kinetics sec 3

what is the absorption of vancomycin

poor oral bioavailability

what is the distribution of vanc

distributes widely in the body tissue except for CSF

20-30% absorption through inflamed meninges

what is the secretion of vanc

oral: primarily feces

IV: 80-90% unchanged in the urine

what is the clearance of vanc

varies with CrCl

what is the half-life of vanc

6-7 hour

what what the recommended AUC/MIC ratio and surrogate marker in the 2009 guidelines

AUC/MIC >/=400mg/h*L

recommended Cmin (trough) of 15-20mg/K

what was found in the 2015 guidelines

treatment failure was greatest with AUC/MIC

what is the major limitation of the 2009 guidelines

focused on achieving AUC/MIC targets more than toxicodynamic concerns

for practical purposes, chose to recommend Cmin, which is a poor surrogate for AUC

how is vanc associated AKI defined

increase in SCr of >/= 0.5mg/dL or a 50% increase from baseline

decrease in CrCl of 50% from baseline

how long does it take for vanc associated AKI to present

4-17 days

what are the outcomes of vanc associated AKI

full recovery of renal function is uncommon

significantly decreases long-term survival rates and increases morbidity

prolongs hospitalizations and increases costs

when is vanc associated AKI increased

when Cmin is maintained 15-20mg/L

when AUC is 650-1300mg*h/L

what value drives efficacy of vanc

AUC of >/=400mg*h/L

what values drive risk of AKI

AUC and Cmin

what are factors that contribute to AKI

increased weight, pre-existing renal dysfunction, critical illness, concurrent nephrotoxic meds

what is the normal dosing of vanc

15-20mg/kg (actual body weight) q8-12h

what is the loading dose

20-35mg/kg (actual body weight) given over 2-3 hours

when are loading doses given

to rapidly achieve target concentrations in critically ill patients

what is the target AUC for vanc

400-600 mg*hour/L

what timeline do you want to achieve target AUC

within 24-48 hours

what is the difference between Cmin and AUC monitoring

Cmin is practical but insufficient for monitoring

AUC guided dosing is recommended

what is the cutoff point for MIC in vanc

2

what is the bayesian prior model based on

general population

what is the bayesian conditional posterior model based on

individual patient's observed drug concentration

when is Cmax drawn

1-2h after end of infusion

when is Cmin drawn

immediately before next dose

what is the formula for ke

(ln Cssmax- lnCSSmin)/t

what is the formula for Ceoi

Cmax/e^-ket

how does using the extrapolated start of infusion estimate AUC

slightly over-predicts true AUC

how do you calculate the AUC24

add the AUC for the amount of doses in 24 hours

AUC12 + AUC12

how can you adjust dose when AUC exceeds range

extend interval

keep interval the same and lower dose

how can you adjust dose when AUC is lower than the range

shorten the interval

keep interval the same and increase dose

what is the formula for Csoi'

Ceoi'/e^ket

why do you collect peak samples 1-2hours after the end of infusion

assure avoidance of the alpha phase (distribution)

do aminoglycosides exhibit concentration dependent killing or time dependent

concentration dependent

what is the absorption of AG

no oral absorption

rapid and complete absorption from IM

what is the distribution for AG

distribute into ECF, volume status greatly impacts concentration

Vd increases with fluid overload and decreases with dehydration

how is AG eliminated

unchanged in the urine

what are the therapeutic serum concentrations for gent and tobramycin

peak: 4-10mg/L

trough <2mg/L

what are the therapeutic serum concentrations for amikacin

peak: 15-30mg/L

trough <10mg/L

what is the normal half life for AG

2-3 hours

what is the rationale for multiple daily dosing

prevents plasma levels from falling below MIC

optimizes bactericidal action once an MBC was reached

what is the downside of multiple daily dosing

toxicity is primarily associated with high peak plasma concentrations

what is the rationale for once daily dosing

concentration dependent killing

less adaptive resistance

post antibiotic effect

less toxicity because renal transporters are overloaded

what ratio of MIC produces optimal response for AG

8-12xs MIC

what is adaptive resistance

refractoriness of bacteria to AG, bactericidal effect of subsequent doses is decreased after initial dose

AG downregulate their own energy into bacterial cells

what are the 2 phases of AG bactericidal action

phase 1: rapid killing that increases with an increase in concentration

phase 2: adaptive resistance occurs. slow killing, unrelated to concentration

what is the mechanism of nephrotoxicity seen in AG

AG bind to brush border membrane in proximal tubular cells, small amounts are reabsorbed via endocytosis and pinocytosis and stored within lysosomes and inhibit lysosomal phospholipase

this results in an accumulation of phospholipid material leading to lysosome burst, cell death, and tubular necrosis

what type of kinetics do AG display

first-order

what is the rationale for the peak and trough values for AG

attainment of adequate peak: good efficacy in infection

attainment of low trough: minimizes the risk of nephrotoxicity and ototoxicity

when do you use actual, ideal, and adjusted body weight

acutal: <100% of ideal

ideal: 100-130% of ideal

adjusted: >130% of ideal

what is the recommended dosing for gent/tobra

3-5mg/kg/day in equally divided doses q6-8 hours

what is traditional dosing for gentamicin for synergy

1mg/kg IV q8h

what is the alpha phase

equliibrium between IS and IV spaces

what is the beta phase

from the IV space into urine via glomerular filtration

what is the gamma phase

from renal tubules into renal cortex and back

responsible for accumulation and nephrotoxicity

what are the peak and trough values for once daily dosing

peak: 20-30mg/L

trough: <1mg/L

what are C/I for once daily dosing

pregnancy, ascites, hemodynamic instability, unstable renal function, burns >20%

what is the dosing for once daily gentamicin

7mg/kg

what are the dosing intervals based on CrCl and the hartford nomogram

>/=60: q24h

40-59: q36

20-39: q48

<20: monitor

how long after dose do you plot on hartford nomogram

6-14 hours

what are the limitations of hartford nomogram

designed to achieve fixed peak and trough

don't allow clinician to individualize dosing

based on average PK parameters

do not provide a method for dose adjustment

what effect does potassium have on digoxin concentrations

digoxin binds to the Na/K ATPase. when potassium is high, the binding affinity of digoxin to the pump is reduced

with hypokalemia, the drug can be more toxic

what causes the ventricular arrhythmias seen in high concentrations of digoxin

an paradoxical increase in sympathetic outflow

what is the absorption of digoxin

well absorbed orally (70-80% bioavailable)

what do inhibitors of P-gp do to the AUC of digoxin

increase it by >25%

what drugs are inhibitors of P-gp

amiodarone, carvedilol, DHP CCBs, non-DHP CCBs

what do inducers of P-gp do to the AUC of digoxin

decrease it by 20%

what drugs are inducers of P-gp

st. john's wort

what is the distribution of digoxin

30% bound to plasma protein

large Vd

does not distribute to adipose tissue (use IBW for obese patients and actual body weight for underweight patients)

what type of compartment model does digoxin have

two compartment

effect not seen until drug distributes into peripheral compartment

how is digoxin excreted

primarily unchanged in the urine

why is the method of excretion important

it is greatly dependent on renal function and cardiac output

what are the ideal concentrations for digoxin

0.5-2 ng/mL

what are the ADRs for digoxin

GI upset, neurotoxicity (blurred or yellow vision, halos, confusion, dizziness, unusual dreams), cardiotoxicity (arrhythmias), electrolyte abnormalities

how does digifab treat digoxin toxicity

it is a fragment of an antibody that will neutralize digoxin

what is the half-life of digifab

15 hours

why can digifab be used in prophylactic doses

it has low risk of toxicity

what is the therapeutic range for digoxin in heart failure

0.5-0.9ng/mL

what is the therapeutic range for digoxin for arrhythmias

0.5-2.0 ng/mL

what bioavailability is used when determining IV loading doses

1

what is the CLm for HF patients and nonHF patients

HF: 20mL/min

nonHF: 40mL/min

what variables are involved in fick's law of diffusion

permeability, surface area, drug concentration gradient, thickness of the membrane

diffusion rate is directly proportional to...

permeability, surface area, concentration gradient

diffusion rate is indirectly proportional to...

thickness

how does blood flow affect these factors

no effect on permeability

minimal effect on surface area

minimal effect on thickness

HUGE effect on concentration gradient

what does solubility depend on

particle size/shape, pH, stability, mixing conditions

what leads to poor bioavailability of drugs

poor aqueous solubility or poor permeability

what must occur before a drug can be asborbed

it must first dissolve in GI fluids

what are strategies to enhance dissolution rate of pooly soluble drugs

reduce particle size, salt formation, complex formation, surfactant use, lipid based formulations

what factors impact rate of diffusion

blood flow, solubility, concentration of formulation, absorbing surface area, route of admin, GI tract status

what is the action of P-gp

pumps substrates back into the lumen

how does variable expression of P-gp change drug concentrations

high expression of P-gp leads to lower concentrations of drug getting absorbed across the GI tract

the compartment in which the drug is more highly ionized will contain the higher drug concentration, why?

ionized drug cant cross the membrane to leave the compartment

what 3 factors determine the ionization of a drug

if the drug is an acid or a base

drug pKa

drug pH

what are the characteristics of HA form of an acidic drug

unionized, absorbably

what is the simplified form of henderson-hasselbach for weak acids

pKa-pH=log(unionized/ionized)

what is the simplified form of the henderson-hasselbach for weak bases

pKa-pH=log(ionized/unionized)

what is the pH of plasma

7.4

what is the pH of CSF

7.3