Tetracyclines

Protein synthesis
inhibitors
TCs Chlor.

ML
AGs

LZ LA
 Introduction:
 Tetracyclines are a group of broad-spectrum antibiotics whose general
usefulness has been reduced with the onset of bacterial resistance.
Despite this, they remain the treatment of choice for some specific
indications.
G+ve
G-ve (also anaerobes)
Plasmodium
Protozoa infetion
Mycoplasma’s
Rikkettsiae
Spirochetes
H.influenza
 Protein synthesis inhibitor
 Bacteriostatic
 Recognized by the inclusion of cycline in their official names.
Tetracyclines-----
 DISCOVERY AND SOURCE:
The first member of the group to be discovered
was Chlortetracycline (Aureomycin) in the late
1940s by Duggar, a scientist employed by
Lederle Laboratories who derived the substance
from a golden-colored, fungus-like, soil-dwelling
bacterium named Streptomyces aureofaciens.
Oxytetracycline (Terramycin) was discovered
shortly afterwards by AC Finlay et al., it came
from a similar soil bacterium named
Streptomyces rimosus.
Tetracyclines-----
 Chemistry:
 Tetracyclic nucleus-derivatives of polycyclic
naphthacene carboxamide.
Tetracyclines-----
 Classification 1:
Tetracyclines-----
 Classification 2:
Tetracyclines-----
Antimicrobial spectrum:
spectrum
•G+ve
•G-ve
•Rikkettsiae prowazoki
•Rikkettsiae rikkettsie
•Mycoplasma pneumoniae
•Chlamydia trachomatis
•Treponema pallidum
•Borrellia spp
•Yersinia pestis spp
•Brucella melitensis
•Francisella tularensis
•Protozoal spp; Plasmodium spp
•Bacillus anthraces
•Vibrio cholera
•Amoeba
Spectrum of Activity
 Tetracyclines-----
Clinical uses:
uses
1.Tetracyclines are drug of choice for
A.Chlamydial infections
Trachoma (infectious blindness)
Lymphogranuloma venerum (also called venereal disease
 Sexually transmitted);
PID like enarometitis, sulphingitis,Urithritis
B. Mycoplasma pneumoniae infection (Pneumonia)
C. Rickettial infections
Rocky mountain spotted fever
Typhus fever
Rikkettsial fox
Q-fever
Scrub fever
D. Spirochetes infections (Borrelia), lyme disease
(bite of a tick infected with Borrelia) .
Tetracyclines:
Tetracyclines are broad-spectrum antibiotics that
inhibit protein synthesis. In contrast to penicillins and
Cephalosporins, these are bacteriostatic.
These drugs have two serious limitations:
1.Bacteriostatic
2.Adverse drug reactions
All tetracycline have similar MOC, Clinical
indication, AD. There are however some differences in
PK.
CHEMISTRY
Protein synthesis (For figure see rage and Dale
book)
Protein synthesis takes place in the ribosomes.
Eukaryotic and prokaryotic ribosomes are different,
and this provides the basis for the selective
antimicrobial action of some antibiotics. The bacterial
ribosome consists of a 50S subunit and a 30S subunit
, whereas in the mammalian ribosome the subunits are
60S and 40S. The other elements involved in peptide
synthesis are messenger RNA (mRNA), which forms
the template for protein synthesis, and transfer RNA
(tRNA), which specifically transfers the individual
amino acids to the ribosome. The ribosome has three
binding sites for tRNA, termed the A, P and E sites.
To initiate translation, mRNA, transcribed from the
DNA template (see below), is attached to the 30S
subunit of the ribosome. The 50S subunit then binds to
the 30S subunit to form a 70S3 subunit, which moves
along the mRNA such that successive codons of the
messenger pass along the ribosome from the A
position to the P position. Antibiotics may affect
protein synthesis at any one of these stages.
Fig.
Steps in bacterial protein synthesis and targets of
several antibiotics. Amino acids are shown as
numbered circles. The 70S ribosomal mRNA complex
is shown with its 50S and 30S subunits. In step 1, the
charged tRNA unit carrying amino acid 8 binds to the
acceptor site A on the 70S ribosome. The peptidyl
tRNA at the donor site, with amino acids 1 through 7,
then binds the growing amino acid chain to amino acid
8 (transpeptidation, step 2). The uncharged tRNA left
at the donor site is released (step 3), and the new
8-amino acid chain with its tRNA shifts to
the peptidyl site (translocation, step 4). The antibiotic
binding sites are shown schematically as triangles.
Chloramphenicol (C) and macrolides (M) bind to the
50S subunit and block transpeptidation (step 2). The
tetracyclines (T) bind to the 30S subunit and prevent
binding of the incoming charged tRNA unit (step 1).
Classification (SETH book, IMP)
Tetracyclines are divided into three classes depending
upon their dosage, plasma half life and frequency of
administration.
1. Short acting tetracycline
These have half life in the range of 6-12 hours and are
frequently administered at the dose of 250-500 mg
two to four times daily and are incompletely absorbed.
Name Plasma half life Hrs
1.Chlortetracycline (Natural) 6
2. Oxytetracycline (Natural) 9
3. Tetracycline (Natural) 8
2.Intermediate acting tetracycline
These have half lives of about 12-16 hours and are
frequently administered at the dose of 300-600 mg
once daily and are also incompletely absorbed.
Demeclocycline (Natural) 12 Hrs
Methacycline (Semi-synthetic) 13 Hrs
3.Long acting tetracycline
These have half lives of about 16-18 hours and are
almost completely absorbed.
Doxycycline (Semi-synthetic) 18 Hrs
Minocycline (Semi-synthetic) 16 Hrs
2nd Classification (Internet)
According to source:
1.Naturally-occurring
Tetracycline
Chlortetracycline
Oxytetracycline
Demeclocycline
2. Semi-synthetic
Doxycycline
Lymecycline
Meclocycline
Methacycline
Minocycline
Rolitetracycline
According to duration of action: (Internet)
Short-acting (Half-life is 6-8 hrs)
1.Tetracycline
2. Chlortetracycline
3. Oxytetracycline
Intermediate-acting (Half-life is ~12 hrs)
1.Demeclocycline
2.Methacycline
Long-acting (Half-life is 16 hrs or more)
1.Doxycycline
2.Minocycline
3. Tigecycline
PK
All tetracycines are administered by oral route. Oral
absorption of Tetracyclines is somewhat incomplete
and irregular. The absorption is lowest for
Chlortetracycline (30%), intermediate for tetracycline,
oxytetracycline and demeclocycline (60-80 %) and
high for doxycycline and minocycline (95-100).
Absorption of tetracyclines is interfered by concurrent
ingestion of milk and milk products, antacids,
Calcium, Iron, Magnesium salts, Bismuth
subsalicylate and alkaline medium. They form chelates
with Divalent and Trivalent cations which are
insoluble and unabsorbable. Thus Milk, antacid and
oral iron reduce absorption. These should be given 1
hour before or after tetracyclines.
Tetracycline are well distributed into tissues and body
fluids. They can cross Placental barrier but not the
Blood brain barrier. These are mainly excreted in urine
by Glomerular filtration and should be avoided in in
the presence of renal dysfunction. However
Minocycline and doxycycline are are eliminated by
biliary excretion may be used in renal
dysfunction.Some of tetracyclines undergo
enterohepatic circulation. Some of tetracyclines
undergo enterohepatic circulation.Tetracyclines also
pass into mother milk.Passage of tetracyclinnes into
mother milk and foetal circulation exposes foetus and
sucking infant to tetracycline toxicity.
Carbamazepine, phenytoin, barbiturates, and chronic
alcohol ingestion may shorten the half-life of
doxycycline 50% by induction of hepatic enzymes that
metabolize the drug.
PK (Rang and Dale)
The tetracyclines are generally given orally but can
also be administered parenterally. The absorption of
most preparations from the gut is irregular and
incomplete but may be improved in the absence of
food. Because tetracyclines chelate metal ions
(calcium, magnesium, iron, aluminium), forming non
absorbable complexes, absorption is decreased in the
presence of milk, certain antacids and iron
preparations. Minocycline and doxycycline are
virtually completely absorbed.
MOA;
It has been proposed that Tetracylines bind mainly to
30 S subunit of bacterial ribosome and prevent the
access of amino aceyl tRNA to the acceptor site on the
mRNA-ribosome complex and thus prevention of
addition of amino acids to the growing peptide chain.
Note;
The bacteriostatic tetracycines tend to suppress the
infection and require phagocytes to completely
eradicate bacteria.
Antibacterial spectrum;
Tetracyclines are broad spectrum antibiotics and are
effective against gram + and – Ve bacteria. The
organisms inhibited by tetracyclines include;
1.H.influenzae
2.Brucella
3.Pneumococci
4.Vibrio cholera
5.Gonnococci
6.Actinomycetes
7.Chlamydia 8.Rickettsia 9.Treponema pallidum
Clinical uses:
1.Tetracyclines are drug of choice for
A. Chlamydial infections like Trachoma, Psittachosis,
lymphogranuloma venereum
B. Mycoplasma pneumoniae infection (Pneumonia)
C. Rickettial infections (Typhus fever, Q fever)
D. Spirochetes infections (Borrelia) Like Relapsinf fever, lyme
disease.
E. Actinomycetes infection
2. Tetracyclines have been used for intestinal
amebiasis and in Malaria.
3.It is effective againsgt +ve & -ve bacteria.
4.A tetracycline usually in combination with an
aminoglycoside is indicated for plague, tularemia, and
brucellosis.
Resistance
Three mechanisms of resistance to tetracycline
analogs have been described: (1) impaired influx or
increased efflux by an active transport protein pump;
(2) ribosome protection due to production of proteins
that interfere with tetracycline binding to the
ribosome; and (3) enzymatic inactivation. The most
important of these are production of an efflux pump
and ribosomal protection.
Dosage:
Chlortetracycline 250-500 mg/6 hours.
Oxytetracycline Same
Tetracycline Same
Demeclocycline 300 mg/12 h
Methacycline Same
Doxycycline 200 mg on 1st day then
100mg/day
Minocycline 100 mg/12 hours
Doxycycline is the drug of choice b/c it requires once
daily dosing, absorption is not impaired by food and it
is safely administered in renal impairement.
Adverse effects;
1.GIT:
Nausea, vomiting, and diarrhea. If tetracyclines have
been used for more than few days, superinfection with
Pseudomonas, Proteus, Resistant coliform,
Staphylococci and candida takes place.Over growth
with these organisms leads to GIT upsets.
Pseudomeemranous colitis with the over growth of C.
difficile is very serious and even may be
fatal. Treatment is with oral Metronidazole or
vancomycin.Part of GIT symptoms may be due to
vitamin B deficiency that is synthesize by intestinal
flora due intestinal sterilization by the use of
tetrecyclines.Supplementry Vitamin B complex may
relieve some of the symptoms.
2.Bone and Teeth;
Tetracyclines chelate calcium and gets deposited in
newly formed bones and teeth giving rise to yellow or
brown discoloration that ultimately leads to deformity
and inhibition of growth. Tetracyclines are therefore
contraindicated during pregnancy especially during the
last 2 trimester and lactation, and to infants and
children below 8 years of age.
3. Hepatotoxicity especially in pregnant mothers
and in high doses.
4. Renal toxicity
5. Photosensitization especially with demeclocycline.
6. Vestibular disturbance with minocycline and high
dose of doxycycline.
Preparations available;
1.Terramycin by Pfizer pharma
Cap: Oxytetracycline----250 mg
2.Wellcodox by GSK
Cap. Doxycycline---100 mg
3.Vibramycin by Pfizer Pharma
Tab/Cap Doxycyclin --100 mg
4.Minoderm by Stiefel Pharma
Tab; Minocycline 100 mg
Typhus:
It is disease caused by louse borne bacteria.
1.Epidemic typhus:
Etiology: Rickesstia prowazekii and is transmitted by
human body louse.
Signs & symptoms:
1.Fever 2.Cough 3. Rashes 4.Severe muscle pain
5. Chills 6. Decrease in B.P 7. Sensitivity to high
Delirium
Rickesstia prowazekii grows in louse gut and is
excreted in feaces.The disease is then transmitted to
uninfected humans who scratches the louse bite
(which itches) and rubs the feaces into the wound.
Incubation period is 2 weeks.
2.Scrub Typhus:
It is a type of typhus caused by orientia tsustsugamus
and is transmitted by chiggers.
Signs & Symptoms:
Fever, Headach, muscle pain, cough, GIT symptoms.
Rockey mountain spotted fever:
Most severe and most frequently reported rickettsial
illness caused by R.rickettsii, a species of bacteria that
is spread to humans by ticks (Vector).
Signs & Symptoms:
Fever, Headach, Muscle pain, and rash.
Q Fever:
It is an infection caused by caused by coxiella burnetii
(Bacteria). Cattle, sheep and goats are primary source
of C, burnetti. Organisms are excreted in urine, milk
and faeces of the infected animals. In humans it occurs
by the inhalation of organisms from the air.
Signs & Symptoms:
High fever 104-105 Fo, Headach, Malaise, Myalgesia,
confusion, Sore throat, Chills, sweat, Non productive
cough,nausea, vomiting, diarrhoea.
Lymphogranuloma venereum: It is STDS, Etiology
is Chlamydia trachomatis. It is infection of lymphatics
and lymph nodes.
Trachoma:
Chronic infectious disease of the conjunctiva and
cornea producing photophobia, pain, lacrimation.
Etiology is Chlamydia trachomatis.
Brucellosis:
It is caused by Brucella abortus. It is transmitted from
sheep, goat, cattle, rabbit etc.It involves reticular
endothelial system.
Signs & Symptoms: Fever, sweating, malaise, &
Weight loss.
Cholera:
Etiology: Vibrio cholera
Signs & Symptoms
Painless watery stool, saline depletion and vomiting.
Tularemia:
Etiology: Francisella tularensis
It is transmitted by the bite of flies, fleas etc.
Signs & Symptoms
Fever, Headach, Weakness, Back pain, Malaise.