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PH1.10 | PH1.10 | Individualized Pharmacotherapy in Special Populations — SDL Guide — SDL Guide (Part 2)

Geriatric Pharmacology: Polypharmacy, Reduced Clearance, and Altered Sensitivity

Elderly patients (conventionally defined as age ≥65, though 'physiological age' is more relevant than calendar age) experience a constellation of age-related physiological changes that alter drug pharmacokinetics in multiple directions simultaneously — making geriatric prescribing among the most complex clinical skills.

Pharmacokinetic changes in the elderly:

Absorption: generally preserved, though reduced gastric acid production (achlorhydria common with age) and reduced GI motility may slightly slow absorption rate without substantially changing bioavailability for most drugs.

Distribution: body composition changes dramatically — fat mass increases (typically 18–36% to 36–45% of body weight), lean mass and total body water decrease. Highly lipophilic drugs (benzodiazepines, lipid-soluble beta-blockers) have an increased Vd and prolonged t½ in the elderly. Plasma albumin falls with age, malnutrition, and chronic illness — the free (active) fraction of highly protein-bound drugs increases, potentially causing enhanced effects at standard doses.

Metabolism: hepatic mass decreases by 25–35% between ages 20 and 75, and hepatic blood flow decreases by approximately 40%. First-pass extraction of high-clearance drugs (propranolol, lidocaine, morphine) is reduced, increasing bioavailability. Phase I CYP450 activity declines moderately with age; Phase II glucuronidation is relatively preserved.

Excretion: renal function declines at approximately 1 mL/min/year after age 40. By age 75, a patient may have only 50% of the GFR of a 25-year-old, even with a normal serum creatinine — because reduced muscle mass with age reduces creatinine production, masking the fall in GFR. The Cockcroft-Gault equation (CrCl = [(140 − age) × weight(kg)] / [72 × serum creatinine(mg/dL)] × 0.85 for females) is essential for detecting reduced renal function in elderly patients with misleadingly normal creatinine levels.

Pharmacodynamic changes in the elderly: beyond PK alterations, elderly patients often exhibit enhanced sensitivity to CNS-active drugs (benzodiazepines, opioids, antipsychotics) due to age-related changes in receptor density and CNS reserve. Even standard doses of benzodiazepines can cause falls, confusion, and respiratory depression in frail elderly patients — the basis of the Beers Criteria, a consensus list of potentially inappropriate medications for older adults.

Polypharmacy (commonly defined as ≥5 concurrent medications) is prevalent in the elderly — the majority of patients over 75 take 5 or more drugs. Each additional drug adds the risk of drug-drug interactions, reduces adherence, and increases the cumulative burden of adverse effects. Deprescribing — systematically reviewing and discontinuing medications where the risk-benefit balance is unfavourable — is as important a clinical skill as prescribing.

Pharmacotherapy in Pregnancy and Lactation

Pregnancy creates a physiological environment that alters virtually every pharmacokinetic parameter, while simultaneously creating a second patient — the developing foetus — who has no direct voice in the risk-benefit calculation. Rational pharmacotherapy in pregnancy requires understanding both dimensions.

Pharmacokinetic changes in pregnancy: plasma volume expands by approximately 40–50% during pregnancy, diluting plasma albumin and increasing Vd for many drugs. GFR increases by 40–65% above non-pregnant values, accelerating renal excretion of renally cleared drugs (e.g., ampicillin and digoxin may require dose increases to maintain therapeutic levels in late pregnancy). Gastric motility is reduced (progesterone effect), slowing absorption. Hepatic blood flow increases but hepatic enzyme activity changes variably. These changes are dynamic — they evolve across the three trimesters — making dose optimisation in pregnancy a moving target.

Teratogenicity is the capacity of a drug to cause structural or functional abnormalities in the developing embryo or foetus. The critical period for structural teratogenesis is the period of organogenesis — approximately 3 to 8 weeks after fertilisation (weeks 5–10 of the last menstrual period). During this window, major organ systems (heart, CNS, limbs, palate) are forming; drug exposure during this period carries the highest risk of major malformations. Before week 3, the embryo is generally unaffected (all-or-nothing principle: either the embryo is destroyed or it survives with normal development). After week 8, structural malformations are less likely but functional deficits and growth restriction remain possible.

The US FDA pregnancy category system (ABCDE) — still widely used in Indian teaching despite being replaced in the US by a Labelling Rule format — classifies drugs by human and animal teratogenicity data:
- Category A: adequate human studies show no foetal risk.
- Category B: animal studies show no risk, but no adequate human data; or animal studies show risk but human studies do not.
- Category C: animal studies show adverse foetal effects; no adequate human data — potential benefit may justify risk.
- Category D: evidence of human foetal risk; benefit may justify risk in serious situations (e.g., phenytoin, valproate — used in epilepsy with counselling).
- Category X: foetal risks clearly outweigh any benefit — contraindicated in pregnancy.

Drugs contraindicated in pregnancy (Category X or equivalent high-risk): thalidomide (limb malformations; phocomelia), warfarin (embryopathy, nasal hypoplasia, stippled epiphyses — weeks 6–9; CNS defects later in pregnancy), methotrexate and misoprostol (abortifacient; foetal malformations), isotretinoin and other retinoids (CNS, cardiac, facial malformations), valproic acid (neural tube defects, autism spectrum, cognitive impairment — Category D/X depending on indication), ACE inhibitors (foetal renal dysgenesis, oligohydramnios — contraindicated in 2nd and 3rd trimesters), NSAIDs in 3rd trimester (premature closure of ductus arteriosus).

For anticoagulation in pregnancy: warfarin crosses the placenta and is teratogenic; heparin (unfractionated and LMWH) does not cross the placenta (large, charged molecule) — heparin is the anticoagulant of choice throughout pregnancy. For analgesia: paracetamol is the safest analgesic in pregnancy (all trimesters); NSAIDs are acceptable in 1st and 2nd trimesters at low dose but contraindicated in the 3rd. Penicillins and cephalosporins are generally safe (Category B).

Lactation: drug excretion into breast milk is determined by the drug's physicochemical properties — lipophilic, non-ionised, low-molecular-weight, low-protein-bound drugs enter milk more readily. The milk:plasma ratio quantifies this; a ratio > 1 indicates concentration in milk exceeds plasma concentration. The absolute infant dose = milk drug concentration × milk volume consumed — drugs with high milk:plasma ratio but very low absolute dose may still be safe. Practical guidance: drugs considered generally safe during breastfeeding include paracetamol, ibuprofen, most penicillins/cephalosporins, and many antihypertensives (nifedipine, labetalol). Drugs to avoid: chloramphenicol (grey baby risk), metronidazole (taste changes; some concern), cytotoxic drugs, lithium, radioactive compounds.

Drug / Class	Pregnancy safety	Key risk	Recommendation
Paracetamol	Category B	None established at therapeutic doses	Drug of choice for analgesia/antipyresis
Aspirin (low dose)	Category C (high dose D/X in 3rd trimester)	Ductus arteriosus closure (3rd trimester); PPH	Avoid 3rd trimester; low-dose for specific indications
NSAIDs (e.g. ibuprofen)	Category C (D/X in 3rd trimester)	Premature ductus closure; oligohydramnios	Avoid 3rd trimester
Warfarin	Category X (1st trimester; D later)	Embryopathy (wks 6–9), CNS defects	Contraindicated; use heparin
Heparin / LMWH	Category B	Does not cross placenta	Anticoagulant of choice in pregnancy
Tetracyclines	Category D	Bone/tooth development impairment	Contraindicated in pregnancy and children < 8 yrs
Penicillins / Cephalosporins	Category B	Generally none established	Safe; drugs of choice for infections
ACE inhibitors	Category D (2nd/3rd trimester)	Foetal renal dysgenesis, oligohydramnios	Avoid 2nd and 3rd trimesters
Valproic acid	Category D	Neural tube defects, cognitive impairment	Use only if no alternative; folic acid supplementation mandatory
Isotretinoin	Category X	Severe CNS/cardiac/craniofacial malformations	Absolutely contraindicated; negative pregnancy test required

Dose Adjustment in Hepatic and Renal Impairment

Organ impairment is the most quantitatively tractable domain of special population prescribing, because validated scoring systems allow clinicians to estimate the degree of functional loss and apply it to dosing decisions in a systematic way.

Renal impairment reduces excretion of renally cleared drugs. The standard tool for estimating residual renal function in clinical practice is the Cockcroft-Gault equation:

CrCl (mL/min) = [(140 − age) × weight in kg] / (72 × serum creatinine in mg/dL) × 0.85 (if female)

This equation is important because serum creatinine alone is an unreliable marker of GFR in the elderly (reduced muscle mass lowers creatinine production, giving a falsely normal creatinine despite reduced GFR), in the obese (increased muscle mass elevates creatinine without GFR change), and in muscle wasting. The CrCl estimate guides dose reduction and interval extension for renally cleared drugs. Key rules:

• Metformin is contraindicated (not merely dose-reduced) when eGFR falls below 30 mL/min/1.73m²; used with caution between eGFR 30–45. The risk is lactic acidosis from metformin accumulation in the setting of reduced renal excretion and impaired lactate clearance. There is no lower-dose safe threshold — it should be stopped.
• Aminoglycosides (gentamicin, tobramycin, amikacin) are entirely renally excreted; doses must be reduced and intervals extended proportionally to CrCl. Therapeutic drug monitoring (peak and trough levels) is mandatory.
• NSAIDs should be avoided in renal impairment — by reducing renal prostaglandin synthesis, NSAIDs impair the afferent arteriolar dilation that compensates for reduced perfusion pressure, precipitating acute-on-chronic kidney injury.
• Digoxin is 60–80% renally excreted unchanged; dose reduction is essential in renal impairment (as the hook case illustrated).

Hepatic impairment reduces both Phase I and Phase II drug metabolism and, in advanced disease, reduces albumin synthesis (increasing free drug fraction) and impairs biliary excretion. The Child-Pugh score (classifying cirrhosis as Child-Pugh A, B, or C) is used to guide drug dosing in hepatic disease: Child-Pugh A = mild impairment, minimal dose adjustment needed for most drugs; Child-Pugh B = moderate impairment, significant dose reductions required; Child-Pugh C = severe impairment, many drugs contraindicated or require major dose reduction.

Clinically important hepatic impairment adjustments:
- Morphine and other opioids: enhanced and prolonged effect due to reduced Phase II glucuronidation; reduced doses, extended intervals, careful monitoring for sedation and respiratory depression.
- Benzodiazepines: accumulate in hepatic impairment and can precipitate hepatic encephalopathy; shorter-acting agents metabolised by conjugation only (oxazepam, lorazepam — 'LOT' — no Phase I needed) are preferred.
- Paracetamol: normally safe but requires dose reduction in Child-Pugh C (reduced glutathione stores; reduced capacity to detoxify NAPQI).
- Metformin: also contraindicated in significant hepatic impairment (reduced lactate clearance by the liver → lactic acidosis risk, independent of renal function).
- Warfarin dose reduction may be needed in hepatic impairment due to reduced synthesis of clotting factors (independent of warfarin metabolism).

Drug	Primary elimination	eGFR 30–45: dose adjustment	eGFR < 30: action	Hepatic impairment note
Metformin	Renal (unchanged)	Use with caution	Contraindicated	Also contraindicated (lactic acidosis)
Digoxin	Renal (60–80% unchanged)	Reduce dose / extend interval	Major reduction; TDM mandatory	Dose adjustment minor
Aminoglycosides	Renal (entirely)	Reduce dose, extend interval, TDM	Major reduction; TDM essential	Minor adjustment
NSAIDs	Hepatic/renal	Use with caution or avoid	Avoid	Avoid (hepatotoxicity risk)
Morphine	Hepatic (Phase II glucuronidation)	Standard dose possible	Monitor carefully	Reduce dose significantly
Amoxicillin	Renal (primarily)	Mild dose reduction	Reduce 50% or use IV	Minor adjustment