Describes pharmacology of Newer Tetracycline class of antimicrobials

1. Newer TETRACYCLINES
Dr. SHAKEEB
DHORAJIWALA(JR II)
• Dr. KANCHAN RAO
SINGH

2. INTRODUCTION:
• Naphthacene derivatives, made up by fusion of four
partially unsaturated cyclohexane radicals
• crystalline bases of these compounds are pale yellow,
slightly bitter and sparingly soluble in water.
• They form water soluble sodium salts. Hydrochloride
derivatives are even more soluble
• Are more stable at acid pH.

3. Historical Aspects:
• Systematic screening of a multitude of soil microorganisms
for potential antibiotic activity by the American
Pharmaceutical Industry resulted in the discovery of
tetracyclines.
• The first member chlortetracycline, isolated from
Streptomyces aureofaciens was introduced in 1948,
followed by oxytetracycline derived from Streptomyces
rimosus in 1950
• In the year 1953 tetracycline was prepared by catalytic
hydrogenation of chlortetracycline.
• Since then other semi-synthetic tetracyclines have been
introduced

4. Problems with older tetracyclines:
• Tetracycline resistance: This has been demonstrated by
many organisms including Staphylococci, Group A
Streptococci, H. influenzae, Pneumococci, and E. coli.
• Resistance may develop through several mechanisms and
can be passed from one organism to another by transfer of
plasmids called R-factors that contain genetic information for
the development of resistance.
• In resistant organisms, accumulation of the drug is absent.
• Promiscuous and often indiscriminate use has gradually
narrowed the field of their usefulness

5. Adverse reactions
 Allergy
 Photosensitivity
 GI tract
 Superinfections
 Pseudomembranous colitis
 Teeth and bones
 Antianabolic effects
 Liver
 Kidney
 Benign intracranial hypertension
 Miscellaneous: local thrombosis/Jarish Herxheimer reaction/
peptic ulcers/steatorrhea and vitamin K deficeincy

6. Need for newer tetracyclines:
• The subsequently developed members have high lipid
solubility, greater potency
• Intestinal absorption is unaffected by presence of food
• Minimal alteration of intestinal flora therefore problem of
superinfection is minimized.
• Longer half-lives so frequency of dosing reduced and
ensures better compliance.
• Incidence of adverse effects- minimum

7. Newer tetracycline in a nutshell:
Variant of
Tetracycline
Doxyxcycline Minocycline Demeclocycli
e
Tigecycline
Source: Semisynthetic Semisynthetic Streptomyces
Aurofeofacien
s
Synthetic
derivative of
Minocycline
Potency: High High(<minocy
cline)
Intermediate High
Intestinal
absorption(%):
95-100 95-100 60-80 Poor
Plasma protein
binding:
High High High Low
Elimination: Primarily
excreted fecally
as conjugates
Primarily
metabolized
with excretion
in urine and
bile
Partial
metabolisms
low renal
exctretion
Bile-80%
Urine-20%
Plasma T1/2(in
hrs):
18-24 18-24 16-18 37-67

8. Variant of
Tetracycline
Doxyxcycline Minocycline Demeclocyclin
e
Tigecycline
Dosage: 200 mg
initiallythen
100 mg B.D.
200 mg
initiallythen
100 mg B.D.
300 mg B.D. 50 mg I.V.
infusion over
30-60 min 12
hourly
Intestinal Flora
status:
Least affected Least affected Moderately
affected
Intermediate
Diarrhoea(inci
dence):
Low Low Intermediate Intermediate
Specific
toxicity:
Phototoxicity Vestibular Highly
phototoxic,
Diabetes
Insipidus
Pancreatitis

9. ADME of Tetracyclines:
Absorption:
• Form insoluble complexes by chelation with calcium,
magnesium and aluminium and hence, substances like milk that
contain calcium, and antacids reduce their absorption. Ingestion
of food and iron interferes with their absorption.
• mainly absorbed from the duodenum and the upper small
Intestine
Distribution
• peak plasma level is reached within 3 to 4 hours so administered
at 6 hourly intervals in order to maintain their therapeutic plasma
concentration
• IM- produce peak plasma levels within 1 hour and adequate
levels are maintained for 12 hours
• concentrated in liver, bone marrow, enamel of unerupted teeth
and lungs.
• They cross the placental barrier and are also secreted in milk.
Their concentration in the ocular fluids is poor.

10. Metabolism:
• Metabolised in the liver
• Concentrations in the bile are 5-20 times those in the plasma as
they undergo enterohepatic circulation
Excretion:
• metabolites excreted mainly in the
urine by glomerular filtration. In anuria, the plasma t½ of
tetracycline is 4 to 5 days and
that of oxytetracycline 2 to 3 days
• Doxycycline and minocycline are eliminated by non-renal route

11. Mechanism of action:

12. Properties:
 Physical properties:
• The crystalline bases of these compounds are pale
yellow, slightly bitter and sparingly soluble in water.
• However, they form water soluble sodium salts.
• Tetracyclines are more stable at acid pH

13. Chemical properties and interactions:
•They are tetracene derivative and interacts with the other
compounds in the following ways:
oChelates bi/tri-valent ions like Ca2+,Mg2+,Fe3+,Zn2+,Al3+ and
and forms insoluble complexes milk and products, antacids
and cathartics containing ions with subsequent reduction in
bioavailability
oInterferes with bactericidal action of Penicillin
o Enzyme inducers like Phenytoin, carbamazepine,
barbiturates decreases the half life of tetracyclines.
oPotentiates anti-coagulant action of coumarin derivatives
like warfarin.

14. Uses:
I)Empirical:
• When nature and sensitivity of infecting organism is not known, in
cases of mixed infection. However in serious infections they are
avoided.
II) Drug of first choice in:
1.Venereal diseases:
a)Chlamydial nonspecific urethritis/endocervicitis
b)Lymphogranuloma venereum c) Granuloma inguinale
2.Atypical Pneumonia due to M.Pneumonia and psittacosis
3) Cholera
4)Brucellosis

15. Uses:
5) Plague
6) Relapsing fever
7)Rickettsia infections
III) Drug of second choice in place of:
1)penicillin/ampicillin for tetanus/anthrax/actinomycosis and
listeria infection
2) ceftriaxone, amoxicillin or azithromycin for gonorrhoea,
especially for penicillin resistant non-PPNG; also in patients allergic
to penicillin.
3)Ceftriaxone for syphilis in patients allergic to penicillin
4) Penicillin for leptospirosis; doxycycline 100 mg BD for 7 days is
curative. Weekly doxycycline (200 mg) as prophylaxis.

16. Uses:
5) Azithromycin for pneumonia due to Chlamydia pneumoniae
6) Ceftriaxone/azithromycin for chancroid
7) Streptomycin for tularemia
IV) Other infective conditions:
1) Urinary tract infections
2) Community-acquired pneumonia,
3) Amoebiasis
4) adjuvant to quinine or artesunate for chloroquine-resistant P.
falciparum malaria
5) Acne vulgaris
6) Propionibacterium acnes
7) Chronic obstructive lung disease

17. Conclusion:
 Tetracyclines are broad spectrum bacteriostatic antibiotics.
However in order to tackle the problems of drug resistance and
superinfection, highly judicious use is advocated limiting its use
to treat infections where highly selective and less toxic anti-
microbial agents are not available.
 Although with the availability of semi-synthetic and synthetic
derivatives the utility of tetracyclines has increased, however the
limitations still exists for e.g. when used in treatment of hospital
acquired/ventilator-associated chest infections, mortality was
found to be higher in a comparative trial,in tigecycline group than
in the comparator group.