13.3 Special Populations: Pharmacotherapy in Pregnancy, Lactation & Geriatrics (Deprescribing / Beers)

Special Populations: Pharmacotherapy in Pregnancy, Lactation & Geriatrics

Prescribing and dispensing medications in vulnerable physiological populations—pregnant individuals, nursing mothers, and older adults—demands rigorous understanding of altered pharmacokinetics, transplacental/mammary drug transfer, and age-related pharmacodynamic vulnerabilities. Pharmacists serve as essential clinical gatekeepers, preventing medication-induced congenital anomalies, shielding nursing infants from fatal toxicities, and mitigating polypharmacy and adverse drug events in geriatric patients through structured deprescribing.

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Pharmacotherapy in Pregnancy: Maternal Physiology & Pharmacokinetics

Pregnancy triggers profound anatomical and physiological adaptations that significantly alter drug disposition across all trimesters:

                     MATERNAL PHARMACOKINETIC ADAPTATIONS

      VOLUME & FLUIDS                    RENAL ELIMINATION                   HEPATIC METABOLISM
┌──────────────────────────────┐   ┌──────────────────────────────┐   ┌──────────────────────────────┐
│ • Total plasma volume +50%   │   │ • Renal blood flow +50–80%   │   │ • CYP3A4, 2D6, 2C9 INDUCED   │
│ • Extracellular fluid expands│──►│ • GFR increases by ~50%      │──►│   (higher doses required)    │
│ • Vd of hydrophilic drugs    │   │ • Accelerated clearance of   │   │ • CYP1A2, 2C19 INHIBITED     │
│   substantially increases    │   │   lithium, penicillins, LMWH │   │ • Albumin drops (free drug ↑)│
└──────────────────────────────┘   └──────────────────────────────┘   └──────────────────────────────┘

1. Cardiovascular & Fluid Dynamics: Total plasma volume increases by 40% to 50%, while total body water expands by 6 to 8 liters. This markedly expands the volume of distribution ($V_d$) for hydrophilic medications (e.g., beta-lactam antibiotics, aminoglycosides, lithium), leading to lower peak serum concentrations and necessitating higher or more frequent dosing.
2. Renal Clearance Acceleration: Renal plasma flow and Glomerular Filtration Rate (GFR) rise by approximately 50% beginning in the first trimester. Renally eliminated drugs (e.g., lithium, ampicillin, cefazolin, low-molecular-weight heparins, digoxin) exhibit accelerated systemic clearance, often requiring dose increases and therapeutic drug monitoring.
3. Hepatic Cytochrome P450 Modulation: Circulating progesterone and estrogen induce specific CYP isoforms while down-regulating others:
   • Induced Enzymes (Increased Clearance): CYP3A4, CYP2D6, and CYP2C9 activity increases, often requiring dose escalations of antidepressants (sertraline, venlafaxine), anticonvulsants (lamotrigine, phenytoin), and beta-blockers (metoprolol).
   • Inhibited Enzymes (Decreased Clearance): CYP1A2 and CYP2C19 activity decreases, prolonging the half-life of substrates such as theophylline and caffeine.
4. Protein Binding & Free Drug Fraction: Serum albumin concentrations fall by 20% to 30% due to maternal hemodilution. For highly protein-bound medications (e.g., phenytoin, valproic acid), total serum concentrations decline, while the unbound (free, pharmacologically active) concentration may remain normal or rise. Monitoring total drug levels can be misleading and lead to inappropriate dose increases; free drug levels must be measured.

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Placental Drug Transfer & Teratogenic Windows

Determinants of Placental Transfer

The human placenta is a semi-permeable lipid membrane separating maternal and fetal circulations. Virtually all drugs cross the placenta to some extent via passive non-ionic diffusion, influenced by:

• Molecular Weight: Drugs with low molecular weight (< 500 Da) cross readily; drugs between 500 and 1000 Da cross more slowly; very large macromolecules (> 1000 Da, such as insulin, heparin, and certolizumab pegol) do not cross the placenta in clinically significant amounts.
• Lipid Solubility: Highly lipophilic drugs (e.g., general anesthetics, opioids, benzodiazepines) cross rapidly into fetal tissues.
• Degree of Ionization: Un-ionized drugs cross maternal-fetal membranes rapidly.
• Maternal Protein Binding: Highly protein-bound drugs cross more slowly, though fetal albumin levels rise in the third trimester, occasionally reversing concentration gradients.

Critical Windows of Teratogenicity

                      GESTATIONAL TIMELINE OF VULNERABILITY

      WEEKS 1–2 (Post-Conception)         WEEKS 3–8 (Organogenesis)          WEEKS 9 TO TERM (Fetal Period)
┌────────────────────────────────────┐  ┌───────────────────────────┐  ┌─────────────────────────────────┐
│ • Pre-implantation phase           │  │ • PEAK TERATOGENIC WINDOW │  │ • Growth & functional maturation│
│ • "All-or-None" Period             │─►│ • Major structural birth  │─►│ • Functional deficits, growth   │
│ • Embryo either dies and aborts    │  │   defects (cardiac, limbs,│  │   restriction, CNS impairment   │
│   or fully repairs and survives    │  │   craniofacial, neural)   │  │ • Fetotoxicity (ACEi/ARBs, NSAID)│
└────────────────────────────────────┘  └───────────────────────────┘  └─────────────────────────────────┘

1. Pre-Implantation Phase (Weeks 1 to 2 post-conception): The "All-or-None" period. Toxic insults at this stage either destroy the pluripotential blastocyst (resulting in unnoticed spontaneous miscarriage) or damage only a few cells that are fully replaced without structural malformations.
2. Embryonic Period / Organogenesis (Weeks 3 to 8 post-conception): The critical window of maximal teratogenic susceptibility. Fundamental organ systems (neural tube, heart, limbs, eyes, palate) form during this brief 6-week period. Teratogenic exposures produce major, permanent structural congenital malformations.
3. Fetal Period (Weeks 9 to Term): Organs are formed but undergo cellular differentiation, growth, and functional maturation. Drug exposures during this window typically produce functional anomalies, growth restriction, behavioral/cognitive deficits, or neonatal toxicities/withdrawal (e.g., ACE inhibitor-induced oligohydramnios and renal failure; NSAID-induced premature ductal closure; neonatal abstinence syndrome).

Major Human Teratogens & Associated Anomalies

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Clinical Management of Common Conditions in Pregnancy

                  FIRST-LINE PHARMACOTHERAPY IN PREGNANCY

       CONDITION                         PREFERRED FIRST-LINE AGENT
┌──────────────────────────────┐    ┌──────────────────────────────────────────────┐
│ Nausea & Vomiting (NVP)      │───►│ Pyridoxine / Doxylamine (Diclectin) delayed  │
│ Hypertension                 │───►│ Labetalol, Methyldopa, or Nifedipine XL      │
│ Diabetes Mellitus (GDM/T2D)  │───►│ Subcutaneous Insulin (does not cross placenta)│
│ Acute Pain / Fever           │───►│ Acetaminophen (NSAIDs contraindicated late) │
│ Anticoagulation (VTE)        │───►│ Low-Molecular-Weight Heparin (LMWH: dalteparin│
└──────────────────────────────┘    └──────────────────────────────────────────────┘

1. Nausea and Vomiting of Pregnancy (NVP)

• First-Line Pharmacotherapy: Pyridoxine 10 mg + Doxylamine 10 mg delayed-release tablets (Diclectin). Initiated at 2 tablets at bedtime; can be titrated up to 4 tablets daily (1 morning, 1 afternoon, 2 bedtime).
• Non-Pharmacologic / OTC: Dietary modifications (frequent small meals, high protein), ginger (up to 1 g/day in divided doses), and P6 acupressure wristbands.
• Second-Line / Refractory: Dimenhydrinate (50–100 mg PO/PR Q4–6H PRN), metoclopramide (5–10 mg PO TID), or promethazine. Ondansetron is reserved for refractory hyperemesis gravidarum (used with caution after 10 weeks gestation to avoid small potential risks of oral clefts).

2. Chronic & Gestational Hypertension

• Therapeutic Blood Pressure Target: SOGC (Society of Obstetricians and Gynaecologists of Canada) guidelines target systolic BP 130–139 mmHg and diastolic BP 80–89 mmHg.
• First-Line Antihypertensives:
  • Labetalol: Combined alpha-1 and non-selective beta-blocker (100–400 mg PO BID to TID);
  • Methyldopa: Centrally acting alpha-2 agonist (250–500 mg PO BID to QID; safe historical record, but causes maternal sedation and depression);
  • Nifedipine XL / Long-Acting: Dihydropyridine calcium channel blocker (30–60 mg PO once daily).
• Strictly Contraindicated: ACE inhibitors, ARBs, and direct renin inhibitors (cause severe fetotoxicity and renal dysgenesis). Atenolol is avoided due to clinically significant fetal growth restriction.

3. Diabetes in Pregnancy (Gestational & Pre-Existing)

• First-Line Pharmacotherapy: Insulin is the gold standard (Diabetes Canada guidelines). Large polypeptide structure prevents transplacental passage, eliminating direct fetal drug exposure while delivering precise maternal glycemic control. Regimens utilize human isophane (NPH), regular insulin, or rapid-acting analogues (aspart, lispro) and long-acting detemir.
• Oral Antihyperglycemics: Metformin and glyburide cross the placenta. Metformin may be considered second-line when insulin is refused or clinically unfeasible, but insulin remains primary.

4. Pain and Fever

• First-Line Analgesic / Antipyretic: Acetaminophen is the agent of choice across all three trimesters at therapeutic doses (maximum 4 g/day).
• NSAID Contraindications & Fetal Risks:
  • Third Trimester Warning: Systemic NSAIDs are strictly contraindicated in the third trimester (from 28 weeks onward; Health Canada advisories warn against use from 20 weeks onward).
  • Fetal Complications: NSAID inhibition of fetal prostaglandin synthesis causes premature constriction and closure of the ductus arteriosus, leading to secondary fetal pulmonary hypertension. Furthermore, NSAIDs impair fetal renal perfusion, causing oligohydramnios, neonatal anuria, and prolonged maternal labor.

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Pharmacotherapy in Lactation & Infant Safety

When evaluating maternal drug safety during lactation, clinicians must quantify infant exposure and understand drug transfer into human milk.

Key Lactation Metrics

1. Milk-to-Plasma (M/P) Ratio: Concentration of drug in breast milk divided by concentration in maternal plasma. An M/P ratio < 1.0 indicates limited transfer, whereas > 1.0 indicates concentration in milk.
2. Relative Infant Dose (RID): The gold-standard metric for assessing infant drug exposure: $\text{RID} = \frac{\text{Infant Dose via Milk (mg/kg/day)}}{\text{Maternal Dose (mg/kg/day)}} \times 100\%$
   • RID < 10%: Universally accepted as clinically safe for full-term, healthy infants for the vast majority of therapeutic agents.
   • RID > 10%: Warrants caution, therapeutic reassessment, or infant monitoring.
3. Properties Minimizing Milk Transfer: High maternal plasma protein binding (> 90%), high molecular weight (> 800 Da), low lipid solubility, short maternal elimination half-life, and poor infant oral bioavailability (e.g., aminoglycosides, vancomycin, and certolizumab are poorly absorbed by the infant gut).

Critical Safety Warnings in Nursing Mothers

• Other Medications Generally Avoided in Breastfeeding: Systemic cytotoxic chemotherapy, radioactive diagnostic isotopes (temporary interruption), and amiodarone (very high iodine content and long half-life, with infant thyroid effects).
• Lithium needs specialist input rather than an automatic ban: infant serum levels can reach a meaningful fraction of the mother's. If breastfeeding continues, the full-term, healthy infant needs monitoring: lithium level, TSH, creatinine, hydration status, and signs of lethargy or poor feeding.

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Geriatric Pharmacotherapy: Age-Related PK/PD Changes

Aging causes progressive, predictable physiological declines that alter pharmacokinetics (what the body does to the drug) and pharmacodynamics (what the drug does to the body):

                      AGE-RELATED PHARMACOKINETIC SHIFTS

    BODY COMPOSITION                   HEPATIC METABOLISM                   RENAL CLEARANCE
┌──────────────────────────────┐   ┌──────────────────────────────┐   ┌──────────────────────────────┐
│ • Total body water DECREASES │   │ • Hepatic mass drops 20–40%  │   │ • GFR drops ~1 mL/min/yr     │
│ • Body fat INCREASES         │──►│ • Phase I oxidation DECLINES │──►│ • Sarcopenia masks high Cr   │
│ • Lipophilic drugs (diazepam)│   │ • Phase II conjugation       │   │ • ALWAYS calculate CrCl with │
│   have prolonged half-lives  │   │   PRESERVED (Lorazepam safe) │   │   Cockcroft-Gault equation   │
└──────────────────────────────┘   └──────────────────────────────┘   └──────────────────────────────┘

1. Pharmacokinetic Alterations in Older Adults

• Absorption: Gastric acid secretion declines (achlorhydria), raising gastric pH. This impairs the dissolution and absorption of calcium carbonate (calcium citrate is preferred because its absorption is acid-independent), iron, and vitamin B12.
• Distribution:
  • Decreased Total Body Water: Hydrophilic drugs (e.g., digoxin, ethanol, lithium, aminoglycosides) distribute into a smaller volume, producing significantly higher peak serum concentrations.
  • Increased Percentage Body Fat: Lipophilic drugs (e.g., diazepam, chlordiazepoxide, flurazepam) distribute into an expanded fat reservoir, dramatically prolonging their elimination half-life (diazepam half-life can extend from 30 hours in a young adult to over 90 hours in a geriatric patient, causing cumulative daytime sedation and falls).
  • Decreased Serum Albumin: Modest albumin declines increase the free unbound fraction of acidic drugs (e.g., warfarin, phenytoin, furosemide).
• Hepatic Metabolism: Hepatic blood flow declines by 20% to 40% and liver mass shrinks. Phase I CYP450 microsomal oxidation, reduction, and hydrolysis pathways decline significantly, slowing clearance of diazepam, alprazolam, and theophylline. Conversely, Phase II glucuronidation, sulfation, and acetylation pathways are well preserved in aging. The "LOT" benzodiazepines (Lorazepam, Oxazepam, Temazepam) undergo direct Phase II glucuronidation and are preferred when a benzodiazepine is unavoidable.
• Renal Elimination: Renal mass and functioning nephrons decline progressively. GFR drops by roughly 1 mL/min/year after age 40. Crucially, serum creatinine alone is an unreliable index of renal function in the elderly; sarcopenia (loss of muscle mass) produces less creatinine daily, allowing a severely impaired elder (CrCl < 30 mL/min) to exhibit a deceptively "normal" serum creatinine (e.g., 75 µmol/L). Pharmacists must always calculate estimated creatinine clearance using the Cockcroft-Gault equation.

2. Pharmacodynamic Alterations in Older Adults

• Exaggerated Central Sensitivity: Heightened sensitivity to central nervous system depressants, including benzodiazepines, opioids, sedative-hypnotics, and general anesthetics, due to altered receptor density and blood-brain barrier permeability.
• Blunted Baroreceptor Reflexes: Impaired autonomic baroreceptor responsiveness increases the frequency and severity of orthostatic hypotension, falls, and syncope when taking antihypertensives, alpha-blockers (tamsulosin, terazosin), or vasodilators.

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AGS Beers Criteria & STOPP/START Criteria

The American Geriatrics Society (AGS) Beers Criteria and the European STOPP/START criteria identify Potentially Inappropriate Medications (PIMs) in older adults:

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Anticholinergic Cognitive Burden (ACB)

Anticholinergic medications block muscarinic acetylcholine receptors centrally and peripherally. In older adults, cumulative exposure—termed Anticholinergic Cognitive Burden (ACB)—is directly associated with acute delirium, progressive cognitive decline, Alzheimer disease exacerbation, falls, and all-cause mortality.

• Peripheral Symptoms: Dry mouth, blurred vision, cycloplegia, anhidrosis, tachycardia, constipation, and urinary retention.
• Central Symptoms: Agitation, memory impairment, hallucinations, drowsiness, confusion, and acute delirium.
• Cumulative Burden: Combining multiple low-potency anticholinergic drugs (e.g., ranitidine + furosemide + metoprolol) can produce high overall anticholinergic toxicity equivalent to a single high-potency agent (e.g., oxybutynin or amitriptyline).

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Canadian Deprescribing Network (CaDeN) Algorithms

The Canadian Deprescribing Network (CaDeN) provides validated, evidence-based algorithms for discontinuing potentially inappropriate medications:

                       CaDeN STRUCTURED DEPRESCRIBING PROTOCOLS

     PPI DEPRESCRIBING                 SEDATIVE-HYPNOTIC TAPERING           ANTIPSYCHOTIC IN DEMENTIA
┌─────────────────────────────┐       ┌─────────────────────────────┐       ┌─────────────────────────────┐
│ • Indication: GERD > 8 wks  │       │ • Chronic BZD / Z-drug use  │       │ • Used for BPSD > 3 months  │
│ • Halve daily dose for 2 wks│───►   │ • Slow hyperbolic taper:    │───►   │ • Slow taper: reduce dose by│
│ • Step down to PRN use      │       │   reduce dose by 25% every  │       │   25% to 50% every 2 weeks  │
│ • Non-pharm lifestyle advice│       │   1 to 2 weeks over months  │       │ • Monitor behavioral rebound│
└─────────────────────────────┘       └─────────────────────────────┘       └─────────────────────────────┘

1. Proton Pump Inhibitor (PPI) Deprescribing

• Target Population: Adults taking a PPI for ≥ 4 to 8 weeks for uncomplicated heartburn, mild GERD, or uninvestigated dyspepsia whose symptoms have resolved.
• Exclusions (Must Continue PPI): Barrett's esophagus, severe erosive esophagitis (Los Angeles Grade C or D), documented history of bleeding gastrointestinal ulcers, or ongoing chronic NSAID therapy with high GI risk.
• Tapering Strategy: Reduce the daily dose by 50% (e.g., from pantoprazole 40 mg daily to 20 mg daily) for 2 weeks, then step down to on-demand / PRN use, or switch to an H2-receptor antagonist (famotidine 20 mg PRN). Counsel patients on managing transient rebound acid hypersecretion (lasting 10 to 14 days) using dietary modifications and antacids.

2. Benzodiazepine & Z-Drug Deprescribing

• Target Population: Older adults (≥ 65 years) taking benzodiazepines or Z-drugs for insomnia or anxiety.
• Protocol: Never stop abruptly due to seizure and severe rebound insomnia risks. Implement a structured, gradual hyperbolic taper, reducing the total daily dose by 25% every 1 to 2 weeks, slowing to 10% to 15% reductions near the tail end of the taper over a total duration of 6 to 16 weeks. Co-prescribe Cognitive Behavioral Therapy for Insomnia (CBT-I).

3. Antihyperglycemic De-intensification in Frail Elderly

• Target Population: Frail older adults, individuals with dementia, or those with limited life expectancy where tight glycemic control provides zero microvascular benefit while increasing the hazard of fatal hypoglycemic falls.
• Guideline Targets: Diabetes Canada recommends relaxing HbA1c targets to 7.1% to 8.5% in frail older adults. Deprescribe or reduce doses of sulfonylureas (glyburide) and insulins when HbA1c drops < 7.0%.

4. Antipsychotic Deprescribing in Dementia

• Target Population: Patients treated with atypical antipsychotics (risperidone, quetiapine, olanzapine) for Behavioral and Psychological Symptoms of Dementia (BPSD) whose symptoms have stabilized for at least 3 months.
• Rationale: Antipsychotic monographs carry a Health Canada boxed serious warning for a 1.6-fold increase in all-cause mortality and increased stroke risk in elderly patients with dementia.
• Protocol: Taper the daily dose by 25% to 50% every 1 to 2 weeks, closely observing for recurrence of severe verbal/physical aggression or distress.

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Clinical Case Scenario: Comprehensive Geriatric Medication Review

An 82-year-old female (weight 48 kg, serum creatinine 80 µmol/L) is admitted to a subacute rehabilitation unit following a ground-level fall resulting in a fractured right wrist. Her past medical history includes osteoporosis, mild cognitive impairment, insomnia, and heartburn. Her medication list includes: amitriptyline 25 mg PO at bedtime (for sleep), diphenhydramine 25 mg PO PRN (for sleep), pantoprazole 40 mg PO daily (taken for 5 years without documented ulcer disease), and glyburide 5 mg PO daily for type 2 diabetes (most recent HbA1c is 6.2%).

Pharmacist Clinical Assessment & Deprescribing Plan:

1. Renal Function Calculation (Cockcroft-Gault): $\text{CrCl} = \frac{(140 - 82) \times 48 \times 1.2}{80} \times 0.85 = \frac{3,340.8}{80} \times 0.85 \approx 35.5\text{ mL/min}$ (PEBC formula-sheet version: constant 1.2 with creatinine in µmol/L, then × 0.85 for a female.) Note: Despite a normal serum creatinine (80 µmol/L), her actual renal clearance is moderately impaired (36 mL/min).
2. Beers Criteria & Anticholinergic Deprescribing:
   • Amitriptyline & Diphenhydramine: Both are high-potency anticholinergic and sedative medications causing cognitive impairment, ataxia, and falls. Immediately discontinue diphenhydramine; initiate a gradual 2-week taper of amitriptyline. Replace with sleep hygiene and behavioral interventions.
   • Glyburide: Strictly inappropriate in older adults with CrCl < 50 mL/min and an HbA1c of 6.2%, posing an immediate risk of severe hypoglycemia and recurrent falls. Discontinue glyburide and transition to diet alone or low-dose metformin (500 mg daily) with a relaxed HbA1c target of 7.1% to 8.5%.
   • Pantoprazole: Long-term unindicated use increases fracture risk and impairs calcium absorption. Initiate CaDeN PPI deprescribing protocol: step down to pantoprazole 20 mg daily for 2 weeks, then transition to PRN antacid use.