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Protein synthesis inhibitors 30s, Other important uses, Side effects,…
Protein synthesis inhibitors 30s
Other important uses
Inflammatory acne (tetracycline and minocycline).
Community acquired pneumonia (doxycycline).
Skin and soft tissue infection (doxycycline and minocycline).
meningococcal carrier state(minocycline), malaria prophylaxis(doxycycline), Amoebiasis(doxycycline), SIADH (demeclocycline is used),
As secondary drugs for gonorrhea, syphilis and chlamydial infection,
pleurodesmosis in malignant
pleural effusion (doxycycline as a sclerosing agent), leprosy(minocycline),
peptic ulcer by H.pylori(tetracycline).
Anthrax, tularemia, leptospirosis and periodontitis (doxycycline), nocardiosis and mycobacterial infections (minocycline).
Side effects
Demeclocycline(maximum) and doxycycline can result in photosensitivity.
Minocycline may lead to dose dependent vestibular toxicity.
Diabetes insipidus may be precipitated by ADH antagonistic action of demeclocycline.
Tetracyclines also possess anti-anabolic effects.
They may increase intracranial pressure (pseudotumor cerebri) and cause bulged frontanelle in young infants.
Treatment of young children < 8 years with tetracycline may cause dentition abnormalities like dental enamel hypoplasia, yellowish brown discolouration of teeth.
High doses of tetracycline may lead to hepatic necrosis especially in pregnant females.
Outdated tetracycline use may lead to fanconis syndrome a type of renal tubular acidosis.
Tetracyclines may exacerbate pre-existing renal dysfunction. although these are not directly nephrotoxic.
Tetracyclines may cause superinfection diarrhea and pseudomembranous colitis.
Gastrointestinal side effects are most common adverse effects.
Tetracyclines are contraindicated in pregnancy due to the risk of fetal tooth enamel dysplasia and irregularities in the fetal bone growth.
Resistance to aminoglycosides
Resistance to these drugs develops due to the formation of inactivating enzymes
which acetylate, phosphorylate or adenylate the aminoglycosides.
All aminoglycosides except amikacin are susceptible to these enzyme.
Thus amikacin may be effective against organisms resistant to other aminoglycosides.
Streptomycin
Streptomycin is the first line drug for the treatment of tuberculosis, plague and tularemia.
Streptomycin is also used in Endocarditis in combination with a cell wall–active agent.
Amikacin
Amikacin is used in UTI, Lung infections, including cystic fibrosis exacerbations, Nosocomial sepsis of unknown origin.
Amikacin is a second line drug for the treatment of tuberculosis and is also used for MDR tuberculosis.
Plazomicin
Plazomicin is used in UTI.
Similar to amikacin, with activity against some gram-negative bacilli resistant to other aminoglycosides.
Paromomycin
Paromomycin is used in cryptosporidium infection, intestinal amebiasis, and Leishmaniasis.
It is used as IM for visceral leishmaniasis and topically for cutaneous leishmaniasis.
MOA
Tetracyclines bind to the 30S subunit, block tRNA binding to the A site, and thereby inhibit protein synthesis.
General features
General: Bacteriostatic;
Oral formulations interact with orally administered cations (calcium, iron, aluminum);
Avoid in pregnancy and children < 8 years due to permanent tooth discoloration and photosensitivity.
Tetracycline and derivatives:
Important drugs:
Tetracycline (PO/Topical)
Oxytetracycline (IV/PO)
Doxycycline (IV/PO)
Minocycline (IV/PO/Topical)
Demeclocycline (PO)
Omadacycline (IV/PO)
Eravacycline (IV)
Sarecycline (PO)
Glycylcycline: Tigecycline (IV)
Pharmacokinetics
All tetracyclines undergoes enterohepatic circulation.
All tetracycline are excreted primarily in the urine except doxycycline.
Doxycycline is excreted in feces and thus can be used in the presence of renal failure.
Half life of doxycycline and minocycline are longer than tetracyclines.
Development of resistance
Tetracyclines are broad spectrum bacteriostatic drugs.
Development of resistance to tetracycline is mainly due to the development of efflux pumps.
most preferred tetracycline
Doxycycline is the most preferred tetracycline for most indications
due to more favorable activity, tolerability, and frequency of administration.
Minocycline
Minocycline is similar to doxycycline, with improved activity vs. staphylococci, Acinetobacter, and Stenotrophomonas maltophilia.
drug of choice
Tetracyclines are drug of choice for
lymphogranuloma venerum, granuloma inguinale,
atypical pneumonia due to chlamydia,
Cholera, brucellosis with rifampicin,
plague prophylaxis, relapsing fever, lymes disease,
rickettsial infections and chlamydial infections.
Tigecycline
Tigecycline are more resistant than tetracyclines to efflux pumps developed by the organisms.
Main indication of tigecycline is serious complicated skin and skin structures infection, intraabdominal infections and community acquired pneumonia.
It is used against MRSA, VRSA, enterococci and anaerobes.
Omadacycline
Omadacycline is approved for the treatment of adults with acute bacterial skin and skin structure infections (ABSSSIs)
and for the treatment of adults with community-acquired bacterial pneumonia (CABP).
Eravacycline
Eravacycline is a tetracycline class antibacterial indicated
for the treatment of complicated intra-abdominal infections in patients 18 years of age and older.
Sarecycline
Sarecycline is a tetracycline-derived oral antibiotic, specifically designed for acne,
and is approved by the Food and Drug Administration (FDA) in 2018
for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris (AV) in patients 9 years of age and older.
MOA
The primary intracellular site of action of the aminoglycosides is the 30S ribosomal subunit.
Aminoglycosides interfere with the initiation of protein synthesis, leading to the accumulation of abnormal initiation complexes;
The drugs also can cause misreading of the mRNA template and
Incorporation of incorrect amino acids into the growing polypeptide chains.
General features
Aminoglycosides—Inhibitors of Bacterial Protein Synthesis General: Bactericidal, no GI absorption
Oral administration used only for bowel decontamination or intestinal parasites.
They have poor CSF penetration.
They undergo renal elimination.
Nephrotoxicity, ototoxicity (cochlear and vestibular), neuromuscular blockade are the important adverse effects of aminoglycosides.
Drugs
These include streptomycin, gentamicin, kanamycin, tobramycin, amikacin, sisomicin, netilmicin, neomycin, plazomicin, paromomycin, framycetin.
CDK and PAE
Aminoglycosides exhibit CDK and have prolonged PAE.
Therefore administered as single daily dose.
Aminoglycosides are bactericidal inhibitors of protein synthesis.
inactive against anaerobes
Their penetration across the cell wall is dependent on the oxygen dependent transport system.
Therefore the drugs are inactive against anaerobes.
Their transport is enhanced if used along with cell wall synthesis inhibitors like penicillins.
donot cross BBB
These are not absorbed orally and donot cross the blood brain barrier.
Excretion
These are excreted primarily by glomerular filtration
and their dose should be decreased in renal insufficiency.
Against pseudomonas
Gentamicin, tobramycin and amikacin are effective against gram negative organisms including pseudomonas except salmonella.
However these are not reliable for gram positive organisms if used alone.
Synergistic effects with other antibiotics
Aminoglycosides produce synergistic effects against gram positive bacteria
when combined with beta lactams or vancomycin.
Gentamicin
Gentamicin is used in
UTI, Peritonitis, Endocarditis in combination with a cell wall–active agent, Plague and Tularemia.
Tobramycin
Tobramycin is used in
UTI, Lung infections, including cystic fibrosis exacerbations, Nosocomial sepsis of unknown origin.
Neomycin
Neomycin is used in minor skin infections, Bowel preparation prior to intra-abdominal surgery, Bladder irrigation.
It has similar activity to gentamicin but only used topically, not systemically.
It can cause skin rash.
Spectinomycin
Spectinomycin is a drug related to aminoglycosides
which is used as single dose treatment for
penicillinase producing Neisseria gonorrhoea (PPNG) and for gonorrhoea in penicillin allergic patient.
Nephrotoxicity, ototoxicity, and neuromuscular blockade
Amikacin, kanamycin and neomycin are like to cause hearing loss whereas streptomycin and gentamicin cause predominantly vestibular dysfunction.
Tobramycin cause both abnormalities equally.
Nephrotoxicity maximum with neomycin> gentamicin minimum with streptomycin.
Ototoxicity maximum with amikacin(auditory) streptomycin(vestibular) minimum with netilmicin.
Neuromuscular blockade: neomycin> streptomycin least with tobramycin.
Aminoglycosides and tetracyclines act at 30s ribosome so remember AT 30 years.
Tetracyclines
Newer drugs
Aminoglycosides