1. RATIONAL DRUG THERAPY DR.SELVAN

2. INTRODUCTION Choosing a safe and effective treatment regimen for pediatric patients can be challenging. Multiple patient variables such as developmental physiology, past medical history, pharmacokinetic and pharmacodynamic properties, desired therapeutic outcomes and psychosocial issues need to be considered when designing appropriate drug therapy regimen for children.

3. Developing a pediatric drug regimen 1) Pharmacokinetic consideration : a) Absorption : a) Absorption : Oral drug absorption in children can be unpredictable owing to variation in gastric pH, emptying time and intestinal transit time. At birth gastric pH is neutral and it reaches adult values by 3 months of age Oral drug absorption in children can be unpredictable owing to variation in gastric pH, emptying time and intestinal transit time. At birth gastric pH is neutral and it reaches adult values by 3 months of age b) Distribution: b) Distribution: Drugs administered parenterally have erratic and unpredictable distribution in neonates due to poor perfusion, decreased muscle mass, and difference in percentage of TBW Drugs administered parenterally have erratic and unpredictable distribution in neonates due to poor perfusion, decreased muscle mass, and difference in percentage of TBW

4. Plasma protein concentration which is lower in neonates can affect the plasma levels of highly protein bound drugs like phenytoin. They approach adult levels by 10 to 12 months of age. Plasma protein concentration which is lower in neonates can affect the plasma levels of highly protein bound drugs like phenytoin. They approach adult levels by 10 to 12 months of age. C) Metabolism: C) Metabolism: Hepatic enzymatic activity is reduced in neonates but as the infant grows its ability to metabolise medication increases. Hepatic enzymatic activity is reduced in neonates but as the infant grows its ability to metabolise medication increases. D) Elimination: D) Elimination: At birth GFR is < 50% of adult value. Hence elimination is prolonged and dosing intervals for renally eliminated drugs like gentamicin needsto be adjusted accordingly. By 6 months of age the GFR increases to 90% of adult value. At birth GFR is < 50% of adult value. Hence elimination is prolonged and dosing intervals for renally eliminated drugs like gentamicin needsto be adjusted accordingly. By 6 months of age the GFR increases to 90% of adult value.

5. 2) Pharmacodynamic consideration: The aim of this consideration is to maximize drug effect and minimize drug toxicity. The aim of this consideration is to maximize drug effect and minimize drug toxicity. The drug effect may be either The drug effect may be either a) concentration dependent: e.g.. Amino glycosides. a) concentration dependent: e.g.. Amino glycosides. b) Time dependent: b) Time dependent: e.g.. Penicillin. e.g.. Penicillin.

6. Drug selection 1) Patient specific factors: a) physiologic: a) physiologic: 1.Hyperbilirubinemia: Ceftriaxone can displace bilirubin and induce kernicterus in newborn. 1.Hyperbilirubinemia: Ceftriaxone can displace bilirubin and induce kernicterus in newborn. 2. Newborn immaturity : 2. Newborn immaturity : G.I. malabsorption : oral drugs are unreliably absorbed during the first month. G.I. malabsorption : oral drugs are unreliably absorbed during the first month. Renal insufficiency : penicillin and amino glycosides need extended dosing interval. Renal insufficiency : penicillin and amino glycosides need extended dosing interval. Hepatic insufficiency : Phenobarbital, morphine and diazepam in newborns need low doses and extended intervals. Hepatic insufficiency : Phenobarbital, morphine and diazepam in newborns need low doses and extended intervals.

7. 3.Malnutrition : Drugs like phenytoin, warfarin have increased action due to decreased protein binding. 4.Short bowel syndrome : Oral drugs have erratic absorption. 5.Coordination of swallow : Oral drugs can be swallowed by kids >3 years old. B) PSYCHOLOGICAL: Cognitive ability: Decreased understanding of directions can lead to non compliance or delayed recognition of side effects. Cognitive ability: Decreased understanding of directions can lead to non compliance or delayed recognition of side effects.

8. C) PSYCHOSOCIAL: Low socio economic status, illiteracy, broken homes have problems with purchasing and compliance of drugs. D) COMPLIANCE: It depends on palatability palatability schedule schedule volume volume side effects side effects

9. Drug specific factors: A drug with wide therapeutic index has a wide margin of safety than one with narrow therapeutic index. Hence they are selected for initial treatment if possible. A drug with wide therapeutic index has a wide margin of safety than one with narrow therapeutic index. Hence they are selected for initial treatment if possible. e.g. wide – paracetamol, BZDs, cephalosporins, penicillins, ranitidine. e.g. wide – paracetamol, BZDs, cephalosporins, penicillins, ranitidine. narrow – aminoglycosides, anticonvulsants, digoxin, heparin, opiates,theophylline, chemotherapy agents. narrow – aminoglycosides, anticonvulsants, digoxin, heparin, opiates,theophylline, chemotherapy agents.

10. 3) Routes of administration : 1) Oral route : Easiest, least expensive and most convenient. Its not appropriate in very young infants and in short bowel syndrome. 2) Rectal route : 2) Rectal route : Its reserved for those who cannot take oral medications. However drug distribution with it is not uniform. Its reserved for those who cannot take oral medications. However drug distribution with it is not uniform. 3) Parenteral route : 3) Parenteral route : It’s the most reliable method of administration and preferred in severely ill patients. It’s the most reliable method of administration and preferred in severely ill patients.

11. 4) Drug dosing Methods based on weight : - simple, convenient, and widely accepted. - Drugs with wide therapeutic index can be rounded off to a standard dose whereas those with narrow index have to be correlated with plasma drug levels Methods based on BSA : - More accurate. - Used for chemotherapeutic agents,and antiretroviral agents.

12. Methods based on age : - Least accurate. - Appropriate only for children with avg. ht. and wt DRUG INTERACTIONS: - Can occur between several drugs or between drugs and food - Usually due to overlapping of metabolism of two drugs. - Inducers –CBZ, phenobarbitol, phenytoin, rifampicin. - Inhibitors – cisapride, erythromycin, valproate, fluconazole.

13. PREVENTING MEDICTION ERRORS : - Decimal point placement – for doses less than one put a leading zero in front of the decimal point. - Abbreviation – should be avoided - Legibility - Maximum dosing – for children > 40 kg adult dose should be used.

14. GUIDELINES FOR RATIONAL PRESCRIPTION I. Make a specific diagnosis II. Consider the pathophysiology of diagnosis selected : If the disorder is well understood the prescriber is in a better position to select effective therapy. III. Select a specific therapeutic objective or goal and medications should be selected based on it. IV. Select a drug of choice

15. V. Determine the appropriate dosing regimen to obtain desired therapeutic levels and the drug must be inexpensive, easily available and should be prescribed in generic name. VI. Drug interaction and adverse effects must be taken into account before initiating combination of drugs. VII. Device a plan for monitoring the drugs action and determine an end point for the therapy. VIII. Plan a programme for patient education.