Pharmacokinetics: Absorption, Distribution, Metabolism, Excretion — Age Factors

Pharmacokinetics: Absorption, Distribution, Metabolism, Excretion — Age Factors

A practical guide for nurses, clinicians, and medical professionals.

What Is This?

Pharmacokinetics (PK) describes how the body handles drugs—absorption, distribution, metabolism, and excretion (ADME)—across the lifespan. Clinicians use this knowledge to dose safely, avoid toxicity, and optimize therapy in pediatric, adult, and geriatric patients.

Why it matters today: - Polypharmacy in aging populations increases drug interactions. - Pediatric dosing errors remain a leading cause of adverse events. - Precision medicine tailors treatments based on age-related PK differences.

Why It Matters

Real-World Impact

1. Pediatrics:
2. Neonates have immature liver enzymes (CYP450), leading to slower drug metabolism (e.g., morphine toxicity risk).

3. Gastric pH is higher in infants, reducing absorption of acidic drugs (e.g., penicillin).

4. Geriatrics:

5. Reduced renal clearance (e.g., digoxin toxicity in elderly patients with CKD).

6. Increased body fat alters distribution of lipophilic drugs (e.g., diazepam).

7. Critical Care:

8. Sepsis accelerates drug metabolism (e.g., faster vancomycin clearance).
9. Obesity changes volume of distribution (e.g., higher loading doses of hydrophilic drugs like gentamicin).

Problem solved: Prevents underdosing (treatment failure) and overdosing (toxicity) by accounting for age-related physiological changes.

Core Concepts

1. Absorption (How Drugs Enter the Bloodstream)

• Route matters:
• Oral: Slower in neonates (immature gut motility) and elderly (reduced gastric emptying).
• IM/SubQ: Faster in infants (higher muscle blood flow) but erratic in elderly (reduced perfusion).

• Transdermal: Enhanced in neonates (thin skin) but reduced in elderly (thicker stratum corneum).

• Key age factors:

• Neonates: Higher gastric pH-? absorption of acidic drugs (e.g., phenobarbital).
• Elderly:-GI blood flow-slower absorption of oral drugs (e.g., levodopa).

2. Distribution (Where Drugs Go in the Body)

• Body composition changes:
• Neonates: 70–80% water-higher volume of distribution (Vd) for hydrophilic drugs (e.g., gentamicin).

• Elderly:-fat,-water-lower Vd for hydrophilic drugs, higher for lipophilic drugs (e.g., diazepam).

• Protein binding:

• Neonates:-albumin-? free drug (e.g., phenytoin toxicity risk).
• Elderly:-albumin-? free drug (e.g., warfarin bleeding risk).

3. Metabolism (How Drugs Are Broken Down)

• Liver enzyme maturity:
• Neonates: CYP450 enzymes (e.g., CYP3A4) are immature-slower metabolism (e.g., caffeine half-life: 3–4 days vs. 5 hours in adults).
• Children (1–12 yrs): Faster metabolism than adults (e.g., theophylline clearance peaks at age 2).

• Elderly:-liver blood flow-slower metabolism (e.g., morphine clearance-by 30%).

• Phase II reactions:

• Glucuronidation (e.g., acetaminophen) is underdeveloped in neonates-risk of toxicity.

4. Excretion (How Drugs Leave the Body)

• Renal function:
• Neonates: GFR is 30–50% of adult levels-? clearance (e.g., aminoglycosides).
• Elderly: GFR declines ~1% per year after 40-? clearance (e.g., digoxin, lithium).
• Creatinine clearance (CrCl) estimation:
  • Cockcroft-Gault (adults): (140 - age) × weight / (72 × SCr) (× 0.85 for females).
  • Schwartz formula (pediatrics): (k × height) / SCr (k = 0.413 for children).

How It Works: A Drug’s Journey Through the Body

1. Absorption:
2. Drug enters bloodstream (oral, IV, transdermal, etc.).

3. Age factor: Neonates absorb oral drugs slower; elderly absorb transdermal drugs slower.

4. Distribution:

5. Drug binds to proteins (e.g., albumin) or distributes into tissues.

6. Age factor: Neonates have more water-hydrophilic drugs (e.g., gentamicin) spread more.

7. Metabolism:

8. Liver enzymes (CYP450) break down the drug.

9. Age factor: Children metabolize drugs faster; elderly slower.

10. Excretion:

11. Kidneys filter drug/metabolites into urine.
12. Age factor: Neonates and elderly have reduced GFR-slower clearance.

Example: Acetaminophen in a Neonate vs. Adult | Step | Neonate (1 week old) | Adult | |---------------|----------------------|-------| | Absorption | Slower (higher gastric pH) | Normal | | Distribution | Higher Vd (more water) | Lower Vd | | Metabolism | Slow (immature glucuronidation) | Fast | | Excretion |-GFR-longer half-life | Normal GFR |

Hands-On: Applying Age-Based Dosing

Prerequisites

• Basic pharmacology knowledge (e.g., half-life, clearance).
• Access to dosing calculators (e.g., Lexicomp, UpToDate).
• Patient data: age, weight, serum creatinine (SCr), liver function tests (LFTs).

Step-by-Step Example: Gentamicin in a Neonate

Scenario: 3-day-old preterm infant (weight: 2 kg, SCr: 0.8 mg/dL) needs gentamicin for sepsis.

1. Check renal function:
2. Schwartz formula: (0.413 × 40 cm) / 0.8 = 20.65 mL/min/1.73m² (normal for neonate: 20–40).

3. Interpretation: Mildly reduced GFR-adjust dose.

4. Calculate dose:

5. Standard neonatal dose: 4–5 mg/kg every 24–48 hours (longer interval due to-GFR).

6. Dose for this patient: 5 mg/kg × 2 kg = 10 mg IV q36h.

7. Monitor levels:

8. Peak (30 min post-dose): 5–10 mcg/mL.
9. Trough (just before next dose): <2 mcg/mL (to avoid nephrotoxicity).

Expected outcome: - Therapeutic levels without toxicity. - If trough >2 mcg/mL-increase dosing interval.

Common Pitfalls & Mistakes

1. Ignoring renal function in elderly patients.
2. Mistake: Using adult dosing for an 80-year-old with SCr 1.2 mg/dL (may still have-GFR).

3. Fix: Calculate CrCl (Cockcroft-Gault) before dosing renally cleared drugs (e.g., digoxin).

4. Assuming children are "small adults."

5. Mistake: Giving a 5-year-old half the adult dose of theophylline (children metabolize it faster).

6. Fix: Use weight-based or BSA-based dosing (e.g., mg/kg or mg/m²).

7. Overlooking protein binding in neonates.

8. Mistake: Giving phenytoin to a neonate without adjusting for-albumin-free drug toxicity.

9. Fix: Monitor free phenytoin levels (target: 1–2 mcg/mL).

10. Using adult GFR equations for pediatrics.

11. Mistake: Applying Cockcroft-Gault to a 3-year-old.

12. Fix: Use Schwartz formula for children <18.

13. Neglecting body composition changes in obesity.

14. Mistake: Dosing lipophilic drugs (e.g., propofol) based on actual weight in an obese patient-overdose.
15. Fix: Use adjusted body weight (ABW) for hydrophilic drugs, ideal body weight (IBW) for lipophilic drugs.

Best Practices

Pediatric Dosing

• Use weight-based dosing (mg/kg) for most drugs.
• Avoid adult fixed doses (e.g., "1 tablet" for a 2-year-old).
• Double-check calculations (e.g., amoxicillin 90 mg/kg/day-divide by frequency).

Geriatric Dosing

• Start low, go slow (e.g., 50% of adult dose for benzodiazepines).
• Monitor renal function (CrCl <30 mL/min-adjust renally cleared drugs).
• Avoid anticholinergics (e.g., diphenhydramine)-risk of delirium.

Drug Monitoring

• Therapeutic drug monitoring (TDM): Check levels for narrow-therapeutic-index drugs (e.g., vancomycin, digoxin).
• Peak/trough timing:
• Aminoglycosides: Peak 30 min post-dose, trough just before next dose.
• Vancomycin: Trough 30 min before 4th dose.

Special Populations

• Pregnancy:-GFR-may need higher doses of renally cleared drugs (e.g., ampicillin).
• Liver disease:-metabolism-reduce doses of hepatically cleared drugs (e.g., morphine).
• Obesity: Use IBW for lipophilic drugs, ABW for hydrophilic drugs.

Tools & Frameworks

Real-World Use Cases

1. Neonatal Sepsis (Gentamicin Dosing)

• Scenario: 1-week-old preterm infant (2 kg) with suspected sepsis.
• Challenge: Immature renal function-risk of toxicity.
• Solution:
• Dose: 5 mg/kg IV q36h (longer interval due to-GFR).
• Monitor: Trough <2 mcg/mL to avoid nephrotoxicity.

2. Elderly Patient with Atrial Fibrillation (Digoxin Dosing)

• Scenario: 75-year-old female (60 kg, SCr 1.4 mg/dL) with AFib.
• Challenge:-GFR-risk of digoxin toxicity.
• Solution:
• Calculate CrCl: (140 - 75) × 60 / (72 × 1.4) = 38 mL/min.
• Dose: 0.125 mg PO daily (50% of standard dose).
• Monitor: Trough level 0.5–0.9 ng/mL.

3. Pediatric Asthma (Theophylline Dosing)

• Scenario: 6-year-old (20 kg) with severe asthma.
• Challenge: Children metabolize theophylline faster than adults.
• Solution:
• Dose: 10 mg/kg/day PO (divided q6–8h).
• Monitor: Peak level 10–20 mcg/mL.

Check Your Understanding (MCQs)

Question 1

A 2-day-old neonate (3 kg) is prescribed phenobarbital for seizures. The standard adult dose is 100 mg. What is the most appropriate initial dose for this patient?

A. 30 mg IV once B. 15 mg IV q12h C. 6 mg IV q24h D. 100 mg IV once

Correct Answer: B. 15 mg IV q12h - Explanation: Neonates require lower doses (5–8 mg/kg/day) due to immature liver metabolism. 15 mg q12h = 10 mg/kg/day (safe range). - Why the distractors are tempting: - A: Too high (10 mg/kg single dose-risk of toxicity). - C: Too low (2 mg/kg/day-subtherapeutic). - D: Adult dose-dangerous for a neonate.

Question 2

An 80-year-old male (70 kg, SCr 1.5 mg/dL) is prescribed digoxin 0.25 mg PO daily for heart failure. His CrCl is 35 mL/min. What is the best action?

A. Proceed with 0.25 mg daily. B. Reduce dose to 0.125 mg daily. C. Increase dose to 0.375 mg daily. D. Check a digoxin level in 1 week.

Correct Answer: B. Reduce dose to 0.125 mg daily - Explanation: Digoxin is renally cleared; CrCl <50 mL/min-reduce dose by 50% to avoid toxicity. - Why the distractors are tempting: - A: Standard dose-risk of toxicity in renal impairment. - C: Higher dose-contraindicated in renal dysfunction. - D: Monitoring is good, but dose adjustment is priority.

Question 3

A 5-year-old child (20 kg) with pneumonia is prescribed amoxicillin. The adult dose is 500 mg q8h. What is the most appropriate pediatric dose?

A. 125 mg q8h B. 250 mg q8h C. 500 mg q8h D. 1000 mg q8h

Correct Answer: B. 250 mg q8h - Explanation: Pediatric amoxicillin dose is 20–40 mg/kg/day (divided q8h). 250 mg q8h = 37.5 mg/kg/day (within range). - Why the distractors are tempting: - A: Too low (18.75 mg/kg/day-subtherapeutic). - C: Adult dose-overdose risk for a child. - D: Double the adult dose-dangerous.

Learning Path

Beginner (1–2 Weeks)

1. Master ADME basics (absorption, distribution, metabolism, excretion).
2. Learn age-related changes (neonates, children, elderly).
3. Practice CrCl calculations (Cockcroft-Gault, Schwartz formula).

Intermediate (2–4 Weeks)

1. Study drug-specific adjustments (e.g., gentamicin in neonates, digoxin in elderly).
2. Use dosing calculators (Lexicomp, UpToDate).
3. Review TDM protocols (vancomycin, aminoglycosides).

Advanced (4+ Weeks)

1. Analyze drug interactions in polypharmacy (e.g., warfarin + antibiotics in elderly).
2. Apply PK in critical care (e.g., sepsis, obesity, liver failure).
3. Explore pharmacogenomics (e.g., CYP2D6 variants in codeine metabolism).

Further Resources

Books

• Pediatric Pharmacotherapy