Tetracyclines
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