Tetracyclines

Tetracyclines are broad spectrum antibiotics with activity against aerobic and anaerobic Gram positive and Gram negative organisms, rickettsiae, mycoplasma and chlamydiaThere is high incidence of development of resistance against these drugs

Classification

Tetracyclines and its CongenersTetracyclineChlortetracyclineOxytetracyclineDemeclocyclineMethacyclineDoxycyclineMinocycline

According to Generations

First Generation(Dose intervals shorter)

Chlortetracycline Oxytetracycline Tetracycline Demeclocycline

Second Generation(Dose interval longer) Minocycline Methacycline Doxycycline

Third Generation Glycylcycline

Are synthetic glycylamido derivatives of minocycline

(Not currently Available)

Spectrum Of Tetracyclines

Bacteria: In general Tetracyclines are more active

against Gram positive organisms than Gram negative organisms.

Due to superior anti-microbial activity they are usually used in treatment of infections caused by gram +ve organisms

S. pneumonia, H. influenzae (Doxycycline)

Pseudomonas pseudomallei, brucellaHaemophilus ducreyi (chancroids), vibrio

cholera, ligionella pneumophila, campylobacter jejuni,

Helicobacter pylori, yersinia pestis, yersinia enterocolitica, francisella tularensis, pasteurella multocida

Rickettsiae Rocky mountain spotted fever, murine

typhus, epidemic typhus, scrub typhus, rickettsial pox, Q. fever

Miscellaneous:Spirochetes – Borrelia recurrentis, borrelia

burgdorferi, treponema pallidum (syphilis), treponema pertenue, mycobacterium marinum.

The activity against chlamydia and Mycoplasma has become particularly important.

Strains of Mycobacterium marinum also are susceptible.

Effects on intestinal flora. (important feature) Incompletely absorbed from GIT. High concentrations reach the bowel

therefore intestinal flora is markedly altered. They give yellow-green discolouration to

stool and soft consistency. May also cause pseudomembranous colitis

(Toxin from Clostridium defficile)

Mechanism Of action:

The drug enters the microorganisms through channels in the cell wall – The Porins (protein channels) through energy dependent transport ( as described in aminoglycosides). The entry into gram positive organisms is not clear but it is definitely through porins and energy dependant.

Once inside the cell:The tetracyclines (tetracycline,

doxycycline, demeclocycline, minocycline, etc.) block bacterial translation by binding reversibly to the 30S subunit and distorting it in such a way that the anticodons of the charged tRNAs cannot align properly with the codons of the mRNA.

Mechanism of development of resistance

against tetracyclines

Decreased accumulation as a result of decreased antibiotic influx or acquisition of energy dependent pathway

Decreased access of tetracyclines to ribosomes because of presence of ribosome protection proteins

Enzymatic inactivation of tetracyclines

Tetracyclines [Tetra-cycles]Inhibit 30S ribosomal unit [4 wheels parked inside 30S] Effective against:

oChlamydia [Clam] oLime disease [Severed Lime]oSpirochetes [Spiral]oRickettsia [Racket]oMycoplasma [My cop plasma amorphous shape]oVibrio [Comma shaped bacillus from clams]

Eliminated first into bile, reabsorbed and then excreted by kidney [hungry kidney first licking with a green tongue] Causes tooth and bone discoloration in children [spotted tooth] Calcium and Magnesium (e.g. antacids, dairy) decrease absorption from GI [California surfer with a magnet pulling back the tetra-cycle] Hepatotoxic [Severed liver] Phototoxicity [Burning sun] Blurry vision [Blurred eye] due to increased intracranial pressure Doxycycline [Dog is cycling] is eliminated exclusively in bile [Sinking into bile puddle] Minocycline [mine cycle] enters the brain and endolymph, causing vertigo and vomiting

Pharmacokinetics

Absorption: Incomplete absorption from GIT The percentage of oral dose absorbed empty stomach:

Chlortetracycline 30 % Oxytetracycline Demeclocycline 60% -- 80% Tetracycline Doxycycline 95 % Minocycline 100 %

They are more absorbed when taken empty stomachImpaired absorptions with dairy products. Aluminum hydroxide gel, calcium, magnesium, iron, zinc salts, bismuth subsalicylates

Distribution: Widely distributed throughout the body into the

tissue secretions, including urine and prostate. Accumulation in the reticuloendothelial cells of

liver, spleen, bone marrow and in the bones, dentine and enamel of un-erupted teeth.

They cross placental barrier They are found in the breast milk.

Excretion: The primary route of elimination is through kidneys Minocycline is significantly metabolized in the liver.

Route of Administration: Oral Parenteral Local

Therapeutic uses

Rickettsial infections:Life saving drugs in rickettsial infections

like Rocky Mountain spotted fever, recrudescent epidemic typhus, murine typhus, scrub typhus, rickettsial pox, Q. fever.

Mycoplasma Infections:Mycoplasma pneumoniae

Chlamydia:Lymphogranuloma Venereum ( 1st line. Doxy. Drug of

choice)

Pneumoniae, bronchitis or sinusitis caused by chlamydia pneumoniae

Trachoma (contraindicated in early childhood – azythromycin is indicated)

Non specific urithritis – usually due to chlamydia trachomatis.

Sexually Transmitted Diseases: Effective for uncomplicated gonococcal infections ( although

ceph. 3rd gen. Are more prescribed)

Bacillary Infections: Brucellosis Tularemia Cholera

Acne: Used for treatment of acne. These drugs may act by

inhibiting propionibacteria which reside in the sebaceous follicles and metabolize lipids into irritating free fatty acids.

Adverse Effects:

GIT: Epigastric burning, distress, abdominal discomfort,

nausea, vomiting, diarrhea Pseudomembranous colitis

PhotosensitivityHepatic toxicity Oxytetracycline and tetracycline are less hepatotoxic.

Renal ToxicityDiscolouration of teeth in children (brown-yellow)

Hypersensitivity reactions Urticaria, fixed drug eruptions, exfoliative

dermatitis, burning eyes

Increased Intracranial pressure (psuedotumor cereberi)

Biological effects other than Allergic reactions: Superinfection Pseudomembranous colitis

Miscellaneous Thrombophlebitis often followed by I/V injections Long term therapy may produce changes in the

peripheral blood picture Increase intracranial pressure leading to tense

bulging fontanels in young infants. Minocycline may cause vestibular toxicity,

dizziness, ataxia, nausea and vomiting.

Contraindications:Pregnant ladiesChildren under 8 years

Unused Drug should be discarded