Download Pharmcokinetics in Critical Care

Pharmacokinetics in Critical
Care
Objectives
review basic pharmacokinetic &
pharmacodynamic principles
apply these principles to scenarios
commonly encountered in critical care
Pharmacokinetics
describes the movement of drugs through
the body
4 phases:
– absorption
– distribution
– metabolism
– elimination
Pharmacodynamics
describes the action of a drug once it
reaches the target tissue
relationship between drug concentration &
effect can be used clinically
Important Definitions
Linear or First-Order Kinetics
– constant % of drug eliminated per unit of time
– increased drug concentration proportional to
increased dose
– elimination proportional to drug concentration
– shown by most drugs
Important Definitions
Non-Linear or Zero-Order Kinetics
– constant amount (vs %) of drug eliminated
per unit of time
– drug concentration changes not proportional
to dose changes
– often a function of metabolic enzyme
saturation
– eg. alcohol, phenytoin
Important Definitions
Half-life (t1/2)
– time required for half of an administered drug
to be eliminated
Steady State
– rate of drug being administered = rate being
eliminated
– results in constant serum levels
– achieved in 4-5 half-lives
– achieved more quickly with loading doses
Case
74 yo male admitted to ER with hypoxemic
respiratory failure
diagnosed with CAP; intubated &
transferred to ICU
started on:
– Ceftriaxone 1 g IV q24h
– Azithromycin 500 mg IV q24h
Case
pt weaned & extubated within 2 days then sent to
ward
stepped down to levofloxacin 500 mg PO q24h for 7
days total
on Day 6, Code 66 is called for respiratory failure
– transferred back to ICU
– reintubated
– antibiotics changed back to IV
pt improves quickly & is sent back to ward within 2
days
Case
What went wrong?
– during ICU stay, the patient was started on
continuous enteral feeds
– when antibiotics were stepped down to oral,
no instructions were left to hold the feeds 2
hours pre/post administration
– binding interaction ultimately lead to
levofloxacin treatment failure
Binding Interactions
affected classes:
– quinolones, phenytoin, tetracyclines
often dramatic effects on peak
concentration & time to peak
worst offender = phenytoin
– hold feeds for administration
– always order capsules for NG admin; liquid
adsorbs more to feeding tubes
Other Issues with Drug Absorption
ileus: watch for high residuals, usually
confirmed radiographically
ischemic bowel
N/V/D
malabsorption/short gut syndrome
hemodynamic instability
– may impact gut perfusion
Advantages of Oral Meds
improves patient’s sense of well being
minimizes potential for phlebitis or line
infections
earlier ICU discharge
up to 8-fold savings in drug acquisition
Case
RS, a 48 yo (wt 85 kg) male, presents to ER with
3 day history of cough, dyspnea, & fever
initial investigations reveal Sp02 84% & LLL
opacity on CXR
RS has a positive history for EtOH & currently
resides in a homeless shelter
empiric antibiotics started for CAP
– Ceftriaxone 2 g IV q24h
– Azithromycin 500 mg IV q24h
Case
following intubation & stabilization, RS is
admitted to ICU
during the first 3 days of admission, he
demonstrated clinical improvement & the team
was able to wean his vent settings to minimal
support
on Day 4, his 02 requirements increased, along
with increased suction passes, & he developed a
new consolidation on CXR
antibiotics broadened to Tazocin 3.375 g IV q6h
& vancomycin 1 g IV q12h to cover VAP
Case
as per protocol, a vancomycin pre-level
was drawn prior to 3rd dose
– level comes back at 4 mg/L
Vancomycin Dosing
use actual body weight
loading dose
– helps to attain therapeutic concentrations
more quickly
– 25-30 mg/kg
– be cautious in renal failure
maintenance dose
– 30-60 mg/kg/day divided q8-12h
Vancomycin Monitoring
follow trough levels (peaks have limited
clinical utility)
– to start, measure pre-3rd or pre-4th dose
levels (to ensure serum concentration has
reached steady state)
target levels dependent on tissue
penetration at various sites
– CNS: 20-25 mg/L
– lungs: 15-20 mg/L
– skin/soft tissue:10-15 mg/L
Back to the Case
following the pre-3rd level of 4 mg/L, the
team reassesses the dose/interval on
rounds
– target level = 15-20 mg/L
– 60 mg/kg/day x 85 kg = 5100 mg ÷ q8h =
1700 mg
– round to nearest 250 mg = 1500 mg q8h
new dose pre-3rd level = 18 mg/L
Case
KM, a 38 yo male (wt 75 kg), presents to
ER in status epilepticus
intubated en route by EMS & given
midazolam 5 mg x 3 doses
upon arrival, loaded with phenytoin 1 g &
started on propofol infusion @ 50
mcg/kg/min
transferred to ICU once stable
Case
the following morning, propofol was
weaned down & turned off
that evening, the patient began to
experience tonic-clonic seizure activity
propofol restarted & kept on overnight
phenytoin monitoring:
– level comes back following morning at 7
µmol/L (ref range 40-80 µmol/L)
– albumin 22  corrected level = 13 µmol/L
Case
based on this level:
– a phenytoin ‘mini-load’ of 500 mg was given
– maintenance dose increased to 150 mg q8h
EEG showed abatement of seizure activity
– propofol again weaned & turned off
once awake, extubated & sent to ward
repeat phenytoin level: 88 µmol/L (Alb 25)
– Corrected = 147 µmol/L
Phenytoin Pharmacokinetics
non-linear aka Michaelis-Menton kinetics
– phenytoin demonstrates saturable metabolism
–
http://otm.oxfordmedicine.com/content/vol5/issue1/images/large/med-9780199204854-graphic010004.jpeg
Impact of Hypoalbuminemia
phenytoin is 90% plasma protein bound
– normally, only 10% of phenytoin is unbound &
able to exert a therapeutic effect
changes in serum albumin can drastically
change the amount of unbound phenytoin
albumin is an acute phase reactant so
levels almost always decreased in critical
illness
Phenytoin Dosing
loading dose
– 15-20 mg/kg IVPB
– max infusion rate = 50 mg/min
– always check compatibilities - incompatible
with dextrose solutions
– Oral: 15-20 mg/kg in 3 divided doses q2-4h
maintenance dose
– start at 100 mg q8h (4-7 mg/kg/day)
IV to PO conversion 1:1
Phenytoin Monitoring
time to draw levels
– 2-4 hours after IV loading dose (not common)
– trough level ~1 h before next dose; first level
3-4 days after initiation (or earlier if seizure
activity still present)
correcting for albumin
– low albumin with CrCl > 25 mL/min
Cpcorrected=
Cpreported
0.02 x albumin (g/L) + 0.1
– Use 0.01 x albumin + 0.1 for CrCl < 25
mL/min
Phenytoin Monitoring
free vs. total phenytoin levels
– free levels indicate the unbound fraction of
phenytoin
– ref range: 4-8 µmol/L
– useful when:
adequate dose & sub-therapeutic level
pt with therapeutic level has signs of toxicity
pt has known derangement in volume of
distribution, eg. critically ill, pregnant, renal failure,
cirrhosis, burns
Phenytoin: Dose Adjustment
do not adjust dose more than once a week
nomogram for adjusting phenytoin dose
level < 20
increase x 100-200 mg
qd
level 20-30
increase x 100 mg qd
level 31-40
increase x 50 mg qd
level>40
increase x 30 mg qd
From: Phenytoin Pharmacokinetics
Training Manual. Duane Bates. AHS
Back to the Case
repeat phenytoin level = 88 µmol/L (147)
– likely a product of saturable metabolism
despite the high corrected level, KM is not
demonstrating signs of toxicity
– toxicity: nystagmus, ataxia, CNS changes
maintenance dose changed from 150 mg
IV q8h to 300 mg PO daily.
– follow-up levels in therapeutic range
Case
LB, an 86 yo female (wt 60 kg) admitted to
CV ICU following CABG x 2
long bypass pump time due to bleeding
arrives on unit heavily sedated:
– fentanyl 100 mcg/h
– midazolam 5 mg/h
decision made to keep at RASS of -2 to -3
until following morning
Case
next morning, her hemodynamic
parameters are stable
plan to wean sedation to minimize pressor
& ventilation settings
fentanyl weaned to 25 mcg/h & midazolam
turned off
by afternoon:
– RASS score still –2
– unable to be extubated due to LOC
Case
the following day:
– LOC starts to improve
– RASS score returns to 0
– still requiring ventilatory support
the next morning:
– Patient passes SBT, has cuff leak, & a
reasonable LOC to allow airway protection
Volume of Distribution (Vd)
describes rate & extent of plasma transfer
of a drug
determined by several factors:
– lipophilicity:
increased lipophilicity = increased distribution
(including distribution past BBB)
– plasma protein binding
increased PPB = decreased distribution
– drug polarity
– tissue blood flow
Midazolam Distribution
highly lipid soluble, i.e. large Vd
easily penetrates BBB
accumulates in adipose tissue
– leads to creation of depot effect
drug continues to leach out of adipose tissue even
after the medication is discontinued
Case
RR, 65 yo male (wt 75 kg), admitted to
medicine ward following GI bleed
medical history significant only for CAD
pre-admission meds:
– ASA 81 mg qd
– atorvastatin 80 mg qhs
– metoprolol 25 mg bid
– ramipril 10 mg qd
Case
urea breath test confirms presence of
Helicobacter pylori
started on eradication therapy:
– amoxicillin 1000 mg bid
– clarithromycin 500 mg bid
– lansoprazole 30 mg bid
Case
on Day 4 of antibiotics, RR begins to
experience muscle weakness/tenderness
on Day 5, he develops flank pain &
darkened urine
labs show a CK of 8000 U/L
managed with supportive care aimed at
maintaining adequate urine output
Drug Metabolism
aka biotransformation
process of enzyme-catalyzed changes in
drug structure
– increases hydrophilicity to promote excretion
occurs at many sites in the body
– liver, gut, lungs, kidney, brain
consists of Phase I & Phase II reactions
Consequences of Drug
Metabolism
Substrate
Active
Toxic
Inactive
Non-toxic
Metabolite
Inactive
Non-toxic
Active (Pro-drug)
Toxic (Reactive
Metabolite)
Cytochrome P450 Metabolism
Phase I oxidative metabolism
most common & important of all metabolic
pathways
– catalyzes metabolism for 60-80% of marketed
drugs
over 270 gene families identified
– 18 known in humans
CYP families 1, 2 & 3 most clinically
relevant
Contribution of CYP-P450 to Drug
Metabolism
Adapted from: Clin Pharmacokinet
1997; 32:210
Medication Classes Implicated
in CYP-Mediated DIs
CYP 3A4
CYP 2C9
CYP 2C19
CYP 2D6
CYP 1A2
Substrates
Benzos
Midazolam
Cyclosporine A
Tacrolimus
CCBs
Statins
PIs
NSAIDs
S-warfarin
Phenytoin
Propranolol
Omeprazole
Diazepam
Codeine
SSRIs/TCAs
Venlafaxine
DM
Risperidone
Haloperidol
Beta-blockers
R-warfarin
Clozapine
Caffeine
Theophylline
Imipramine
Inhibitors
Azoles
Clarithromycin
Erythromycin
Cimetidine
Grapefruit juice
Azoles
Ritonavir
Azoles
Fluoxetine
Sertraline
Omeprazole
Ritonavir
Methadone
Cimetidine
SSRIs (>Paxil)
Venlafaxine
Fluphenazine
Haloperidol
Azoles
Clarithromycin
Erythromycin
Cimetidine
Grapefruit juice
Inducers
Phenobarbital
Rifampin
Dexamethasone
Carbamazepine
St John’s Wort
Phenytoin
Phenobarbital
Rifampin
Phenobarbital
Rifampin
None reported
Phenobarbital
Rifampin
Phenytoin
Omeprazole
Smoking
www.aafp.org/afp/980101ap/cupp.html
Case: Pharmacogenetics
LR, 78 yo female (wt 65 kg), admitted to
CV ICU following aortic valve replacement
2 hours post-op, she flips into atrial
fibrillation with HR in the 120s
management
– amiodarone 150 mg fast loading dose, then 1
mg/min infusion for 6 h, 0.5 mg/min for 18 h
– no beta blockers due to continuing need for
pressor support
Case: Pharmacogenetics
following 24 hours of amiodarone, LR
remains in atrial fibrillation, but her pressor
support has been weaned off & she’s been
extubated
team decides to try beta-blockade for rate
control
– started on metoprolol 12.5 mg po bid
– amiodarone continued at 0.5 mg/min
Case: Pharmacogenetics
following her 3rd dose of metoprolol, LR
converts back to sinus rhythm
after her next dose, she starts to develop
bradycardia with a HR of 45-49
metoprolol is held & amiodarone is
converted to oral
pt maintains sinus rhythm in the 60s-70s
Pharmacogenetics
genetic polymorphisms in drug
metabolizing enzymes, transporters or
receptors can cause clinically relevant
effects on efficacy & toxicity of drugs
individuals respond differently to drugs
there are poor, intermediate, & ultra-rapid
metabolizers
Pharmacogenetics
Back to the Case
metoprolol is metabolized by the CYP-2D6
isoenzyme
– if LR is a poor metabolizer, metoprolol could
accumulate, leading to bradycardia
other beta-blockers affected include:
– labetalol
– carvedilol
– propranolol
Case
EB, 45 yo female (wt 55 kg), who is
quadriplegic from long-term care, presents
to ER with hypoxic respiratory failure
requiring intubation
recently hospitalized for cellulitis
started on empiric antibiotics:
– Tazocin 3.375 g IV q6h
– vancomycin 1 g IV q12h
Case
pre-3rd vanco dose level = 28 µmol/L
SCr = 110 µmol/L
u/o ~30 mL/h
CrCl ~50 mL/min
Case
How can this level be explained?
due to quadriplegia, her baseline SCr = 30
µmol/L
so an increase to 110 µmol/L is suggestive
of acute renal failure
Serum Creatinine
creatinine = breakdown product of creatine
freely filtered by kidney; acts as a
surrogate for glomerular filtration
this assumption is based on normal &
consistent production of creatinine
Serum Creatinine
conditions that impact use of SCr as a
surrogate for GFR include:
– malnourishment
– highly catabolic states
– muscle wasting: MS/muscular dystrophy
– para/quadriplegics
– elderly
In these groups, always refer to the
patient’s baseline SCr when making
assumptions about renal function
Back to the Case
based on the vanco level of 28 mg/L, the
following adjustments were made:
– 55 kg x 15 mg/kg = 825 mg
dose changed to 750 mg & interval to q24h
subsequent levels came back in the
therapeutic range
Case
KC, 58 yo male (wt 70 kg) with ESRD
secondary to diabetic nephropathy,
presents to ER c/o right leg pain with fever
(T 39.2) & leukocytosis (WBC 24.4)
physical exam reveals a large ulcer on
KC’s right foot & initial blood cultures grow
gram-ve bacilli
he usually has hemodialysis 3 times a
week
Case
empiric antibiotics are initiated as follows:
– Tazocin 2.25 g IV q8h (plus top-up prn)
– vancomycin 1 g IV (if level < 15 pre-dialysis)
due to moderate hypotension, he is
transferred to ICU for monitoring
decision is made to convert to CRRT to
manage hypotension (hoping to avoid
pressors)
Case
the following day on rounds, the clinical
pharmacist wonders why the antibiotics
have not been adjusted for CRRT
Dialysis in Critical Care
CRRT: Continuous renal replacement
therapy
– used in hemodynamically unstable patients
– labour-intensive & costly
IHD
– patients are converted to IHD once
hemodynamically stable enough to handle
removal of large volumes of fluid
Dialysis & Drugs
assessment of a drug’s pharmacokinetic
profile will indicate how it is impacted by
dialysis
– look at Vd & PPB
– drugs that are dialyzable are cleared more
rapidly on CRRT
– remember to adjust doses
– refer to Critical Care CRRT dosing chart on
iweb
Dialysis & Drugs
remember to re-adjust drug doses once a
patient converts back to IHD, otherwise
the patient can become toxic
resources for dialysis dosing
– Clinical pharmacist
– Dispensary pharmacist (evening hours)
– Lexi-Comp or Micromedex
Important Drugs in Renal
Disease
antibiotics
milrinone
phenytoin
digoxin
meperidine, morphine, midazolam