Amino-glycosides.pdf

Release of the drug from its dosage form. L = Liberation Movement of drug from the site of administration to the blood circulation. A = Absorption Pharmacokinetic processes which follow a given dosage regimen. Process by which drug diffuses or is transferred from intravascular space to extravas...

Release of the drug from its dosage form. L = Liberation Movement of drug from the site of administration to the blood circulation. A = Absorption Pharmacokinetic processes which follow a given dosage regimen. Process by which drug diffuses or is transferred from intravascular space to extravascular space (body tissues). D = Distribution Chemicalconversionortransformationof drugs into compounds which are easier to eliminate. M = Metabolism Elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes. E = Excretion LADME scheme Drug input L = Liberation A = Absorption D = Distribution LADME processes Drug output "disposition of drug" M = Metabolism E = Excretion Our main focus is on IV administered drugs, shown to be efficacious without causing toxicity in the majority of patients. Bactericidal antibiotics used in treatment of serious gram-negative systemic infections. Active against most strains of Staphylococcus aureus and S. epidermidis. Most strains of enterococcus resistant to aminoglycosides. Anaerobic bacteria are universally resistant Introduction Aminoglycoside transport into cells is Amino glycosides must be administered Reason parenterally In most instances, amino glycosides must be administered by oxygen-dependent Poor absorption from GIT intravenous infusions Gentamycin Tobramycin Three most commonly monitored amino glycoside antibiotics Amikacin Concentration-dependent killing Certain concentration to kill Means Significant post-antibiotic effect Remain effective even after stop giving the Antibiotic Means Pharmacodynamic properties of aminoglycosides MIC Aminoglycosides eliminate bacteria quickest when their concentration is appreciably above 10 times of MIC for an organism; Minimum Inhibitory Concentration Referred to as concentration dependent activity. Persistent suppression of bacterial growth following antibiotic exposure. Exhibitsignificantpost-antibioticeffect(PAE) Trough levels can drop below the MIC of targeted bacteria for a sustained period without decreasing efficacy. PAE Once daily dosing Volume of distribution (V) Key parameters Equal to Clcr Clearance(Cl) 1.Therapeutic serum concentration; Conventional dosing DOSING AND MONITORING OF DRUG LEVELS OF AMINO-GLYCOSIDES 0.25 L /Kg Less clearance Less dose AUC24 2-3 hrs Normal renal function T1/2 30-60 hr Functionally Anephric patient Very water soluble Polar Poorly lipid soluble Bioavailability Poorly absorbed when administered orally Must be administered parenterally for treatment of systemic infections As known, it's ineffective against Anaerobic Bacteria Gentamicin For Tobramycin Netilmicin increased if trough levels consistently exceed for these three drugs risk of ototoxicity and nephrotoxicity For Concentration-toxicity relationships 2 mg/ml trough levels consistently greater than 10 mg/ml have been associated with a higher risk of ototoxicity and nephrotoxicity Amikacin Would maximize concentration The higher the concentration ideal dosing regimen the more extensive and the faster is the degree of bactericide. Quickest important predictor of efficacy. aminoglycosides eradicate bacteria best when they achieve a Peak/MIC ratio of at least Peak/MIC ratio 8-10 Important to give a large enough dose to produce a peak level 8 to 10 times greater than the MIC. Alpha (distribution) When given by IV infusion over 30 minutes Follows a 3-compartment pharmacokinetic model ß (elimination) Gamma (tissue release) Distribution phase usually not observed. When infused over one hour Gamma phase begins approximately sixteen hours post infusion. Drug that was tissue bound to various organs is released. Pharmacokinetics Amount released from tissue is very small Accumulates over time Pharmacodyamic properties of AG's form the basis of AG toxicity EI (extended - interval) dosing. Concentration dependent activity of AG's demonstrates that a large dose (5mg/kg) is needed to maximize killing. Persistent(post-antibiotic)effectofAG's allows a dosing interval of Aminoglycosides "IV Route" 24-36 hours Extended interval provides a beneficial wash out period during the gamma (tissue- release) phase thus decreasing the incidence of toxicity. 0.25L/kg ( 0.1-0.5 L/kg ) Distributes very poorly into adipose tissue. Amino glycoside V (L)= 0.25L/kg×Non- obese, Non-excess fluid weight (kg) +0.1(excess adipose weight (kg)+ excess third space fluid weight (kg) Estimated as the ideal body weight and the patient's total weight without excess third space fluid. Non-obese,non-excess fluid weight Volume of distribution Excess third space fluid weight estimated clinically. Pediatric patients younger than 5 years of age Children after age of 5 years Cl cr for males (ml/min) Cl crfor females (ml/min) Clearance Cuz Childs have more water So more volume of distribution Amino glycoside V (L)=(0.5 L/kg{age in years/5x 0.25})(weight in kg) In children 1to 5 years Eliminated almost entirely by Volume of distribution of 0.5 L/kg V of 0.25L/kg generally used. Renal route (140-Age)(Weight)/(72)scrss) (140-Age)(Weight)/(72)scrss) Patient's weight represents normal ratio of muscle mass to total body weight. Correct estimates of creatinine clearance can only be obtained if Serum creatinine is at steady state. Ignored in most patients Non-renal clearance Significant in patients whose renal function is significantly diminished. Cystic fibrosis patients A major body burn AG elimination exhibits a close linear correlation with creatinine clearance. 50% increase in elimination rate. Increases the basal metabolic rate resulting in increase in AG elimination. hyper metabolic Eliminate AG's more rapidly ICU patients Elimination rate Not possible to predict the exact effect of disease state on drug elimination. Special populations require intensive monitoring, usually on a daily basis. Function of the volume of distribution and clearance. Elimination half life Renal function varies considerably among individuals : half life also variable Initial aminoglycoside dose and dosing interval should be selected with care. Relatively short half-life Small but significant distribution phase. Correct timing of the sample collection important. Samples for peak serum conc. be obtained 1 hour after the maintenance dose has been initiated. males in kg Ideal Body weight TIME TO SAMPLE 50+(2.3)( Height in inches >60) Females in kg 45+(2.3)( Height in inches >60) Drug infused over about 30 minutes Infusion period Acceptable range for the infusion period If longer than 40 minutes 20-40 minutes. Peak concentrations should be obtained approximately 30 minutes after the end of the infusion to ensure that distribution is complete. C :concentration at some time t later C°: = C / ekt T= time from the measured plasma concentration (C) to the earlier plasma concentration (C°) When sampled at a time that extends beyond the expected peak Calculate plasma concentration at the earlier time by simply rearranging the Eq C =C°ekt This equation used to back-extrapolate plasma concentration to the clinical peak which is 1 hour after the start of the infusion. Where C°: Initial plasma concentration Pharmacokinetic parameters can be estimated using a One-compartment model Two plasma samples Proper timing of serum sampling is critical. Measure the peak level 15 to 30 minutes after completion of the IV infusion Precautions Measure the peak level 90 minutes after an IM injection. Drawing the peak too soon will result in inaccurate analysis to avoid the distributive phase. In most cases