Dosing in Hepatic and Renal Dysfunction Flashcards
What are the primary functions of the liver?
- Primary site of drug metabolism
- Site of plasma protein synthesis
- Maintenance of body homeostasis
- Important as an excretory organ
What are some some factors that influence the liver’s impact on drug ADME?
- Patient characteristics
- Obesity vs. Anorexia
- Ethnicity
- Sex
- Pregnancy, Hormone levels
- Smoking, Alcohol - Liver Disease
- Loss of functional tissue
- Disorganized hepatocytes
- Shunts - Concomitant drug admin.
- Enzyme/transporter induction
- Enzyme/transporter inhibition
- Epigenetic mechanisms
What are the manifestations of hepatic dysfunction on drug PK?
- Decreased drug metabolizing capacity
- Altered plasma protein binding
- Altered hepatic blood flow
What is the impact of decreased drug metabolizing capacity on high and low extraction ratio drugs?
High E (IV): No impact
High E (oral): no change to t1/2, reduced Cls, and increase in Css
Low E (IV): increase in t1/2, reduced Cls, and increase in Css
Low E (oral): increase in t1/2, reduced Cls, and increase in Css
What is the impact of reduced protein binding on high and low extraction ratio drugs?
All drugs: reduction in Vd
High E (IV): no change in Css, av, increase in Css,unbound
HIgh E (oral): change in Css, ave and non change in Css, unbound)
Low E (IV): change in Css, ave and non change in Css, unbound)
Low E (oral): change in Css, ave and non change in Css, unbound)
What is the impact of reduced hepatic blood flow on high and low extraction ratio drugs?
High E (IV):
Review notes
What are the different categories of hepatic function tests?
- Model Substrate Markers (exogenous)
- Biochemical Markers (endogenous)
- Clinical Variables (Child-Pugh Score)
Review slide 10 and 11 for detailed info on hepatic function tests
What does the Child-Pugh score evaluate?
It is a hepatic function test based on clinical variables (ex. edema, serum bilirubin, serum albumin, INR)
What are the risk factors that contribute to the Child-Pugh Score?
- Ascites
- Encephalopathy
- PTT
- Serum bilirubin
- Serum albumin
- INR
Can results from hepatic function tests predict change in hepatic clearance?
No, due to differences in multiple pathologies and multiple drug metabolizing pathways
What are the basic principles of dosing with hepatic dysfunction?
- Dose on an individualizred basis (alter dose based on hepatic clearance and F)
- Need to known safety profile, PK of drug, and severity of dysfunction
- Then use best clinical judgement and monitor
Review slide 16 for impacts of hepatic dysfunction on ADME processes
What are the major functions of the kidneys?
- Primary site of water-soluble drug/metabolite excretion
- Maintenance of body homeostasis
- Renal Disease
- Patient Characteristics
What are the manifestations of renal dysfunction on drug PK (include secondary factors)?
- Absorption (secondary due to uremia)
- Decreases gastic emptying, and unchanged or decreased F - ALtered plasma protein binding and Vd
- Water soluble drugs: increased Vd
- Weak acid drugs: increase fu(b) and Vd
- Weak basic drugs: no change in fu(b) and Vd - Altered tissue binding (in ESRD)
- Increase in fu(T) and decreased Vd - Drug metabolizing enzyme activity
- Decrease in Clint due to uremic blood - Reduced renal clearance (primary)
What factors determine the impact of renal dysfunction on systemic clearance?
- Fraction of dose eliminated unchanged by the normal kidney (fe)
- Extent to which kidney function (KF) is decreased
What are some commonly used proxies for glomerular function?
- Daily urinary protein excretion rate
- Urine albumin-creatinine ratio (ACR)
- Serum creatinine concentration
What are some commonly used proxies for tubular function?
- Fractional excretion of sodium
- Serum creatinine concentration
What is the most commonly used index for GFR?
Creatinine Clearance (calculated from SCr values from blood work)
What are some assumptions made to use SCr to estimate Creatinine Clearance?
- Constant creatine production and conversion to creatinine
- Creatinine freely filtered
- Accurate serum creatinine determination
When should pharmacists consider making a dosing change in a patient with renal dysfunction?
- Renal clearance should be a major route
- If renal function is below 70% of normal function
- If GFR is below 60, then may need to adjust dose based on creatinine clearance
- Dialysis patients
What are the two methods for changing the dosing regimen in renal dysfunction?
- Recommendations from manufacturers (most common in practice)
- Tozer Method (manually determine dosing changes)
Review slides 28 to 37 for the Tozer Method
