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Transcript
Protein synthesis Inhibitors
Dr. Naza M. Ali
Lec-8 3 -1-2017
Tetracyclines
• They are a group of closely related
compounds consist of four fused rings with a
system of conjugated double bonds.
• Substitutions on these rings are responsible
for variation in the drugs pharmacokinetics,
which cause small differences in their clinical
efficacy.
Tetracyclines
Mechanism of action
Entry of tetracycline into susceptible organisms
is mediated both by
1. Passive diffusion
2. An energy-dependent transport protein
mechanism unique to the bacterial inner
cytoplasmic membrane.
• The drug binds reversibly to the 30S subunit
of the bacterial ribosome,
• blocking access of the amino acyl-tRNA to
the mRNA-ribosome complex at the acceptor
site.
Resistance
Widespread resistance to
tetracyclines limits their
clinical use
The most commonly naturally occurring resistance
1. An inability of the organism to accumulate the drug.
2. Enzymatic inactivation of the drug and production of
bacterial proteins that prevent tetracyclines from binding
to the ribosome.
Classification of Tetracyclines according to T 1/2
Examples
Short- acting
Half-life in hrs
6-8
Tetracycline
Oxytetracycline
Chlotetracycline
Intermediate
acting
Demeclocycline
Long-acting
12
18
Doxycycline
Minocycline
Pharmacokinetics
Absorption
•
Tetracyclines are adequately absorbed after oral
ingestion.
• Administration with dairy products or other substances
that contain divalent and trivalent cations (Mg or Al
antacids or iron supplements) decreases absorption,
for tetracycline due to the formation of nonabsorbable
chelates .
Distribution:
• The tetracyclines concentrate well in the bile, liver,
kidney, gingival fluid, and skin.
• They bind to tissues undergoing calcification (teeth ,
bones).
• Only minocycline and doxycycline achieve therapeutic
levels in CSF.
• Minocycline also achieves high levels in saliva and tears,
rendering it useful in eradicating the meningococcal
carrier state.
• All tetracyclines cross the placental barrier and
concentrate in fetal bones and dentition.
Elimination
• Tetracycline is primarily eliminated unchanged in urine
• Minocycline undergoes hepatic metabolism and is
eliminated to a lesser extent via the kidney.
• In renally compromised patients, doxycycline is
preferred, as it is primarily eliminated via the bile into
the feces.
Clinical uses
1. Primary uses
• Mycoplasma pneumoniae ( cause of community acquired
pneumonia in young adults and in people who live in close
connes, such as in military camps).
• Chlamydia trachomatis ( sexually transmitted disease , It
causes urethritis, pelvic infammatory disease).
• Rocky mountain spotted fever Rickettsiae ( is characterized
by fever, chills, and aches in bones and joints).
• Cholera (is caused by Vibrio cholerae)
2. Secondary uses
• are alternative in treatment of syphilis.
• prophylaxis against infection in chronic bronchitis
• in treatment of acne
3. Selective uses
• GIT ulcer cause by H.pylori
Tetracycline
• Meningococal carrier state
Minocycline
• Lyme disease
Doxycycline
• Prevention of malaria
Doxycycline
• Treatment of amebiasis
Doxycycline
• In managment of patients with ADH-secreting tumors
Demeclocycline
Adverse effects
1. Gastric discomfort
2. Effects on calcified tissues
This may cause discoloration and hypoplasia of teeth
and a temporary stunting of growth.
The use of tetracyclines is limited in pediatrics.
3. Hepatotoxicity
4. Phototoxicity:
Severe sunburn in patient who exposed to sun or
ultraviolet rays (tetracycline & demeclocycline)
5. Vestibular dysfunction:
Dizziness, vertigo, and tinnitus with minocycline,
which concentrates in the ear and affects function.
Doxycycline may also cause vestibular dysfunction.
6. Pseudotumor cerebri:
Benign, intracranial hypertension ( headache & blurred
vision)
Glycylcylines
 Tigecycline is the first available member of a new class
of antimicrobial agents called glycylcyclines.
 is structurally similar to the tetracyclines
 has a broad-spectrum activity against multidrugresistant gram-positive,
 some gram-negative , anaerobic organisms.
 is indicated for treatment of complicated skin and soft
tissue infections & complicated intra-abdominal infections.
Chloramphenicol
• A broad-spectrum antibiotic,
• Is restricted to life-threatening infections for which
no alternatives exist.
Mechanism of action
• Chloramphenicol binds reversibly to the bacterial
50S ribosomal subunit and inhibits protein
synthesis at the peptidyl transferase reaction
• Due to some similarity of mammalian mitochondrial
ribosomes to those of bacteria, protein and ATP
synthesis in these organelles may be inhibited at high
circulating chloramphenicol levels, producing bone
marrow toxicity.
•
( The oral formulation of chloramphenicol was
removed from the US market due to this toxicity.)
Resistance
1. Occurs through the formation of acetyl transferase
enzyme that inactivates chloramphenicol.
2. With an inability of the antibiotic to penetrate the
organism so change in permeability may be the basis of
multidrug resistance.
Mechanism of action of
chloramphenicol.
aa = amino acid.
Antimicrobial spectrum
• Is either bactericidal or bacteriostatic
• A broad-spectrum antibiotic, is active not only
against bacteria but also against other microorganisms,
rickettsiae.
• Chloramphenicol has excellent activity against
anaerobes.
• Not active against Pseudomonas aeruginosa,
chlamydiae.
Clinical uses
• Because of its toxicity, has very few uses as a
systemic drug.
• It is a backup drug for severe infections caused by
Salmonella & for the treatment of pneumococcal &
meningococcal meningitis in beta-lactam sensitive
persons
Pharmacokinetics
• Chloramphenicol may be either IV or orally
• It is completely absorbed via the oral route
because of its lipophilic nature, and is widely
distributed throughout the body.
• It readily enters the normal CSF.
• Chloramphenicol primarily undergoes hepatic
metabolism to an inactive glucuronide, which is
secreted by renal tubule & eliminated in urine.
• Dose reductions are necessary in patients with
liver dysfunction or cirrhosis.
• Chloramphenicol is secreted into breast milk.
Toxicity
1. GIT disturbance (candidiasis)
2. Anemia:
• Hemolytic anemia occurs in patient with low
G6-phosphate dehydrogenase
• Reversible anemia is dose related
• A plastic anemia is independent of dose and may
occur after the therapy ceased.
3. Gray baby syndrome: in neonates if the dosage
regimen of drug is not properly adjusted.
3. Gray baby syndrome:
•
•
•
•
Neonates have a low capacity to glucuronylate the antibiotic,
they have under developed renal function,
a decreased ability to excrete the drug,
which accumulates to levels that interfere with the function
of mitochondrial ribosomes.
This leads to poor feeding, depressed breathing, cardiovascular
collapse, cyanosis & death.
Adults who have received very high doses of the drug can also
exhibit this toxicity.
Drug interactions:
• Chloramphenicol inhibits some of the hepatic
mixed-function oxidases and, thus, blocks the
metabolism of drugs
• such as warfarin and phenytoin,so elevating
their concentrations and potentiating their
effects.