Download Tetracyclines Mechanism of Action

Antimicrobials
Protein Synthesis Inhibitors
(Tetracyclines & Linezolid)
Laith Mohammed Abbas Al-Huseini
M.B.Ch.B., M.Sc, M.Res, Ph.D
Department of Pharmacology and Therapeutics
Introduction
• A number of antibiotics exert their antimicrobial effects by targeting
bacterial ribosomes and inhibiting bacterial protein synthesis.
• Bacterial ribosomes are composed of 30S and 50S subunits
(mammalian ribosomes have 40S and 60S subunits).
• In general, selectivity for bacterial ribosomes minimizes potential
adverse consequences encountered with the disruption of protein
synthesis in mammalian host cells.
• However, high concentrations of drugs such as chloramphenicol or the
tetracyclines may cause toxic effects as a result of interaction with
mitochondrial mammalian ribosomes, since the structure of
mitochondrial ribosomes more closely resembles bacterial ribosomes.
Tetracyclines
• Class of antibiotics having a nucleus four fused cyclic rings
with a system of conjugated double bonds.
• Derived from a golden-coloured, fungus-like, soil-dwelling
bacterium named Streptomyces aureofaciens
• Substitutions on these rings alter the individual
pharmacokinetics and spectrum of antimicrobial activity.
Mechanism of Action
• Tetracyclines enter susceptible organisms via passive diffusion
and by an energy-dependent transport protein mechanism
unique to the bacterial inner cytoplasmic membrane.
• Tetracyclines concentrate
intracellularly in susceptible
organisms.
• The drugs bind reversibly to the
30S subunit of the bacterial
ribosome.
• This action prevents binding of
tRNA to the mRNA–ribosome
complex, thereby inhibiting
bacterial protein synthesis.
Spectrum of Antibacterial Activity
• Tetracyclines are active against many gram-positive and
gram-negative bacteria, including mycobacteria and
anaerobes.
• Rickettsiae, chlamydiae, protozoa, spirochetes and
mycoplasmas are also sensetive.
• 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, if that is the mechanism of
resistance.
Classification
• Tetracycline
• Chlortetracycline
• Oxytetracycline
• Demeclocycline
• Methacycline
• Doxycycline
• Minocycline
Short-acting (6-8 hours)
Intermediate-acting (12 hours)
Long-acting (16-18 hours)
Pharmacokinetics
• Absorption: oral administration is
approximately 30% for
chlortetracycline; 60–70% for
tetracycline, oxytetracycline,
demeclocycline, and methacycline;
and 95–100% for doxycycline and
minocycline.
• Distribution: The tetracyclines
concentrate well in the bile, liver,
kidney, gingival fluid, and skin.
Moreover, they bind to tissues
undergoing calcification (for example,
teeth and bones) or to tumors that
have a high calcium content.
Pharmacokinetics
• Only minocycline and doxycycline achieve therapeutic levels
in the cerebrospinal fluid (CSF).
•All tetracyclines cross the placental barrier and concentrate in
fetal bones and dentition.
•Elimination: Tetracycline and doxycycline are not hepatically
metabolized.
• Tetracycline is primarily eliminated unchanged in the urine,
whereas 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.
Therapeutic Uses
1. Empirical therapy: Tetracyclines are often employed when the nature
and sensitivity of the infecting organism cannot be reasonably
guessed.
2. First choice in:
(a) Venereal diseases
(b) Atypical pneumonia
(c) Cholera
(d) Brucellosis
(e) Plague
(f) Relapsing fever
(g) Rickettsial infections
3.
(a)
(b)
(c)
(d)
(e)
(f)
Second choice in:
Tetanus, anthrax, actinomycosis and Listeria infections.
Gonorrhoea
Syphilis
Leptospirosis
pneumonia due to Chlamydia pneumoniae.
Chancroid and tularemia.
Therapeutic Uses
4. Other situations in which tetracyclines may be used are:
(a) Urinary tract infections: Odd cases in which the organism has been
found sensitive.
(b) Community-acquired pneumonia, when a more selective antibiotic
cannot be used.
(c) Amoebiasis: along with other amoebicides for chronic intestinal
amoebiasis.
(d) As adjuvant to quinine or artesunate for chloroquine-resistant P.
falciparum malaria.
(e) Acne vulgaris: prolonged therapy with low doses may be used in
severe cases.
Adverse Effects
1.Gastric discomfort: Epigastric distress commonly results from
irritation of the gastric mucosa and is often responsible for
noncompliance with tetracyclines. Esophagitis may be minimized
through co-administration with food (other than dairy products) or
fluids and the use of capsules rather than tablets.
2. Effects on calcified tissues: Deposition in the bone and primary
dentition occurs during the calcification process in growing
children. This may cause discoloration and hypoplasia of teeth and
a temporary stunting of growth.
The use of tetracyclines is limited in pediatrics.
3. Hepatotoxicity: Rarely hepatotoxicity may occur with high
doses, particularly in pregnant women and those with preexisting
hepatic dysfunction or renal impairment.
4. Phototoxicity: Severe sunburn may occur in patients receiving a
tetracycline who are exposed to sun or ultraviolet rays.
This toxicity is encountered with any tetracycline, but more
frequently with tetracycline and demeclocycline.
Patients should be advised to wear adequate sun protection.
5. Vestibular dysfunction: Dizziness, vertigo, and tinnitus may
occur particularly with minocycline, which concentrates in the
endolymph of the ear and affects function.
Doxycycline may also cause vestibular dysfunction.
6. Pseudotumor cerebri: Benign, intracranial hypertension
characterized by headache and blurred vision may occur rarely in
adults.
7. Contraindications: The tetracyclines should not be used in
pregnant or breast-feeding women or in children less than 8 years
of age.
Resistance
Three mechanisms of resistance:
(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.
Minocycline
• 200 mg orally daily for 5 days, can eradicate the
meningococcal carrier state, but because of side effects and
resistance of many meningococcal strains, ciprofloxacin or
rifampin is preferred.
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.
Tigecycline
• It is the first member of a new class of synthetic tetracycline
analogues (glycyl-cyclines), has several unique features.
•Its spectrum is very broad includes methicillin resistant
staphylococci (MRSA), multidrug-resistant streptococci,
vancomycin-resistant enterococci (VRE), extended-spectrum
β-lactamase–producing gram-negative bacteria.
• Many tetracycline-resistant strains are susceptible to
tigecycline because it is not affected by the common resistance
determinants.
• Formulated for i.v. administration only (poorly absorbed
from GIT), is given as a 100 mg loading dose, then 50 mg
every 12 hours.
• As with all tetracyclines, tissue and intracellular penetration
is excellent.
• Elimination is primarily biliary, and no dosage adjustment is
needed for patients with renal insufficiency.
• Approved for treatment of skin and skin-structure infection,
intra-abdominal infections, and communityacquired
pneumonia.
• Not effective for urinary tract infections.
• The most common side effect is nausea and occasionally
vomiting. Others are epigastric distress, diarrhoea, skin
reactions, photosensitiviy injection site complications and
superinfections.
Linezolid
• A synthetic oxazolidinone developed to
combat resistant gram-positive organisms,
such as methicillin-resistant Staphylococcus
aureus, VRE, and penicillin-resistant
streptococci.
• Binds to the bacterial 23S ribosomal RNA of
the 50S subunit, thereby inhibiting the
formation of the 70S initiation complex.
• Its antibacterial action directed primarily
against Gr+ve organisms, such as
staphylococci, streptococci, and enterococci,
as well as Corynebacterium species and
Listeria monocytogenes.
• Moderately active against Mycobacterium tuberculosis and
may be used against drug-resistant strains.
• Generally is bacteriostatic. However, it is bactericidal against
streptococci.
• Resistance primarily occurs via reduced binding at the target
site.
• Cross-resistance with other protein synthesis inhibitors does
not occur.
• Completely absorbed after oral administration, widely
distributed throughout the body.
• The drug is excreted both by renal and non-renal routes.
•The most common adverse effects are gastrointestinal
upset, nausea, diarrhea, headache, and rash.
• Possesses nonselective monoamine oxidase activity
and may lead to serotonin syndrome if given
concomitantly with large quantities of tyraminecontaining foods.
• Irreversible peripheral neuropathies and optic
neuritis have been associated with greater than 28 days
of use