marrow -

Non dose related (idiosyncratic)
Dose and duration of therapy related
(Due to mammalian mitochondrial protien synthesis
Inhibition )

Gray baby syndrome: vomiting,
flaccidity, hypothermia, gray color,
shock, collapse
Due to blockade of electron transport in
liver , heart, stomach
 Superinfection