Post on 12-Mar-2020
1
Tetracyclines
• In 1948, chlorotetracycline (CT) was the first tetracycline
isolated from Streptomyces aureofaciens.
• They were widely employed until ß-lactams took over.
• It is orally active broad spectrum but now is rarely used
in systemic preparations.
• They are bacteriostatic, broad-spectrum antibiotics they
are isolated mainly from Streptomyces aureofaciens
(Golden color).
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Tetracyclines
OH
CONH2
OH
R1
OH
R3
O O
N(CH3)2H
OH
R4R2
H
ABCD
1
456
9
7
Antibiotic R1 R2 R3 R4
Tetracycline H CH3 OH H
Chlortetracycline Cl CH3 OH H
Oxytetracycline H CH3 OH OH
Demeclocycline Cl H OH H
Methacycline H CH2 CH2 OH
Doxycycline (S) H H CH3 OH
Minocycline (S) N(CH3)
2
H H H
3
Source
• Tetracycline (TC) semisynthyezed from chlortetracycline
and now is produced from a mutant Strep. aureofaciens
which lacks enzyme responsible for incorporation of Cl in
position 7.
• Demeclocycline, produced from a mutant Strep.
aureofaciens which lacks enzyme responsible for
incorporation of CH3 group in C-6.
• Oxytetracycline produced from mutant Strep.
aureofaciens and Strep. rimosus which have enzyme
responsible for incorporation of OH group in position 5.
4
MOA
• Tetracyclines are bacteriostatic and at high
concentration they are bactericidal.
• Inhibition of protein synthesis is responsible for the
inhibition of growth by these drugs.
• Tetracyclines bind to both ribosomes and m-RNA.
• In bacteria, tetracyclines inhibits protein synthesis by
blocking the binding of aminoacyl-tRNA to the mRNA-
ribosome complex.
• But once aminoacyl-tRNA is bound to the 30S subunit
TC can not dissociate it.
5
Resistance
• Via activation of the efflux system, mediated by active
transport protein, results in reduction of intracellular
tetracyclines.
• Ribosomal protection in which bacterial protein synthesis
apparatus is rendered resistant to the action of
tetracyclines by an inducible cytoplasmic protein.
• Enzymatic oxidation.
6
Spectrum
• they have a very broad spectrum of antibacterial activity
that includes both gram positive and negative micro-
organisms.
• The newer tetracyclines are more lipophilic agents as
doxycyclin and minocyclin which are more active against
gram positive (Staph.aureus, Streptococci and Sterpt.
Pneumoniae) bacteria than the older tetracyclines.
• Tetracyclines are active against Niesseria gonorrhea and
N. meningitides as well as E.coli, Klebsiella and
Enterobacter.
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Spectrum
• Proteus mirabilis and Pseudomonas aeruginosea are
resistant.
• Most strains of H. influnzea have remained susceptible.
• They are active against several unusual gram negative
bacteria like Brucella, Francisella and Yersinia species.
• They are also active against Spirochetes (Treponema),
Actinomyces, and Mycoplasma.
• They are inactive against fungi because they do not
penetrate into the fungal cells.
• However, if a low concentration of amphotericin B is
present, entry of minocyclin and doxycyclin into fungal
cells is facilitated resulting in synergistic effect.
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Spectrum
• Tetracyclines are active against Chlamydia, genital
Mycoplasma and highly effective in the treatment of non-
gonococci urethritis.
• They are DOC for lymphogranuloma.
• They are 2nd alternative after penicillin for treatment of
Syphilis.
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Spectrum
• Tetracyclines and chloramphenicol combination is highly
effective against Rickettsial infections of all types
including Q-fever and Rocky mountain spotted fever.
• In peptic ulcer (Heliobacter pylori), tetracyclines is used
to be a part of its triple therapy (tetracycline,
metronidazole, Bi subsalicyalte).
• Tetracyclines are given orally in low doses for treatment
of Acne vulgaris.
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Absorption
• They are absorbed from GIT.
• They form stable chelates with Ca, Mg, Fe, and Al.
• Formation of these complexes decrease absorption of
the drugs.
• Therefore tetracyclins should never be administered with
milk, antacids, and ferrous sulphate.
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Distribution• Protein binding is highest with deoxycyclin, intermediate
with minocyclin and lowest with oxytetracyclin.
• Tetracyclin readily penetrates into most tissues
particularly high levels are achieved in liver and kidney.
• Tissues penetration is directly related to the lipid
solubility of the individual tetracycline.
• Both doxycyclin and minocyclin are lipid soluble and
thus these drugs have excellent tissue penetration.
• Minocyclin is 10 times more soluble than tetracycline.
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Distribution
• Penetration into CSF is poor.
• They readily pass across human placenta and enter fetal
circulation.
• They do not bind to bone that is readily formed.
• The deposition of tetracyclines in growing enamel of
teeth and growing nail is responsible for some
cosmetically undesirable effects of these drugs.
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Excretion
• Tetracyclines are eliminated by both renal and extra-
renal mechanism.
• All drugs are excreted by liver into bile by an active
transport.
• Because these drugs are accumulated with impaired
renal function, they should not be administered to
patients with renal failure.
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Pharmacokientic
Tetracyclins Oral
Dose
(mg)
Dose
Interval
(hr)
Abs.% T1/2 (hr) Excretion Protein
Binding %
I-Short acting:
1.Tetracyclin
1.Oxytetracyclin
500
500
6
6
70-80
60
8
9
Renal
Renal
60
30
II-Intermed. acting:
1.Demeclocyclin 300 12 66 12-14 Renal &
hepatic
85
III-Long-acting:
1.Doxycyclin
2.Minocyclin
100
100
24
12
93
98
15-20
12-13
Hepatic
Hepatic
90
75
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Adverse Effects
• Irritative effects
• Super- infection
• Effects on teeth and bone
• Hepatic and renal toxicity
• Effect on skin
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Irritative Effect
• Tetracyclines are irritative substance, when given i.v. or
i.m. they cause thrombophlebitis and pain (vine inflammation and
blood clot).
• Oral doses causing epigastic burning, abdominal
discomfort, nausea, vomiting and diarrhea.
• To avoid these side effects, tetracyclines should not be
given at bedtime and should not be given to patient with
symptoms of esophageal reflux.
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Super-infection
• Because of their broad spectrum activity , therapy with
tetracycline is associated with high incidence of super-
infection particularly in patients with diabetes and
reduced immune function.
• Tetracycline therapy is associated with production of
enterocolitis due to Clostridium and Staph.
• Tetracycline therapy must be stopped, patient need to
get plenty of fluid and electrolytes and shift to
vancomycin.
• Super infection with Candida albicans occur in
osopharynex, vagina, and bowel.
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Effects on Teeth and Bones
• Increasing exposure to tetracycline produces a
progressively darker yellow shade in teeth.
• Coloration is accelerated by exposure to light due to
photo-oxidation (tetracycline- calcium orthophosphate
complexes).
• This case is dose dependent.
• Tetracyclines can pass through placenta and breast
tissue.
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Hepatic and Renal Toxicity
• They cause hepatotoxicity which is characterized by
diffuse fatty infiltration of liver.
• In case of patient with renal failure, most of tetracyclines
accumulate to toxic levels in the body may produce
azotemia (inhibition of protein synthesis in the tissues).
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Effect on Skin
• All tetracyclines cause phototoxicity manifested by
abnormal sunburn reactions and tingling sensations.
• These reactions are rapidly reversible.
• Demeclocycline and doxycycline cause this reaction
more frequently than other tetracyclines.
• The lowest frequency is with minocycline
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SAR
• Any changes at the 1, 10, 11, 12 and 12a positions will
completely abolish activity, even changes in the
stereochemical configuration.
• 2-position, will lead to a decreased activity, even
substitution to the amide.
• 4-position, the amine is essential, but mono-substitution
is also active, amine must be in the α-position.
OH
CONH2
OH
R1
OH
R3
O O
N(CH3)2H
OH
R4R2
H
ABCD
1
456
9
121110
12a 2
7
8
27
SAR
• 5-position can have a hydroxyl, keto group or hydrogen,
and all are active.
• 6-position, both substitutions are not necessary.
• 7-position, Cl, F, Br, NO2 (electron withdrawing groups,
draws electrons away from a reaction center) and a
tertiary amine are all active.
• 8-position, any electron withdrawing or donating group is
still active.
• 9-position is recently being studied to overcome bacterial
resistance.
OH
CONH2
OH
R1
OH
R3
O O
N(CH3)2H
OH
R4R2
H
ABCD
1
456
9
121110
12a 2
7
8
28
Tetracycline (Hostacycline, Micycline)
• Bright yellow crystalline powder, stable in air and
darkens in color on exposure to strong sunlight.
• Stable in acid medium at a higher pH than 2 , more
stable than chlorotetracycline in alkaline medium but
such solution rapidly lose potency.
• Has become the most popular due to its higher plasma
level than oxytetracycline and chlorotetracycline.
OH
CONH2
OHOH
OH
O O
N(CH3)2
OH
H3C
ABCD
Tetracycline
29
Chlorotetracycline
• It is used as HCl salt, which is bright yellow crystalline
powder.
• Can be used orally or parenetrally.
• It is no more used because of its poor bioavailability.
OH
CONH2
OHOH
OH
O O
N(CH3)2
OH
H3CH
Cl
ABCD
Chlortetracycline
30
Oxytetracycline (Oxytetryne)
• Pale yellow color, bitter crystalline powder.
• Absorbed rapidly from GIT.
• It is used orally and i.m.
OH
CONH2
OHOH
OH
O O
N(CH3)2
OH
H3CH
OH
ABCD
Oxytetracycline
31
Methacycline
• More potency than tetracycline and longer serum t1/2.
• Greater stability due to removal of OH group in ring C
which prevent the formation of isotetracycline by alkali.
OH
CONH2
OHOH O O
N(CH3)2
OH
HCH2 OH
ABCD
Methacycline
32
Demeclocycline
• Differ from chlorotetracycline by absence of CH3 in ring C.
• Slower rate of elimination through the kidney.
• Lower incidence of teeth discoloration.
OH
CONH2
OHOH
OH
O O
N(CH3)2
OH
ClH
ABCD
Demeclocycline
33
DoxycyclineDoxydar- Vibramycin- Doxymycin- Tolexine
• 6-α-Methyl epimer is more than 3 times as active as it's
β- isomer.
• Absence of 6- OH group increases it lipid solubility.
• Very stable in acid and alkali.
• Has a long biological t1/2.
• Absorbed very well from GIT.
OH
CONH2
OHOH O O
N(CH3)2
OH
HCH3
OH
ABCD
Doxycycline
34
Minocycline
• The most potent member.
• As doxycycline lack 6-OH group.
• Active against MRSA (Methicillin-Resistant Staphylococcus aureus).
• Very useful in chronic bronchitis.
OH
CONH2
OHOH O OOH
HN
CH3H3C
N
CH3H3C
ABCD
Minocycline
35
Rolitetracycline
• Used as i.m or i.v.
• Water soluble (1:1).
• Used when oral tetracycline is not suitable.
• No longer widely used.
OH
CONH
OHOH
OH
O O
N(CH3)2
OH
H3C
ABCD
Rolitetracycline
NH2C
pyrrolidinomethyl