Paediatric pharmacology

drugs and therapy for paediatric age group

1. Dr.K.Sathishbabu 2 nd year PG Department of Pharmacology PAEDIATRIC PHARMACOLOGY

2. OVERVIEW Pharmacokinetic process in Paediatric patients Pharmacodynamic process in paediatric patients Paediatric dosage forms and compliance Paediatric drug dosage Drug use in Lactation 21/05/2020 2 PAEDIATRIC PHARMACOLOGY

3. INTRODUCTION Physiologic processes - influence pharmacokinetic variables in the infant change significantly in the first year of life Special attention must be paid to pharmacokinetics Pharmacodynamic differences between pediatric & other patients have not been explored and except for those specific target tissues that mature at birth 21/05/2020 3 PAEDIATRIC PHARMACOLOGY

4. Pharmacokinetic processes 21/05/2020 4 PAEDIATRIC PHARMACOLOGY

5. Absorption Blood flow at the site of drug administration : Absorption from IM or SC injection in neonates - rate of blood flow to the muscle or subcutaneous area injected. Physiologic conditions - reduce blood flow Cardiovascular shock & Heart failure Vasoconstriction due to sympathomimetic s 21/05/2020 5 PAEDIATRIC PHARMACOLOGY

6. Sick preterm infants : very little muscle mass Complicated by diminished peripheral perfusion to these areas. Absorption becomes irregular & difficult to predict : Drug may remain in the muscle and be absorbed more slowly than expected 21/05/2020 6 PAEDIATRIC PHARMACOLOGY

7. If perfusion suddenly improves → sudden and unpredictable increase in the amount of drug entering the circulation → high and potentially toxic concentrations of drug Examples : Cardiac glycosides, Amino glycosides and Anticonvulsants 21/05/2020 7 PAEDIATRIC PHARMACOLOGY

8. 2. Gastro intestinal function : Gastric acid secretion : Full term infants → begins soon after birth Preterm infants → occurs more slowly (highest conc → 4 th day of life) Drugs – partially / totally inactivated by low pH 21/05/2020 8 PAEDIATRIC PHARMACOLOGY

9. Gastric emptying time : prolonged in 1 st day (6-8h) Stomach – drug may absorbed more completely In small intestine – delayed therapeutic effect Peristalsis : In neonates – irregular & slow Slow peritalsis  Increased absorption  Toxicity Fast peristalsis  Decreased absorption 21/05/2020 9 PAEDIATRIC PHARMACOLOGY

10. Gastro intestinal enzymes : low Pancreatic enzymes : low (upto 4 months) Bile acids & Lipase : low Oral drug absorption (bioavailability) of various drugs in the neonate compared with older children and adults 21/05/2020 10 PAEDIATRIC PHARMACOLOGY

11. 3 . Rectal absorption : Faster & more predictable Diazepam suppository is given rectally to control febrile seizures in children < 5yrs 4. Transdermal absorption : Faster Skin is thin & more permeable 21/05/2020 11 PAEDIATRIC PHARMACOLOGY

12. Distribution Body weight in the form of water : Neonate (70–75%) > adult (50–60%) ECF : Neonate (40% of BW) > adult (20% of BW) Many drugs are distributed through the ECF space Volume of the ECF compartment - important in determining the concentration of drug at receptor sites 21/05/2020 12 PAEDIATRIC PHARMACOLOGY

13. Total body fat : Preterm infants is about 1% of total body weight, compared with 1.5% in full-term neonates Organs accumulate smaller concentrations of lipid soluble drugs in less mature infants 21/05/2020 13 PAEDIATRIC PHARMACOLOGY

14. Plasma protein binding : Protein binding is lower because Albumin and total protein concentrations are lower in neonates until 1 year Qualitative differences in binding proteins Competitive binding by molecules such as bilirubin and free fatty acids, which circulate in higher concentrations in neonates and infants 21/05/2020 14 PAEDIATRIC PHARMACOLOGY

15. Result may be, Increased free drug concentrations Greater drug availability at receptor sites Higher pharmacologic effects and adverse effects at lower drug concentrations Drugs given to a neonate with jaundice → displace bilirubin from albumin → greater permeability of the neonatal blood-brain barrier → bilirubin may enter the brain → kernicterus Example – sulphonamides 21/05/2020 15 PAEDIATRIC PHARMACOLOGY

16. Metabolism Metabolism of most drugs occurs in the liver Drug-metabolizing activities → cytochrome P450 dependent enzymes low in early neonatal life than later Neonates – decreased ability to metabolize drugs Glucuronide formation reaches adult values between the third and fourth years of life 21/05/2020 16 PAEDIATRIC PHARMACOLOGY

17. Many drugs have slow clearance rates and prolonged elimination half-lives → the neonate is predisposed to adverse effects from drugs that are metabolized by the liver Example : Chloramphenicol can produce grey baby syndrome 21/05/2020 17 PAEDIATRIC PHARMACOLOGY

18. Mother receiving drugs (eg, phenobarbital) → induce early maturation of fetal hepatic enzymes. ↓ The ability of the neonate to metabolize certain drugs will be greater than expected ↓ Less therapeutic effect and lower plasma drug concentrations (when usual neonatal dose is given) 21/05/2020 18 PAEDIATRIC PHARMACOLOGY

19. During toddlerhood (12–36mon) → the metabolic rate of many drugs exceeds adult values → necessitating larger doses per kilogram than later in life Comparison of elimination half-lives of various drugs in neonates and adults 21/05/2020 19 PAEDIATRIC PHARMACOLOGY

20. Excretion Glomerular filtration in neonate : 30–40% of the adult value (lower in preterm) After 3 rd week, GFR is 50–60% of adult value By 6–12 months, GFR reaches adult values During toddlerhood, GFR exceeds adult values → necessitating larger doses per kg than in adults Eg : Digoxin 21/05/2020 20 PAEDIATRIC PHARMACOLOGY

21. Drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life. Eg : Ampicillin, Aminoglycosides Tubular function : In infants tubular secretion rates are approx. 20% Doesn’t achieve adult values until 6-7months of age In neonates tubular reabsorption is decreased 21/05/2020 21 PAEDIATRIC PHARMACOLOGY

22. Pharmaco dynamic process Appropriate use of drugs has made possible the survival of neonates with severe abnormalities Indomethacin – Rapid closure of PDA Prostaglandin E1 – Ductus remain open in TGA Neonates → more sensitive to the central depressant effects of opioids → necessitating extra caution on exposure to some narcotics 21/05/2020 22 PAEDIATRIC PHARMACOLOGY

23. At birth, the function of drug transporters may be very low Eg : P-glycoprotein (pumps morphine from the blood-brain barrier back to the systemic circulation) → neonates are substantially more sensitive to the CNS depressant effects of morphine 21/05/2020 23 PAEDIATRIC PHARMACOLOGY

24. ELIXIRS SUSPENSIONS Flavoured solutions of drug in sugar syrup or glycerol along with higher proportion of alcohol Liquid medicament containing insoluble substances which are homogenously distributed throughout vehicle with or without help of suspending agents. Drug molecules are dissolved & evenly distributed ; Shaking not required Undissolved particles and uneven Distribution ; Shaking required First dose from the bottle and the last dose should contain equivalent amounts of drug First doses from the bottle may contain less drug than the last doses → less than the expected plasma concentration or effect of the drug may be achieved Eg. Vit B - complex elixir Eg. Milk of magnesia, phenytoin susp. Paediatric dosage form 21/05/2020 24 PAEDIATRIC PHARMACOLOGY

25. COMPLIANCE Reasons for non compliance : Measuring errors Spilling Spitting out Discontinuation of antibiotics after feeling better Measuring compliance : Random pill counts Measurement of serum concentrations Use of computerized pill containers 21/05/2020 25 PAEDIATRIC PHARMACOLOGY

26. Paediatric drug dosage & Calculation Most reliable paediatric dose information – provided by the manufacturer in the package insert In absence of explicit paediatric dose recommendations , an approximation can be made by methods based on age, weight or surface area 21/05/2020 26 PAEDIATRIC PHARMACOLOGY

27. Rules regarding this aren’t precise and should not be used if the manufacturer provides a paediatric dose When paediatric doses are calculated (either from one of the methods set forth below or from a manufacturers dose), the paediatric dose should never exceed the adult dose 21/05/2020 27 PAEDIATRIC PHARMACOLOGY

28. Age, Weight & Surface area Calculations of dosage based on age or weight are conservative and tend to underestimate the required dose 21/05/2020 28 PAEDIATRIC PHARMACOLOGY Clark’s rule (Weight): Dose = Adult dose  Weight (kg) 70 OR Dose = Adult dose  Weight (lb) 150 Young rule (Age) : Dose = Adult dose  Age (years) Age +12

29. Catzel Rule : = surface area of the child (in m 2 ) x Adult dose 1.76 m 2 21/05/2020 29 PAEDIATRIC PHARMACOLOGY Doses based on surface area are more likely to be adequate

30. Monitoring parameters It give an idea about therapy management in prolonged treatment Pediatric vital signs, biochemical and Hematology parameters change through childhood 21/05/2020 30 PAEDIATRIC PHARMACOLOGY

31. 21/05/2020 31 PAEDIATRIC PHARMACOLOGY

32. Drug use in Lactation Most drugs administered to lactating women are detectable in breast milk. Fortunately, the concentration of drugs achieved in breast milk is usually low The total amount the infant would receive in a day is substantially less than “therapeutic dose” 21/05/2020 PAEDIATRIC PHARMACOLOGY 32

33. Optimal time to take medication: 30–60 minutes after nursing and 3–4 hours before the next feeding This may allow time for drugs to be partially cleared from the mother’s blood, and the concentrations in breast milk will be relatively low 21/05/2020 PAEDIATRIC PHARMACOLOGY 33

34. Milk is slightly more acidic (pH 7.0) than plasma → weak bases that become more ionised. Non-electrolytes like alcohol (ethanol) can readily enter into the milk independently of the pH. Majority of the drugs get into the milk by passive diffusion although active transport may occur in a few cases. Eg. Iodide 21/05/2020 PAEDIATRIC PHARMACOLOGY 34

35. The amount of a drug transferred into the milk depends on various factors. Maternal volume of distribution : lipid soluble drugs > water soluble drugs Results in low plasma levels relative to the dose. Plasma protein binding : Only unbound drug in the plasma is able to diffuse into the milk. Highly protein bound drugs cannot be detected in breast milk 21/05/2020 PAEDIATRIC PHARMACOLOGY 35

36. 21/05/2020 PAEDIATRIC PHARMACOLOGY 36 Drugs Effects on infant Choral hydrate Drowsiness if infant is fed at peak conc. in milk Heroin, Morphine Prolong Neonatal narcotic dependence Iodine (radioactive) Thyroid suppression in infants Glucocorticoids affect the growth and development due to premature fusion of epiphysis Methadone Prolong Neonatal narcotic dependence Signs of opioid withdrawal in infants if mother stops taking methadone or stops breast feeding abruptly Phenobarbital Sedation Tetracycline Discoloration of teeth

37. Summary There are many pharmacokinetic and pharmaco dynamic changes as a child develops. C aution is particularly needed in the premature and term neonatal population to avoid pharmacological errors P harmacological variation amongst neonates and infants emphasize the need to titrate many drugs to effect 21/05/2020 PAEDIATRIC PHARMACOLOGY 37

38. Physiological and Pathological factors can alter drug handling Hepatic metabolism is determined by developing hepatic enzyme systems and by blood flow Enzyme systems in the developing child are variable and complex. This gives reduced predictability of how a drug will affect a young child 21/05/2020 PAEDIATRIC PHARMACOLOGY 38

39. P aediatric patient’s ability to clear a drug changes rapidly in the first few months of life; often a child can clear drugs faster than an adult Oral administration is far more acceptable to children compared to the intramuscular route 21/05/2020 PAEDIATRIC PHARMACOLOGY 39

40. References Bertram G Katzung. Special Aspects of Perinatal & Pediatric & Geriatric Pharmacology. Basic & clinical pharmacology.13 th edition. Pg – 1390-1417 Felix Bochner. Medication during Pregnancy, Lactation, Chlidren & Elderly. Handbook of clinical pharmacology; 2 nd edition. Pg – 43-64 21/05/2020 PAEDIATRIC PHARMACOLOGY 40

41. Sumner J. Yaffe Neonatal and Pediatric Pharmacology: Therapeutic Principles in Practice 2010 R.S.Satoskar. Drugs, Pregnancy and Infant; Pharmacology and Pharmacotherapeutics; 24 th edition. Pg – 1694 – 1705 21/05/2020 PAEDIATRIC PHARMACOLOGY 41

42. THANK YOU