Download Toxicokinetics 2004

Toxicokinetics
is not rocket science
Kent R. Olson, MD
Medical Director, SF Division
California Poison Control System
...a
stepwise
approach
to
complicate
simple
kinetics
concepts
and
freak out
fellows
Dr. Bart’s blackboard fun™ presents ...
Kinetics for DUMMIES !
1. Absorption
2. Distribution
3. Elimination
Case 1
 Biff
says he drank “2 beers”
 His serum ethanol = 0.28 gm/dL
 Possible
 How
Questions:
big is Biff?
 How big are his beers?
 How honest is Biff about his beers?
“2 beers” = ? EtOH
 Assume:
 Pint-sized:
500 mL each
 6.8% EtOH v/v
 EtOH ~ 0.7 g/mL
Calculation:
1000mL x 6.8mL EtOH/100mL beer x 0.7 g/mL
= 47.6 g EtOH
Absorption
“First-pass effect”
 Removal
of drug after ingestion, by:
 Enzymes
in the gut wall
 Uptake by the liver
 Vomiting, AC, WBI, etc
 Ethanol:
first-pass removal ~ 6-7%
Biff’s absorbed dose: down to 44.5 g
(47.6 x 93.5% = 44.5)
EtOH FP effect modified by:
 Gastric
emptying time
 Food
 Medications
(eg, Reglan, ranitidine)
 Gender
 Age
Most rapid and complete
EtOH absorption:
• older
• female
• empty stomach
• on metoclopramide
Some drugs w/ high FP effect
a.k.a. “low bioavailability”
 Propranolol
 Cyclosporine
 Morphine
 Desipramine
& other TCAs
 Implications:
 FP
removal can be saturated in an OD
 Greater proportion of drug will reach the
systemic circulation
Other absorption issues:
 Delayed
or altered absorption
 Massive
OD
 GI motility altered by drug effect
Anticholinergics
 Opioids

 Solubility
 Modified-release
preparations
Modified-release
preparation
Tylenol “Extended Relief” ingestion
1000
Serum APAP level
100
APAP
(mg/L)
10
Prob. Toxic
Poss. Toxic
1
0
5
10
15
20
Note: co-ingestion of Nyquil plus up to 44 g Tylenol ER
Ref: Bizovi K et al: J Toxicol Clin Toxicol 1995; 33:510
25 hrs
Volume of Distribution (Vd)
 Where

Vd
the drug goes
=
amount in body
Cp
= mg/kg / mg/L = L/kg



Total body water = 0.7 L/kg or ~ 50 L
ECF = 0.25 L/kg or about 15 L in adult
Plasma = 0.07 L/kg or ~ 5 L
 For
EtOH: Vd ~ 0.7 L/kg
Vd for some common drugs
Large Vd:

camphor
 antidepressants
 digoxin
 opioids
 phencyclidine
 phenothiazines
Small Vd:

alcohols
 lithium
 phenobarbital
 phenytoin
 salicylate
 valproic acid
Back to Biff’s beers . . .
 How
big is Biff?
If Vd = amount in body, then
Cp
0.7 L/kg x Biff (kg) =
44.5 g
0.28 g/dL
and Biff = 22.7 kg (50 lb) ??
Practice Question:
 Boff
ingested the contents of his
mother’s old Rx of theophylline
 What is the highest possible serum
concentration he could achieve?
 Boff
weighs 80 kg
 Vd theophylline 0.5 L/kg
 Bottle had # 20 pills 300 mg Theo-Dur
Cp = dose / Vd
Max dose = 20 x 300 = 6000 mg
Vd = 0.5 L/kg x 80 kg = 40 L
Max Cp = 6000 mg = 150 mg/L
40 L
Try this on your own:
How many vials of Digoxin-Fab
would be needed to neutralize a
digoxin serum concentration of 4
ng/mL? (assuming equilibrium)
 Vd
= 6 L/kg
 50 kg elderly woman
 Each vial binds ~ 0.5 mg digoxin
Question:
 Joe
has a serum phenytoin level of
10 mg/L w/ serum albumin 4.4 gm/dL
 Josette
has a serum phenytoin level
of 5 mg/L w/ albumin 2.2 gm/dL
 What
do they have in common?
Protein binding
Cnormal binding =
(1 – fu)
fu = fraction unbound
C’
P’
Pnormal
+ fu
Cnormal binding =
5 mg/L
(1 – 0.1)
2.2
4.4
+ 0.1
Cnormal binding =
5 mg/L
0.55
= 9.09 mg/L
Some drugs w/ high Pr binding
 Carbamazepine
 Phenytoin
 Salicylic
acid
 Valproic acid
 Warfarin
 Note:
fu = 0.2
0.1
0.16
0.15
0.03
Pr binding can be saturated in
OD, resulting in greater free fraction
Effect of saturated Pr binding
Plasma
protein
bound drug
Plasma
proteins
SATURATED
Free drug
Drug
in
tissues
Free drug
Drug
in
tissues
Salicylate: increasing
Vd with incr. dose
pH
and
Vd
Salicylate is a Weak Acid (pKa 3.5)
TISSUES
BLOOD
URINE
(pH 6.8)
(pH 7.4)
(pH variable)
SH
SH
SH
H+
H+ + S-
Acidosis
+
S-
Alkalosis
H+ + S-
Remember Henderson-Hasselbalch?
protonated species
Log
= pKa – pH
unprotonated species
OR . . .
protonated/unprotonated = 10pKa-pH
Question:
 What
is the proportion of salicylate in
the non-ionized (protonated) state
compared with the ionized (nonprotonated) state in urine with:
pH
= 3.5 ?
pH
= 7.5 ?
Answer:
 pH
3.5
Protonated / nonprotonated = 103.5-3.5
Salicylic acid / salicylate = 100 = 1
Ratio = 1:1
 pH
7.5
Protonated / nonprotonated = 103.5-7.5
Salicylic acid / salicylate = 10-4
Ratio = 1:10,000
Dose was 150 mg IV . . . Vd = ?
Dose was 150 mg IV . . . Vd = ?
Cp at
t=0
~ 7.5 mg/L
Vd = dose / Cp
= 150 / 7.5
= 20 L
Digoxin OD in a child
Lithium
Elimination:
Can you say “haff-life”?
Half-life = the
time it takes
for the Cp to
drop in half
1 half-life
2 half-lives
No. of half-lives
1
2
3
4
5
6
Increment
50%
25%
12.5%
6.25%
3.125%
1.5625%
Percent of maximum
50%
75%
87.5%
93.75%
96.875%
98.4375%
Slope =
K =the
slope
of
proportion
of
drug elimination
per unit time
(natural log graph)
What is Clearance? (Cl)
VOLUME
per unit
TIME
cleared
of the drug
units = mL/min or L/hr
Clearance calculation:
 If
the reported Cl is 200 mL/min,
What is the Half-life?
How much drug is gone after 2 hours?
“They reported the CLEARANCE was
really good - - - 200 mL/min . . .”

But, Cl is expressed in mL/min . . .
(NOT mg/min or gm/hr or tons/day)

Total drug elimination depends on drug
concentration:
mcg/mL x mL/min = mg/min
Now try again:
 Cl
is 200 mL/min
 Drug
concentration is 1000 ng/mL
Cl x Cp = 200 mL/min x 1000 ng/mL
= 200,000 ng/min
= 200 mcg/min
= 0.2 milligrams/minute !
What is the relationship
between Cl and Vd?
Slope = Cl
Vd
t 1/2 =
0.693 Vd
Cl
First-order kinetics
a.k.a.
“concentrationdependent”
kinetics
Elimination is LINEAR
when plotted on
semi-log graph
What happens in OD?
 Saturation
of normal routes of
elimination  “zero-order kinetics”
First-order
Half-life = 1 hour
Hours
Level
00:00
60
01:00
30
02:00
15
03:00
7.5
Zero-order
Elim. = 30 mg/L/hr
Hours
Level
00:00
210
01:00
180
02:00
150
03:00
120
Nonlinear kinetics
Css =
Km x dose rate
Vm – dose rate
Vm = maximum rate of metabolism
Km = Cp at which the rate of
metabolism is ½ of maximum
What happens
when
the dose = Vm?
Other factors affecting
elimination rate in OD
 Continued
absorption from the GUT
 Combined
effect on Cp vs time plot
makes it appear that half-life prolonged
 Hepatic
 Decreased
hepatic blood flow
 Liver damage
 Renal
 Oliguria
due to hypotension
 Acute renal failure
Clearance can be:
 Metabolic
(ClM)
 Renal (ClR)
 Lungs (ClL)
 etc (Cletc)
“Intrinsic clearance”
(by the body)
 and
even hemodialysis (ClHD) and
other extracorporeal methods
 Total
Cl = ClM + ClR + ClL + Cletc + ClHD
Extracorporeal removal
ARTERY
or
VEIN
VEIN
Blood
from
patient
Return
to
patient
Hemodialysis
Question:
 What
is the hemodialysis clearance
of Endital™, a new (but not very
effective) antidepressant?
 Vd
= 40 L/kg
 Cp = 1000 ng/mL
 Cout = 340 ng/mL
 Dialysis flow rate = 300 mL/min
Hemodialysis Cl
Cout
Cin
Flow rates = 250-350 mL/min (w/catheter)
Extraction ratio =
Cin – Cout
Cin
Clearance = Flow rate x Extraction ratio
Extraction =
ratio
1000 - 340
1000
ClHD = flow rate x ER
= 300 x 2/3
= 200 mL/min
= 2/3
What’s the “half-life” on HD?
t 1/2 =
0.693 Vd
Cl
= 0.693 x 40 L/kg x 100 kg / 12 L/hr
= 231 hours !
OK, what’s really the half-life?
t 1/2 =
0.693 Vd
Cl
Need to use
Cltotal not ClHD
Clintrinsic = 1500 mL/min (90 L/hr)
Ctotal = 90 L/hr + 12 L/hr (HD) = 102
t1/2 = 0.693 x 4000 L / 102 L/hr
= 27.2 hours
Continuous Renal Replacement Therapy
(CVVH)
Cp
(or vein)
Rate of ultrafiltrate production = up to 3 L/hr
Cultrafiltrate
Volume/time
(CVVHD)
Clearance =
x
(or vein)of ultrafiltrate
Cplasma
Cu
Beckmann U et al:
JTCT 2001; 39:393-7
Estimate for Lithium
 Usual
renal Cl 25-35 mL/min
 Hemodialysis adds 100-150 mL/min
 But
only for 3-4 hours at a time
 Rebound between dialysis sessions
 CVVH
 But
adds 20-35 mL/min
can be provided continuously
 Volume cleared ~ 50L/day
vs 36 L/day w/ 4 hours of HD
 No rebound