621: Lecture 18-20

Hct

Hct

• hematocrit

• fraction of blood volume occupied by cells

Hct for women

0.40

Hct for men

0.45

Mechanism for reabsorption is primarily……

passive diffusion from tubule lumen into bloodstream (peritubular capillary) across tubule epithelial cell membranes (these cells have tight junctions)

__________ provides a larger driving force for diffusion

H2O reabsorbed along the tubule

Key factors of Reabsorption

• lipophilicity (lipid/water partition coefficient, K)

• % unionized (calculate from pKa and pH using the H-H eq)

  • molecular size (MW or radius)

Urine pH can be altered by what

• diet

• drugs

  • clinical state

sodium bicarbonates increase/decrease pH

increase

Ammonium chloride increase/decreases pH

decreases

For an acid very polar in its unionized form

there is minimal reabsorption (pH independent)

For a non-polar weak acid

(pKa >8 or % ionized >98%)

there is extensive reabsorption

For a non-polar strong acid

(pKa <2 or 100% ionized )

There is minimal reabsorption

For a non-polar weak acid

(3<pKa<7.5)

minimal to extensive reabsorption (pH sensitive)

If an overdosed drug also exhibits pH-sensitive reabsorption then…..

if the drug is a base…

give an agent to decrease pH (such as ammonium chloride) to increases % ionized

If an overdosed drug also exhibits pH sensitive reabsorption then…..

if the drug is a acid…

give na agent to increase pH (sodium bicarbonate) to increase @ ionized

PK studies are recommended for renal impairment if

• Drug or active metabolite that is eliminated unchanged in the urine (fe) is >0.3

• therapeutic proteins and peptides with a molecular weight of less than 69 kDa

  • if drugs are likely to be used in patients with end-stage renal disease(ESRD), evaluate the impact of dialysis on drug and metabolite PK

PK studies can be considered if

PK of drugs that are eliminated predominantly via non renal routes

PK studies may not be important if

• gaseous or volatile drugs and active metabolites that are primarily eliminated through the lungs

• single-dose administration

• therapeutic protein >69 kDa

  • locally acting drugs with limtied system absorption

Why for some drugs, renal disease also reduces non-renal clearance?

possibly due to the inhibition of enzymes transporter by circulating uremic toxins

why for some drugs, renal disease may increase non-renal clearance?

• possibly due to increased opportunity for elimination by or upregulation in other clearance processes

• reduced protein binding in CkF, increased free drug for clearance

best indicator of kidney function

GFR

GFR

• glomerular filtration rate

• amount of blood that passes through the glomeruli each minute (mL/min)

  • used to evaluate the renal function for classifying chronic kidney disease and for renal dosage adjustments

factors related to GFR

• age, sex, and body size

• kidney function is proportional to body and kidney size

• kidney function inversely proportional to age

• average GFR differs in sex

Serum Creatinine (Scr)

• by-product of muscle metabolism

• freely filtered (>90%), actively secreted (<105)

• used to estimate renal function

limitations of creatinine-based renal function stimulation

• CrCl is dependent upon muscle mass

• muscle mass is highly variable among individuals

• creatinine production may not be stable in malnourished individuals, those with hepatic disease or critical illness

• non-renal elimination of creatine by gut metabolism can contribute to inaccurate assessment of GFR in patients with ESRD (end-stage renal disease)

  • Scr lags behind GFR by 1-2 days

why does SCr lag behind GFR by 1-2 days?

• slow acclimation

• increased tubular secretion

  • increasing extra-renal clearance

Cockcroft-Gault Method

• not used for chronic kidney disease staging, but still used for drug dosing

  • estimates creatinine clearance, not GFR

Underweight, BMI = <18.5

use ABW for C-G equation

Normal weight, BMI = 18.5-24.9

used IBW for C-G equations

overweight, BMI = 25-29.9

used AdjBW for C-G equations

Obese, BMI >30

used AdjBW for C-G equations

CKD-EPI and MDRD vs C-G

CKD-EPI and MDRD

• Scr is now measured using an isotope dilution Mass spec.

• includes variables for SCr, age, gender, and race (for MDMD)

• calculate eGFR normalized by body surface area

C-G

• developed using the old method for creatinine lab measurement, may overestimate by 1-=20%

• estimates creatine clearance

• still widely used for drug dosing

CKD-EPi vs MDRD

CKD-EPI

• validated patients >18 yo

• caucasian and AA with and without kidney disease, diabetes, and solid organ transplant

MDRD

• validated in patients 19-70 yo with lower levels of GFR, caucasian and AA, non-diabetic, and did not have a kidney transplant

• accurate only if eGFR <60 mL/min/1.73 m2

what is preferred - CKD-EPI vs MDRD?

CKD-EPI

24 hr urine collection

useful for people with increased/decreased SCr due to changes in muscle mass rather than changes in kidney function

Can pharmacist correct dosing for renal function per most hospital policies when the impact of renal function on drug dosing is known?

YES

Dose adjustments for renal impairment

1. estimate the renal function of the patient

2. determine the fraction of renal clearance (fe) of the drug

3. calculate the “adjustment factor” for the patient

4. determine the new dose or dosing interval or both.

assumptions when calculating the adjustment factor?

• drug elimination is linear, 1st order, 1-BCM

• GFR and tubular function decreases in a parallel fashion

• other PK paramters remain the same

• metabolites are not pharmacologically active or do not accumulate in renal disease

• drug effects are not affected by renal disease

cautions when renally impaired

• absorption, plasma protein binding, and drug distribution may be affected

• metabolism and drug transport in the liver and gut may be altered

calculating new dosing interval and dose using AF

1. determine new dosing interval with the same dose

2. then determine the new dosing interval with the new dose

ways to adjust doses for renal dysfunction

• change the dose and dosing interval

• change dose without changing dosing interval

• change the dosing interval without changing doses