dialysis

what is chronic kidney disease?

• abnormalities of kidney structure or function present for over 3 months that have implications on health

• progressive disorder and stages classified based on the eGFR and albuminuria

• 10-15% of the population with some degree of CDK

• heightened risk of medication-related problems: dosing errors in patients with CKD still occur at an alarming rate

what are the drug absorption and bioavailability changes in CKD?

• delayed gastric emptying time and intestinal motility: leads to impact on Tmax and Cmax of drugs

• biovailability more variable in a patient with impaired kidney function

• uremia decreases GI absorption of drugs and alters first-pass hepatic metabolism

high gastric pH:

• excess urea in the saliva transformed to ammonia by gastric urease

• resulting alkalization affects the ionization and dissolution of drugs

what are the distribution changes in CKD?

• altered Vd (e.g. dehydration, muscle wasting)
• altered plasma protein and tissue binding of drugs

what are the metabolism changes in CKD?

• uremia slows the rate of phase I metabolism and some phase II metabolism pathways
• dependent on the kidneys for the removal of drug metabolites from the body
• complicated impact on drug metabolism, including changes in the expression of several CYP enzymes (intestinal and hepatic) and transporters reported

what are the elimination changes in CKD?

• renal CL depends on glomerular filtration rate, tubular reabsorption, and tubular secretion
• ↓ GFR → ↓ renal CL → ↑ plasma t_1/2

what are the dialysis treatment options for CKD?

• inpatient hemodialysos
• home hemodialysis
• automated peritoneal dialysis
• continuous ambulatory peritoneal dialysis

what is renal replacement therapy?

• aka hemodialysis, or simply dialysis
• achieves the extracorporeal removal of waste products, such as creatinine and urea, and free water from the blood when the kidneys are in a state of kidney failure
• process of removing heparinized blood from the body, passing through a semipermeable membrane on the opposite side of a dialysate
• the "clean" blood is then returned to the patients
• vascular access: IV catheter, arteriovenous fistula
• waste and fluid removal: diffusion and ultrafiltration; concentration gradient against the dialyzer membrane

what are dialyzers for hemodialysis?

high flux (most common):

• blood flow ~500 mL/min
• 3-4 hrs sessions, 3 times a week
• fibers: polysulfone, polymethylmethacrylate, polyacrylonitrile

what is dialysate for hemodialysis?

• countercurrent flow
• 500-800 mL/min
• various solutes and anticoagulants

what are the measures of adequacy of hemodialysis?

• urea reduction rate (URR): >70% is considered adequate

Kt/V:

• Kt: dialyzer CL of urea

• T: duration of dialysis

• V: volume of blood cleared from urea

• goal: ≧1.3

what are the properties of a dialyzable drug for hemodialysis?

• MW < 5000 daltons
• Vd < 1L/kg
• protein binding < 90%
• low lipid solubility

what is peritoneal dialysis?

• type of dialysis that uses the peritoneum in a person's abdomen as the membrane through which fluid and dissolved substances are exchanged with the blood
• to remove excess fluid, correct electrolyte problems, and remove toxins in those with kidney failure
• solution infused into peritoneal cavity and peritoneal membrane acts as dialyzer
• dialysate: high dextrose solution containing various solutes and anticoagulants

what is the peritoneal physiology?

• contains 100mL liquid
• can expand to hold several liters
• surface area of 1-2m^2
• allows passage of larger MW substances
• catheters are used to gain access to the peritoneal cavity

what are the types of peritoneal dialysis?

• continuos cyclic: cycler at night, day dwell
• continuous ambulatory peritoneal dialysis: 3 daily exchanges, 1 long bedtime dwell

what are the measures of adequacy of peritoneal dialysis?

• Kt/V where Kt = D/P * volume drained
• D/P: dialysate to plasma urea concentration
• should be ~2.0 per week

what is the peritoneal dialysis prescription?

• number of exchanges (CAPD)
• volume
• concentration of solutes

what is the hemodialysis prescription?

• flow rate
• duration of dialysis
• dialyzer

what are the properties of a dialyzable drug for peritoneal dialysis?

• Vd < 1L/kg
• protein binding < 96%
• can better clear large molecules up to 15000-20000 daltons

what are the primary questions when evaluating the influence fo dialytic therapies on the PK of a drug?

• whether the drug dosage should be adjusted because of dialysis
• if so, by how much
• the timing of drug administration relative to dialysis

what is intermittent hemodialysis (IHD)?

• most common dialysis method used in ESRD patients in the united states
• study to include both on- and off-dialysis periods
• important to record the blood flow, dialysate flow, and the make and model of the dialyzer used in the study to interpret study results and extrapolate to other dialysis conditions

what is continuous renal replacement therapy (CRRT)?

for critical care medications likely to be used in patients on CRRT, the findings from IHD studies might not be sufficient to derive dosing recommendations for patients using this modality

what are the drug levels in hemodialysis?

• measurement of pre- and post-HD plasma concentrations
• can calculate an elimination rate constant which describes the decay of drug plasma concentration during hemodialysis and OFF dialysis

what is the process of the quantification of drug loss during hemodialysis?

1. calculate fraction of drug loss during hemodialysis (f_L)
2. calculate fraction of total elimination occurring during HD (f_D)
3. fraction of drug initially in the body that is eliminated by HD (f_el)

• may be significant if >30%