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Amino glycosides do not absorbed from GIT. Amino glycosides do not enter CSF. Rapidly excreted by the kidney
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They are water-soluble, stable in solution, and more active at alkaline than at acid pH.
Mechanism of Action
1.
Aminoglycosides diffuse through porin of gram-negative bacteria and enter the periplasmic space.
Divalent cations (Ca2+ and Mg2+), Hyperosmolarity, A reduction in pH, and Anaerobic conditions
Once inside the cell they bind to their targets in the 30S and
or 50S ribosomal subunit and interfere with protein synthesis by:
Premature termination of translation with detachment of the ribosomal complex and incompletely synthesized
protein.
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The resulting defective proteins may be inserted into the cell membrane, leading to altered permeability and further
A.
Binds to the 30S ribosomal subunit and interferes with initiation of protein
synthesis by fixing the 30S-50S ribosomal complex at the start codon (AUG) of mRNA.
B.
Premature termination of translation with detachment of the ribosomal complex and incompletely synthesized protein,
C.
Incorporation of incorrect amino acids (indicated by the X), resulting in the production of abnormal or nonfunctional proteins
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2.
The +vely charged aminoglycoside binds to vely charged sites on the outer bacterial membrane, thereby disrupting membrane integrity.
This rapid action at the outer membrane probably accounts for most of the bactericidal activity.
Mechanism of Resistance
1.
Deletion of the porin, deletion of transport proteins or mutation leading to altered membrane gradient.
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2.
3.
Ribosomal alteration
The receptor proteins on the 30S ribosomal subunit may be altered as a result of mutation.
Antibacterial Spectrum
Have little or no activity against anaerobic microorganisms. Their action against most gram-positive bacteria is limited,
They should not be used as single agents to treat infections caused by gram-positive bacteria.
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Adverse Effects
1.
Ototoxicity
Can cause both vestibular and auditory ototoxicity, both of which can be irreversible.
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2.
Nephrotoxicity AG can diffuse from the tubular lumen subsequent endocytosis and accumulation in lysosomes;
Within the lysosomes, it will bind to anionic phospholipids, inhibiting lysosomal phospholipase A2 lysosomal distension, rupture, and release of acid hydrolases and the aminoglycoside into the cytosol
Free aminoglycoside then binds to other cellular organelles degeneration and cell necrosis.
The severity of aminoglycoside nephrotoxicity is additive with that of vancomycin, polymixin, furosemide, enflurane, cisplatin etc
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3.
Neuromuscular blockade
High dose produce curare like effects such as apnea and respiratory paralysis.
4.
Hypersensitivity reaction
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Therapeutic Uses
Endocarditis
The use of penicillin that alters the cell wall structure can markedly increase the enterance of aminoglycosides into the bacteria and this is an excellent example of synergism between antibiotics.
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Meningitis
Tuberculosis
Streptomycin is used.
Other infection
Tetracyclines
Individual tetracycline differ significantly in their pk All of the tetracycllines are orally active
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Classification
Tetracycline, Oxyteracyclline
Intermediate acting
Demeclocyclline , Methacyclline
Long acting
Doxycyclline, Minocyclline
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Mechanism of Action
Their primary mode of action is inhibition of protein synthesis. TTCs enter gram ve bacteria by passive diffusion through the porin proteins and by energy-dependent active transport that pumps all tetracyclines across the cytoplasmic membrane.
Mammalian cells lack this transport ( Do not actually accumulate the drug )
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Once inside the cell they bind to 30S ribosomal subunit and thereby prevent the binding of aminoacyl transfer RNA (tRNA) to the A site (acceptor site) on the 50S ribosomal unit.
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Therapeutic Uses
The TTCs are the drug of choice in infections with Mycoplasma pneumoniae, Chlamydiae, Rickettsiae, and some Spirochetes.
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Demeclocycline inhibits the action of ADH in the renal tubule and has been used in the treatment of inappropriate secretion of ADH or similar peptides by certain tumors.
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Adverse Effects
Gastrointestinal
Epigastric burning and distress, abdominal discomfort, nausea, vomiting, and diarrhea may occur.
TTCs affect normal flora, for example Pseudomembranous colitis caused by overgrowth of Clostridium difficile is a potentially life-threatening complication
Readily bound to calcium deposited in newly formed bone or teeth in young children.
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.
If the drug is given for long periods to children under 8 years of age, similar changes can result.
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Kidney Toxicity
Tetracyclines other than doxycycline may accumulate to toxic levels in patients with impaired kidney function.
Intravenous injection can lead to venous thrombosis. Intramuscular injection produces painful local irritation and should be avoided.
Photosensitization
Observed as abnormal sunburn reaction, Is particularly associated with demeclocycline and doxycycline administration.
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Vestibular Reactions
Dizziness, vertigo, nausea, and vomiting have been particularly noted with doxycycline at doses above 100 mg.
Hypersensitivity reactions
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Chloramphenicol
venezuelae.
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Mechanism of Action
Chloramphenicol inhibits protein synthesis in bacteria, and to a lesser extent, in eukaryotic cells.
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The interaction b/n peptidyltransferase and its amino acid substrate cannot occur, and peptide bond formation is inhibited
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Mechanism of Resistance
Resistance also can result from decreased permeability and from ribosomal mutation.
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Spectrum of Activity
Chloramphenicol is a broad-spectrum antibiotic that is effective against gram-positive and gram-negative bacteria, including Rickettsia, Mycoplasma, and Chlamydia spp.
It is bacteriostatic against most species, It may be bactericidal against H. influenzae, Neisseria meningitis, and S. pneumoniae
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Adverse Effects
1.
Hematological Toxicity
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The bone marrow depression is dose related and is reversible on discontinuation of CAF.
treatment is available.
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2.
Newborn infants, especially those born prematurely, cannot adequately conjugate chloramphenicol to form the glucuronide; they also have depressed rates of glomerular and tubular secretion.
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Nausea and vomiting, unpleasant taste, diarrhea, and perineal irritation after oral administration.
Tissues that have a high rate of oxygen consumption may be particularly susceptible to chloramphenicol effects on mitochondrial enzyme systems encephalopathy and cardiomyopathy have been reported.
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Clinical Uses
Chloramphenicol is no longer recognized as the treatment of choice for any bacterial infection other effective antimicrobial agents are available in almost all instances.
It is now reserved for treatment of life-threatening infections in patients who cannot take safer alternatives because of resistance or allergies.
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3.
4.
Anaerobic Infections
Other uses
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Drug interaction
Inhibits cytochrome P450 isozymes warfarin, dicumarol, phenytoin, chlorpropamide, antiretroviral protease inhibitors, rifabutin, and tolbutamide.
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Macrolides
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Oleandomycin is not commonly used, its acetylated derivative, Troleandomycin, is available for oral use.
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Mechanism of Action
Macrolides bind to the 50S ribosomal subunit of bacteria at or very near the site that binds chloramphenicol.
inhibit the translocation step where in a newly synthesized peptidyl tRNA molecule moves from the acceptor site on the ribosome to the peptidyl donor site.
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But not to the 80S mammalian ribosome; this accounts for its selective toxicity
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Mechanisms of resistance
Drug efflux by an active pump mechanism. Ribosomal protection by inducible or constitutive production of methylase enzymes which modify the ribosomal target and decrease drug binding.
3.
4.
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Antibacterial Spectrum
The macrolides are effective against a number of organisms, including Mycoplasma spp., H. influenzae, Streptococcus spp. (including S. pyogenes and S. pneumoniae), staphylococci, gonococci, Legionella pneumophila, and other Legionella spp.
Clarithromycin is very active against H. influenzae, Legionella, and Mycobacterium avium-intracellulare, whereas
Azithromycin is superior against Neisseria, and H. influenzae but less active against mycobacterial species.
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Clinical Uses
1.
mycoplasma infections.
2.
Legionnaires' Disease
3.
Chlamydial Infections.
During pregnancy, erythromycin base is recommended as first-line therapy for chlamydial urogenital infections.
4.
Diphtheria
Erythromycin is very effective for acute infections or for eradicating the carrier state.
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5.
Erythromycin is the drug of choice. Clarithromycin and Azithromycin also are effective.
6.
Clarithromycin 500 mg, in combination with omeprazole, 20 mg, and amoxicillin, 1 g, each administered twice daily for 10 to 14 days, is effective for treatment of peptic ulcer disease caused by H. pylori
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7.
Mycobacterial Infections.
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8.
Syphilis.
Erythromycin has been used in the treatment of early syphilis in patients who are allergic to penicillin, but it no
longer is recommended.
9.
Other uses
Adverse Effects
Gastrointestinal Effects
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Liver Toxicity
It is caused primarily by erythromycin estolate and rarely by the ethylsuccinate or the stearate.
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Allergic reactions - fever, eosinophilia, and skin eruptions. Erythromycin has been reported to cause cardiac arrhythmias, including QT prolongation with ventricular tachycardia.
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Drug Interactions
Erythromycin and clarithromycin inhibit CYP3A4 and are associated with clinically significant drug interactions.
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