Amino-glycosides (1).pdf

DOSING AND MONITORING OF DRUG LEVELS OF AMINO-GLYCOSIDES LADME scheme Pharmacokinetic processes which follow a given dosage regimen. L = Liberation Release of the drug from its dosage form. A = Absorption Movement of drug from the site of administration to the blood circulation. D = Distribution Pro...

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