Aminoglycosides Dosing & Monitoring PDF

Objectives • To understand the Pharmacokinetics of aminoglycosides. • To learn about the behaviour of various aminoglycosides. DOSING AND MONITORING OF DRUG 1 LEVELS OF AMINOGLYCOSIDES 1 2 LADME scheme LADME : Pharmacokinetic processes which follow a given dosage regimen. L = Liberation, Releas...

Objectives • To understand the Pharmacokinetics of aminoglycosides. • To learn about the behaviour of various aminoglycosides. DOSING AND MONITORING OF DRUG 1 LEVELS OF AMINOGLYCOSIDES 1 2 LADME scheme LADME : 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, • Chemical conversion or transformation of 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. 3 4 LADME processes : Two classes, Drug input and Drug output. Input processes : L = Liberation, A = Absorption, 5 6 Aminoglycosides Output processes, or disposition of drug are: Introduction ●Bactericidal antibiotics used in treatment of serious gram-negative systemic infections. 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. 7 ● Active against most strains of Staphylococcus aureus and S. epidermidis. ● Most strains of enterococcus resistant to aminoglycosides. 8 •In most instances, amino glycosides must be administered by intravenous infusions. Anaerobic bacteria are universally resistant Aminoglycoside transport into cells is oxygen-dependent • Gentamycin, •Amino glycosides must be administered parenterally. • Tobramycin Reason: • Amikacin. •Absorption from gastrointestinal tract poor. . •Three most commonly monitored amino glycoside antibiotics : 9 10 ● Pharmacodynamic properties of aminoglycosides • Exhibit significant post-antibiotic effect (PAE). ● Concentration-dependent killing ● Significant post-antibiotic effect ● Aminoglycosides eliminate bacteria quickest when their concentration is appreciably above 10 times of MIC for an organism; • 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. ● Referred to as concentration dependent activity. 11 12 Key parameters; 1.Therapeutic serum concentration; Conventional dosing: Once daily dosing Gentamicin,Tobramycin Peak:5-8mg/L 20mg/L Trough <2mg/L Undetectable --------------------------------------------------------------------------------------------------Amikacin Peak:20-30mg/L 60mg/L Trough <10mg/L Undetectable --------------------------------------------------------------------------------------------------2.Volume of distribution (V) 0.25L/Kg --------------------------------------------------------------------------------------------------3.Clearance(Cl) Equal to Clcr Functionally Anephric patients 0.0043L/Kg/hr Surgically Anephric patients 0.0021L/Kg/hr Hemodialysis 1.8L/hr --------------------------------------------------------------------------------------------------- 4.AUC24 70-100 mg. hr/L 5.T 1/2 Normal renal function Functionally Anephric patient 2-3 hrs. 30-60 hr. 13 14 Concentration-toxicity relationships BIOAVAILABILITY(F): ● Very water soluble ● Poorly lipid soluble. ● Poorly absorbed when administered orally. ● Must be administered parenterally for treatment of systemic infections. -------------------------------------------------------------------------------15 ● For gentamicin, tobramycin and netilmicin risk of ototoxicity and nephrotoxicity increased if trough levels consistently exceed 2 mg/ml. ● For amikacin, trough levels consistently greater than 10 mg/ml have been associated with a higher risk of ototoxicity and nephrotoxicity 16 ● For AG's the ideal dosing regimen would maximize concentration, -grickest ● The higher the concentration, the more extensive and the faster is the degree of bactericide. ● 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. 17 18 Pharmacokinetics ● When given by IV infusion over 30 minutes Follows a 3-compartment pharmacokinetic model; Alpha (distribution), ß (elimination), and S • Amount released from tissue is very small, • Accumulates over time, contributing to AG toxicity. 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. 19 20 Extended-interval (or "once-daily") aminoglycoside Dosing gained popularity in recent years. ● Pharmacodyamic properties of AG's form the basis of EI dosing. Although this model accurately represents the time course of AG serum levels, it cannot be used clinically because of its complexity. Therefore, the simpler one compartment model is widely used, and does, in fact, accurately predict serum AG levels . ● Concentration dependent activity of AG's demonstrates that a large dose (5mg/kg) is needed to maximize killing. 21 22 Volume of distribution(v): • Persistent (post-antibiotic) effect of AG's allows a dosing interval of 24-36 hours. -> ● 0.25L/kg ( 0.1-0.5 L/kg ) Range ↳ Average • ● Extended interval provides a beneficial wash out period during the gamma (tissuerelease) phase, thus decreasing the incidence of toxicity. ● Distributes very poorly into adipose tissue. van ● Amino glycoside V (L)= 0.25L/kg×Nona write ↳ normal obese, Non-excess fluid weight (kg) +0.1(excess adipose weight (kg)+ excess third space fluid weight (kg) Gies Patient kam 23 Liter zu obesity elemen es . 24 • Pediatric patients younger than 5 years of Childs age cuz & • 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. • Volume of distribution of 0.5 L/kg. • In children 1to 5 years more werfen um ↳ Huss why • V of 0.25L/kg generally used. 26 CLEARANCE (cl) Eliminated almost entirely by the renal route. Non-renal clearance, : 0.0021L/kg/hr or 2.5 mL/min/70kg. Cl crfor females (ml/min)=(0.85)× (140-(Age)(Weight) (72)scrss) Correct estimates of creatinine clearance can only be obtained if : • Ignored in most patients, • Significant in patients whose renal function is significantly diminished. Patient's weight represents normal ratio of muscle mass to total body weight Serum creatinine is at steady state. 27 d distribution • After 5 years of age Cl cr for males (ml/min)=(140-Age)(Weight)/(72)scrss) more bl • Amino glycoside V (L)=(0.5 L/kg-{age in years/5x 0.25})(weight in kg) 25 , 28 • ICU patients : Elimination rate • Often hyper metabolic AG elimination exhibits a close linear correlation with creatinine clearance. • Eliminate AG's more rapidly. ● Cystic fibrosis patients : • Not possible to predict the exact effect of disease state on drug elimination, 50% increase in elimination rate. ● A major body burn : • Special populations require intensive monitoring, usually on a daily basis Increases the basal metabolic rate resulting in a marked increase in AG elimination. 29 30 Objectives Elimination half life. ● Function of the volume of distribution and clearance. • To study the exact time to sample aminoglycosides. • To find the acceptable range for the infusion period. • To know the precautions taken during sampling period ● Renal function varies considerably among individuals : half life also variable ● Initial aminoglycoside dose and dosing interval should be selected with care 31 32 Ideal Body weight • TIME TO SAMPLE • Relatively short half-life Ideal body weight for males in kg = 50+(2.3)( Height in inches >60) • 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 for females in kg = 45+(2.3)( Height in inches >60) 33 34 When sampled at a time that extends beyond the expected peak, • Drug infused over about 30 minutes ; • Acceptable range for the infusion period : 20-40 minutes. Calculate plasma concentration at the earlier time by simply rearranging the Eq. C =C°ekt • If longer than 40 minutes, Where C°: Initial plasma concentration, • 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 35 36 • This equation used to back-extrapolate plasma concentration to the clinical peak which is 1 hour after the start of the infusion. • T= time from the measured plasma concentration (C) to the earlier plasma concentration (C°) • Pharmacokinetic parameters can be estimated using a • One-compartment model and • Two plasma samples in most cases. 38 37 Conclusion 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. 39 • Aminoglycosides are poorly absorbed when administered orally. • Must be administered parenterally for treatment of systemic infections. • When given by IV infusion over 30 minutes, amino glycosides follow a 3compartment pharmacokinetic model; alpha (distribution), ß (elimination), and gamma (tissue release). 40