PK Exam 1

dose (how much and how often) and the resulting plasma concentration

pharmacokinetics relates to the relationship between...

true

T/F pharmacokinetics parameters like clearance, volume of distribution, and half life do not change with dose for drugs with linear PK

false

T/F pharmacokinetic parameters like clearance, volume of distribution, and half life change with dose for drugs with linear PK

false (will change because non-linear)

T/F pharmacokinetic parameters like clearance, volume of distribution, and half life do not change with dose for drugs with non-linear PK

linearly

how does steady state plasma drug concentration change with dose for drugs with linear PK

drug concentration in the plasma and pharmacological response

pharmacodynamics is the relationship between...

PD

PK/PD is typically non-linear

PK

PK/PD is typically linear

slide 9

slide 9

clearance

volume of serum or blood completely cleared of the drug per unit time

clearance

__________ is considered to be the most important PK parameter because it determines the maintenance dose that is required to obtain a certain steady state serum concentration

clearance

_________ determines the maintenance dose that is required to obtain a certain steady state serum concentration

- intrinsic clearance is the maximal ability of the liver to remove drug in the absence of flow limitations and binding to cells or proteins in the blood
- the unbound "free" fraction of drug in the blood
- liver blood flow

hepatic clearance is a function of....

microsomes or cultured hepatocytes

measure the rate of metabolite formation in intrinsic clearance using....

- glomerular filtration rate (GFR)
- free fraction of drug in the blood (fb)
- clearance via renal tubular secretion
- fraction of drug reabsorbed in the kidney (FR)

physiological determinants of renal clearance

free drug (not bound to protein)

what can get filtered through the glomerulus

no clearance

if 100% of drug is bound to protein what will the clearance be?

100% clearance

if no drug is bound, what will the clearance be?

hypothetical volume that relates serum concentration to the amount of drug in the body

volume of distribution

- volume of the blood (Vb)
- volume of the tissues and organs (Vt)
- degree of binding to plasma proteins and tissue components (fb, ft)

fb = free fraction of drug in blood
ft = free fraction of drug in tissues

physiological determinants of volume of distribution

~ 40 L (total body water)

V = Vb + fb/ft (Vt)
V = Vb + 1 (Vt)
V = Vb + Vt
V = 5L + 35L
V = 40 L (total body water)

if free fraction in blood and tissues is 1 (no binding) wha tis V equal to

5L

V = Vb + fb/ft (Vt)
V = Vb + 0/ft (Vt)
V = Vb + 0(Vt)
V = Vb
V = 5L

what will be the V for a drug with very high protein binding in the blood (fb = 0)

infinity

V = Vb + fb/ft (Vt)
V = Vb + fb/0 (Vt)
V = infinity

What is the upper limit of V

it determines the time to reach steady state during continuous infusion or multiple dosing
- it determines the dosage interval of the drug

why is half life important

3-5 half lives

concentrations obtained between _____ half lives after dosing can be considered to be at steady state

volume and clearance

independent parameter of kinetics (only dependent on physiological conditions)

half life and elimination
depend on clearance and volume

dependent parameter of kinetics and what they depend on

unsaturated

for drugs with saturated/unsaturated metabolism, clearance is constant and does not change with dose

saturated

for drugs with saturated/unsaturated metabolism, clearance is no constant and changes with dose

bioavailability

fraction of administered dose that is delivered to the systemic circulation

- intrinsic clearance
- fb
- LBF on both Fh and systemic clearance (Clh)

for drugs given orally, one must consider the potential impact of changes in...to determine how plasma levels could be impacted

- intrinsic clearance
- fb
- LBF on systemic clearance (Clh)

for drugs given intravenously, one must consider the potential impact of changes in....to determine how plasma levels could be impacted

no drugs will get past

if ERH is close to 1, no/all drugs will get past 1st pass metabolism

most all drugs will get past

if ERH is close to 0, no/all drugs will get past 1st pass metabolism

decrease

an increase in intrinsic clearance will increase/decrease Fh

increase (more drug will enter the body)

an increase in liver blood flow will increase/decrease Fh

increase (which will increase the removal of drug)

an increase in liver blood flow will increase/decrease systemic clearance

false, the more dose, the faster it will get cleared when giving po

T/F a larger dose given po needs a dosage adjustment

true

T/F a larger dose given IV needs a dosage adjustment

1. decrease dose and keep interval the same; easier for IV drugs
2. increase dosing interval and keep dose the same; easier for oral drugs

options to decrease dose in low creatinine clearance in a renally cleared drug and if it should be used for po/IV drugs

peak decreases and trough increases

what happens to the peak and trough when you decrease dose and keep interval the same

peak decreases and trough decreases

what happens to the peak and trough when you increase dosing interval and keep the dose the same

increase dosing interval and keeping the dose the same

what type of change (decreasing dose or increasing interval) is similar to a normal dose/dosing interval in a normal patient

11-14

practice chapter 3 slides 11-14

y intercept

non-renal clearance is found where on a graph

volume of distribution

gentamicin _____ decreases in renal disease

volume of distribution

digoxin _____ decreases in renal disease

- mechanism of gentamicin and digoxin = increase endogenous metabolites and these metabolites compete for binding with...
1. plasma proteins: which will increase free fraction of drug in blood, which will increase volume
2. tissue proteins: which will increase free fraction of drug in tissues which will decrease volume

why does the volume of distribution of digoxin and gentamycin decrease in renal disease

clearance and volume are decreasing at the same time

k = Cl / Vd

slope, (k, t1/2) does not change with renal disease, why

decrease

intrinsic clearance will increase/decrease with liver disease

decreases

liver blood flow will increase/decrease with cirrhosis

increase

fb will increase/decrease with liver disease

there is a decrease in the number of enzymes

why does intrinsic clearance decrease with liver disease

- decrease in plasma protein
- increase in bilirubin

why does fb increase with liver disease

Cl = dose / AUC
decrease AUC means clearance will increase, therefore, the dose should be increased in hepatic impairment

if dalvance AUC is decreased in moderate and severe hepatic impairment, why should you increase the dose

the drug will be free and metabolized more easily (probably won't need as high of a dose)

if the liver is failing and plasma proteins decrease what will happen with a highly protein bound drug (like warfarin)

hepatic clearance = LBF(fb * intrinsic clearance) / LBF

equation for drugs with low hepatic extraction ratio (less than 0.3) LBF >> fb * intrinsic Cl
hepatic clearance = [LBF (fb * intrinsic clearance)] / [LBC.+ Fb * intrinsic clearance]

hepatic clearance = LBF(fb * intrinsic clearance) / fb * intrinsic clearance

equation for drugs with high hepatic extraction ratio (greater than 0.7) LBF << fb * intrinsic clearance
hepatic clearance = [LBF (fb * intrinsic clearance)] / [LBC.+ Fb * intrinsic clearance]

FH= 1

equation for low clearance drugs capacity limited metabolism ERh < 0.3 (LBF >> fb*intrinsic clearance)
FH = LBF / (LBF + fb*intrinsic clearance)

FH = LBF / fb * intrinsic clearance

equation for high clearance drugs perfusion limited metabolism ERh > 0.7 (LBF <

increases

as clearance decreases, half life will increase/decrease

decrease

as clearance increases, half life will increase/decrease

increase

as clearance decreases, steady state level concentration will increase/decrease

decrease

as clearance increases, steady state level concentration will increase/decrease

increase

as steady state concentration increases, unbound steady state concentration will increase/decrease

decrease

as steady state concentration decreases, unbound steady state concentration will increase/decrease

increase

as free fraction of drug in blood increases, hepatic clearance will increase/decrease

decrease

as free fraction of drug in blood decreases, hepatic clearance will increase/decrease

increase

as free fraction of drug in blood increases, volume will increase/decrease

decrease

as free fraction of drug in blood decreases, volume will increase/decrease

stay the same

as volume increases and clearance increases, half life will increase/decreases

stay the same

as volume decreases and clearance decreases, half life will increase/decrease

decrease

as clearance increases, total steady state level will increase/decrease

increase

as clearance decreases total steady state level will increase/decrease

stay the same

as total steady state level decreases and free fraction of drug in blood increases, unbound steady state will increase/decreases

stay the same

as total steady state level increases and free fraction of drug in blood decreases, unbound steady state will increase/decrease

- HF = decreased cardiac output, decreased blood flow to the liver, kidneys, muscle, intestines
- reduced hepatic clearance--high extraction ratio drugs
- reduced renal clearance
- reduced volume of distribution
- incomplete/delayed oral absorption--reduced blood flow and edema
- half life--difficult to predict because of simultaneous change sin clearance and volume of distribution

influence on PK parameters if patient has heart failure
- hepatic clearance:
- renal clearance:
- volume of distribution:
- oral absorption:
- half life:

IV: decrease dose because reduced hepatic clearance will cause decrease in LBF
oral: don't have to change dose because there is a decrease in liver blood flow and FH will decrease

in reduced hepatic clearance with high extraction ratio drugs, what are the dose adjustments for oral/IV

high to low

in a semi-permeable membrane, toxin and drugs move from low/high concentration to low/high concentration

efficient removal

if a drug is < 500 daltons (theophylline, lidocaine) , what effect will this have on dialysis removal

intermediate clearance

if a drug is 500-1000 daltons (aminoglycoside, digoxin) what effect will this have on dialysis removal

not removed by conventional membranes (newer, "high flux" membranes have a larger pore size and can remove large molecules such as vancomycin)

if a drug is > 1000 daltons ( vancomycin) what effect will this have on dialysis removal

water solubility favors removal, lipid solubility decrease removal

water and lipid solubility and the effect it has on dialysis removal

increased binding causes increased removal

plasma protein binding and the effect is has on dialysis removal

increase in volume will decrease removal

volume of distribution and the effect it has on dialysis removal

false, must wait at least 2 hours

T/F you can draw a drug level right after dialysis to determine replacement dose

true, must wait at least 2 hours

T/F you cannot draw a drug level right after dialysis to determine replacement dose

underwater weighing

oldest method, measures weight and volume of water displaced; measure above ground weight and assume constant density for fat and fat-free tissue; calculate fraction of bodyweight composed of fat

skinfold measurement

uses caliper, assumes total fat correlates with subcutaneous fat, not accurate

false

T/F skinfold measurement is accurate

bioelectrical impedance analysis (BIA)

measures current across body; body fat and bone impede current, aqueous conduct current, most frequently used

dual x-ray absorptiometry

bone, fat, and lean tissue attenuate x-ray beam differently

- underwater weighing
- skinfold measurement
- bioelectrical impedance analysis
- dual energy x-ray absorptiometry

direct measurements of weight and obesity

- body mass index
- body surface area
- ideal body weight
- lean body weight
- predicted normal weight

indirect measurements of weight and obesity

body mass index

total body weight (kg) divided by square of height (m)

lead body weight

total weight devoid of fat

predicted normal weight

expected normal weight of a obese individual

- physiochemical properties of drug
- plasma protein binding
- tissue blood flow

volume of distribution depends on...

low

polar/hydrophilic drugs have a low/high logP

high

hydrophobic drugs have a low/high logP