Tetracyclines & Macrolides Fall 2024 PDF

ANTIMICROBIALS Tetracyclines and macrolides Dr Abdulaziz Alobaid [email protected] Tetracyclines Oral / IV Ø High lipophilicity O Ø Better bioavailability Ø High tiss...

ANTIMICROBIALS Tetracyclines and macrolides Dr Abdulaziz Alobaid [email protected] Tetracyclines Oral / IV Ø High lipophilicity O Ø Better bioavailability Ø High tissue penetration & distribution Tetracyclines - ADME Route of administration Tetracycline, doxycycline and minocycline: – Can be administered as oral and IV: Oral (peak plasma concentration in 2-4 h). IV 0 (peak plasma concentration within 30 min). Tigecycline: – Tigecycline is available only for parenteral administration (IV). All tetracyclines – AUC/MIC correlates with efficacy of tetracyclines. Normal levels of tetracyclines achieved in the serum after oral dosing range from 2 to 5 mcg/mL. The majority of tetracyclines require dosing two to four times daily to maintain therapeutic concentrations e in the serum. That said, doxycycline and minocycline have longer elimination half-lives and permit once or twice daily dosing. Tetracyclines - ADME Route of administration Tetracycline, doxycycline and minocycline: – Available as tablets/capsules, extended-release tablets/capsules and injections (IV). Tigecycline: – Tigecycline is available only for parenteral administration (IV). Tetracyclines - ADME Absorption Concurrent ingestion of divalent and trivalent cations (e.g., Ca2+, Mg2+, Al3+, Fe2+/3+, and Zn2+) impairs absorption due to chelation. Dairy products, antacids, aluminum hydroxide gels; calcium, magnesium, and iron or zinc salts; bismuth subsalicylate; and dietary iron and zinc supplements can interfere with absorption of tetracyclines. Tetracycline: – The oral bioavailability of tetracycline can be reduced to 50% if administered with food. Doxycycline and minocycline: – Doxycycline and minocycline: ∼ 90% oral absorption (with or without food). All tetracyclines – Absorption occurs in stomach & proximal part of small intestine. Tetracyclines - ADME Distribution urine prostat Tetracyclines distribute widely throughout the body including urine and prostate à low serum levels that may be inadequate to treat bacteremias (presence of bacteria in the bloodstream) with an endovascular source. antegut totreat The degree of tissue penetration correlates to lipid solubility: I serum level – Minocycline > doxycycline > tetracycline. bactermias – They accumulate in reticuloendothelial cells of the liver, spleen, and bone marrow and in bone, dentine, and enamel of unerupted teeth. Tetracycline and minocycline: Doxycycline and tigecycline: É s – ∼ 70% protein binding. – ∼ 90% protein binding. Tetracyclines - ADME Metabolism & excretion Tetracycline is eliminated primarily by the kidney, although it is also concentrated in the liver, excreted in bile, and partially reabsorbed via enterohepatic recirculation. Doxycycline and minocycline – Doxycycline is metabolized by the liver à no dose adjustment in patients with renal dysfunction. – Minocycline is extensively metabolized by the liver à no dose adjustment in patients with renal dysfunction. Tigecycline is mostly excreted unchanged with feces along with a small amounts of metabolites. – Hence, no dose adjustment is needed in patients with renal dysfunction. – Specific dosage adjustment recommendations in hepatic disease are available for tigecycline. Macrolides  a inactivgastic Macrolides – ADME - Erythromycin Absorption Distribution Erythromycin base is inactivated by gastric acid and Protein binding: 70 - 80% (erythromycin is hence incompletely absorbed from the upper base) and higher for the estolate. small intestine. The serum half-life of erythromycin is about Administered as enteric coated tablets or as capsules containing enteric coated pellets that dissolve in the duodenum. 1.5-2 h. towhanae Cmax reached in 4 h. Esters of erythromycin base (e.g., stearate, estolate, and ethylsuccinate) have improved acid stability, and their absorption is less altered by food. Metabolism & excretion were insoluble Food should not be taken concurrently with Erythromycin is concentrated in the liver erythromycin base or the stearate formulations; preferably administered on empty stomach (2h and excreted in the bile. before or after meals). Hepatic first-pass metabolism For erythromycin estolate & ethylsuccinate, delayed contributes significantly to erythromycin release tablets can be administered 'intact' without metabolism after an oral dose. regard to meals. Intravenous slow infusion (erythromycin Dosage reduction à not necessary in lactobionate) over 20-60 min to minimize pain due patients with impaired renal function. to vein irritation. 4 h  7 s l Erythromycin H20 Erythromycin acid degradation in stomach à inactive ketal Erythromycin enteric-coated Erythromycin enteric-coated tablets aciddegrade pellets in capsules Erythromycin wagner Erythromycin eye Erythromycin topical Erythromycin ointment gel lactobionate (IV) Water-soluble IV  50 Macrolides – ADME - Clarithromycin first bassIbioavil 807 had a 19 hydra Absorption Distribution Administered as: Protein binding: 80%. – Pk 2hrelease Immediate (IR) & Pk Sho extended release The serum half-life of clarithromycin is (ER) tablets. about 3-7 h. – Oral suspension. 0 IV – Intravenously. Clarithromycin is absorbed rapidly from the GI tract Metabolism & excretion after oral administration, but hepatic first pass Clarithromycin is metabolized in the liver metabolism reduces its bioavailability to 50%. to several metabolites: metabolite Clarithromycin is acid stable → better bioavailability Gus – The mostactive active 14-hydroxyclarithromycin compared to erythromycin. metabolite is the most significant. – Hence, enteric coating is not needed. Excreted in the urine (10-35%). – Therefore, caution should be Peak concentrations at 2 h after oral exercised in administering this administration (immediate release) and 8 h antibiotic to patients with impaired (extended release). hepatic function. metabolite hydroxymelaturouyan  I Clarithromycin m a f Immediate Extended Oral IV release 2 release suspension Mom EE  I Macrolides – ADME - Azithromycin Absorption Distribution in Him Administered as: – Immediate release (IR) & extended release (ER) tablets. É Distributes widely throughout the body → greater drug concentration in tissue > simultaneous serum concentration. Distributed to inflamed tissues à 8 – Oral suspension. macrophages, phagocytes and fibroblasts. – Intravenously. Azithromycin is acid stable → better bioavailability compared to erythromycin. Metabolism & excretion – Hence, enteric coating is not needed. Azithromycin undergoes hepatic metabolism to inactive metabolites, but te biliary excretion is the major route of elimination. – Only 12% is excreted unchanged in the urine. The elimination half-life (40 - 68 h) is prolonged because of extensive tissue binding subsequent release of drug from tissues – Therefore, can be given once daily. Thank you! 3Jans 40 48 Nt I ight pasmobut p