antiarrythmics metabolized by what CYP?
2D6
fluoxetine and paroxetine metabolized by what CYP?
2D6
antipsychotics metabolized by what CYP?
2D6
metoprolol and carvedilol metabolized by what CYP?
2D6
not atenolol
codeine and tramadol metabolized by what CYP?
2D6
CYP2D6 metabolizes what % of drugs?
25-30
2D6 poor metabolizer genotype?
4/4 or 4/6
5-10% of whites
1% of asians
What % of whites are 2D6 UMs?
5%
duplication of gene metabolizer?
UM
2D6 PM have what symptoms with antipsychotics?
extrapyridimal
CYP2C9 poor metabolizer genotype?
- 2, *3 in whites
* 5 only in blacks
What gene is key factor explaining dose variability of warfarin?
VKORC1
phenytoin is metabolized by what CYP?
2C9
warfarin is metabolized by what CYP?
2C9
NSAIDS (ibuprofen, diclofenac) are metabolized by what CYP?
2C9
ARBs are metabolized by what CYP?
2C9
glipizide, glyburide metabolized by what CYP?
2C9
CYP2C19 UM genotype?
*17
25% of whites
CYP2C19 PM genotype?
*2, *3
1-3% whites
13-23% asians
clopidogrel metabolized by what CYP?
2C19
prodrug
PPIs metabolized by what CYP?
2C19
diazepam is metabolized by what CYP?
2C19
citalopram, escitalopram metabolized by what CYP?
2C19
cyclophosphamide metabolized by what CYP?
2C19
bupropion metabolized by what CYP?
2B6
efavirenz metabolized by what CYP?
2B6
nevirapine metabolized by what CYP?
2B6
propofol metabolized by what CYP?
2B6
methadone metabolized by what CYP?
2B6
CYP2B6 PM genotype?
*6, *16
Which has higher conc. of nevirapine/efavirenz?
516GG or 516TT
516TT
PM genotype
CYP3A4 PM genotype?
*22
CYP3A4 UM genotype?
1B, Por28
CYP3A5 wild type genotype?
1/1 (normal expression)
80% african American
highest activity, highest dose requirement
CYP3A5 PM genotype?
3/3
85% whites
lowest activity, lowest dose requirement
caffeine, theophylline metabolized by what CYP?
1A2
clozapine, olanzapine metabolized by what CYP?
1A2
heterocyclic amines metabolized by what CYP?
1A2
What CYP is inducible by smoking 1PPD?
CYP1A2
What genes code for P-gp?
ABCB1, MDR1
What P-gp SNP is a silent mutation?
C3435T
TT less active (impaired efflux)
P-gp:
3435TT
more or less drug gets into blood?
more
P-gp:
3435CC or 3435CT
more or less drug gets into blood?
less
What CYP2C19 genotype is UM?
*17
white 25%
What CYP3A4 genotype is UM?
1B, Por28
What CYP3A5 genotype is UM?
1/1
80% african American
What CYP2D6 genotype is UM?
duplication of gene
white 5%
How is fosphenytoin dosed?
phenytoin sodium equivalents (PE)
1PE = 1mg phenytoin sodium = 1.5mg fosphenytoin sodium
Which dosage forms of phenytoin have salt factor (S) of 0.92?
capsules and injection
Which dosage forms of phenytoin have salt factor (S) of 1?
suspension and chewable tabs
Is phenytoin highly protein bound?
yes
90%
What CYPs metabolize phenytoin?
2C9 and 2C19
95% hepatic
Non-Linear PK of phenytoin:
enzyme induction has what effect on Vmax?
increased Vmax
Non-linear PK of phenytoin:
hepatic cirrhosis has what effect on Vmax?
decreased Vmax
Non-linear PK of phenytoin:
competitive inhibition has what effect on KM?
increased Km
Non-linear PK of phenytoin:
decreased plasma protein binding has what effect on Km?
decreased Km
Do children have different Vmax and Km than adults for phenytoin?
yes
What is phenytoin adult Vmax and Km?
Vmax: 7 mg/kg/day
Km: 4mg/L
Which is relatively water insoluble?
phenytoin or fosphenytoin?
phenytoin
fosphenytoin water soluble
Phenytoin IV injections should not exceed what rate?
50mg/min
risk of hypotension
fosphenytoin max IV infusion rate is what?
150mg PE/min
100mg PE fosphenytoin = 100mg phenytoin sodium
Which has more rapid absorption?
phenytoin capsules or tabs
tabs
multiple doses/day required
capsules extended release
What is bioavailability of oral phenytoin?
100%
Phenytoin loading dose?
15-20mg/kg
1000mg/day
phenytoin maintenance dose?
children: 5-10mg/kg/day
adults: 4-6mg/kg/day (300-400max/day)
older adults: 200 mg/day max
What is the “magic” dose for phenytoin?
there is no magic dose
nystagmus occurs with what phenytoin conc.?
> 20ug/mL
ataxia occurs with what phenytoin conc.?
> 30ug/mL
seizures occur with what phenytoin conc.?
> 50-60ug/mL
phenytoin therapeutic range (total con.)?
10-20ug/mL
phenytoin unbound therapeutic range?
1-2ug/mL
Low albumin causes of increased unbound phenytoin:
liver disease pregnancy burns trauma malnourishment
can cause unbound phenytoin to be as high as 30-40%
endogenous compound displacement causes of increased unbound phenytoin:
hyperbilirubinemia
jaundice
liver disease
can cause unbound phenytoin to be as high as 30-40%
exogenous compound displacement causes of increased unbound phenytoin?
warfarin
valproic acid
aspirin (over 2g/day)
NSAIDs
can cause unbound fraction to be as high as 30-40%
Units of phenytoin loading dose?
mg
Units of phenytoin maintenance dose?
mg/day
warfarin inhibits what two natural anticoagulants?
proteins C and S
also inhibits activation of coagulation factors VII, IX, X, II
S-warfarin is metabolized by what CYP?
2C9
R-warfarin is metabolized by what CYP?
3A4, 2C19
What % of warfarin is protein bound?
99%
Which clotting factor has longest half-life?
II
60 hours
When is peak effect of warfarin reached?
72-96hrs (3-4 days)
Why does antibiotic use with warfarin cause increased bleeding risk?
gut flora produce vitamin K2. When these bacteria are killed there is less K2 production. Since warfarin inhibits activation of vit. K, the less there is present, the more effective warfarin is
grapefruit
increase or decrease warfarin effect?
increase
“F’s and G’s” increase
fish oil, ginkgo, fenugreek, garlic, grapefruit
St. John’s wort
increase or decrease warfarin effect?
decrease
CYP inducers decrease:
St. John’s wort
smoking
vitamin K
affects warfarin sensitivity?
2C9 or VKORC1?
VKORC1
more prevalent in asians
What CYP inducing antibiotic decreases warfarin effect?
rifampin
other CYP inducers that decrease:
barbiturates, carbamazepine, phenytoin
barbiturates
increase or decrease warfarin effect?
decrease
carbamazepine
increase or decrease warfarin effect?
decrease
phenytoin
increase or decrease warfarin effect?
decrease
SMX/TMP
increase or decrease warfarin effect?
increase
metronidazole
increase or decrease warfarin effect?
increase
fluoroquinolones
increase or decrease warfarin effect?
increase
azole antifungals
increase or decrease warfarin effect?
increase
amiodarone
increase or decrease warfarin effect?
increase
levothyroxine
increase or decrease warfarin effect?
increase
steroids
increase or decrease warfarin effect?
increase
fenofibrate/gemfibrozil
increase or decrease warfarin effect?
increase
warfarin:
INR goal for mechanical mitral valve?
2.5-3.5
2-3 for VTE TX and prevention, and bioprosthetic valves, aortic valves
What is a standardized prothrombin time that represents what you’d expect from a healthy adult pt?
international normalized ratio (INR)
higher than 1 = bleeding risk
lower than 1 = clotting risk
How often is warfarin monitored if pt stable for 6+ months?
q 8-12 weeks
How often is warfarin monitored initially?
q 2-3 days until INR achieved
then q 1-2 weeks until INR achieved x 2, then q 4 weeks until INR stable for 2 readings
Do you give vitamin K if pts’s INR is <10 and they aren’t bleeding?
no
anticoagulant reversal:
contains clotting factors, protein C and S, and heparin
PCC (Kcentra)
anticoagulant reversal:
promotes synthesis of clotting factors?
vitamin K
do not use IM (causes hematoma)
What do you give if warfarin pt has INR 10+ with major bleeding?
PCC
with or without vitamin K
aminoglycoside BBW for?
ototoxicity
nephrotoxicity
pregnancy
What is aminoglycoside spectrum?
gram (-) only
can be used for synergy against gram (+)
are aminoglycosides bactericidal or bacteriostatic?
bactericidal
are aminoglycosides concentration or dose dependent?
concentration
peak:MIC
AG extended interval optimizes ___ dependent killing.
concentration
higher doses with more time in between
reduces toxicity by using PAE
uses nomogram to determine intervals
AG synergy uses what kind of dosing?
weight based
1mg/kg IV q8h
gentamicin trough < 2
max 3mg/kg/day
What kind of dosing is used for plazomicin?
extended interval
What is preferred AG dosing strategy?
extended interval
Unless:
pregnant, ascites, or other fluid abnormality, changing renal fxn, CrCl < 20, or hemodialysis
Extended interval dose for tobramycin/gentamicin?
7mg/kg
Extended interval dose for amikacin?
15mg/kg
don’t forget to divide amikacin level by 2 to plot on nomogram!!
infusion time for plazomicin?
30mins
other Ads 1hr
population data for AG Vd calculation?
0.25-0.35L/kg
population data for AG Ke calculation?
0.00293(CrCl) + 0.014
Cap CrCl at what # for AG calculations?
120ml/min
What weight is used for vanc dosing?
TBW
What parameter determines effectiveness of vanc?
bioavailability
AUC:MIC
What is goal AUC24 for vanc?
400-600 with MIC of 1
AEs of vanc?
red man syndrome
nephrotoxicity
ototoxicity
What Vd is used for vanc dosing?
0.7-0.8L/kg
MSSA bacteria developed what mutation to become MRSA?
MecA
Vanc population PK loading dose?
20-35mg/kg
TBW
VAnc population PK maintenance dose?
15-20mg/kg
q8-12hrs
TBW
Vanc population PK Ke calculation?
0.00083(CrCl) + 0.0044
Bayesian modeling Vanc monitoring:
Collect how many levels after 1st and 2nd dose?
2
2 level PK approximation Vanc monitoring:
Collect how many levels after 4th dose?
2
don’t forget to add up AUCs to tao 24 hrs in calculation
indications for hemodialysis in ESRD pts: AEIOU
acidemia electrolyte abnormalities intoxication (methanol, lithium, aspirin) overload uremia
Are SCr and BUN reliable in hemodialysis?
no
accumulate in dysfunction
what is sieving coefficient ?
how well drug is dialyzed
0 = does not cross 1 = freely crosses
Vanc in renal replacement therapy, focus on what?
pre-dialysis serum conc.
What is goal vanc. conc. in RRT?
15-20mg/L
When to take vanc level with RRT?
day of dialysis prior to HD
What is max dose of vanc in RRT?
3g
use TBW
Administer vanc before or after HD?
after
AG in RRT:
re-dose when level is less than 1?
pulse dosing
Use what weight for AG RRT?
ABW, IBW, TBW
IBW
traditional dosing only
