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2. Altered Pharmacokinetics In Pediatrics & Geriatrics By: Yalda.H.Ardakani

3. Introduction • Pediatrics : Branch of medicine dealing with the development of disease and disorders in children. • Children are not “miniature adults”

4. Subdivisions in children • Subdivision in children: Preterm newborn infant Newborn infant (Birth-28 days) Infant(28 Days-23 months) Young Child (2-5 years) Old Child (6-11 years) Adolescent(12-18 years)

5. General considerations • Pediatric patients were always considered in the pastfor treatment as MINI ADULTS. • In 1998, FDA required drug manufacturers to determine whether existing were sufficient to support information on pediatric use for drug labeling purpose . • Only 20-30% of approved drugs have pediatric labeling.

6. General considerations • Infancy and childhood is a period of rapid growth and development of organ systems and so ….. Scaling adult doses to infants based on body weight or surface area does not account for developmental changes that affect drug disposition.

7. Dose adjustment in pediatrics Dosage is adjusted based on pharmacokinetic data of a given age group for the desired response.

8. Pediatric dosage forms • Pediatric dosage forms should permit more accurate dosing and patient compliance. • Pediatric drug formulations may also contain different drug concentrations compared to the adult drug formulation. • Alternative drug delivery may be required.

9. potential sources of differences in pharmacokinetics Differences in pharmacokinetics body composition Absorption maturity of liver Kidney function Receptor response

10. Absorption in the Pediatric Patient • Absorption in the Pediatric Patient • Gastrointestinal absorption • Percutaneous absorption • Intra muscular absorption

11. Absorption - GI • Gastrointestinal pH changes • Gastric enzymes • Gastrointestinal flora • Gastric emptying & GI motility • Bile acids & biliary function

12. Absorption - GI • Gastrointestinal pH changes • Gastric pH is neutral at birth, and approaches adult values approximately in 3 month in full-term infants, so…. • Bioavailability increased for acid-labile drugs (penicillin derivatives) • Bioavailability decreased for drugs requiring acid to be absorbed. (Phenobarbital)

13. Absorption - GI • Gastric emptying • Delayed and unpredictable in newborns . • Reaches adult values at ~6 month. • GI motility • Slow in newborns; may be increased in children. • Usually affects the rate but not the fraction of drug absorbed. • The impact on absorption is usually minimal but is unpredictable.

14. Absorption - Skin • Percutaneousabsorption • Directly related to the degree of skin hydration. • Directly related to the perfusion of subcutaneous layer • Inversely related to the thickness of the stratum corneum. • Thinnest in premature neonate • Premature infant has a significantly less effective skin barrier to absorption of drugs and toxins • Hexachlorophenetoxic to immature infants • hydrocortisone over dosage

15. Absorption - Intramuscular • Intramuscular • Highly susceptible to variance in absorption due to... - reduced blood flow to skeletal muscles, -weak muscle contractions . • Because of pain associated with injection and the risk of nerve damage…. Infants 0.5ml Older children 1ml

16. Pediatric Distribution • Body Composition •  total body water & extracellular fluid •  adipose tissue & skeletal muscle • Protein Binding • albumin, bilirubin, 1-acid glycoprotein • Tissue Binding • compositional changes

17. Pediatric Distribution-Body Composition •  total body water & extracellular fluid •  adipose tissue & skeletal muscle Intra Cellular water Extra Cellular water Protein Fat Others

18. Pediatric Distribution Newborn Infant Children Adults Elderly Volume of Distribution of sulfisoxazole

19. Pediatric Distribution-Protein Binding 30.2 17.3

20. Pediatric Renal Function • Glomerular filtration rate • Low at birth • GFR doubles by 1 week of age • Adult values by 6-12 months of age • Tubular function • Secretory function impaired at birth • Glomerulo-tubular imbalance • Adult values by 1 year of age

21. GentamicinClearance Premature (<37 weeks) Full term Postnatal Age Gentamicin Clearance [L/kg•hr]

22. Pediatric Renal Function • Therapeutic implications • Estimation of renal function necessary for determining dose regimen for drugs with extensive renal clearance • Ex. Ceftazidime, famotidine, aminoglycosides. • Measurement of drug levels often necessary • Some drugs also alter renal maturation or renal blood flow . • Ex betamethsone, indomethacin

23. Elimination Half-Lives of Drugs in Infants and Adults

24. Pediatric Hepatic Function • Phase 1 (oxidation, hydrolysis, reduction, demethylation) • Activity low at birth • Mature at variable rates • Oxidative metabolism increases rapidly after birth • Alcohol dehydrogenase reaches adult levels at 5 yrs • Phase I enzyme activity in young children can actually exceed adult levels.

25. Pediatric Hepatic Function • Phase 2 (conjugation, acetylation, methylation) • Conjugation: • Glucuronidation: - at birth • Sulfatation: ­ at birth • Acetylation: - at birth

26. G:S kel 0.3 0.15 0.75 0.17 1.6 0.19 1.8 0.18 Acetaminophen Metabolism % of Dose

27. Cytochrome P450 (CYP) Enzymes • Half of all drugs metabolized by CYP3A subfamily. • CYP3A4 is most abundant hepatic P450 enzyme and metabolizes at least 50 drugs. CYP3A7 CYP3A4 >1yr 1-7d <24h Adult <30w >30w 8-28d 1-3mo 3-12mo Fetus Postnatal Age

28. Relative Half-lives of CYP3A Substrates

29. Relative Half-lives of CYP1A2 Substrates

30. Dosing of Drugs in Infants and Children

31. Dosing of Drugs in Infants and Children

32. Dosing of Drugs in Infants and Children

33. Practice Problem • The elimination half-life of penicillin G is 0.5 hr in adults and 3.2 hr in neonates (0 to 7 days old). Assuming that the normal adult dose of penicillin G is 4 mg/kg every 4 hours, calculate the dose of penicillin G for an 5 Kg infant. hr

34. Practice Problem (cont.) Dose=4 mg/kg Weight= 5 kg Alternatively, 10 mg every 12 hr would achieve the same . • Dose=4*5=20 mg every 24 hr

35. خداوند برکتی عظیم به تو بخشیده است. تو چه چیزی به ”او“ تقدیم می کنی ? هر روز، چیزی، هر چند کوچک به ”او“ تقدیم کن. از روی عشق و به نیازمندان.

36. The Aging Imperative • Persons aged 65y and older constitute 13% of the population and purchase 33% of all prescription medications • By 2040, 25% of the population will purchase 50% of all prescription drugs

37. Definition • Chronologically, the elderly have been classified as the… • young old (ages 65–75 years), • old (ages 75– 85 years), • old old(age > 85 years).

38. Specific Therapeutic Challenge of Prescribing for the Elder Patient • Principle factors: • Altered Pharmacokinetics • Multiple and severe illness • Multiple drug therapy • Poor adherence

39. Aging • Most body organs  in size with age  fewer cells to carry out organ functions • Pharmacological changes: • Drug absorption • Drug distribution • Drug metabolism • Drug excretion

40. Pharmacokinetic changes (Absorption) • Changes to intestinal tract: • decreased blood flow • reduced absorptive surface area • decreased gastric secretions • decreased motility • Result: • SLOWED rate of drug absorption • Delayed time to peak concentration • Peak drug level: • tends to decrease with age • same amount of drug will be absorbed but over a longer period of time

41. Pharmacokinetic changes (Absorption)

42. Pharmacokinetic changes (Distribution) • Distribution of Drugs: • Increased body fat • Decreased lean muscle mass • Decreased serum albumin • Decreased cardiac output • Decreased total body water

43. Effects of Aging on Volume of Distribution

44. Pharmacokinetic changes (Metabolism) • For drugs with extensive first-pass metabolism, BAmay increase because less drug is extracted by the liver • Decreased liver mass • Decreased liver blood flow • Decreased activity of hepatic enzymes • morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline, nortriptyline

45. Metabolic Pathways

46. Pharmacokinetic changes (Metabolism) Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)

47. Pharmacokinetic changes (Excretion) • Excretion of Drugs: • Decreased renal blood flow • Decreased glomerular filtration rate • Decreased tubular secretion • Decreased number of nephrons • Decreased drug clearance: atenolol, gabapentin, H2 blockers, digoxin, allopurinol

48. Determining Creatinine Clearance • Measurement of Creatinine Clearance • Time consuming • Requires 24 hr urine collection • Estimate • CockroftGault equation (IBW in kg) x (140-age) ------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)

49. Estimating GFR in the Elderly • Creatinine clearance (CrCl) is used to estimate glomerular rate • Serum creatinine alone not accurate in the elderly •  lean body mass  lower creatinine production •  glomerular filtration rate • Serum creatinine stays in normal range, masking change in creatinine clearance

50. Age Scr CrCl 30 1.1 65 50 1.1 53 70 1.1 41 90 1.1 30 Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman Example: