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).

2

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.

7

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.

8

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.

9

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.

10

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.

11

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.

12

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.

13

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.

14

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

15

Adverse Effects

• Irritative effects

• Super- infection

• Effects on teeth and bone

• Hepatic and renal toxicity

• Effect on skin

16

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.

17

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.

18

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.

19

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).

20

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

26

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