6.11: Therapeutics in Special Populations: Paediatrics & Geriatrics

Therapeutics in Special Populations: Paediatrics & Geriatrics

Paediatric and geriatric patients represent two clinical extremes where standard adult dosing guidelines do not apply. Pharmacists must adapt clinical decision-making based on developmental and age-related changes in pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body).

Paediatric Pharmacokinetic Alterations

Paediatric patients, particularly neonates (birth to 28 days) and infants (29 days to 1 year), display unique pharmacokinetic parameters that change rapidly with age.

1. Absorption

• Gastric pH: Neonates have a gastric pH > 4 (often neutral at birth, pH 6–8) due to immature acid secretion. It reaches adult levels (pH 1.5–3) by age 2. Consequently, acid-labile drugs (e.g., benzylpenicillin, ampicillin) show increased absorption, whereas weak acids (e.g., phenobarbital, phenytoin) show decreased absorption.
• Gastric Emptying & Intestinal Motility: Delayed and irregular in neonates, maturing to adult patterns by 6–8 months. This delays the time to reach peak plasma concentration ($T_{\max}$) for many oral medications.
• Percutaneous Absorption: Greatly increased in infants due to a thin stratum corneum and a high body surface area-to-weight ratio. Topically applied compounds (e.g., hydrocortisone, salicylic acid) can achieve significant systemic absorption and cause toxicity.

2. Distribution

• Body Water Content: Neonates are "water babies," with total body water comprising approximately 70–80% of their body weight (compared to 50–60% in adults). Hydrophilic drugs (e.g., aminoglycosides like gentamicin, beta-lactams) distribute widely, requiring higher weight-based doses (mg/kg) to achieve therapeutic peak concentrations.
• Body Fat: Reduced in neonates (~12–15% of body weight), increasing to adult levels later. Lipophilic drugs (e.g., diazepam) have a smaller volume of distribution ($V_{\text{d}}$).
• Protein Binding: Plasma proteins (albumin and $\alpha_1$-acid glycoprotein) are reduced in concentration and have lower binding affinity in neonates. This increases the free (active) fraction of highly bound drugs (e.g., phenytoin).
• Bilirubin Displacement (Kernicterus Risk): Endogenous bilirubin competes with drugs for albumin binding sites. Certain drugs (e.g., ceftriaxone, sulfamethoxazole) can displace bilirubin from albumin, allowing free bilirubin to cross the blood-brain barrier and cause irreversible brain damage (kernicterus). Ceftriaxone is contraindicated in neonates for this reason.

3. Metabolism

• Hepatic Enzyme Maturity: Cytochrome P450 (CYP) enzymes and conjugation pathways (Phase II) are immature at birth. Neonates have a prolonged half-life for drugs like paracetamol, phenytoin, and morphine.
• The "Toddler Peak": By ages 1 to 9 years, hepatic metabolic capacity often exceeds adult levels on a per-kilogram basis. Children in this age bracket may require higher relative doses and shorter dosing intervals for drugs like theophylline and carbamazepine.

4. Elimination

• Renal Function: Glomerular filtration rate (GFR) and tubular secretion are only 10–30% of adult levels at birth. Renal clearance matures rapidly over the first few weeks and reaches adult levels by 8–12 months. Drugs cleared by the kidneys (e.g., gentamicin, penicillins) require extended dosing intervals in neonates.

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Paediatric Dosing Calculations & Safety Pitfalls

1. Calculations: Paediatric dosing must be calculated individually based on actual body weight (mg/kg) or body surface area (BSA, $\text{mg/m}^2$). The use of age-based formulas (e.g., Young’s, Clark’s, or Fried’s rules) is outdated, unsafe, and clinically obsolete.
2. Liquid Formulation Pitfalls:
   • Concentration Confusion: Paracetamol liquid is available in different strengths (e.g., Infant drops 100 mg/mL, Children's liquid 24 mg/mL or 48 mg/mL). Dispensing or administering the wrong strength is a major source of toxic overdoses. Pharmacists must always specify the dose in milligrams (mg) and the volume in millilitres (mL) based on the specific bottle concentration.
   • Measuring Devices: Household teaspoons vary widely (2.5 to 9 mL) and must never be used. Pharmacists should supply and instruct parents on the use of oral syringes or calibrated measuring cups.
   • Harmful Excipients: Neonates lack the metabolic pathways to clear certain excipients. Propylene glycol can cause lactic acidosis, hyperosmolality, and seizures. Benzyl alcohol (used as a preservative) can cause the fatal "gasping syndrome" (characterised by respiratory depression, metabolic acidosis, and cardiovascular collapse). Ethanol should be avoided.

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Geriatric Pharmacokinetic Changes

Aging is associated with progressive physiological decline, affecting all phases of pharmacokinetics:

Renal Function Estimation in the Elderly

Serum creatinine alone is a poor indicator of renal function in the elderly. Due to age-related sarcopenia (loss of skeletal muscle), creatinine production is reduced. An elderly patient may have a "normal" serum creatinine (e.g., 80 micromol/L) but have severe renal impairment. Pharmacists must estimate creatinine clearance ($\text{CrCl}$) using the Cockcroft-Gault equation:

$\text{CrCl (mL/min)} = \frac{(140 - \text{Age}) \times \text{Weight (kg)}}{0.814 \times \text{Serum Creatinine (\mu mol/L)}} \quad [\times 0.85 \text{ for females}]$

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Geriatric Pharmacodynamic Alterations

Elderly patients display altered receptor sensitivity, making them highly vulnerable to specific drug classes:

1. Central Nervous System (CNS) Sensitivity: Increased blood-brain barrier permeability and changes in receptor density/affinity lead to heightened sensitivity to benzodiazepines, opioids, and psychotropics. This causes excessive sedation, cognitive impairment, confusion, and ataxia (increasing falls risk).
2. Baroreceptor Reflex Blunting: Age-related arterial stiffening blunts the baroreceptor response to postural changes. Antihypertensives, vasodilators, tricyclic antidepressants, and diuretics significantly increase the risk of orthostatic (postural) hypotension, leading to syncope and falls.
3. Cholinergic System Decline: Elderly individuals have a baseline reduction in cholinergic neurons. Anticholinergic drugs (e.g., amitriptyline, oxybutynin, promethazine) cause severe central adverse effects (delirium, confusion, memory impairment) and peripheral adverse effects (dry mouth, blurred vision, constipation, urinary retention, tachycardia).

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Beers Criteria & Deprescribing Principles

The Beers Criteria (and the Australian equivalent guidelines, such as the AMH Aged Care Companion) identify Potentially Inappropriate Medications (PIMs) in the elderly.

Key PIMs to Avoid:

• Long-acting Benzodiazepines (e.g., Diazepam): High risk of accumulation, prolonged sedation, cognitive decline, and falls.
• Tricyclic Antidepressants (e.g., Amitriptyline): Highly anticholinergic, sedating, and causes orthostatic hypotension.
• NSAIDs (e.g., Indomethacin, Ibuprofen): High risk of gastrointestinal bleeding/ulceration, renal impairment, and fluid retention (which can precipitate or worsen heart failure).
• Antipsychotics (e.g., Risperidone, Haloperidol): Used for Behavioural and Psychological Symptoms of Dementia (BPSD). They are associated with an increased risk of stroke, rapid cognitive decline, and all-cause mortality. Use should be restricted to short-term, non-pharmacological refractory cases where there is severe distress or immediate danger.

Deprescribing Principles

Deprescribing is the systematic process of identifying and discontinuing medications where existing or potential harms outweigh benefits.

• Steps: 1) Reconcile all medications, 2) Identify PIMs and drugs without an active indication, 3) Assess safety of stopping (tapering vs. abrupt cessation), 4) Implement the plan, 5) Monitor for withdrawal or return of symptoms.
• Tapering Requirements:
  • Proton Pump Inhibitors (PPIs): Abrupt cessation causes rebound gastric acid hypersecretion. Taper over 2–4 weeks (e.g., reduce dose by 50% or change to alternate-day dosing).
  • Beta-blockers: Abrupt withdrawal can cause rebound tachycardia, hypertension, and myocardial infarction. Taper gradually over 1–2 weeks.
  • Benzodiazepines & SSRIs: Gradual tapering over weeks to months is required to prevent withdrawal syndromes.