Section 4.14: Therapeutic Decision-Making in Special Populations (Geriatrics, Pediatrics, Pregnancy, Lactation)

Therapeutic Decision-Making in Special Populations

Therapeutic decision-making in special populations (geriatrics, pediatrics, pregnancy, and lactation) requires clinical pharmacists to understand pharmacodynamic and pharmacokinetic differences. These patients have unique physiological characteristics that alter drug disposition and increase susceptibility to toxicities.

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1. Geriatric Pharmacotherapy & Beers Criteria

Age-Related Physiological Changes

• Renal Clearance: Decreased glomerular filtration rate (GFR) and renal blood flow lead to accumulation of renally cleared drugs.
• Body Composition: Decreased total body water and muscle mass, with increased body fat percentage. Water-soluble drugs (e.g., Digoxin, Lithium) have a decreased volume of distribution ($V_d$), leading to higher serum concentrations. Lipid-soluble drugs (e.g., Diazepam) have an increased $V_d$, prolonging their half-life.
• Hepatic Metabolism: Decreased hepatic blood flow and phase I (oxidative) metabolism. Phase II (conjugation) metabolism is generally preserved.

American Geriatrics Society (AGS) Beers Criteria

The Beers Criteria list potentially inappropriate medications (PIMs) that should be avoided in older adults (aged >= 65 years):

• Benzodiazepines & Z-drugs (e.g., Zolpidem): Avoid due to an increased risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents.
• First-Generation Antihistamines (e.g., Diphenhydramine, Hydroxyzine): Highly anticholinergic. Avoid due to risk of confusion, dry mouth, blurred vision, urinary retention, and constipation.
• Tricyclic Antidepressants (TCAs - e.g., Amitriptyline): Strongly anticholinergic and cause orthostatic hypotension.
• NSAIDs (e.g., Ketorolac, Naproxen): Avoid chronic use due to high risk of GI bleeding and peptic ulcer disease, acute kidney injury, and fluid retention (worsening heart failure).
• Sulfonylureas (specifically Glyburide): High risk of severe, prolonged hypoglycemia. Preferred alternatives are short-acting secretagogues (Glipizide) or other antidiabetic classes.
• Antipsychotics (SGA and FGA): Avoid use for behavioral symptoms of dementia unless non-pharmacological options have failed and the patient is a threat to self or others. They carry a black box warning for an increased risk of stroke and all-cause mortality in elderly patients with dementia-related psychosis.

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2. Pediatric Pharmacotherapy

Pediatric drug dosing is calculated on a milligram-per-kilogram (mg/kg) basis or using Body Surface Area (BSA) to prevent toxicity.

Excipient Safety in Neonates

Certain additives commonly found in adult formulations are highly toxic to neonates (especially premature infants):

• Propylene Glycol: Used as a solvent. Accumulation in neonates causes CNS toxicity, seizures, hyperosmolality, and metabolic acidosis.
• Benzyl Alcohol: Used as a preservative. Causes Gasping Syndrome in neonates, characterized by metabolic acidosis, respiratory distress, CNS depression, convulsions, and cardiovascular collapse.
• Ethanol: Avoid due to neurotoxicity and hypoglycemia.

Age-Specific Pediatric Contraindications

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3. Pharmacotherapy in Pregnancy

Regulatory Classification

The FDA transitioned from the traditional letter categories (A, B, C, D, X) to the Pregnancy and Lactation Labeling Rule (PLLR). The PLLR provides narrative summaries of risk, clinical considerations, and data registries under three sections:

1. Pregnancy (includes labor and delivery)
2. Lactation (includes nursing mothers)
3. Females and Males of Reproductive Potential (includes contraception and pregnancy testing recommendations)

Critical Teratogens to Avoid

• ACE Inhibitors / ARBs: Cause renal dysgenesis, oligohydramnios, and neonatal skull hypoplasia in the 2nd/3rd trimesters.
• Isotretinoin: Highly teratogenic, causing severe craniofacial, cardiac, and CNS abnormalities. Dispensing requires strict safety registry (iPLEDGE) compliance.
• Warfarin: Fetal warfarin syndrome (nasal hypoplasia, chondrodysplasia punctata, CNS abnormalities). Enoxaparin (LMWH) is the preferred anticoagulant in pregnancy.
• Valproic Acid: Neural tube defects (spina bifida) and developmental delays.
• Tetracyclines: Bony hypoplasia and deciduous tooth staining.
• Methotrexate: Fetal death and congenital malformations.

Managing Common Conditions in Pregnancy

• Hypertension: Preferred agents are Labetalol, Methyldopa, or Nifedipine ER. Avoid ACE inhibitors, ARBs, and direct renin inhibitors.
• Diabetes: Insulin is the gold standard and preferred agent, as it does not cross the placenta. Metformin is used as an alternative.
• Asthma: Budesonide is the preferred inhaled corticosteroid due to the largest volume of safety data in pregnancy.

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4. Lactation Safety

Drug transfer into breast milk is determined by passive diffusion and physicochemical properties of the drug:

• Factors Favoring Drug Transfer into Milk: Low molecular weight (< 500 Da), high lipid solubility, low protein binding, and low ionization. Weak bases tend to accumulate in breast milk because milk is slightly more acidic (pH ~7.2) than maternal plasma (pH ~7.4), leading to ion trapping of the drug in the milk.
• Relative Infant Dose (RID): The percentage of the maternal weight-adjusted dose received by the infant via breast milk. An RID < 10% is generally considered safe and compatible with breastfeeding.
• References: Hale's Medications and Mothers' Milk classifies drug safety into five categories: L1 (Safest), L2 (Safer), L3 (Moderately Safe), L4 (Possibly Hazardous), and L5 (Hazardous). The NIH online database LactMed is also a primary clinical resource.