Age-Related Changes in Pharmacokinetics

General Principles of Age-Related PK - Tiny Tots & Golden Oldies

• Pharmacokinetics (ADME) vary significantly at age extremes.
• Tiny Tots: Immature organs (liver, kidney); ↑Total Body Water (TBW), ↓protein binding.
• Golden Oldies: ↓Organ function (renal, hepatic); ↓TBW, ↑fat; ↓albumin.
• Impacts drug dosing, efficacy, and toxicity.

⭐ Reduced renal clearance in geriatrics is a major cause of adverse drug reactions (ADRs).

Pediatric PK: Absorption & Distribution - Sponge Bob & Skinny Jeans

Absorption:

• Gastric pH: ↑ (alkaline) in neonates (adult by 2-3 yrs).
• Gastric emptying: ↓, irregular (adult by 6-8 mo).
• Percutaneous: ↑ (thin skin, ↑hydration, ↑SA:weight). ⚠️Toxicity.

Distribution:

• TBW: ↑ (75-80%); ECF: ↑.
  • ↑ Vd water-soluble drugs (gentamicin). 📌 Sponge Bob

  ⭐ Neonates have higher Vd for water-soluble drugs.

• Body Fat: ↓ (preterm 1%, term 15%).
  • ↓ Vd lipid-soluble drugs (diazepam). 📌 Skinny Jeans
• Protein Binding: ↓ (↓albumin, ↑bilirubin) → ↑free drug.

Pediatric PK: Metabolism & Excretion - Liver & Kidney Kickstart

• Liver Metabolism (Hepatic Clearance):
  • Phase I (e.g., CYP450 oxidation): Activity significantly ↓ in neonates/infants; matures by 1-2 years.
  • Phase II (Conjugation):
    • Glucuronidation: Markedly ↓ in neonates (matures 2-4 yrs).
    • Sulfation: Relatively well-developed at birth.
  • Implication: Slower metabolism → prolonged drug half-life ($t_{1/2}$), ↑ toxicity risk. Careful dosing needed.
• Kidney Excretion (Renal Clearance):
  • GFR: Significantly ↓ (approx. 30-40% of adult values); matures by 6-12 months.
  • Tubular Secretion: Also ↓; matures over the first year.
  • Implication: Reduced renal drug elimination → prolonged $t_{1/2}$. Dose/interval adjustments critical.

⭐ Glucuronidation pathways mature late in neonates, increasing risk of Gray Baby Syndrome with chloramphenicol.

Geriatric PK: Absorption & Distribution - Senior Shifts & Stashes

• Absorption:
  • ↓ Gastric acid (↑pH), ↓GI motility & blood flow.
  • Rate may ↓; extent usually unchanged.
• Distribution:
  • Body Composition: ↓Total body water, ↓lean mass, ↑total body fat. (📌 Seniors Stash Fat!)
  • Protein Binding: ↓Albumin (→ ↑free acidic drugs e.g. warfarin); ↑Alpha-1-acid glycoprotein (AAG).
  • Volume of Distribution (Vd): ↓ for water-soluble (e.g. lithium); ↑ for lipid-soluble (e.g. diazepam).

⭐ Increased body fat in elderly means larger Vd for lipophilic drugs, prolonging effects & toxicity risk.

Geriatric PK: Metabolism & Excretion - System Slowdown Saga

• Metabolism (Liver):
  • ↓ Hepatic blood flow & liver mass.
  • ↓ Phase I (CYP450) reactions (oxidation, reduction) significantly.
  • Phase II (conjugation) relatively preserved.
  • Leads to: ↓ first-pass effect, ↑ drug $t_{1/2}$.
• Excretion (Kidney):
  • ↓ Renal blood flow & GFR (by ~1% per year after 40).
  • ↓ Tubular secretion.
  • Leads to: ↓ drug clearance, ↑ drug accumulation.
  • 📌 Estimate $CrCl$ (e.g., Cockcroft-Gault); serum creatinine unreliable alone.

⭐ Phase I (oxidative) metabolism declines more significantly than Phase II (conjugation) in the elderly.

Clinical Implications & Dosing Adjustments - Age-Wise Dosing Dilemmas

• Pediatrics: Immature organs affect drug handling; dose per kg/BSA. Monitor closely for efficacy & toxicity.
• Geriatrics: ↓ Renal function common (Cockcroft-Gault: $CrCl = \frac{(140 - Age) \times Wt (kg)}{72 \times SCr (mg/dL)} (\times 0.85 \text{ if female})$); ↑ drug sensitivity.

⭐ Polypharmacy is a major risk factor for ADRs in the elderly.

High‑Yield Points - ⚡ Biggest Takeaways

• Neonates: Higher gastric pH, slower gastric emptying, ↑ transdermal absorption.
• Pediatrics: ↑ Total Body Water (↑ Vd water-soluble drugs); ↓ protein binding (↑ free drug).
• Pediatrics: Immature liver enzymes (↓ metabolism); ↓ GFR (prolonged drug half-life).
• Geriatrics: ↓ Total Body Water, ↑ body fat (alters Vd); ↓ serum albumin (↑ free drug).
• Geriatrics: ↓ Hepatic metabolism (especially Phase I); reduced liver blood flow.
• Geriatrics: Most critical: ↓ Renal GFR leads to drug accumulation and toxicity.