Pharmacology I - Anti-Infective (Protein Synthesis) PDF

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جامعة النجاح الوطنية

Dr. Sana' AL Aqqad

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pharmacology antibiotics infections clinical pharmacy

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These notes cover the topic of anti-infective pharmacology, focusing on antibiotics that interfere with protein synthesis. Specific antibiotics and their mechanisms are discussed, as well as their uses and related considerations such as tolerance, toxicity, and drug interactions. The document also details the uses of various antibacterials and their routes of administration. This document is likely lecture notes.

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Pharmacology I Anti-infective (Interfere with Protein Synthesis) Dr. Sana’ AL Aqqad Ph.D. in Clinical Pharmacy & Therapeutics [email protected] Classification of antibiotics: ❑Antibiotics that Target the Cell wall:...

Pharmacology I Anti-infective (Interfere with Protein Synthesis) Dr. Sana’ AL Aqqad Ph.D. in Clinical Pharmacy & Therapeutics [email protected] Classification of antibiotics: ❑Antibiotics that Target the Cell wall: ❑Antibiotics that Block Protein ▪ B-Lactam Antibiotics***** Production: ▪ Glycopeptides: Teicoplanin* & ▪ Rifamycins vancomycin* ▪ Aminoglycosides** (gentamycin) ▪ Colistin ▪ Macrolides** (Azithromycin) ▪ Ketolides ▪ Tetracyclines and Glycylcyclines ❑Antibiotics that Target DNA and ▪ Chloramphenicol Replication: ▪ Clindamycin* ▪ Sulfa Drugs ▪ Streptogramins ▪ Quinolones: ciprofloxacin*, ▪ Linezolid levofloxacin* ▪ Nitrofurantoin ▪ Metronidazole** (Flagel)® Macrolides Macrolide antibiotics follow the old adage: “jack of all trades, master of none’’ ❑ Target ribosomes→ bind to 50S→ suppress protein synthesis & bacterial growth ❑ Active against: some gram+ve/-ve some atypical bacteria some mycobacteria Some spirochetes. But → Not reliably effective against most bacteria in any one group. Effective against some staphylococci and streptococci & atypical bacteria Not active against: ✓ methicillin-resistant staphylococci (MRSA) ✓ penicillin-resistant streptococci ✓ Enterococci & Enterobacteriaciae (E.Coli, klebsiella) ✓ anaerobic. Most aerobic GM-ve bacilli are resistant But some Neisseria, Bordetella pertussis, Moraxella catarralis, and Haemophilus strains are susceptible. Treat: pharyngitis, otitis media, sinusitis, tonsititis, and bronchitis, especially in PCN-allergic patients. Treat/ part of treat→ atypical pneumonia, usually caused by organisms like Mycoplasma pneumoniae, Legionella pneumonia ❑ Major Clinical Uses TYPES USAGE Erythromycin RTI with streptococci, pneumococci, Legionella pneumophila, Mycoplasma pneumoniae, or Chlamydia pneumoniae Azithromycin, ▪ RTI with organisms sensitive to & erythromycin + Haemophilus influenzae, Clarithromycin Moraxella catarrhalis, Mycobacterium Clarithromycin ▪ Used to treat Helicobacter pylori (H. pylor) infections in standard triple therapy protocol ❑ Erythromycin ✓ The oldest of the macrolides (1952) ✓ Short t1/2→ q6hs ✓ Spectrum of activity nearly similar to clarithromycin and azithromycin ✓ Lacks significant activity against H. influenzae→ less useful than the other macrolides in the treatment of respiratory infections. ✓ Can be used to treat bronchitis, pharyngitis, sinusitis, otitis media, and infections in PCN-allergic patients. ✓ Erythromycin is less well tolerated → it is being replaced by newer agents. ❑ Clarithromycin ✓ Twice daily ✓ Has somewhat greater activity (than erythromycin) against: ✓ aerobic GM+ve bacteria ✓ H. influenzae ✓ Azithromycin and clarithromycin have a greater oral bioavailability and achieve higher tissue conc. than erythromycin. ✓ Clarithromycin is the most active against H. pylori. ✓ Used to treat URTI (same as erythromycin) & CAP ❑ Azithromycin ✓ Azicare®, Azimex®, Zitocin® ✓ Once daily (better compliance) ▪ 500 mg PO for 1 day → then 250 mg PO q24h for 4 days; ▪ Capsule, suspension, IV ✓ Somewhat better activity against aerobic gm -ve bacteria and is useful in the treatment of H. influenzae. ✓ Main advantages → taken up in high amounts by tissues and then slowly released over subsequent days. ✓ Uses: similar to clarithromycin (URTI, CAP) ✓ Advantage: No numerous drug interactions seen with erythromycin and clarithromycin. ❑ Macrolides Toxicity ✓ In general, → macrolides are safe drugs, causing several relatively mild adverse reactions. ✓ GI symptoms ✓ Erythromycin is associated with GI symptoms (N,V,D) abdominal pain, ✓ Thrombophlebitis following IV administration. (Azithro.) ✓ Clarithromycin: abnormal taste ✓ Clarithromycin & azithromycin are usually tolerated quite well ✓ QT prolongation ✓ Major drug interactions: Erythromycin then clarithromycin but not azithromycin (little effect) are also capable of inhibiting the cytochrome P-450 system and thereby affecting levels of other drugs. ✓ LFT abnormalities (particularly erythromycin). ✓ Erythromycin also has correlations with hepatotoxicity in pregnant women → use with caution (category B1) ✓ Clarithromycin→ B3 use is not recommended unless needed 15 Clindamycin ▪ Chemically classified as a lincosamide (related to macrolides) ▪ MOA: →very similar to macrolides (bind 50S of ribosome) ▪ Strength: 300mg/600mg IV→ 3-4 times/day ▪ Commonly used today: ▪ IV ▪ Oral (Denacine)® caps. 300 & 150 ▪ topical ▪ vaginal ovules ▪ Oral dose : 150 to 300 mg PO q6–8h ✓ excellent oral bioavailability (90%) ✓ Oral use limited by GI side effects ▪ IV dose: 600 to 900 mg IV q8h. ▪ Available form MOH: 100 mg cap, 300 mg inj ▪ Spectrum like that of erythromycin ✓Active against GM+ve (many strains MRSA)→ gain more importance, Streptococci → even penicillin-resistant ) ✓Not active against aerobic GM-ve (intrinsically resistant ) ▪ Additional activity against most anaerobes, including: ▪ B. fragilis (some stains are resistance) ▪ Clostridium perfringens→ gram –ve anaerobic bacteria ▪ Penetrates well into the bone and abscess cavities. ❑ S.E → major toxicity of clindamycin, which has limited its use ▪ GI symptoms: Nausea, abdominal cramping ▪ Diarrhea (could be bloody diarrhoea )→ Occurrence of (0.01% to 10% of individuals)→pseudomembranous colitis. ▪ metallic / unpleasant taste/loss of appetite ▪ Hypersensitivity ▪ Esophageal ulceration* ▪ Clindamycin should not be injected IV undiluted as a bolus but should be infused over at least 10-60 minutes. * Given in 3 or 4 equal doses *Penetrate the CSF poorly ❑ Used for treatment of: ▪ Topical preparations of the drug are used for the treatment of acne. ▪ Bone and joint infections: osteomyelitis ▪ Aspiration pneumonia ▪ Lung abscesses ▪ Skin and soft tissue infections (by strep, staph. & anaerobes) ▪ Bacterial vaginosis. ▪ Pelvic inflammatory disease PID: 900 mg IV q8h (combination W. genta.) ▪ Intra-abdominal infections ✓→ metronidazole is used more commonly for intra-abdominal infections (clindamycin has less reliable activity against B. fragilis). ▪ Prophylaxis against endocarditis during dental procedures in individuals with valvular heart disease Aminoglycosides Inhibit protein synth. (ribosomes are the target). Active against gram +ve /-ve bacteria. Often used in combination (synergistic effect) with cell wall–active agents (PCN, & cephalon, vanc.). Streptomycin in 1944→ Neomycin in 1949→ gentamicin in 1963→ tobramycin in 1967→ and amikacin in 1972 Excellent activity against aerobic gram-ve bacteria (unlike vancomycin) ▪ Active to a lesser degree against aerobic gram +ve bacteria. ▪ No activity against anaerobic ▪ Uptake of aminoglycosides is enhanced by antibiotics that inhibit bacterial cell wall synthesis → and tend to be synergistic with cell wall–active antibiotics. ▪ IV/IM ▪ Topical ▪ Eye drops ▪ Oral (poor absorption) ▪ Resistance rare → Some exists gentamicin > tobramicin > amikacin. ▪ Require renal dose adjustment ▪ Close monitoring of Peak & trough ❑ S.E: 1. nephrotoxicity 5-10% (reversible when detected early) 2. ototoxicity. ▪ Risk factors for nephrotoxicity (↑ risk to 50%): ✓ Age (cautiously in older patients) ✓ Preexisting kidney disease (cautiously use in patients with renal failure (dosage adjustments may be necessary) ) ✓ Concomitant nephrotoxins ✓ Sustained trough > 1 mg/dL ✓ Diuretic use (Lasix) ▪ Nephrotoxicity usually observes 4-5 d→ short period teat. Is safe ▪ This risk decreases by the single daily dose ▪ Cross-resistance among aminoglycosides is common ▪ Doses: ▪ Extended-interval dosing: q24 hrs (more convenient) ▪ Traditional dosing → q8hrs reserved for life-threatening infections/ pregnant women/endocarditis/burn > 20 % body ❑ Traditional dosing → q8hrs ▪ Peak and trough conc. should be obtained with 3rd or 4th dose and then every 3 to 4 days, along with regular serum Cr. monitoring. ❑ Extended-interval dosing: q24 hrs (more convenient) ▪ A drug concentration is obtained 6 to 14 hours after the 1st dose ▪ Monitor drug conc. 6 to 14 hours after the dosage at least every week and a serum cr. at least 3 times a week ❑ Gentamicin ▪ Gentamicin is the most used: 20 mg, 80 mg amp. ▪ Traditional dosing→ LD =2 mg/kg IV (2 to 3 mg/kg in the critically ill) ▪ followed by 1.0 to 1.7 mg/kg IV q8h (peak, 4 to 10 mg/mL; trough,

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