Transcript Document

Drugs acting on ribosome
By
Dr. Mohamed Abd Almoneim Attia
TETRACYCLINES
Examples :tetracycline, oxytetracyclin, and doxycyclin.
Antibacterial spectrum
Tetracyclines display broad-spectrum activity and are effective
against:
1-Most gram-positive, many gram-negative bacteria and
anaerobic bacteria.
2-Rickettsia, Coxiella, Mycoplasma and Chlamydia, Brucella.
3-Spirochetes, Actinomycines, Protozoa.
4-Helico bacter pylori.
Mechanism of action
1-Tetracyclines bind to the 30S ribosome preventing the
addition of amino acids to the growing peptide chain.
2-They chelate some cations necessary for enzymatic action in
bacteria e.g. Ca, Mg and Mn.
Pharmacokinetic :
Absorption:
These antibiotics are partially absorbed from the stomach and upper
gastrointestinal tract and the amounts remaining may alter bacterial
flora leading to super infection.
Calcium (milk and Ca. antacids), magnesium (Mg hydroxide),
aluminum hydroxide and iron interfere with their absorption since
they form insoluble chelates with tetracyclines.
Food did not impair absorption of doxycyclin. Because absorption of
doxycycline is rapid and complete ,it has weak effect on intestinal
flora.
Distribution:
Tetracyclines are distributed throughout body tissues and fluids.
Doxycycline is the most lipid-soluble, while oxytetracycline is the
least lipid soluble.
The tetracyclines penetrate the uninflamed meninges and cross the
placental barrier. It is concentrated in the liver and bile. Because of
their chelating properties with calcium they tend to be deposited in
growing bones and teeth causing yellow discoloration.
Metabolism and excretion:
Tetracyclines are metabolized in the liver and are
concentrated and excreted in the bile then
reabsorbed.
Doxycycline is excreted primarily in feces (not renal
excretion). The other tetracyclines are eliminated
primarily in the urine by glomerular filtration.
Therapeutic uses
The use of tetracyclines became limited because of
other safe and bactericidal antibiotics, the appearance
of tetracycline- resistant strains as well as their various
adverse effects.
1-Mycoplasma pneumoniae although other agents may
be equally effective.
2-The tetracyclines are still the drugs of choice for the
treatment and prophlaxsis of cholera .
3-Combination regimen to treat gastric and duodenal
ulcer disease caused by helicobacter pylori.
4-Tetracyclines are clinically effective in acne . Minocycline and
doxycycline are superior in treatment of acne. They act by decreasing
fatty acids of sebum.
5- Diseases caused by Rickettsia (Typhus) and Coxiella.
6- Granuloma inguinale and relapsing fever.
7- The chlamydial diseases (trachoma, lymphogranuloma venereum).
8- Nonspecific urethritis and mixed bacterial infection of respiratory
tract e.g. sinusits, bronchitis.
9-They are also effective in the treatment of brucellosis and infections
caused by pasteurella (plague).
10Tetracyclines are second choice in other diseases resistant
to penicillins and in patients sensitive to penicillins e.g.
syphilis, chancroid, gonorrhea, actinomycosis, anthrax and
shigellosis.
11-Bacillary and amoebic dysentery as adjuvant therapy
(Oxetetracycline is the most active one, it acts indirectly by
modifying the intestinal flora necessary for amoebae to
survive in bowel lumen).
12-Tetracycline in combination with quinine may be an
alternative treatment of plasmodium falciparum malaria
when resistance has developed to fancidar.
13-Local applications of tetracycline e.g. eye ointment for
treatment of eye infections.
Adverse effects
1-Gastrointestinal disturbance:
nausea, vomiting, epigastric burning and hyperacidity This can
be prevented by giving tetracycline after meals. Antacids may
help but avoid those containing Al, Mg and milk because they
chelate tetracycline preventing its absorption.
Diarrhea may occur secondry to tetracycline treatment due to:
The irritative effect of tetracycline on GIT (leading to frequant
fluid stools which do not contain blood or leucocytes).
Superinfection of bowel (see before)e.g.Pseudomembranous
colitis caused by the overgrowth and production of toxins by
clostridium difficile (which is cytotoxic to mucosa leading to
ulcer, severe diarrhoea, fever, shreds of mucosa in stools with
large number of neutrophils. Diarrhea in these cases could be
treated by vancomycin orally or metronidazole with stopping of
the causative agent).
2-Disorders of epithelial surfaces
e.g. sore throat, sore tongue, black hairy tongue, perioral
soreness. The cause is decreased synthesis of Vit. B12 and mild
superinfection.
3-Yellow staining of both the deciduous and permanent teeth
and dental enamel hypoplasia (increased susceptibility to
caries, as well as retardation of bone growth) because of their
chelating properties with calcium.This can occur if tetracyclines
are administered after the fourth month of gestation or if they
are given to children less than 8 years of age, this is a further
reason for avoiding their use during pregnancy. Doxycycline is
less likely to cause tooth discoloration
4-Hepatotoxicity and pancreatic damage
occurs infrequently but may be fatal if it is given during
pregnancy, with large dose IV and in presence of renal
dysfunction.
5-Photosensitivity
observed as abnormal sunburn reaction, is
particularly associated with doxycycline
administration
6-Fanconi-like syndrome occurs with out-dated
tetracyclines.
7-Teratogenesis, when administered early in
pregnancy.
8-Hypersensitivity reactions.
Contraindications
1-Hypersensitivity to tetracyclines.
2-Severe hepatic disease.
3-Concomitant administration of total parenteral nutrition as it
leads to decreased utilization of amino acids for protein synthesis.
4-It should be avoided in patients with peptic ulcer, renal disease,
children (less than 8 years of age), pregnancy and lactation.
Interactions
1-Avoid simultaneous ingestion of dairy products (milk & cheese),
antacids,
2-Laxative or iron containing products with tetracyclines because of
chelating action of tetracyclines.
3-Avoid doxycyclin in alcoholic patients because ethanol causes
induction of hepatic enzymes leading to decrease serum level of
antibiotic.
4-With oral anti-coagulants, tetracyclines decrease vitamin K
synthesis in intestinal lumen leading to potentiation of anticoagulant effect.
CHLORAMPHENICOL
Mechanism of action
Chloramphenicol inhibits protein synthesis by
binding to the 50S ribosomal subunit and preventing
peptide bond formation.
Antibacterial spectrum
Chloramphenicol is a broad-spectrum antibiotic. As
with tetracyclines, it is effective against gram-positive
and gram-negative bacteria, including Salmonella,
Rickettsia, Mycoplasma and Chlamydia.
Chloramphenicol is also effective against most
anaerobic bacteria, including Bacteroides fragilis.
Pharmacokinetic properties
Absorption:
Chloramphenicol is rapidly and completely absorbed
from the gastrointestinal tract and not affected by food
ingestion or metal ions.
Since absorption is rapid and complete after oral
administration, there is less alteration of bacterial flora
with less susceptability to superinfection.
Distribution:
Chloramphenicol penetrates body fluids and tissues well.
The drug penetrates the brain and CSF with high
concentration and crosses the placental barrier.
Metabolism and excretion:
Renal elimination is by tubular secretion of metabolite and glomerular filtration of active drug.
Therapeutic uses
The serious and potentially fatal nature of chloramphenicol-induced bone marrow suppression
restricts its use to a few life-threatening infections in which the benefits outweigh the risks.
1-It was the drug of choice in typhoid fever, but now other safe and more effective drugs are
used e.g. ciprofloxacin and amoxycillin.
2-It is a good choice for the treatment of pyogenic meningitis (Since effective CSF levels are
obtained), particularly that caused by Haemophilas influenza. Although the 3rd generation
cephalosporins are peferred.
3-In treating other invasive infections caused by H. influenzae, such as arthritis, osteomyelitis
and epiglottis
4-Treatment of serious anaerobic infections of brain caused by penicillin- resistant bacteria,
such as B-fragilis.
5-Rickettsial disease: Chloramphenicol is an alternative to tetracycline.
6-Topical treatment of both ear and eye infections.
Adverse effects
1-Toxic bone marrow depression: The bone marrow
depression is dose related.
It is recognized as anemia, thrombocytopenia or leukopenia
(agranulocytosis). It is reversible on discontinuation of the
chloramphenicol.
Treatment of agranulocytosis:
1-Stop the drug.
2-Fresh blood transfusion.
3-Cortisone to inhibit reaction.
4-Penicillin to eradicate streptococcal infection in the throat.
5-Bone marrow stimulants e.g. growth factor (G-CSF), vitamin
B complex, adenine sulphate, pentose nucleotide.
2-Gray baby syndrome:
It occurs in newborn infants with large doses, especially those born
prematurely. It is due to immature hepatic conjugating mechanism and in
adequate renal excretion which leads to high levels of chloramphenicol. This
syndrome is characterized by abdominal distention, vomiting, progressive
cyanosis, irregular respiration, hypothermia, flaccid paralysis and vasomotor
collapse. Mortality is high (40%).
3-Gastrointestinal disturbance: nausea, vomiting, diarrhea and glossitis.
4-Superinfection: It usually occurs after 5 –10 days.
5-Hypersensitivity reactions: skin rashes, fever, angioedema (not frequent).
6-Optic neuritis and encephalopathy: (rare).
Drug Interactions
Chloramphenicol inhibits the activity of the liver microsomal enzymes and
thus enhances the activity of drugs, such as dicoumarol, diphenylhydantoin
and tolbutamide which are normally degraded by these enzymes.
BACITRACIN, VANCOMYCINS, POLYMYXINS AND SODIUM
FUSIDATE (MINOR ANTIBIOTICS)
They are relatively toxic drugs and have only limited use in
chemotherapy. It is usually used topically.
BACITRACIN
Mechanism of action
Bacitracin prevents cell wall synthesis.
Antimicrobial spectrum
Bacitracin inhibits gram-positive cocci and a few gram-negative
organisms.
Therapeutic uses
it is mainly used topically alone or in combination with other
antibiotics (Notably polymyxin-B and neomycin) or
hydrocortisone (as anti-inflammatory) in the form of creams,
ointments and aerosol preparations.
Adverse effects : nephrotoxicity.
VANCOMYCIN
Mechanism of action
Vancomycin inhibits cell wall synthesis.
Antimicrobial spectrum
It has a narrow-spectrum activity (only against gram-positive
bacteria).
Therapeutic uses
It is mainly used in:
1-Vancomycin is also the drug of choice in patients in whom
pseudomembranous colitis (antibiotic associated colitis) has
developed 2-Methicillin-resistant Staphylococcus aureus infections
3-Other infections due to susceptible organisms e.g. streptococci,
bacillus anthracis, corynebacterium diphtheria, clostridium tetani
and difficile.
Adverse effects
1-The major adverse effect associated with
vancomycin therapy is ototoxicity.
2-"Red neck syndrome": More commonly, the
intravenous infusion of vancomycin can result in the
occurrence of chills, fever and a maculopapular skin
rash often involving the head and upper thorax due
to histamine release.
THE POLYMYXINS
polymyxin B and colistin (polymyxin E) are used in the
treatment bacterial diseases.
Antimicrobial spectrum
The polymyxins are active against facultative gramnegative bacteria and P. aeruginosa and coliform
organisms in particular.
Therapeutic uses
1-In combination with neomycin, polymyxin B is used as
a bladder irrigant to reduce the risk of catheterassociated infections.
2-Polymyxin B also is applied topically in combination
with other antibiotics for infections of skin, eye or ear.
Adverse effects
1- Nephrotoxicity.
2-Neurotoxicity. recognized by perioral
paresthesia, numbness, weakness, ataxia and
blurred vision.
3-These drugs precipitate respiratory arrest (due
to Neuromuscular blocking effect) especially
both in patients given muscle relaxants during
anesthesia and in persons suffering from
myasthenia gravis.
SODIUM FUSIDATE (Fucidin)
It inhibits protein synthesis by binding to 50 S
ribosomal subunit. It is active against gram-positive
bacteria and some gram-negative diplococci
Good penetration into bone and pus.
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