1. TETRACYCLINES

2. 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.

3. STRUCTURE

4. CLASSIFICATION Naturally occurring: 1-Tetracycline 2-Chlortetracycline
3-Oxytetracycline Demeclocycline
Semisynthetic occurring:
1-Doxycycline Minocycline
3-Meclocycline Lymecycline
5-Methacycline Rolitetracycline

5. SPECTRUM They are active against the following microorganisms:
gram-positive and gram-negative bacteria
spirochetes
mycoplasmas,
rickettsiae,
Candida albicans
Mycoplasma pneumoniae
Vibrio cholerae
Streptococcus pneumoniee.
Neisserie gonorrhoeae

6. 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.
All rickettsiae and chlamydiae are highly sensitive.
Mycoplasma & Actinomyces are moderately sensitive.
E. histolytica & Plasmodia are inhibited at high concentration
Spirochetes are less sensitive.

7. 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.

8. Susceptible cells concentrate the drug intracellularly
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 mRNA ribosome complex
This prevents addition of amino acids to the growing peptide

9. 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.

10. 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.

11. Mechanism of resistance :
There are three types of tetracycline resistance: 1) Tetracycline efflux. 2) Ribosomal protection. 3) Tetracycline modification.

12. Mechanism Of Resistance

13. 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.

14. 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.

15. 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
Intestinal
absorption
T- intermediate
OxyT- intermediate
intermediate
Complete, no interference by food
Plasma protein
binding
OxyT- Low
Elimination
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 mg
mg BD
200 mg initially,
mg OD

16. Tetracycline(T)
Oxytetracycline (oxyT)
Demeclocycline
(Deme)
Doxycycline(Doxy)
Minocycline(Mino)
Alteration of intestinal flora
Marked
Moderate
Least
Incidence of diarrhoea
High
Intermediate
Low
Phototoxicity
Highest
Specific toxicity
OxyT-less tooth discolouration
More phototoxic
Doxy-low renal toxicity

17. ADVERSE EFFECTS IRRITATIVE ADVERSE EFFECTS 2) DOSE RELATED TOXICITY
Nausea, vomiting, gastric pain and diarrhea
Esophageal ulceration
Intramuscular injection Very painful
Thrombophlebitis of the injected vein
2) DOSE RELATED TOXICITY
LIVER DAMAGE:
Inflammation of liver and jaundice occurs.
Tetracyclines are risky in pregnant women
Can precipitate hepatic necrosis which may be fatal.

18. 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.

19. KIDNEY TOXICITY Administration of outdated tetracycline Damage to renal proximal tubule Renal tubular acidosis (Fanconi-like syndrom)

20. 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.

21. 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.

22. 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).

23. 3.HYPERSENSITIVITY Infrequent with tetracyclines.
Skin rashes, urticaria, glossitis, pruritus even exfoliative dermatitis
Angioedema and anaphylaxis are rare.

24. 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.

25. Decreases the half-life of Doxycycline
DRUG INTERACTION
Antacid Impaired absorption
Carbamazepine
Phenytoin
Barbiturates
Chronic alcohol ingestion
Diuretics Nitrogen retention
Decreases the half-life of Doxycycline

26. PRECAUTIONS
Should not be used during pregnancy, lactation and in children, unless there is no other choice.
They should be avoided in patients on diuretics: blood urea may rise in such patients.
Do not mix injectable tetracycline with penicillins-inactivation occurs.
Should be cautiously used in renal and hepatic insufficiency.

27. USES 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
Rickettsial infections
Brucellosis (a bacterial disease typically affecting cattle and causing undulant fever in humans.)

28. 3. Second choice: To penicillin/ampicillin
For tetanus, anthrax, actinomycosis & listeria infections.
To ciprofloxacin or ceftriaxone
For gonorrhoea.
To cotrimoxazole
For chancroid
To ceftriaxone
For syphilis.
To penicillin
for leptospirosis
To azithromycin
For pneumonia
To ceftriaxone/ azithromycin
For chancroid.
To streptomycin
For tularemia (ulcers at the site of infection, fever, and loss of weight.)

29. 4. Other situations UTI Chronic obstructive lung disease
Community-acquired pneumonia
Amoebiasis
As adjuvant to quinine or sulfadoxine pyrimethamine for chloroquine- resistant P. falciparum malaria
Acne vulgaris

30. THANK YOU - PHARMA STREET