Ceutics - Other Beta Lactams (NN) PDF

É get ANTIMICROBIALS 2. CEPHALOSPORINS an t.ie Gm feb 31  ORAL CEPHALOSPORINS ask.is tionE DOfenfrau Toralbioavalibilt Many of the oral cephalosporins, such as cefaclor, cefadroxil, cefprozil, Cephalexin cephalexi...

É get ANTIMICROBIALS 2. CEPHALOSPORINS an t.ie Gm feb 31  ORAL CEPHALOSPORINS ask.is tionE DOfenfrau Toralbioavalibilt Many of the oral cephalosporins, such as cefaclor, cefadroxil, cefprozil, Cephalexin cephalexin, ceftibuten are acid-stable and have high bioavailability (80%--- 95%). The bioavailability of cefixime, however, is lower (40%---50%). Cephradine e Because most drugs are absorbed from the intestinal mucosa by passive Cefadroxil diffusion, absorption across the intestinal epithelium is enhanced if the Cefaclor E drug is lipophilic. Therefore, some oral cephalosporins are esterified ( eg, cefuroxime axetil) Cefprozil to increase lipid solubility and enhance absorption. Cefixime These prodrugs are hydrolyzed after intestinal absorption by esterases in Cefuroxime the intestinal epithelium to their active metabolites. Nevertheless, their bioavailability is relatively low (25%---50%) and is enhanced by concomitant axetil y food intake. fagggy.gg yyyyyyyyyyyyy p.gg arugtobeassor.ee  6 2nd Phifer 1ST GENERATION CEPHALOSPORINS Cephalexin Oral Cephradine Oral + parenteral Cefadroxil Oral Long acting Cefazolin Parenteral (IV, IM) High plasma protein binding (85%) kidneys stinactive Excretion: mainly renally excreted unmetabolized by glomerular filtration in urine Dose adjustment (reduction) in case of renal impairement 2ND GENERATION CEPHALOSPORINS iiii Parenteral (IV) as cefuroxime sodium poor oral bioavailability Cefuroxime lipophilic better oral absorption iiiiii Oral (suspension, tablets) as Cefuroxime axetil prodrug more Can be orally combined with clavulanic acid. Cross the BBB Cefaclor e Oral More lipophilic (due to Cl) better oral absorption Cefprozil Oral Long acting IV perentrallyonly Cefoxitin t ½ < 1h e Excreted very short unchanged by the kidney 3RD GENERATION CEPHALOSPORINS Parenteral (IV, IM) or High potency Ceftriaxone _e Long acting High protein binding Crystallization with Ca Gonorrhea, meningitis those both usedto u sually treat meningitis I Parenteral (IV, IM) Cefotaxime tore Short t ½ (1h) Good distribution in CNS meningitis Metabolized into less active metabolite it Ceftazidime Parenteral (IV, IM) Short t ½ (1.5 h) ___ Excreted unchanged renally dose adjustment with renal dysfunction Oral suspension, tablets & capsules Cefixime __ Oral bioavailability 40 – 50 % regardless of food Moderate t ½ (3 - 4 h) Excreted unchanged renally dose adjustment with renal dysfunction ADME PG t1/2 = 30 - 90 min veryshort have Cefixime 3-4h except Absorption Ceftriaxone 8h Unmetabolized mostofthem Metabolism Cefotaxime: Metabolized in vivo to desacetyl-cefotaxime (less active ) Glomerular filtration I Excretion Urine & bile Dose adjustment with renal impairment  3rd CEFTRIAXONE & PROTEIN BINDING grey f.fiif If circulation fimmininmin 0 Ceftriaxone undergoes extensive binding to plasma proteins (albumin) neaeno longer half-life (i.e. the drug circulates for longer duration with the blood). The antimicrobial activity & elimination are limited to the unbound fraction of the drug. The free/unbound drug concentration should exceed the minimal inhibitory concentration (MIC) at steady state. Ox This behavior may be advantageous because sustained concentrations above the MIC are preferable to a high peak and then rapidly decreasing concentrations. Patients with hypoalbuminaemia (low albumin level in blood) will affect the PK of ceftriaxone (reduced protein binding, higher level of free drug in blood, shorter half-life, higher volume of distribution). need dose regffmation albuminlevel needdose or SAFETY CRITERIA FOR CEFTRIAXONE ADMINISTRATION TO NEONATES Hyperbilirubinemia (high bilirubin blood level) is one of the most common neonatal disorders at the first days and weeks of life (jaundiced premature infants). Ceftriaxone should be avoided in neonates with hyperbilirubinemia due to potential risk for displacement of bilirubin from albumin which increases the risk of bilirubin encephalopathy. Ceftriaxone competes with bilirubin for binding to human serum albumin (Competitive binding). Ceftriaxone displaces bilirubin from albumin-binding sites concentrations of free bilirubin in the blood. higher 0 This very high bilirubin levels in the blood are deposited in the brain tissue causing irreversible damage to the brain known as bilirubin encephalopathy. 0 vilirubinm.ca  pptinsideoutsidethebody inside withcat outside anotherinfusion CEFTRIAXONE & CALCIUM in b p Blockstheblood vesselsveins 3. CARBAPENEMS GENERAL FEATURES OF CARBAPENEMS There are four FDA-approved carbapenems (imipenem, meropenem, ertapenem, and doripenem) Carbapenems resemble penicillins -lactam ring fused to a five-membered ring. The five- membered ring, however, is unsaturated and does not contain sulfur. -lactams and are among the most broad- spectrum antimicrobials available. They are highly resistant to a variety of beta-lactamases. They are administered viaperentrau.sc IV infusion due to poor oral absorption as they do not readily cross GI membranes. Imipenem-cilastatin and ertapenem can also be delivered intramuscularly. I Carbapenems are distributed widely in the body and are mostly excreted by the kidneys. inactiveform doseadjustm Due to the significant renal elimination of carbapenems, patients with reduced renal function require adjusted dosages/dosing intervals to avoid drug accumulation  wait is IMIPENEM FORMULATIONS Me Imipenem is rapidly metabolized (deactivated) by the human Are cilastatin kidney enzyme dehydropeptidase-1 (DHP-1) in the human renal brush border. willgiveametabolitetnatause.merotoxicity to Coadministration with the DHP-1 inhibitor, cilastatin increases the in vivo half-life, increases tissue penetration and prevents nephrotoxicity. Nephrotoxicity is associated with imipenem if administered without cilastatin due to the renal metabolism of the carbapenem compound. Combination of imipenem-cilastatin with relebactam extends the spectrum against carbapenemase producing bacteria, MDR G-ve bacteria. MEROPENEM & ERTAPENEM moreresistant Meropenem and ertapenem show greater stability towards the DHP-1 system and can be Tdegraded administered without cilastatin. Ertapenem has longer t ½ relative to meropenem allowing once daily dosing (IV infusion). renaissance 0 1 Items Meropenem (70% of the dose) is excreted unchanged in urine over 12 h. Whereas 80% of ertapenem is recovered in urine, with nearly half intact and the other half as the ring-opened metabolite.  ed CONTRAINDICATION OF CARBAPENEMS & VALPROIC ACID e bettertobeavoided notgiventogether Coadministration of meropenem with the antiepileptic agent valproic acid significantly L lowers the serum concentrations of valproic acid to subtherapeutic levels leading to the aggravation of seizures. To solve this: Therapeutic drug monitoring (TDM) of the serum valproate concentration. If carbapenem treatment is required, FEE patients should be given an alternative treatment to valproic acid THANK YOU