Pharmacology II - Protein Synthesis Inhibitors I

Pharmacology II PROTEIN SYNTHESIS INHIBITORS I Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  Protein Synthesis Inhibitors Targeting bacterial ribosomes to inhibit bacterial protein synthesis [Bacter...

Pharmacology II PROTEIN SYNTHESIS INHIBITORS I Dr. Sheryar Afzal College of veterinary Medicine King Faisal University  Protein Synthesis Inhibitors Targeting bacterial ribosomes to inhibit bacterial protein synthesis [Bacterial ribosomes are composed of 30S and 50S subunits (mammalian ribosomes have 40S and 60S subunits)]. Selectivity!! broad spectrum, most are bacteriostatic. Resistance is common (overuse).  4 AMINOGLYCOSIDES Bactericidal Against serious infection caused by aerobic gram-negative bacilli, especially in bacteremia and sepsis, in combination with vancomycin/penicillin for endocarditis and tuberculosis. Can cause serious toxicities (have been replaced to some extent by safer antibiotics, such as the third and fourth generation cephalosporins, the fluoroquinolones, and the carbapenems). ‫…يجري التحميل‬ (TDM) (TDM)  6 AMINOGLYCOSIDES Mechanism of Action Aminoglycosides cross the bacteria cell wall through porin channels and then actively transported across the cell membrane (oxygen- dependent) into the cytoplasm. Bind to 30S subunit of the ribosome to misread the genetic code, which causes incorporation of incorrect amino acids into the peptide and results in a non-functional or toxic protein. This can lead to the production of a protein with alter biological function which may have great effects on normal bacterial metabolism.  6 AMINOGLYCOSIDES Mechanism of Action Bactericidal, concentration dependent [efficacy is dependent on the maximum concentration (Cmax) of drug above the MIC; Target Cmax is 8-10 times > MIC]. Post-antibiotic effect (PAE). The larger the dose, the longer the PAE. Extended interval dosing (a single large dose, once daily vs divided daily doses). This ↓ risk of nephrotoxicity and increases convenience. What causes antibioctic ‫…يجري التحميل‬ resistance? Production of enzymes inactivating aminoglycoside Decreased uptake (E.g.: resulting from mutation or deletion of porin in transport; oxygen-dependent transport process is not functional). Increased efflux The receptor protein on the 30S ribosomal subunit may be deleted or altered as a result of a mutation.  6 AMINOGLYCOSIDES Antibacterial spectrum The aminoglycosides are effective for the majority of aerobic gram-negative bacilli, including multidrug resistant, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enterobacter sp. Often combined with a β-lactam antibiotic to employ a synergistic effect, particularly in the treatment of Enterococcus faecalis and Enterococcus faecium infective endocarditis.  13 AMINOGLYCOSIDES Adverse Effects and nephrotoxic (continued treatment > 5 Ototoxicity days; high doses; elder; renal insufficiency). Concurrent use with ototoxic drug such as cisplatin, loop diuretics (eg, furosemide, ethacrynic acid) or other nephrotoxic antimicrobial agents vancomycin or amphotericin) can potentiate nephrotoxicity and should be avoided if possible. Vertigo may also occur (especially for streptomycin) Neuromuscular paralysis (high dose infused over a short period or concurrent neuromuscular blockers) (Uncommon)  42 Thank you Antibiotics!  11 AMINOGLYCOSIDES Pharmacokinetics Absorption Poor absorption (aminoglycosides are highly polar). Must be given parenterally (except for Neomycin which can cause nephrotoxicity if given parenterally). Administered as 30-60 mins infusion. Distribution Due to hydrophilicity, tissue concentrations may be subtherapeutic Concentrations in CSF are inadequate, even in the presence of inflamed meninges (intrathecal route may be utilized). cross placental barrier and may accumulate in foetal plasma and amniotic fluid (may cause deafness in foetus). Elimination 90% excreted unchanged in the urine (TDM (Therapeutic drug monitoring) is needed for renal impaired patient)  16 Streptomycin Resistance has emerged (Ribosomal resistance to streptomycin develops readily). Mainly used as a second-line agent for tuberculosis (should be used only in combination with others to prevent emergence of resistance). Streptomycin + tetracycline (plague, tularemia and sometimes brucellosis) Penicillin + streptomycin (enterococcal endocarditis and viridans streptococcal endocarditis). Gentamicin has largely replaced streptomycin for these indications, but some isolates are resistant to gentamicin. Ototoxicity (irreversible), nephrotoxicity, foetal auditory toxicity, and neuromuscular paralysis.  21 Gentamicin Isolated from Micromonospora purpurea Against both gram-positive and gram-negative It is active alone, but also as a synergistic companion with beta-lactam antibiotics, against pseudomonas, proteus, enterobacter, klebsiella, serratia, stenotrophomonas, and other gram-negative rods that may be resistant to ‫…يجري التحميل‬ multiple other antibiotics. Should not be used as a single agent to treat staphylococcal infections including pneumonia (resistance develops rapidly, poor lung tissue penetration). TDM is needed  25 Gentamicin Administration Topical (Creams, ointments, and solutions): Treat infected burns, wounds, or skin lesions and the prevention of IV catheter infections. Intrathecal Administration: Treat meningitis caused by gram-negative. Adverse reaction Nephrotoxicity (reversible and mild, need TDM). It occurs in 5–25% of patients receiving gentamicin for longer than 3– 5 days. Ototoxicity (likely irreversible, can cause deafness).  30 Amikacin Against many gram-negative enteric bacteria resistant to many enzymes that inactivate gentamicin and tobramycin Often used for treating severe, hospital-acquired infections with multidrug-resistant Gram- negative bacteria such as Pseudomonas aeruginosa, Acinetobacter, and Enterobacter Liposomal amikacin (inhalation) is being developed to treat respiratory diseases, such as cystic fibrosis, Pseudomonas aeruginosa, non- tubercular mycobacterial infections and bronchiectasis TDM is needed  27 Tobramycin Antibacterial spectrum and pharmacokinetics similar to gentamicin narrow spectrum of activity and is active against Gram-negative bacteria (not active against gram positive Bacteria except for Staphylococcus aureus). Clinically used to eliminate Pseudomonas aeruginosa in respiratory tract infections complicating cystic fibrosis patients (better lung penetration; nephrotoxicity and ototoxicity rarely occur via inhalation due to low systemic absorption). Indicated for life-threatening gram-negative infections: meningitis in neonates, brucellosis, pelvic inflammatory disease, Yersinia pestis infection (plague).  33 Neomycin & Kanamycin Neomycin and kanamycin are closely related. Antimicrobial Activity & Resistance Active against gram-positive and gram-negative bacteria and some mycobacteria. Pseudomonas and streptococci are generally resistant. Limited to topical and oral use (Neomycin is too toxic for parenteral use). Topical Administration Ointments (neomycin-polymyxin-bacitracin combination) treat infected skin lesions. Oral administration: In preparation for elective bowel surgery and hepatic coma  32 Netilmicin Netilmicin shares many characteristics with gentamicin and tobramycin (interchangable). It is only used in the treatment of serious infections particularly those resistant to gentamicin. The dosage and the routes of administration are the same as for gentamicin.