Drug Dosing in Special Populations

Drug Dosing in Special Populations

• The presentation discusses drug dosing considerations for special populations, focusing on renal and hepatic disease, as well as geriatrics.
• Objectives include describing how renal and hepatic disease affect drug elimination/metabolism, accurately calculating renal function using CrCl and eGFR, adjusting medication dosages using those measurements and reference materials, defining lab tests/symptoms for Child-Pugh score calculation, and describing pharmacokinetic/pharmacodynamic changes in geriatric populations.

Renal Disease

• Kidney disease reduces the elimination of most drugs.
• Primarily, glomerular filtration is the route for eliminating most medications.
• Kidney function is measured by the glomerular filtration rate (GFR).
• Average GFR in healthy young adults is ~120-140 mL/min.
• By age 65, average GFR is ~50-60 mL/min.

Renal Drug Elimination Calculations

• Cockcroft-Gault equation calculates creatinine clearance (CrCl):
  • CrCl = (140 - age) × weight (kg) / (72 × serum creatinine (mg/dL)) × 0.85 (if female).
• CKD-EPI equation, recommended by the National Kidney Foundation, calculates estimated GFR (eGFR).
  • eGFRcr = 142 x min(Scr/k, 1)^a x max(Scr/k, 1)-1.200 x 0.9938Age x 1.012 [if female].

CrCl vs. eGFR

• CrCl was the standard for drug dosing until 2010.
• Now, many drugs use eGFR for renal dosing.
• CrCl and eGFR are not interchangeable.

Considerations for Renal Dose Adjustments

• Overdosing consequences should be considered.
• Underdosing consequences depend on therapeutic goals (cure vs. symptom management)
• Always assess the drug's dosing range.
• Dosing adjustments usually start when CrCl or eGFR is <60 mL/min.

Tools for Renal Function Calculation

• Global RPh (www.globalrph.com)
• National Kidney Foundation calculators.
• MD Calc (www.mdcalc.com)

Hepatic Disease

• Lipidsoluble drugs are primarily metabolized by the liver.
• Hepatitis is liver inflammation, decreasing the liver's functional ability.
• Mild cases of hepatitis temporarily decrease metabolization.
• Cirrhosis is a permanent loss of liver function caused by loss of hepatocytes.
• Reduced liver blood flow limits drug delivery.

Determining Hepatic Function: Child-Pugh Score

• There's no single test to assess liver function.
• The Child-Pugh score is used to estimate hepatic function.
• It combines lab values and clinical symptoms (serum albumin, total bilirubin, prothrombin time, ascites and hepatic encephalopathy).
• The score classifies severity, affecting how a drug is metabolized

Dose Adjustments in Hepatic Disease

• Drugs metabolized ≥60% by the liver may require reduced doses.
• Clinical judgment is often needed, as well as using dosing recommendations from reference materials.
• Typical recommendations:
  • C-P Score 8-9: decrease dose ~25%
  • C-P Score >10: decrease dose ~50%

Drug Dosing in Geriatrics

• Aging affects drug metabolism, frequently impacting drug elimination via the kidney.
• Reduced elimination can lead to drug accumulation and toxicity.
• Lower GFR and reduced lean body mass (affecting creatinine production) are among the contributing factors for reduced clearance in the elderly.
• Creatinine may seem normal, while actual clearance is reduced.

Aging and Metabolism

• Liver is the primary site for drug metabolism.
• Decreased liver blood flow and reduced size increase bioavailability and reduce first pass metabolism.
• Reduced metabolizing enzymes result in decreased clearance and prolonged half-life (t1/2)
• Lower doses are usually recommended for the elderly

Pharmacodynamics in Geriatrics

• Time course and intensity of drug effects may change with aging; these changes vary significantly amongst individuals.
• The 2023 updated Beers Criteria classifies inappropriate medications for use in older adults, aiding in the proper drug selection and preventing potential adverse effects.

Adverse Drug Events (ADEs) Prescribing Cascade

• An adverse effect from a drug can be misinterpreted as a new medical condition.
• This misdiagnosis could lead to prescribing another drug, further perpetuating the cycle of adverse effects.

Risk Factors for ADEs in Geriatrics

• Multiple chronic conditions (>6)
• High daily drug doses (>12)
• Numerous medications (>9)
• Prior adverse drug reactions
• Low body weight/mass index
• Age ≥ 85
• Low CrCl (<50 mL/min)

Principles of Prescribing for Older Patients

• Start low, slow increases as appropriate.
• Avoid prescribing multiple new drugs at once.
• Consider deprescribing (removal/lowering doses of unnecessary drugs).