Transcript Tetracycline - PharmaStreet

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INTRODUCTION
• Obtained from soil actinimycetes.
• Introduced in 1948 (chlortetracycline, aureomycin).
• Originally Broad spectrum antibiotic
• Having four cyclic ring nucleus.
• All tetracyclines are slightly bitter solids, weakly water
soluble, their hydrochlorides are more soluble.
• Aqueous solutions are unstable.
• The subsequently developed members have high lipid
solubility, greater potency and some other differences.
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STRUCTURE
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CLASSIFICATION
a)
Naturally occurring:
1-Tetracycline
2-Chlortetracycline
3-Oxytetracycline
4-Demeclocycline
b)
Semisynthetic occurring:
1-Doxycycline
2-Minocycline
3-Meclocycline
4-Lymecycline
5-Methacycline
6-Rolitetracycline
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SPECTRUM
They are active against the following microorganisms:
1.
2.
3.
4.
5.
6.
7.
8.
9.
gram-positive and gram-negative bacteria
spirochetes
mycoplasmas,
rickettsiae,
Candida albicans
Mycoplasma pneumoniae
Vibrio cholerae
Streptococcus pneumoniee.
Neisserie gonorrhoeae
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ANTIMICROBIAL SPECTRUM
• Inhibit all type of pathogen except Fungi and Viruses.
• Cocci:
• All gram positive and gram negative cocci were originally sensitive
• But Strep. pyogenes, Staph. aureus and enterococci have become resistant.
• Sensitive gram positive bacilli:
• Clostridia and other anaerobes, Listeria, Corynebacteria, B. anthracis are inhibited
• but not Mycobacteria.
• Sensitive gram nagetive bacilli:
• H. ducreyi, H. pylori, Yersinia pestis, Y. enterocolitica, and many anaerobes.
• H.influenzae have become insensitive.
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All rickettsiae and chlamydiae are highly sensitive.
Mycoplasma & Actinomyces are moderately sensitive.
E. histolytica & Plasmodia are inhibited at high concentration
Spirochetes are less sensitive.
MECHANISM OF ACTION
• Bacteriostatic.
• Inhibit protein synthesis
• By binding to 30s ribosome in susceptable organism.
• Inhibit binding of aminoacyl tRNA to the acceptor site
of mRNA
peptide chain fails to grow.
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MECHANISM OF ACTION
The Tetracyclines bind to the 30S subunit and prevent binding
of the incoming charged tRNA unit (Inhibit step 1 in bacterial
protein synthesis).
Tetracyclines enter microorganisms
Susceptible cells concentrate the drug intracellularly
Tetracyclines bind to 30S subunit of the bacterial ribosome
Blocking the binding of tRNA to the acceptor site on the mRNAribosome complex
This prevents addition of amino acids to the growing peptide
TRANSPORT OF
TETRACYCLINES
• Sensitive organism have active transport process
which concentrate tetracyclines intracellularly.
• In gram negative bacteria tetracyclines diffuse through
“Porin” channel.
• Some lipid soluble member (Doxycycline and
Minocycline) enter by passive diffusion.
The selective toxicity of tetracyclines:• The carrier involved in active transport of tetracyclines
is absent in the host cells.
• Protein synthesizing apparatus of host cells is less
sensitive to tetracyclines.
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RESISTANCE
• Tetracyclines concentrating mechanism become less
effective.
• Bacteria acquire capacity to pump tetracyclines out.
• Plasmid mediated synthesis of a “Protection” protein
which protects the ribosomal binding site from
tetracyclines.
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Mechanism of resistance :
There are three types of tetracycline resistance:
1) Tetracycline efflux.
2) Ribosomal protection.
3) Tetracycline modification.
Mechanism Of Resistance
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PHARMACOKINETICS
• Incompletely absorbed by g.i.t.
• Absorption is better if taken in empty stomach.
• Doxycycline & Minocycline are completely
absorbed irrespective of food.
• Tetracyclines have chelating property with calcium
and other metals forms insoluble and unabsorbable
complexes.
• Milk, iron preparation, nonsystemic antacids and
sucralfate reduces their absorption.
• Concentrated in liver and spleen and bind to the
connective tissue in bone and teeth.
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• Widely distributed in body
• Variable degree of protein binding: high
(Demeclocycline, Doxycycline, & Minocycline,)
moderate (tetracycline) low (Oxytetracycline)
• Primarily excreted in urine by glomerular filtration.
• They are secreted in milk and affect the infant.
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Tetracycline(T)
Oxytetracycline (oxyT)
Demeclocycline
(Deme)
Doxycycline(Doxy)
Minocycline(Mino)
Source
T- semisynthetic
OxyT- S.rimosus
S.aureofaciens
Doxy- semisynthetic
Mino- semisynthetic
Potency
Low
Intermediate
High
T- intermediate
OxyT- intermediate
intermediate
Complete, no interference
by food
OxyT- Low
T- intermediate
High
High
Rapid renal excretion
Partial metabolism,
Slower renal excretion
Doxy- faeces
Mino- urine and bile
Plasma
6-10 hrs
16-18 hrs
18-24 hrs
Dosage
250-500 mg
300-600 mg BD
200 mg initially,
100-200 mg OD
Intestinal
absorption
Plasma protein
binding
Elimination
Tetracycline(T)
Oxytetracycline (oxyT)
Demeclocycline
(Deme)
Doxycycline(Doxy)
Minocycline(Mino)
Alteration of intestinal
flora
Marked
Moderate
Least
Incidence of diarrhoea
High
Intermediate
Low
Phototoxicity
Low
Highest
Low
Specific toxicity
OxyT-less tooth discolouration
More phototoxic
Doxy-low renal toxicity
ADVERSE EFFECTS
1)
IRRITATIVE ADVERSE EFFECTS
•
Nausea, vomiting, gastric pain and diarrhea
•
Esophageal ulceration
• Intramuscular injection Very painful
• Thrombophlebitis of the injected vein
2) DOSE RELATED TOXICITY
1. LIVER DAMAGE:
• Inflammation of liver and jaundice occurs.
• Tetracyclines are risky in pregnant women
• Can precipitate hepatic necrosis which may be fatal.
2. KIDNEY DAMAGE
• Prominent only in the presence of existing kidney disease.
• All tetracyclines, except doxycycline, accumulate and enhance renal
failure.
• A reversible fancony syndrome ( inadequate reabsorption in the proximal
renal tubules of the kidney. ) like condition is produced by outdated
tetracyclines due to proximal tubular damage caused by degraded
products-epitetracycline, anhydrotetracycline and epianhydrotetracycline.
• Exposure to acidic PH, moisture and heat favours such degradation.
KIDNEY TOXICITY
Administration of outdated tetracycline
Damage to renal proximal tubule
Renal tubular acidosis
(Fanconi-like syndrom)
3. PHOTOTOXICITY
• A sunburn-like or other severe skin reaction on exposed parts is
seen in some individuals.
• A higher incidence has been noted with demeclocycline and
doxycycline.
• Distortion of nails occurs occasionally.
4. TEETH AND BONES
• Have chelating property.
• Calcium-tetracycline chelate gets deposited in developing teeth and bone.
• Given from midpregnancy to 5 months of extrauterine life:• The deciduous teeth are affected: brown discolouration, ill-formed teeth, more
susceptible to caries.
• Given between 3 months and 6 years of age:• Affect the crown of permanent anterior dentition.
• Given during late pregnancy or childhood:• Cause temporary suppression of bone growth.
• Prolonged use:• Deformities and reduction in height
• Repeated courses are more damaging.
5. Antianabolic effect
• Reduce protein synthesis and have an overall catabolic effect.
• Induce negative nitrogen balance and can increase blood urea.
6. Diabetes insipidus
• Demeclocycline antagonizes ADH action and reduces urine concentrating
ability of the kidney.
7. Vestibular toxicity
• Minocycline has produced ataxia (unsteady movement), vertigo and
nystagmus (involuntary movement of eyeball).
3.HYPERSENSITIVITY
• Infrequent with tetracyclines.
• Skin rashes, urticaria, glossitis, pruritus even exfoliative dermatitis
• Angioedema and anaphylaxis are rare.
4. SUPERINFECTION
• They cause marked suppression of the resident flora.
• Higher doses suppress flora more completely greater chance of
superinfection: doses on the lower side of the range should be used
whenever possible.
• The tetracycline should be discontinued at the first sign of
superinfection and appropriate therapy instituted.
DRUG INTERACTION
• Antacid
Impaired absorption
• Carbamazepine
• Phenytoin
• Barbiturates
• Chronic alcohol ingestion
• Diuretics
Nitrogen retention
Decreases the
half-life of
Doxycycline
PRECAUTIONS
1. Should not be used during pregnancy, lactation
children, unless there is no other choice.
and in
2. They should be avoided in patients on diuretics: blood urea
may rise in such patients.
3. Do not mix injectable tetracycline with penicillins-inactivation
occurs.
4. Should be cautiously used in renal and hepatic insufficiency.
USES
1. Treatment of serious/life threatening infections.
2. Drug of first choice in:
a) Venereal diseases
Lymphogranuloma venereum
Granuloma inguinale
b) Pneumonia due to Mycoplasma pneumoniae
c) Cholera
d) Plague
e) Relapsing fever
f) Rickettsial infections
g) Brucellosis (a bacterial disease typically affecting
cattle and causing undulant fever in humans.)
3. Second choice:
a) To penicillin/ampicillin
•
For tetanus, anthrax, actinomycosis & listeria infections.
b) To ciprofloxacin or ceftriaxone
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For gonorrhoea.
c) To cotrimoxazole
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For chancroid
d) To ceftriaxone
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For syphilis.
e) To penicillin
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f)
for leptospirosis
To azithromycin
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For pneumonia
g) To ceftriaxone/ azithromycin
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For chancroid.
h) To streptomycin
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For tularemia (ulcers at the site of infection, fever, and loss of weight.)
4. Other situations
a)
b)
c)
d)
e)
f)
UTI
Chronic obstructive lung disease
Community-acquired pneumonia
Amoebiasis
As adjuvant to quinine or sulfadoxine pyrimethamine for chloroquineresistant P. falciparum malaria
Acne vulgaris
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