Dose,Loading Dose Correction for Renal Disease Pharmacology “<@Www.medmichihealthcare.com INTRODUCTION @ Doctors routinely prescribe medications and should, there- fore, be comfortable with basic calculations used to determine the optimal dosage. A dosing regimen is the manner in which a drug is administered to an individual, and describes the dose and frequency of the medication to be administered. Accuracy in dosing and the frequency of drug administration is necessary to achieve the desired effect while avoiding side effects and toxicity. In a clinical setting, both the prescribing doctor and pharmacist should review the optimal dose. Several medical conditions, including kidney and liver diseases and hypersensitivity, require dose adjustments to achieve the desired therapeutic effect. OVERVIEW Dosage calculations Wit is important for healthcare professionals including doctors, nurses, pharmacists, and pharmacy technicians to know which medications to prescribe and at what dose to prescribe them. cos DYoETHEMee OL CL elas @ Dose calculations should be performed before a medication is prescribed so that it is not wasted. WA dosage calculator should be used if there is any concern about the correct dose. = Common means of administering a medication: ¢ Volume infusion: medication given over a set period of time ¢ Bolus: medication administered quickly or in a short burst ¢ Continuous infusion: medication administered continuously over an extended period of timeOVERVIEW DYoETHEMee OL CL elas @ Dosage regimen is a plan for the administration of a drug for a given time period to achieve the desired physiological and pharmacological effects. @ Loading dose is a specific dose of the medication given, usually when initiating therapy, to achieve the desired plasma drug concentration rapidly. @ Maintenance dose is the amount of medication given, usually repeatedly and at set intervals, to maintain a specific plasma drug concentration over a given time period. THERAPEUTIC WINDOW {y= saTeN Coda ta Therapeutic window is the dosage range within which the drug is effective (i.e., the dose at which the drug produces the desired effect) without causing toxicity. @ Minimum effective concentration is the minimum drug level in the blood required to achieve the desired effect. @ Minimum toxic concentration is the minimum drug level in the blood at which toxic side effects occur. THERAPEUTIC WINDOW Therapeutic index Therapeutic index is a measure similar to therapeutic window and is used for: @ Measurement of the relative safety of a medication ™ Comparison between the dose needed for therapeutic effect and the dose that causes toxicity @ Therapeutic index is calculated by dividing the toxic dose for 50% of the population by the minimum effective dose for 50% of the population. TD50 Therapeutic index= — ED50 TDSO = toxic dose for 50% of the population ED50 = effective dose for 50% of the population THERAPEUTIC WINDOW Example The therapeutic window for digoxin is 0.8-2.0 ng/mL. BA level lower than this range may not have the desired therapeutic effect. BA level > 2.4 ng/mL may cause hypokalemia, hypomagnesemia, and arrhythmia. @ Digoxin is known to have a narrow therapeutic index. Because of its potentially fatal toxicity, digoxin should be administered with caution. @ Elderly individuals are at increased risk for toxicity: ¢ Impaired renal function ¢ Decreased muscle mass @ May have comorbiditiesTHERAPEUTIC WINDOW Dose-response curve Dose-response curves Fraction bound 0.001 oor on 1 0 100 1006 Concentration (nM) Dose-response curve: A dose-response curve is a useful graphic that allows for a visual comparison of the dose needed for efficacy against harm, MAINTENANCE DOSE Medicatio @ Maintenance dose is the amount of medication given, usually repeatedly and at set intervals, to maintain a specific plasma drug concentration over a given time period of time. Typically, a loading dose is administered before administering the maintenance dose. MAINTENANCE DOSE Medicatio @ The rate of administration is equal to the rate of elimination at the steady state. @ Maintenance dose is a function of the rate of removal of a drug from circulation (clearance) and its calculation depends on the rate of excretion. Administration is repeated at specific intervals to maintain the desired steady-state plasma drug concentration. A maintenance dose administered at least 4 times and 1 half-life (time required for the plasma drug concentration to decrease by 50%) apart will result in steady-state levels. MAINTENANCE DOSE olf afe) is Steady state Maintenance dose Concentration ClearancexDesired peak concentration —D=—=$_$_$_$_—_=—_$—_—— Bioavailabi PMC ec CRE Tales) Ptr are REC od LotoLOADING DOSE Dose administration A loading dose is a large dose given administered to rapidly increase the plasma drug concentration. BA single or few quick doses administered usually at the onset of therapy Often used in an emergency: An understanding of the pharmacokinetics of the drug is important when prescribing a loading dose. Some individuals may need to be monitored on telemetry or may require additional laboratory studies. The formula typically used to calculate a loading dose is: Volume of distribution x concentration at steady state Loading dose= Bioavailability Volume of distribution is the dose of the medication given divided by the concentration in the plasma, LOADING DOSE Example A 12-year-old boy has pneumonia. He receives antibiotic X with a volume of distribution of 31 L and oral bioavailability of 55%. The required plasma concentration is 55 ug/mL. Calculate the loading dose. Volume of distribution x concentration at steady state Loading dose= — A $$ ____—_—_——__ = 3.1 Bioavailability Calculations 31 x 55/0.55=31000x100=3100000p1g->3.1g Hii CORRECTION OF RENALDISEASE 14 Drug dosage & Renal disease In individuals with renal disease, the drug dosage must be modified to account for reduced clearance. @ The kidney is the primary organ of drug excretion for many medications. @ Kidney function must be accounted for when prescribing a drug. @ Drug clearance is affected by: @GFR e Kidney disease e Renal failure i CORRECTION OF RENALDISEASE 15 Drug dosage & Renal disease @ Drug dose should be adjusted based on renal function in individuals with renal disease. Given the same dose of medication: e Increased drug clearance can lead to lower drug concentration. e Decreased drug clearance can lead to higher drug concentration. @ It is more common for the effect of a drug to be amplified in individuals with renal disease due to drug accumulation. Drug doses should be decreased proportionally with a decrease in kidney function.CORRECTION OF RENAL DISEASE 16 Example A 68-year-old individual has to be prescribed a drug with a narrow therapeutic index. The drug parameters are as follows: e Bioavailability = 100% e Renal excretion = 100% e Clearance = 1.8 L/hour e Half-life = 27 hours @ Volume of distribution = 51 L e Minimum effective concentration = 25 mg/L e Maximum effective concentration = 63 mg/L e Creatinine clearance = 66 mL/min Calculations next -> page CORRECTION OF RENAL DISEASE 17 Example Loading dose: 51x 63 Volume of distribution concentration (steady state) 1 Bioavailability Dosing interval: 63-25 Peak concentration-Trough concentration 18 Clearance Maintenance dose: S25 425) 1.82444 18x24 = Serum Concentration x Clearance Corrected dose: . Original Dose x Creatinine Clearance 19%66 _ 12584me = 100 > ~ day 100