pharmacokinetics Flashcards
drug has Vd of .35mL/kg. in 70kg patient, what IV loading dose must be administered to achieve a plasma concentration of 8mg/dL
196mg
(.35L/kg x 70 = 24.5L)
(24.5L x 8mg/L) / 1 =
loading dose = (Vd x desired CP) / bioavailability
Vd=
amount of drug/desired plasma concentration
Vd assumes two things
- drug distributes instantaneously (full equilibration occurs at time =0)
- Drug is not subjected to biotransformation or elimination before it fully distributes
review distribution of body water in 70kg patient
tbw
extracellular (plasma volume, ISF)
intracellular
lipophilic drug characteristics
Vd exceeds TBW (>.6L/kg or >42L)
distributes into TBW and fat
requires higher dose to achieve plasma concentration
hydrophilic drug characteristics
Vd less than TBW (<.6L/kg or <42L)
distributes into some or all of body water but not fat
require lower dose to achieve given plasma concentration
Vd is affected by which 2 characteristics
drug (molecular size, ionization, protein binding)
patient (pregnancy and burns)
loading dose=
Vd x (desired plasma concentration/ bio availability)
IV: bio availability =1
clearance is directly proportional to (3)
blood flow to clearing organ
extraction ratio
drug dose
clearance is inversely proportional to (2)
half life
drug concentration in central compartment
review this graph
alpha: redistribution- steepest part of curve
beta: elimination from central compartment- less steep part of curve
A+B represents plasma concentration over time
k12
rate constant for drug transfer from central compartment to peripheral compartment
k21
rate constant for drug transfer from peripheral compartment to central compartment
ke
rate constant for drug elimination from body
describe three compartment model
different rate constants going to and from each compartment.
elimination half life versus elimination half time
time it takes for 50% of drug to be removed after rapid IV injection versus
time it takes for 50% of drug to be removed from the plasma during the elimination phase
amount of drug eliminated and half times
drug is considered eliminated after 96.9% is gone
half time measures what
constant fraction and not constant amount
define context sensitive half time
time required for plasma concentration to fall by 50% after the infusion is stopped
review the context sensitive half time graph as it relates to phenylpiperdines
an acid _______ a proton while a base ________ a proton
acid: donates a proton
base: accepts a proton
ionization is dependent on two things
pH of solution and pKa of drug
pKa =
pH where 50% of drug is ionized and 50% is non ionized
henderson hasslebach equation
pH= pKa + log (base/conjugate acid)
weak bases in an acidic versus basic solution
in an acidic solution, more ionized and water soluble
in a basic solution, more non ionized and lipid soluble
weak acids in acidic versus basic solution
in an acidic solution, weak acids are more non ionized and lipid soluble
in a basic solution, weak acids are more ionized and water soluble
a drug that is a weak acid is paired with
a positive ion such as sodium, calcium, or magnesium
a drug that is a weak base is paired with
a negative ion such as chloride or sulfate
what LA is most likely to undergo fetal ion trapping
lidocaine. (maternal alkalosis and fetal acidosis)
percent change of drug bound by plasma protein
percent change = ((new value- old value)/old value) x 100
(96-98)/96 x 100 = 100% increase in un bound
initial: 98% bound
then: 96% bound
albumin key facts
most plentiful plasma protein
primary determinant of plasma oncotic pressure
t1/2 3 weeks
carries a negative charge
primarily binds with acidic drugs
also binds with neutral and basic drugs
what decreases Cp (plasma clearance) of drugs that bind to albumin (5)
liver disease
renal disease
old age
malnutrition
pregnancy
what kind of drugs that a1 acid glycoprotein bind to
acidic
plasma clearance of drugs that bind to a1 acid glycoproein are decreased by
neonates and pregnancy
plasma clearance of drugs that bind to a1 acid glycoproein are increased by
surgical stress
MI
chronic pain
RA
advanced age
what kind of drugs do beta globulin proteins bind to
acidic
plasma clearance of drugs that bind to beta globulins are increased or decreased by
n/a
zero order kinetics versus first order kineticcs
zero: constant amount of drug is metabolized per unit of time
first: constant fraction of drug is metabolized per unit of time
what kind of metabolism does this represent
zero order kinetics
(more drug than enzyme)
what kind of metabolism does this represent
first order kinetics
(less drug than enzyme)
3 phases of drug metabolism
phase 1: modification (oxidation, reduction, hydrolysis)
phase 2: conjugation
phase 3: excretion
phase 1: modification
biotransformation is carried out by
what happens during 3 reactions
increases polarity
biotransformation via p450 system
oxidation: removes electrons from compound
reduction: adds electrons to a compound
hydrolysis: adds water to a compound to split it apart (usually an ester)
phase 2: conjugation
adds on endogenous, highly polar, water soluble substrate to the molecule. produces a water soluble biologically inactive molecule ready for excretion
some drugs do not need phase 1 and go directly to this
substrates used for phase 2 conjugation
glucoronic acid
glycine
acetic acid
sulfuric acid
methyl group
describe enterohepatic circulation
some conjugates compounds are excreted in the bile, reactivated in the intestine, and then reabsorbed into systemic circulation. usually has long effects
ex) diazepam, warfarin
phase 3: elimination
involves ATP dependent carrier proteins that transport drugs across cell membranes. present in kidneys, liver, GI tract
extraction ratio of 1
100% of the drug delivered to the clearing organ is removed
extraction ratio of .5
means 50% of the drug delivered to the clearing organ is removed.
a perfusion dependent elimination has an extraction ratio of______ and clearance is dependent on ____________________________
> .7
clearance is dependent on liver blood flow. increased liver BF, increased clearance
a capacity dependent elimination has an extraction ratio of ______ and clearance is dependent on ______________________________
<.3
clearance is dependent on changes in hepatic enzyme activity or protein binding
enzyme induction increases clearance
enzyme inhibition decreases clearance
drugs that have low hepatic extraction ratios
rocuronium
diazepam
lorazepam
methadone
thiopental
theophylline
phenytoin
drugs that have intermediate hepatic extraction ratios
midazolam
vecuronium
alfentanil
methohexital
drugs that have high hepatic extraction ratios
fentanyl
sufentanil
morphine
meperidine
naloxone
ketamine
propofol
lidocaine
bupivicaine
metoprolol
propanolol
alprenolol
nifedipine
diazepam
verapamil
examples of enzyme inducers include
tobacco smoke
barrbiturates
ethanol
phenytoin
rifampin
carbamazepine
examples of enzyme inhibitors include
grapefruit juice
cimetidine
omeprazole
isoniazid
SSRI’s
erythromycin
ketoconazole
drugs metabolized via CYP3A4
opioids: fentanyl, alfentanil, sufentanil, methadone
benzos: midaz, diazepam
LA’s: bupiv, ropiv
drugs metabolized by CYP2D6
codeine –>morphine
oxycodone
hydrocodone
drugs metabolized by CYP1A2
theophylline
lipophilic drugs that do not undergo bio transformation have what fate in the renal system
reabsorbed in peritubular fluid via diffusion
two processes that deliver drug to the urine
- GFR: only free fraction unbound drug is filtered at glomerulus
- organic anion (OAT) and cation (OCT) transporters:
drugs that utilize OAT
furosemide, thiazide diuretics, PCN
drugs that utilize OCT
morphine, meperidine, dopamine
acidic urine and drug excretion
favors reabsorption of acidic drugs
excretion of basic drugs
AAA- acidic drugs are better absorbed in acidic medium
alkalotic urine and drug excretion
favors reabsorption of basic drugs
excretion of acidic drugs
BBB- basic drugs are better absorbed in a basic medium
how to help acidify the urine to help eliminate basic drugs
ammonium chloride or cranberry juice
how to help alkalize urine to help eliminate acidic drugs
sodium bicarb or acetazolamide
drugs metabolized by nonspecific plasma esterases (6)
esmolol, remifentanil, atracurium, remimazolam, etomidate, clevidipine
which drug utilizes alkaline phosphatase for metabolism/elimination
fospropofol
drugs metabolized by pseudocholinesterases
succ, cocaine, mivacurium, ester LA’s
drugs metabolized via hoffman elimination
ciisatracurium
atracurium(+ non specific plasma esterases)
peusdocholinesterase deficiency extends DOA of
succ
mivacurium
cocaine
ester LA’s
