Protein Synthesis Inhibitors. Ass Prof. Dr. Naza M. Ali 15 Nov 2018 Lec 8
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1 Protein Synthesis Inhibitors Ass Prof. Dr. Naza M. Ali 15 Nov 2018 Lec 8
2 These drugs selectively inhibit bacterial protein synthesis. The selectivity is due to the differences between bacterial and human ribosomal proteins, RNA, and associated enzymes. Bacteria have 70S ribosomes with 50S and 30S subunits Mammalian cells have 80S ribosomes with 60S and 40S subunits.
3 Macrolides The macrolides are a group of antibiotics with a Large cyclic lactone structure to which one or more deoxy sugars are attached.
4
5 Macrolides -Erythromycin -Clarithromycin -Azithromycin -Roxithromycin -Spiramycin 125mg, 250mg, 500mg 500mg 200mg, 250 mg, 500mg 150mg, 500mg 1,500,000 IU 3,000,000 IU
6 Mechanism of Action Macrolides bind irreversibly to a site on the 50S subunit of the bacterial ribosome, inhibiting the translocation steps of protein synthesis. Also interfere with transpeptidation steps. Bacteriostatic, or bactericidal higher doses
7
8 Antibacterial spectrum Erythromycin: Is effective against many of the same organisms as penicillin G It is used in patients who are allergic to the penicillins (syphilis) It is used in Corynebacterium Diphtheriae
9 Clarithromycin: Same of erythromycin, Also effective against H.influenzae Its activity against intracellular pathogens, is higher than that of erythromycin. Chlamydia, Legionella, Moraxella, H. pylori
10 Azithromycin: Less active against strepto & staphyl than erythromycin More active against respiratory infections due to H.influenzae, Moraxella catarrhalis. Preferred therapy for urethritis due to Chlamydia trachomatis.
11
12 Resistance 1) The inability of the organism to take up the antibiotic or the presence of an efflux pump, both of which limit the amount of intracellular drug. 2) A decreased affinity of the 50S ribosomal subunit for the antibiotic. 3) The presence of a plasmid-associated erythromycin esterase.
13 Pharmacokinetic: Absorption The erythromycin base is destroyed by gastric acid So, either enteric-coated tablets or esterified forms of the antibiotic are administered. All are adequately absorbed upon oral administration Clarithromycin, azithromycin, and telithromycin are stable to stomach acid and are readily absorbed. Food interferes with the absorption of erythromycin & azithromycin, but can increase that of clarithromycin.
14 Distribution: Erythromycin distributes well to all body fluids except CSF. It is one of the few antibiotics that diffuses into prostatic fluid, and it also accumulates in macrophages. Clarithromycin, azithromycin are widely distributed in the tissues. Azithromycin concentrates in neutrophils, macrophages, and fibroblasts.
15 Azithromycin concentration in phagocyte lysosomes can be 40 times higher than in blood and they can enhanced intracellular killing of bacteria by phagocytes Inflammation allows for greater tissue penetration. It has the longest half-life and the higher volume of distribution
16 Pharmacokinetics
17 Elimination: Erythromycin and telithromycin are extensively metabolized hepatically. They inhibit the oxidation of a number of drugs through their interaction with the CYP450 system.
18 Excretion: Erythromycin and azithromycin are primarily concentrated and excreted in the bile as active drugs. Partial reabsorption occurs through the enterohepatic circulation. Clarithromycin and its metabolites are eliminated by the kidney as well as the liver. The dosage of this drug should be adjusted in patients with renal impairment.
19 Excretion
20 Adverse effects 1. GIT irritation 2. Cholestatic jaundice: ( erythromycin estolate form) 3. Ototoxicity: transient deafness at high dosage
21 Contraindication: Patients with hepatic dysfunction should be treated with caution, because these drugs accumulate in the liver. macrolides and ketolides may prolong the QT c interval and should be used with caution in those patients with proarrhythmic conditions or concomitant use of pro arrrhythmic agents.
22 Interactions: Erythromycin, telithromycin, clarithromycin inhibit hepatic metabolism of a number of drugs, lead to toxic accumulations of these compounds. An interaction with digoxin may occur. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of the drug from the enterohepatic circulation.
23
24 Telithromycin - Is a ketolide structurally related to macrolides. -same mechanism of action as erythromycin & a similar spectrum of antimicrobial activity. -some macrolide resistant strains are susceptible to telithromycin.
25 Fidaxomicin Is a macrocyclic antibiotic with a structure similar to the macrolides; Mechansim of action it has a unique mechanism of action. -acts on the sigma subunit of RNA polymerase, -thereby disrupting bacterial transcription, - terminating protein synthesis, -and resulting in cell death in susceptible organisms.
26 Fidaxomicin has a very narrow spectrum of activity limited to gram-positive aerobes and anaerobes. it possesses activity against staphylococci and enterococci It is used primarily against Clostridium difficile. Following oral administration, has minimal systemic absorption and primarily remains within GIT. This is ideal for the treatment of C. difficile infection, which occurs in the gut.
27 This characteristic also likely contributes to the low rate of adverse effects. Hypersensitivity reactions may occur. Fidaxomicin should be used with caution in patients with a macrolide allergy, as they may be at increased risk for hypersensitivity.
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