Antibiotics Lecture Notes PDF

College of Medicine Department of BMS Pharmacology Lecture- Antibiotics/ Protein synthesis inhibitors Dr. Firdaus Nuri 05/01/2025 Dr.Firdaus...

College of Medicine Department of BMS Pharmacology Lecture- Antibiotics/ Protein synthesis inhibitors Dr. Firdaus Nuri 05/01/2025 Dr.Firdaus 1  College of Medicine Outline: 1. Introduction 2. Aminoglycosides 3. Macrolides 4. Tetracyclines 5. Chloramphenicol 6. Others agents from protein synthesis inhibitor 05/01/2025 Dr.Firdaus 2 College of Medicine Objectives By the end of this lecture, you will learn general background about antibiotic (protein synthesis inhibitors) 05/01/2025 Dr.Firdaus 3  College of Medicine Introduction Cell Wall Synthesis: inhibit the synthesis of the bacterial cell wall. Cell Membrane Integrity: Antibiotics such as polymyxins disrupt the bacterial cell membrane, leading to leakage of cell contents and cell death. Nucleic Acid Synthesis: Antibiotics interfere with the synthesis of DNA and RNA, disrupting replication and transcription processes necessary for bacterial cell function and division. Metabolic Pathways: Antibiotics inhibit essential bacterial enzymes involved in folic acid synthesis, which is crucial for DNA and RNA synthesis. Protein Synthesis: Antibiotics bind to bacterial ribosomes, interfering with protein synthesis. This prevents the bacteria from producing essential proteins needed for growth and reproduction. 05/01/2025 Dr.Firdaus 4  College of Medicine Introduction In bacteria, protein synthesis takes place in the cytoplasm. all components necessary for protein synthesis are freely available in the cytoplasm. Protein synthesis involves two main stages: 1. Transcription: RNA polymerase binds to the DNA promoter region, synthesizes a complementary mRNA strand, and releases the mRNA upon reaching a termination sequence. 2. Translation: the mRNA binds to a ribosome, where tRNA molecules bring amino acids that are linked together to form a protein until a stop codon is reached, causing the protein to detach. Ribosomes, composed of rRNA and proteins, facilitate the binding of mRNA and tRNA, ensuring accurate and efficient protein synthesis. 05/01/2025 Dr.Firdaus 5  College of Medicine Protein synthesis Inhibitors Protein synthesis inhibitors are antibiotics that interfere with bacterial protein synthesis, targeting processes such as translation or transcription. 1.Aminoglycosides: e.g., streptomycin, gentamicin 2.Macrolides: e.g., erythromycin, clarithromycin. 3.Tetracyclines: e.g., tetracycline, doxycycline 4.Chloramphenicol: Antimicrobial effects by targeting bacterial ribosomes and inhibiting bacterial protein synthesis. Bacterial ribosomes differ structurally from mammalian cytoplasmic ribosomes and are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits). 05/01/2025 Dr.Firdaus 6  College of Medicine Protein synthesis Inhibitors Mechanism of protein synthesis Ribosomes 50 S mRNA 30 S tRNA 05/01/2025 Dr.Firdaus 7 College of Medicine Aminoglycosides Aminoglycosides (AGs) are antibiotics are polycationic carbohydrates containing amino sugars in glycosidic linkages. They are derived from the soil actinomycetes of the genus Streptomyces (streptomycin, kanamycin, tobramycin, neomycin) and the genus Micromonospora (gentamicin and sisomicin) semisynthetic products (Amikacin and netilmicin) 05/01/2025 Dr.Firdaus 8  College of Medicine Aminoglycosides Common Properties of Aminoglycosides They are highly water-soluble, polar compounds. Aminoglycosides are not absorbed orally (as they ionize in solution)therefore, they are all given parenterally. They remain extracellularly and penetration into CSF is very poor. They are excreted unchanged by the kidneys. They are all bactericidal. They are mainly effective against gram negative organisms. They produce variable degrees of ototoxicity and nephrotoxicity as adverse effects. 05/01/2025 Dr.Firdaus 9  College of Medicine Aminoglycosides MOA 1. Aminoglycosides are actively transported into the bacterial cell. 2. They bind irreversibly to the 30S ribosomal subunit. 3. They inhibit the formation of the initiation complex, cause misreading of mRNA, and lead to premature termination of the protein synthesis. 4. Production of abnormal proteins disrupts the bacterial cell membrane, increasing permeability. lead to bacterial cell death. rRNA 50 S 50 S tRNA aminoglycosides mRNA RNA aminoglycosides 30 S 30 S 05/01/2025 Dr.Firdaus 10 College of Medicine Aminoglycosides Spectrum of Activity Gram-negative: Active against, aerobic gram-negative bacilli, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp Some Gram-positive: Limited activity; used in combination therapy Clinical Uses 1.Severe systemic infections: such as urinary tract infections (UTIs) 2.Endocarditis in combination with other antibiotics. 3.Intra-abdominal infections alongside other antibiotics. 4.Osteomyelitis (bone infections). 5.Surgical prophylaxis to prevent infections in high-risk patients. 6.Pulmonary infections in cystic fibrosis or bronchiectasis (e.g., inhaled tobramycin). 05/01/2025 Dr.Firdaus 11  College of Medicine Aminoglycosides Resistance: Resistance to aminoglycosides occurs via: 1. Efflux pumps 2. Decreased uptake 3. Modification and inactivation by plasmid- associated enzymes: This is a key resistance mechanism. Plasmid-encoded enzymes, such as aminoglycoside acetyltransferases, phosphotransferases, and adenyltransferases, can modify the drug, rendering it inactive. This is one of the most common and well-known mechanisms of resistance to aminoglycosides Note: Each of these enzymes has its own aminoglycoside specificity; therefore, cross-resistance cannot be presumed. 05/01/2025 Dr.Firdaus 12  College of Medicine Aminoglycosides Adverse effects 1. Ototoxicity: (vestibular and auditory) is directly related to high peak plasma concentrations and the duration of treatment. Aminoglycosides accumulate in the endolymph and perilymph of the inner ear. Vertigo (especially in patients receiving streptomycin) may occur. 2. Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular cells disrupts calcium- mediated transport processes. This results in kidney damage ranging from mild, reversible renal impairment to severe, potentially irreversible acute tubular necrosis. 3. Neuromuscular paralysis: This adverse effect is associated with a rapid increase in concentration (for example, high doses infused over a short period) or concurrent administration with neuromuscular blockers. 4. Allergic reactions: Contact dermatitis is a common reaction to topically applied neomycin. Therapeutic drug monitoring of gentamicin, tobramycin, and amikacin plasma concentrations is imperative to ensure appropriateness of dosing and 05/01/2025 to minimize dose-related toxicities. Dr.Firdaus 13  College of Medicine Aminoglycosides Pharmacokinetics: Absorption: Usually IV; some formulations for topical use. the highly polar, structure of the aminoglycosides prevents adequate absorption after oral administration; therefore, all aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum Concentrations Distribution: Poor penetration into cells, but good in extracellular spaces. because of their hydrophilicity, aminoglycoside tissue concentrations may be subtherapeutic, and penetration into most body fluids is variable. Concentrations achieved in CSF are inadequate, even in the presence of inflamed meninges. Elimination: Primarily renal; more than 90% of the parenteral aminoglycosides are excreted unchanged in the urine 05/01/2025 Dr.Firdaus 14  College of Medicine Tetracyclines Tetracyclines consist of four fused rings with a system of conjugated double bonds. Substitutions on these rings alter the individual pharmacokinetics and spectrum of antimicrobial activity. 05/01/2025 Dr.Firdaus 15 College of Medicine Tetracyclines Mechanism of action: rRNA Tetracyclines reversibly binds to receptors on 50 S the 30S ribosomal subunit of the bacteria. tRNA This action prevents binding of tRNA to the mANA-ribosome complex mRNA This prevents the addition of amino acids to the elongating peptide chain, Tetracyclines 30 S preventing synthesis of proteins. 05/01/2025 Dr.Firdaus 16  College of Medicine Tetracyclines Spectrum of Activity Broad-Spectrum: Effective against: Gram-positive bacteria: Staphylococcus aureus, Streptococcus pneumoniae Gram-negative bacteria: Haemophilus influenzae, Helicobacter pylori Atypical organisms: Mycoplasma pneumoniae, Chlamydia spp. Other: Rickettsiae, Borrelia burgdorferi (Lyme disease). Clinical Uses 1. Respiratory Tract Infections 2. Acne 3. Chlamydia Infections 4. Lyme Disease 5. Peptic Ulcer Disease (due to H. pylori) 6. Malaria Prophylaxis and Treatment 05/01/2025 Dr.Firdaus 17  College of Medicine Tetracyclines Oral Bioavailability: 60-80% for most; ~100% for doxycycline and minocycline. Influencing Factors: Reduced by food, especially dairy and foods high in calcium, Absorption iron, magnesium, and aluminium. Tissue Penetration: Widely distributed; limited penetration into cerebrospinal fluid (CSF). Distribution Binding: High affinity for calcium-rich tissues (teeth, bones); high protein binding (~90% for doxycycline and minocycline, ~60% for tetracycline). Primary Routes is renal (kidneys) and biliary (bile). Excretion: Half-life: Tetracycline: 6-12 hours. Doxycycline and Minocycline: 16-24 hours (allowing once or twice daily dosing). 05/01/2025 Dr.Firdaus 18  College of Medicine Tetracyclines Adverse effects 1. Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa. 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. 3. Hepatotoxicity: Rarely hepatotoxicity may occur with high doses, particularly in pregnant women. 4. Phototoxicity: Severe sunburn may occur in patients receiving a tetracycline who are exposed to sun or ultraviolet rays. Patients should be advised to wear adequate sun protection. 5. Vestibular dysfunction: Dizziness, vertigo, and tinnitus may occur. 6. Pseudotumor cerebri: Benign, intracranial hypertension characterized by headache and blurred vision may occur rarely in adults. Contraindications: Pregnancy: Category D (risk of fetal harm), The tetracyclines should not be used in pregnant or breast- feeding women or in children less than 8 years of age. 05/01/2025 Dr.Firdaus 19  College of Medicine Macrolides and Ketolides: The macrolides are a group of antibiotics which one or more deoxy sugars are attached. Examples: ❖Erythromycin, ❖Azithromycin, ❖Clarithromycin. ❖Telithromycin 05/01/2025 Dr.Firdaus 20  College of Medicine Macrolides and Ketolides: Mechanism of action: 50 S bind to a site on the 50S ribosomal subunit inhibiting translocation steps of protein synthesis RNA Stop protein synthesis 30 S Bacteriostatic effect. Ketolides: Overcome resistance → Bacteriostatic and bactericidal effects. 05/01/2025 Dr.Firdaus 21  College of Medicine Macrolides and Ketolides: Spectrum of Activity Gram-positive bacteria: Staphylococcus aureus, Streptococcus pneumoniae. Gram-negative bacteria: Haemophilus influenzae, Moraxella catarrhalis. Atypical pathogens: Mycoplasma pneumoniae, Chlamydia spp., Legionella spp. Clinical Uses Respiratory Tract Infections: Pharyngitis, sinusitis, bronchitis, pneumonia. Skin and Soft Tissue Infections. Sexually Transmitted Infections: Chlamydia. Helicobacter pylori Infection: (with other antibiotics and acid suppressors). Prophylaxis: For bacterial endocarditis and in patients with penicillin allergies. 05/01/2025 Dr.Firdaus 22  College of Medicine Macrolides and Ketolides: Adverse Effects Gastrointestinal: Nausea, vomiting, diarrhea, abdominal pain. Hepatotoxicity: Rare, with elevated liver enzymes. Cardiotoxicity; QT prolongation, risk of arrhythmias. Allergic Reactions: Rash, pruritus. Drug Interactions CYP3A4 Inhibition: Increased levels of drugs metabolized by CYP3A4 (e.g., statins, warfarin). Pharmacokinetics of Macrolides and Ketolides Absorption: Generally well-absorbed orally, affected by food. Distribution: Excellent tissue penetration, high volume of distribution, moderate protein binding. Metabolism: Primarily metabolized in the liver, mainly via CYP3A4 (except azithromycin). Excretion: Mostly excreted in bile (feces), some via urine (clarithromycin). Half-life: Varies (short for erythromycin, longer for clarithromycin and azithromycin). 05/01/2025 Dr.Firdaus 23  College of Medicine Chloramphenicol The use of chloramphenicol, a broad-spectrum antibiotic, is restricted to life-threatening infections for which no alternatives exist. Spectrum of Activity Broad-Spectrum: Effective against Gram-positive and Gram-negative bacteria, and some anaerobes. Clinical Uses Serious Infections: Meningitis, typhoid fever, and other severe bacterial infections. 05/01/2025 Dr.Firdaus 24  College of Medicine Chloramphenicol Mechanism of protein synthesis It binds to the bacterial 50S ribosomal subunit 50 S Inhibition of Peptide Bond Formation Chloramphenicol prevents the elongation of the peptide chain RNA inhibits protein synthesis 30 S inhibits bacterial growth (Bacteriostatic Effect) 05/01/2025 Dr.Firdaus 25  College of Medicine Chloramphenicol Adverse Effects Bone Marrow Suppression: Can cause reversible or irreversible aplastic anemia. Gray Baby Syndrome: Risk in neonates due to reduced metabolism. Other: Nausea, vomiting, diarrhea, allergic reactions. Contraindications Pregnancy: Avoid unless benefits outweigh risks. Neonates: Risk of Gray Baby Syndrome Note: The oral formulation of chlorampheniool was removed from the US market due to this toxicity. Gray baby syndrome. This syndrome is characterized by abdominal distention, vomiting, progressive pallid cyanosis, irregular respiration, hypothermia, and vasomotor collapse. Diarrhea, vomiting and glossitis may develop with high or prolonged doses. 05/01/2025 Dr.Firdaus 26  College of Medicine Others agents from protein synthesis inhibitor 1. Quinupristin/dalfopristin:is a mixture of two streptogramins in a ratio of 30 to 70 Quinupristin and dalfopristin work synergistically. MOA Quinupristin: Binds to the 50S ribosomal subunit, inhibiting peptide elongation. Dalfopristin: Blocks the ribosome's exit tunnel, preventing peptide release. Infections: Treats complicated skin and skin structure infections (CSSSI) Clinical uses caused by resistant Gram-positive organisms. Musculoskeletal: Arthralgia, myalgia. Adverse Effect Liver Function: Monitor liver enzymes due to potential hepatotoxicity. Drug interactions CYP3A4 Inhibitors 05/01/2025 Dr.Firdaus 27  College of Medicine Others agents from protein synthesis inhibitor 2. Oxazolidinones: Linezolid and tedizolid are synthetic oxazolidinones developed to combat gram-positive organisms Linezolid and tedizolid bind to the bacterial 23S ribosomal RNA of the 50S MOA subunit, thereby inhibiting the formation of the 70S initiation complex and translation of bacterial proteins. Infections: Treats complicated skin and skin structure infections , nosocomial Clinical uses pneumonia, and bacteremia caused by susceptible organisms. Mycobacterial Infections: Some efficacy against drug-resistant tuberculosis. Gastrointestinal upset, nausea, diarrhea, headache, and rash. Adverse Effect Thrombocytopenia. Linezolid and tedizolid possess nonselective monoamine oxidase activity 05/01/2025 Dr.Firdaus 28  College of Medicine Others agents from protein synthesis inhibitor 3. Clindamycin: Mechanism: Inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. Spectrum of Activity Effective against Gram-positive cocci (including MRSA) and anaerobic bacteria. Clinical Uses Treats skin and soft tissue infections, dental infections, and intra-abdominal infections. Bone and joint infections, and certain types of bacterial vaginosis. Alternative for patients allergic to beta-lactams 05/01/2025 Dr.Firdaus 29  Q:? 05/01/2025 Dr.Firdaus 30