DOSAGE OF DRUGS,CALCULATION AND CLINICAL APPLICATION

LEARNING OBJECTIVES At the end of lecture student should be able to know, MAINTENANCE DOSE LOADING DOSE PEDIATRIC DOSE EFFECTIVE DOSE MEDIAN EFFECTIVE DOSE LETHAL DOSE MEDIAN LETHAL DOSE

DOSAGE REGIMENS DOSE Quantity of a drug given to the patient at one time to produce certain therapeutic effect. DIFFERENT DOSES MAINTENANCE DOSE LOADING DOSE PEDIATRIC DOSE EFFECTIVE DOSE MEDIAN EFFECTIVE DOSE LETHAL DOSE MEDIAN LETHAL DOSE MAINTENANCE DOSE:

o In most clinical conditions, drugs are administered in a series of repetitive doses or as a continuous infusion in order to maintain a steady state concentration of the drug in the body i.e. just enough drug is given in each dose to replace the drug eliminated since the preceding dose. Therefore calculation of maintenance dose is essential. To maintain a chosen target concentration (Css), rate of drug input (maintenance dose) is equal to rate of drug clearance. Dosing Rate = Rate of clearance at specified target concentration. o Dosing rate (I/V) = Cl TC (Target Concentration) If the desired target concentration is known, clearance of drug will determine dosing rate. If the drug is given by route that has bioavailability less than 100% (oral route) dosing rate is predicted b

Dosing rate (oral) = dosing rate (I/V) F (oral) F is the bioavailability OR Dosing rate = Cl TC o F If intermittent doses are given maintenance dose is calculated as Maintenance dose = Dosing rate Dosing interval. o Example: A target plasma theophylline concentration of 10 mg/L is needed to relieve acute bronchial asthma. Mean clearance of theophylline is 2.8 L/h/70Kg. Since the drug is given intravenously, o dosing rate is = Cl TC

= 2.8 L/h/70Kg 10 mg/L = 28 mg/h/70Kg Therefore, in this patient proper infusion rate would be 28 mg/h. When acute attack is relieved drug can be given orally at every 12 hours. The oral bioavailability of drug is 0.96, the size of each maintenance dose is calculated as:

Maintenance dose = Dosing rate Dosing interval. o As Dosing rate (oral) = dosing rate (I/V) o Therefore F (oral) o Maintenance dose = dosing rate (I/V) Dosing interval. F (oral) o = 28 mg/h 12 h 0.96 = 350 mg. LOADING DOSE: Loading dose is one or series of doses that may be given at onset of therapy to achieve target concentration quickly, it is calculated as Loading dose = TC Vd F o Loading dose may be desirable if time required to attain steady state concentration by the administration of drug at constant rate is long relative to demands of the condition being treated. For example half-life of Lignocaine is one hour. Arrhythmias following myocardial infarction are usually rapidly fatal, and one can not wait for 46 hours to achieve therapeutic concentration of lignocaine by infusion of drug at the rate required to maintain this concentration. Therefore loading dose of Lignocaine is usually given in coronary care unit.

 Disadvantages of loading dose: Patient may be exposed abruptly to toxic concentration of a drug. If drug has long half-life, it will take long time for the concentration to fall, if plasma level of drug is high. Loading dose is usually given intravenously, this is particularly dangerous if loading dose is large and drug is administered rapidly. PEDIATRIC DOSE: Because of the differences in pharmacokinetics in infants and children, they require small doses as compared to adults. The approximation of pediatric doses can be made by methods based on age, weight and surface area. These approximations are not precise and should not be used if manufacturer provides a pediatric dose. YOUNGS RULE: Pediatric dose = Age of child adult dose Age + 12 FRIED RULE: Pediatric dose = Age (in months) adult dose 150 CLARKS RULE: Pediatric dose = Weight (in Kg) adult dose 70 Pediatric dose = Weight (in Lbs) adult dose 150 o Based on surface area: o Pediatric dose = Surface area (in sq. m) adult dose 1.7 Dosage calculation based on surface area is more appropriate than age and body weight. Determination of Drug Dose Calculate Body Surface Area

 Height (cm) x Weight (kg) o 3600

THERAPEUTIC INDEX It is the ratio of median lethal dose (LD50) to median effective dose (ED50). OR It is the measurement that describes the relationship between doses of drugs required to produce undesired and desired effects. o LD50 T I = ED50 Median lethal dose is the minimum amount of drug in mg/Kg body weight that kills 50% of test animals. Median effective dose is the minimum amount of drug in mg/Kg body weight that produces desired effects in 50% of test animals. ED50 is the measure of potency of the drug, lower the dose more potent is drug and vice versa. Therapeutic index is used to evaluate safety and usefulness of a drug, higher the therapeutic index safer will be drug. For safe application of a drug its therapeutic index should be more than one. Penicillins and benzodiazepines have high therapeutic index. Digitalis, G.Anesthetics and Anticancer drugs have low therapeutic index.

 Depending upon therapeutic utility, a drug may have more than one therapeutic indices. Ideally a drug should have LD50 much higher than ED50. STANDARD MARGIN OF SAFETY: Therapeutic index may be misleading if the log dose response curve for effectiveness and toxicity have different slopes i.e. are not parallel. Therefore, standard margin of safety may be more useful. Standard margin of safety shows the percentage by which ED99 (Dose effective in 99% of population) must be increased to cause toxic effects in 1% of population. Formula for standard margin of safety is: o LD1 ------ x 100 o ED99 Therapeutic Index TD50/ED50 Dose-Response Function ED50 Dose-Response Function TD5o Dose-Response Function LD50 Dose-Response Function ED50 ,TD50 ,LD50 Efficacy & Potency Efficacy & Potency Efficacy & Potency Summation Potentiation Causes of Variability in Drug Response

Those related to the biological system Body weight and size Age and Sex Genetics - pharmacogenetics Condition of health Placebo effect Causes of Variability in Drug Response Those related to the conditions of administration Dose, formulation, route of administration. Resulting from repeated administration of drug: o drug resistance; drug tolerance-tachyphylaxis; o drug allergy Drug interactions: o Chemical or Physical; o GI absorption; o Protein binding/distribution; o Metabolism (stimulation/inhibition); o Excretion (ph/transport processes); o Receptor (potentiation/antagonism); o Changes in pH or electrolytes. DOSE RESPONSE RELATIONSHIP Two basic types of dose response relationships have been observed, these are: QUANTAL OR ALL & NONE DOSE RESPONSE RELATIONSHIP: o In this type of relationship a single dose of the drug either produces no effect or produces maximum effect. DOSE RESPONSE RELATIONSHIP o GRADED OR QUANTITIVE DOSE RESPONSE RELATIONSHIP: In this type of relationship as the dose administered to a single subject is increased, the pharmacological response also increases in a gradual fashion.

 The degree of effect produced by increasing the dose of drug eventually reaches steady level. This phenomenon is called ceiling effect and dose at which it occurs is called ceiling dose. Increasing the dose beyond this dose produces undesirable effect. o EFFICACY:

Maximal effect that can be elicited by a drug is called efficacy, it is measured by Emax. Efficacy is more important than potency in selecting drug for clinical use.

o POTENCY: Concentration (EC50) or dose (EC50) of a drug that produces 50% of the maximal effect of that drug is called potency, it is measured by ED50, and lower the ED50 more potent is the drug. THANKYOU