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PROTEIN SYNTHESIS INHIBITORS II

PHARMACOLOGY IV
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Protein Synthesis Inhibitors

TETRACYCLINES MACROLIDES/KETOLIDES
1. Demeclocycline 1. Azithromycin
2. Doxycycline 2. Clarithromycin
3. Minocycline 3. Erythromycin
4. Tetracycline 4. Telithromycin
GLYCYLCYCLINES OTHERS
1. Tigecycline 1. Chloramphenicol
AMINOGLYCOSIDES 2. Clindamycin
1. Amikacin 3. Linezolid
2. Gentamicin 4. Quinupristin/Dalfopristin
3. Neomycin
4. Streptomycin
5. Tobramycin
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TETRACYCLINES
The tetracyclines are a group of closely related compounds that,
as the name implies, consist of four fused rings with a system of
conjugated double bonds. Substitutions on these rings are
responsible for variation in the drugs’ individual pharmacokinetics,
which cause small differences in their clinical efficacy.
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Mechanism of action
Entry of these agents into susceptible
organisms is mediated both by passive
diffusion and by an energy-dependent
transport protein mechanism unique to
the bacterial inner cytoplasmic membrane.
Nonresistant strains concentrate the
tetracyclines intracellularly.
The drug binds reversibly to the 30S subunit
of the bacterial ribosome, thereby blocking
access of the amino acyl-tRNA to the
mRNA-ribosome complex at the acceptor
site. By this mechanism, bacterial protein
synthesis is inhibited.
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Antimicrobial Activity
Tetracyclines are broad-spectrum bacteriostatic antibiotics that
inhibit protein synthesis. They are active against many gram-
positive and gram-negative bacteria, including anaerobes,
rickettsiae, chlamydiae, mycoplasmas, and L forms; and
against some protozoa (eg, amebas).
The antibacterial activities of most tetracyclines are similar
except that tetracycline-resistant strains may be susceptible to
doxycycline, minocycline, and tigecycline, all of which are poor
substrates for the efflux pump that mediates resistance.
Differences in clinical efficacy for susceptible organisms are
minor and attributable largely to features of absorption,
distribution, and excretion of individual drugs.
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Resistance
• Three mechanisms of resistance to tetracycline analogs have
been described:
1. impaired influx or increased efflux by an active transport
protein pump
2. ribosome protection due to production of proteins that
interfere with tetracycline binding to the ribosome
3. enzymatic inactivation

The most important of these are production of an efflux pump

and ribosomal protection.

Any organism resistant to one tetracycline is resistant to all.

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Pharmacokinetics
1. Absorption:
All tetracyclines are adequately, yet incompletely, absorbed
after oral ingestion .
Taking these drugs concomitantly with dairy foods in the diet
decreases absorption due to the formation of nonabsorbable
chelates of the tetracyclines with calcium ions.
Non absorbable chelates are also formed with other divalent
and trivalent cations (for example, those found in magnesium
and aluminum antacids and in iron preparations).
Doxycycline and minocycline are almost totally absorbed on
oral administration.
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Effect of antacids and milk on the absorption of

tetracyclines
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Pharmacokinetics
2.Distribution:
The tetracyclines concentrate in the liver, kidney, spleen, and skin,
and they bind to tissues undergoing calcification (for example,
teeth and bones) or to tumors that have a high calcium content (for
example, gastric carcinoma).
Penetration into most body fluids is adequate.
Although all tetracyclines enter the cerebrospinal fluid (CSF),
levels are insufficient for therapeutic efficacy, except for
minocycline.
Minocycline enters the brain in the absence of inflammation and
also appears in tears and saliva. Although useful in eradicating the
meningococcal carrier state, minocycline is not effective for central
nervous system infections.
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Pharmacokinetics
3. Biotransformation and elimination:
All the tetracyclines concentrate in the liver, where they are, in
part, metabolized and conjugated to form soluble glucuronides.
The parent drug and/or its metabolites are secreted into the
bile.
Most tetracyclines are reabsorbed in the intestine and enter the
urine by glomerular filtration.
Obstruction of the bile duct and hepatic or renal dysfunction
can increase their half-lives.
Unlike other tetracyclines, doxycycline can be employed for
treating infections in renally compromised patients because it is
preferentially excreted via the bile into the feces.
Tetracyclines are also excreted in breast milk.
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Typical therapeutic applications of tetracyclines

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Clinical Uses
• A tetracycline is the drug of choice in infections with
Mycoplasma pneumoniae, chlamydiae, rickettsiae, and
some spirochetes.
• They are used in combination regimens to treat gastric and
duodenal ulcer disease caused by Helicobacter pylori.
• They may be used in various gram-positive and gram-negative
bacterial infections, including vibrio infections, provided the
organism is not resistant.
• In cholera, tetracyclines rapidly stop the shedding of vibrios,
but tetracycline resistance has appeared during epidemics.
• Tetracyclines remain effective in most chlamydial infections,
including sexually transmitted diseases.
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Clinical Uses
• Tetracyclines are no longer recommended for treatment of
gonococcal disease because of resistance.
• A tetracycline—usually in combination with an
aminoglycoside— is indicated for plague, tularemia, and
brucellosis.
• Tetracyclines are sometimes used in the treatment of protozoal
infections, eg, those due to Entamoeba histolytica or
Plasmodium falciparum .
• Other uses include treatment of acne, exacerbations of
bronchitis, community-acquired pneumonia, Lyme
disease, relapsing fever, leptospirosis, and some
nontuberculous mycobacterial infections (eg,
Mycobacterium marinum).
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Clinical Uses
• Tetracyclines formerly were used for a variety of common
infections, including bacterial gastroenteritis, pneumonia
(other than mycoplasmal or chlamydial pneumonia), and
urinary tract infections. However, many strains of bacteria
causing these infections now are resistant, and other agents
have largely supplanted tetracyclines.

• Demeclocycline inhibits the action of antidiuretic hormone in

the renal tubule and has been used in the treatment of
inappropriate secretion of antidiuretic hormone or similar
peptides by certain tumors.
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Adverse Reactions
Hypersensitivity reactions (drug fever, skin rashes) to
tetracyclines are uncommon.
Most adverse effects are due to direct toxicity of the drug or to
alteration of microbial flora.

Gastrointestinal Adverse Effects

Nausea, vomiting, and diarrhea are the most common reasons
for discontinuing tetracycline medication. Nausea, anorexia, and
diarrhea can usually be controlled by administering the drug with
food or reducing drug dosage, or discontinuing the drug.
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Adverse Reactions
Superinfections:
Tetracyclines modify the normal flora, with suppression of
susceptible coliform organisms and overgrowth of pseudomonas,
proteus, staphylococci, resistant coliforms, clostridia, and
candida.

Overgrowths of Candida (for example, in the vagina) or of

resistant staphylococci (in the intestine) may occur.

Pseudomembranous colitis due to an overgrowth of Clostridium

difficile has also been reported.
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Adverse Reactions
Bony Structures and Teeth
Tetracyclines are readily bound to calcium deposited in newly
formed bone or teeth in young children. When a tetracycline is
given during pregnancy, it can be deposited in the fetal teeth,
leading to fluorescence, discoloration, and enamel dysplasia; it
can also be deposited in bone, where it may cause deformity or
growth inhibition.
Because of these effects tetracyclines are generally avoided in
pregnancy. If the drug is given for long periods to children under
8 years of age, similar changes can result.
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Adverse Reactions
Liver Toxicity
Tetracyclines can probably impair hepatic function, especially during
pregnancy, in patients with preexisting hepatic insufficiency and
when high doses are given intravenously. Hepatic necrosis has
been reported with daily doses of 4 g or more intravenously.
Kidney Toxicity
Renal tubular acidosis and other renal injury resulting in nitrogen
retention have been attributed to the administration of outdated
tetracycline preparations. Tetracyclines given along with diuretics
may produce nitrogen retention.
Tetracyclines other than doxycycline may accumulate to toxic
levels in patients with impaired kidney function.
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Adverse Reactions
Local Tissue Toxicity
Intravenous injection can lead to venous thrombosis.
Intramuscular injection produces painful local irritation and should be
avoided.
Photosensitization
Systemically administered tetracycline, especially demeclocycline
can induce sensitivity to sunlight or ultraviolet light, particularly in
fair-skinned persons.
Vestibular Reactions
Dizziness, vertigo, nausea, and vomiting have been noted particularly
with doxycycline at doses above 100 mg.
With dosages of 200–400 mg/d of minocycline, 35–70% of patients will
have these reactions.
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Contraindications
Renally impaired patients should not be treated with any of the
tetracyclines except doxycycline.

Accumulation of tetracycline's may aggravate preexisting

azotemia by interfering with protein synthesis thus promoting
amino acid degradation.

The tetracyclines should not be employed in pregnant or

breast feeding women or children less than 8 years age.
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