Anti Microbial Therapy Protein Synthesis Inhibitors PDF

Anti Microbial Therapy Protein Synthesis Inhibitors Pharmacology 2 (1601310) December 1,2 ,3,4 First Semester 2024-2025 Asst. Prof. Dr. Najlaa Saadi Eighth week, Sunday PhD Clinical Pharmacology Monday ,Tuesday, Wednesday Protein sy...

Anti Microbial Therapy Protein Synthesis Inhibitors Pharmacology 2 (1601310) December 1,2 ,3,4 First Semester 2024-2025 Asst. Prof. Dr. Najlaa Saadi Eighth week, Sunday PhD Clinical Pharmacology Monday ,Tuesday, Wednesday Protein synthesis inhibitors include:  Tetracyclines  Aminoglycosides  Macrolides  Chloramphenicol  Linezolid  Clindamycin Tetracyclines  Broad-spectrum  Bacteriostatic antibiotics  Effective against gram-positive and gram-negative bacteria, as well as other organisms. Classification According to Duration of Action:  Short-acting (Half-life is 6-8 hrs) Tetracycline Chlortetracycline Oxytetracycline  Intermediate-acting (Half-life is ~12 hrs) Demeclocycline Methacycline  Long-acting (Half-life is 16 hrs or more) Doxycycline Minocycline Tigecycline Mechanism of Action of Tetracyclines  Inhibit bacterial protein synthesis.  Enter organisms by passive diffusion and energy-dependent transport through the bacterial inner cytoplasmic membrane.  Concentrate intracellularly.  Bind reversibly to the 30S subunit of the bacterial ribosome in the mRNA translation complex.  Inhibit binding of aminoacyl-tRNA to the mRNA-ribosome complex at the acceptor site. Tetracyclines binds to the 30S ribosomal subunit, thus preventing the binding of aminoacyl-tRNA to the ribosome. aa = amino acid Pharmacokinetic of Tetracycline  Diet decreases absorption due to formation of non-absorbable chelates with calcium ions, divalent, and trivalent cations (found in magnesium and aluminum antacids, and iron preparations).  Doxycycline & Minocycline: Almost fully absorbed orally.  Doxycycline Preferred for parenteral administration. Side Effects of Tetracyclines 1. Epigastric distress: this can be controlled if the drug is taken with foods other than dairy products. 2. Deposition in the bone and primary dentition: occurs during calcification in growing children. & cause discoloration and hypoplasia of the teeth and a temporary stunting of growth. 3. Hepatotoxicity: in pregnant women who received high doses of tetracyclines, especially with pyelonephritis pregnant women Other Side Effects of Tetracyclins 4. Phototoxicity: sunburn, occurs when a patient receiving a tetracycline is exposed to sun or ultraviolet rays (with tetracycline, doxycycline and demeclocycline). 5. Vestibular problems: (dizziness, nausea, and vomiting) occur particularly with minocycline & Doxycycline Other Side Effects of Tetracyclins 6. Pseudotumor cerebri: Benign, intracranial hypertension (reversible) characterized by headache and blurred vision may occur rarely in adults. 7. Superinfections: Overgrowths of Candida in the vagina or of resistant staphylococci in the intestine, Pseudomembranous colitis due to an overgrowth of Clostridium difficile Some Adverse Effects of Tetracycline Contraindications of Tetracyclins :  Renally impaired patients should not be treated with any of the tetracyclines EXCEPT doxycycline. Accumulation of tetracyclines may cause a higher-than-normal level of urea or other nitrogen-containing compounds in the blood)by interfering with protein synthesis, thus promoting amino acid degradation.  Pregnant or breast-feeding women  Children less than 8 years of age. Aminoglycosides Amikacin Gentamicin Tobramycin Streptomycin  Inhibits bacterial protein synthesis  Bactericidal (unlike most protein synthesis inhibitors)  Effective against aerobic gram-negative bacilli, including Pseudomonas aeruginosa  Replaced by safer antibiotics (e.g., third- and fourth- generation cephalosporins, fluoroquinolones, carbapenems) due to toxicities Mechanism of Action of Aminoglycosides  Effective only against aerobic organisms (anaerobes lack the oxygen-requiring transport system), through which the Aminoglycosides diffuse.  Aminoglycosides bind to the 30S ribosomal subunit Distort structure, interfering with protein synthesis initiation.  Cause mRNA misreading, leading to mutations or premature chain termination. Mechanism of Action of the Aminoglycosides Pharmacokinetic of Aminoglycosides  Poorly absorbed from the gastrointestinal tract.  Must be given parenterally, except neomycin, which is used topically for skin infections or orally to prepare the bowel before surgery due to its nephrotoxicity Side Effects of Aminoglycosides Toxicities increase with old age, previous exposure to aminoglycosides and liver disease 1. Ototoxicity: Accumulates in inner ear and destroyed hear cells Deafness may be irreversible and has been known to affect fetuses in utero. Concomitant uses with other ototoxic drug: cisplatin, furosemide, bumetanide, or ethacrynic acid increase the risk. Vertigo and loss of balance (with streptomycin) because these drugs affect the vestibular apparatus. 2. Nephrotoxicity: Mild, reversible renal impairment to severe, irreversible acute tubular necrosis 3. Neuromuscular paralysis The drugs reduce acetylcholine release from prejunctional nerve endings and decrease postsynaptic site sensitivity. Patients with myasthenia gravis are particularly at risk. Administering calcium gluconate or neostigmine promptly can reverse the paralysis.. 4. Allergic reactions: Occurs with the topical application of neomycin. Some Adverse Effects of Aminoglycosides Macrolides  Erythromycin  Clarithromycin  Azithromycin  Dirithromycin  Roxithromycin  Tulathromycin  Ketolides Telithromycin Cethromycin  Spiramycin (Treatment of Toxoplasmosis)  Ansamycins: (Rifamycins) (treatment of tuberculosis, leprosy and AIDS-related mycobacterial infections Note: Non-antibiotic macrolide. The drugs Tacrolimus and Sirolimus are Non-antibiotic macrolide used as immunosuppressants. Mechanism of Action of Macrolides  They are bacteriostatic but can become bactericidal at higher doses.  They bind irreversibly to a site on the 50S subunit of the bacterial ribosome, interfering with protein synthesis. Mechanism of action of erythromycin and clindamycin Pharmacokinetics of Macrolides  Erythromycin comes in various salt forms: estolate, stearate, propionate, and succinate.  Erythromycin estolate is absorbed most effectively when taken orally, regardless of food intake. Administration and Fate of the Macrolide Antibiotics Inhibition Of The Cytochrome P450 System By Erythromycin, Clarithromycin and Telithromycin. Erythromycin  As alternative to penicillin in allergic patients.  As prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease Clarithromycin  Effective against Haemophilus influenzae, intracellular pathogens; Chlamydia, Legionella, Moraxella, and effective against Helicobacter pylori, leprosy, effective against protozoa including Toxoplasma gondii. Azithromycin  Less active against streptococci and staphylococci than erythromycin  More active against respiratory infections due to H. influenzae and Moraxella catarrhalis than erythromycin.  Azithromycin is now the preferred therapy for urethritis caused by Chlamydia trachomatis.  Azithromycin, effective against protozoa including Toxoplasma gondii  Has activity against Mycobacterium avium- intracellulare complex in patients with acquired immunodeficiency syndrome and disseminated infections patients. Telithromycin  This ketolide drug, has an antibacterial spectrum similar to azithromycin.  Its structural modifications neutralize common resistance mechanisms, such as methylase-mediated and efflux-mediated resistance, which often render macrolides ineffective. Adverse Effects of Macrolides 1. Epigastric distress (erythromycin): anorexia, nausea, vomiting, diarrhea. 2. Cholestatic jaundice (erythromycin estolate): hypersensitivity reaction. 3. Other allergic reactions: fever, eosinophilia, rashes. 4. Ototoxicity: transient deafness (erythromycin) at high doses. Contraindications of Macrolides  Hepatic Dysfunction: Use erythromycin, telithromycin, or azithromycin cautiously; telithromycin can cause severe hepatotoxicity.  QTc Prolongation: Telithromycin prolongs the QTc interval; avoid in patients with congenital QTc prolongation or proarrhythmic conditions.  Renal Compromise: Use telithromycin cautiously.  Myasthenia Gravis: Telithromycin is contraindicated. Drug Interactions of Macrolides 1. Erythromycin, telithromycin and clarithromycin are enzyme inhibitors (inhibit metabolism of a number of drugs) 2. This antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin & lead to greater reabsorption of the drug from the enterohepatic circulation. Note: No interactions have been reported for azithromycin. Chloramphenicol  Broad-spectrum antibiotic  Active not only against bacteria but also against other microorganisms, such as rickettsiae.  Pseudomonas aeruginosa is not affected, nor are the chlamydiae.  Chloramphenicol has excellent activity against anaerobes.  Its use is restricted to life-threatening infections (because of its toxicity) Mechanism of Action of Chloramphenicol  Binds to bacterial 50S ribosomal subunit, inhibiting protein synthesis at the peptidyl transferase reaction.  Note: Chloramphenicol can inhibit protein synthesis in mammalian mitochondrial ribosomes at high levels, causing bone marrow toxicity. Administration and Fate of Chloramphenicol Side Effects of Chloramphenicol Anemias: Hemolytic anemia in patients with low glucose 6- phosphate dehydrogenase. Reversible anemia. Aplastic anemia. Gray Baby Syndrome: Neonates have low capacity to glucuronylate the antibiotic and have underdeveloped renal function. Leads to poor feeding, depressed breathing, cardiovascular collapse, cyanosis (gray baby), and death. Also occurs in adults at high doses. Drug Interactions of Chloramphenicol  Inhibit the metabolism warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby elevating their concentrations and potentiating their effects Inhibition of the cytochrome P450 system by chloramphenicol Clindamycin  Mechanism of action it is simillar to that of erythromycin.  Used in the treatment of infections caused by anaerobic bacteria, such as Bacteroides fragilis, which causes abdominal infections associated with trauma Adverse Effect of Clindamycin 1. Pseudomembranous collites by C. difficile (potentially fatal), oral administration of Vancomycin should be reserved for a condition that does not respond to metronidazole. 2. Impaired liver function