Transcript Chapter 41 Tetracyclines and chloramphenicol

Chapter 41 Tetracyclines and
chloramphenicol
Department of pharmacology
Liu xiaokang(刘小康）
2010,3
Common properties of
tetracyclines
• Members:
• Tetracycline, Doxycycline, Minocycline,
Demeclocycline, Methacycline.
• Structure:
• Antibacterial activity:
• Broad-spectrum bacteriostatic antibiotics.
Include G+ and G– aerobe and anaerobe,
ricketts organism, spirochete,
mycoplasma, chlamydia and some
protozoan. But no activity to Enterococci,
Protures and Pseud. aeruginosa.
• Mechanisms:
• (1) Sensitive bacteria can pump
tetracyclines into the cell by energy
dependent system; (2) bind to 30S
ribosomal subunit at a site that blocks
binding of charged tRNA to the "A" site
of the ribosome; (3) Tetracyclines can
inhibit mammalian protein synthesis, but
because they are "pumped" out of most
mammalian cells do not usually reach
concentrations needed to significantly
reduce mammalian protein synthesis.
• Pharmacokinetics:
• Primarily PO. F varies widely with drug &
effect of food. F = 90 to 100%: doxycycline and
minocycline; F=58 to 77%: Others. Food
decreases: Insoluble chelates -- Ca++, Al+++,
Mg++ ; Milk?, Antacids? Some laxatives have
Mg++. Distribution: most tissues and fluid,
especial bind to Ca++ and sedimentate in bones
and teeth. Elimination: Both renal and biliary.
Significant enterohepatic circulation.
• Clinical uses:
• (1) First choice for treatment of rickettsial
infections, eg. exanthematous, Q fever and
Rocky Mountain Spotted Fever and acariasis;
(2) Chlamydia infections, eg. Psittacosis
(Chlamydia psittaci); (3) Mycoplasmas
infection; (3) Spirochete infection, recurrent
fever. (4) bacterial infection: First choice for
treatment of cholera, and Brucella infection.
• Adverse reactions:
• (1) Gastric mucosa, cramps, burning, nausea,
vomiting. Can add food if using minocycline or
doxycycline; (2) superinfection; (3) Brown
discoloration of teeth especially if given during
formative stages and deformation of bone; (4) Liver
Toxicity, May impair hepatic function, especially
during pregnancy and in patients with pre-existing
hepatic insufficiency when high doses are given IV;
(5) Photosensitivity, Especially demeclocycline. (6)
Vestibular reactions, dizziness, vertigo, nausea, and
vomiting, If using minocycline or doxycycline at
high doses.
• Resistance:
• Significant resistance, but still useful. Crossresistance within the group is significant Three
primary resistant mechanisms:
• (1) Decreased intracellular concentration: (a)
Plasmid-borne transporter pumps drug out.
Because of multi-valent plasmids, tetracycline
resistance is often a marker for resistance to other
drugs, e.g., aminoglycosides, sulfonamides, and
chloramphenicol; (b) Decreased penetration in some
bacteria;
• (2) Production of proteins that interfere with
tetracycline binding to ribosomes;
• (3) Enzymatic inactivation.
• Tetracycline:
• Similar with doxycycline in clinical use,
but more adverse reaction
• Doxycycline:
• The major clinic used tetracycline; it is
fast effecting, high efficacy and long-term
duration.
• Used for all indications of tetracyclines
with less adverse reactions, usually
gastrointestinal reaction.
• Minocycline:
• Similar with doxycycline.
Cloramphenicol
• Structure:
• Antimicrobial activity:
• Broad spectrum. Effect on G+ and G–
bacteria, ricketts organism, spirochete,
chlamydia, mycoplasma.
• Mechanism:
• (1) blocks proper binding of aminoacyl moiety to
"A" site. Failure to properly align prevents
Peptidyl transferase enzyme from transferring the
growing chain from the "P" site to the bound
charged tRNA in the "A" site. This stops protein
synthesis.
• (2) Chloramphenicol does inhibit mitochondrial
ribosomal protein synthesis because these
ribosomes are 70S, the same as those in bacteria. It
does not bind to the 80S mammalian ribosomes.
This may be responsible for the dose related
anemia caused by chloramphenicol.
• Pharmacokinetics:
• Rapidly absorbed. Well distributed, in
CSF can reach 60% (45-90%) of plasma
concentration in presence or absence of
meningitis. 90% Eliminated by
glucuronyl transferase (Liver enzyme)
• Clinical uses:
• Resembles tetracyclines, except More
serious hazard so limit use (The risk of
aplastic anemia does not contraindicate
the use of chloramphenicol in situations
in which it is necessary; however, it
emphasizes that the drug should never be
employed in undefined situations or in
diseases readily, safely, and effectively
treatable with other antimicrobial agents)
• (1) More likely for CNS than
tetracyclines, Very effective in
Haemophilus influenzae meningitis, but
several third generation cephalosporins
have replaced CAP as initial therapy
when this organism is suspected.
(cefotaxime, ceftriaxone, and ceftizoxime);
• (2) Universally active vs anaerobic
bacteria, rickettsiae, chlamydia,
mycoplasma.
• Adverse reaction:
• (1) aplastic anemia; (2) Gray Baby
Syndrome; (3) Reversible, dose-related
hematologic toxicity; (4) others.
• Resistance:
• Plasmid borne acetyltransferase is
primary mechanism.
• Drug interaction:
• Inhibits hepatic microsomal cytochrome
P450 enzymes, Depresses hepatic
biotransformation of other drugs prolong
half-lives of many drugs, e.g. dicumarol,
phenytoin, tolbutamide and
chlorpropamide.
•
（The end）