Dose Adjustment

CKD-EPI (eGFR) — Standard for CKD Staging

CKD-EPI is more accurate for GFR estimation and CKD staging but drug dosing recommendations are generally not validated against CKD-EPI. Use Cockcroft-Gault for drug dosing unless product labeling specifies eGFR.

Creatinine limitations: Serum creatinine may overestimate renal function in:

• Elderly (reduced muscle mass)
• Malnourished patients
• Amputees
• Critically ill (acute kidney injury — creatinine lags behind actual GFR decline)

Dose Adjustment Strategies

1. Dose reduction (same interval)

• Reduce individual dose, maintain dosing frequency
• Maintains consistent drug levels but lower peaks
• Preferred for drugs where consistent exposure matters (e.g., beta-blockers)

2. Interval extension (same dose)

• Maintain dose, increase time between doses
• Maintains peak levels but allows more time for elimination
• Preferred for concentration-dependent drugs (e.g., aminoglycosides)

3. Both dose and interval adjustment

• Required for severe renal impairment with narrow therapeutic index drugs

High-Risk Drugs in Renal Impairment

Dialysis Considerations

• Dialyzable drugs: Small molecular weight, low protein binding, low volume of distribution, water-soluble. May need supplemental dosing after dialysis.
• Non-dialyzable drugs: Large molecular weight, high protein binding, high Vd. No supplemental dosing needed.
• Time dosing relative to dialysis sessions when possible.

Hepatic Dose Adjustment

Child-Pugh Classification

• Class A (5-6 points): Mild. Usually no dose adjustment needed.
• Class B (7-9 points): Moderate. Reduce dose of hepatically metabolized drugs by 25-50%. Avoid hepatotoxic drugs when possible.
• Class C (10-15 points): Severe. Avoid hepatically metabolized drugs when alternatives exist. Significant dose reductions required. Consult specialist pharmacy.

Hepatic Metabolism Considerations

• Phase I reactions (CYP450: oxidation, reduction, hydrolysis) are more affected by liver disease than Phase II reactions (conjugation: glucuronidation, sulfation).
• High extraction ratio drugs (>70% first-pass metabolism): Oral bioavailability increases dramatically in liver disease (e.g., morphine, propranolol, verapamil). Reduce oral dose.
• Low extraction ratio drugs: Clearance depends on enzyme activity and protein binding. Reduced albumin increases free fraction.
• Prodrugs requiring hepatic activation: May have reduced efficacy (e.g., codeine to morphine via CYP2D6, clopidogrel activation).

Drugs to Avoid or Use with Extreme Caution

• NSAIDs (GI bleeding, renal impairment, fluid retention)
• Acetaminophen (limit to 2g/day in cirrhosis, avoid if recent alcohol use)
• Sedatives/benzodiazepines (precipitate encephalopathy — prefer short-acting if needed: oxazepam, lorazepam)
• Opioids (reduced clearance, encephalopathy risk — start at 50% dose, titrate slowly)
• Metformin (lactic acidosis risk in decompensated liver disease)

Obesity Dosing

Weight Definitions

• Total Body Weight (TBW) — Actual measured weight
• Ideal Body Weight (IBW) — Devine formula:
  • Males: 50 kg + 2.3 kg per inch over 5 feet
  • Females: 45.5 kg + 2.3 kg per inch over 5 feet
• Adjusted Body Weight (AdjBW) — IBW + 0.4 × (TBW - IBW). Used for drugs partially distributing into adipose tissue.
• Body Surface Area (BSA) — Mosteller formula: BSA (m²) = sqrt[(height(cm) × weight(kg)) / 3600]
• BMI = weight (kg) / height (m)²

Drug Dosing in Obesity: Which Weight to Use

General Principles

• Hydrophilic drugs: Less distribution into adipose tissue → use IBW or AdjBW
• Lipophilic drugs: Greater distribution into adipose → use TBW or AdjBW
• Very high BMI (>40): Consult specialist pharmacy for narrow therapeutic index drugs

Pediatric Dosing

Weight-Based Dosing (mg/kg)

The most common method. Important principles:

• Always calculate the dose AND verify it does not exceed the adult maximum dose
• Use actual body weight unless the child is obese
• Neonatal doses often differ from infant/child doses (immature metabolism)

Body Surface Area (BSA) Dosing

Used for some drugs (especially chemotherapy) where BSA correlates better with drug clearance than weight alone.

BSA is less commonly used for routine pediatric dosing but remains standard in pediatric oncology.

Age-Related Pharmacokinetic Differences

Key Pediatric Dosing Considerations

• Neonates: Reduced clearance for most drugs. Longer half-lives. Lower doses, extended intervals.
• Infants/toddlers (1-3 years): Rapid maturation of metabolism. May need relatively higher mg/kg doses.
• Children (3-12 years): Often require higher mg/kg doses than adults due to relatively larger liver mass and higher metabolic rate.
• Adolescents: Approach adult pharmacokinetics. Transition to adult dosing by weight or fixed dose.

Geriatric Considerations

Age-Related Pharmacokinetic Changes

• Absorption: Generally preserved; some reduction in active transport
• Distribution: Increased body fat (lipophilic drugs accumulate), decreased lean mass, decreased total body water, decreased albumin
• Metabolism: Hepatic blood flow reduced ~40%; CYP activity variably reduced; Phase II metabolism preserved
• Elimination: GFR declines ~1 mL/min/year after age 40; serum creatinine may not reflect this decline due to reduced muscle mass

Geriatric Prescribing Principles

1. Start low, go slow — Begin at 25-50% of adult dose for CNS-active drugs, renally cleared drugs
2. Beers Criteria (AGS) — List of potentially inappropriate medications in older adults
3. STOPP/START criteria — Screening Tool of Older Persons' Prescriptions (STOPP) and Screening Tool to Alert to Right Treatment (START)
4. Anticholinergic burden — Cumulative anticholinergic effects from multiple drugs (cognitive impairment, falls, urinary retention, constipation)
5. Deprescribing — Systematic review and discontinuation of medications that are no longer indicated, beneficial, or appropriate
6. Falls risk — Review psychotropics, antihypertensives, hypoglycemics

Applying This Skill

When adjusting drug doses:

• Always identify the basis for dose adjustment (renal, hepatic, weight, age)
• Use the appropriate formula for renal estimation (Cockcroft-Gault for drug dosing)
• Specify which weight to use for obese patients
• In pediatrics, verify the calculated dose does not exceed the adult maximum
• In geriatrics, consider the cumulative medication burden, not just individual drugs
• Recommend monitoring parameters to assess dose adequacy