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Toxicokinetics is not rocket science

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Title: Toxicokinetics is not rocket science


1
Toxicokinetics is not rocket science
  • Kent R. Olson, MD
  • Medical Director, SF Division
  • California Poison Control System

2
. . . a stepwise approach to complicate simple
kinetics concepts and freak out fellows
3
Dr. Barts blackboard fun presents ...
Kinetics for DUMMIES ! 1. Absorption 2.
Distribution 3. Elimination
4
Case 1
  • Biff says he drank 2 beers
  • His serum ethanol 0.28 gm/dL
  • Possible Questions
  • How big is Biff?
  • How big are his beers?
  • How honest is Biff about his beers?

5
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

6
Absorption
7
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
  • Biffs absorbed dose down to 44.5 g
  • (47.6 x 93.5 44.5)

8
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

9
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

10
Other absorption issues
  • Delayed or altered absorption
  • Massive OD
  • GI motility altered by drug effect
  • Anticholinergics
  • Opioids
  • Solubility
  • Modified-release preparations

11
Modified-release preparation
12
Tylenol Extended Relief ingestion
Serum APAP level
APAP (mg/L)
Prob. Toxic
Poss. Toxic
hrs
Note co-ingestion of Nyquil plus up to 44 g
Tylenol ER Ref Bizovi K et al J Toxicol Clin
Toxicol 1995 33510
13
Volume of Distribution (Vd)
  • Where the drug goes
  • Vd
  • 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

amount in body
Cp
14
Vd for some common drugs
  • Large Vd
  • camphor
  • antidepressants
  • digoxin
  • opioids
  • phencyclidine
  • phenothiazines
  • Small Vd
  • alcohols
  • lithium
  • phenobarbital
  • phenytoin
  • salicylate
  • valproic acid

15
Back to Biffs beers . . .
  • How big is Biff?If Vd amount in body, then
    Cp0.7 L/kg x Biff (kg) 44.5
    g 0.28 g/dLand Biff
    22.7 kg (50 lb) ??

16
Practice Question
  • Boff ingested the contents of his mothers 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

17
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

18
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

19
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?

20
Protein binding
21
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22
C
Cnormal binding
P Pnormal
(1 fu) fu
fu fraction unbound
23
5 mg/L
Cnormal binding
2.2 4.4
(1 0.1) 0.1
24
5 mg/L
Cnormal binding 9.09 mg/L
0.55
25
Some drugs w/ high Pr binding
  • Carbamazepine fu 0.2
  • Phenytoin 0.1
  • Salicylic acid 0.16
  • Valproic acid 0.15
  • Warfarin 0.03
  • Note Pr binding can be saturated in OD,
    resulting in greater free fraction

26
Effect of saturated Pr binding
Plasma protein bound drug
Drug in tissues
Free drug
Drug in tissues
Plasma proteins SATURATED
Free drug
27
Salicylate increasing Vd with incr. dose
28
pH and Vd
29
Salicylate is a Weak Acid (pKa 3.5)
TISSUES (pH 6.8)
BLOOD (pH 7.4)
URINE (pH variable)
SH
SH
SH
H S-
H S-
H S-
Acidosis
Alkalosis
30
Remember Henderson-Hasselbalch?
  • Log
    pKa pH
  • OR . . .

protonated species unprotonated species
protonated/unprotonated 10pKa-pH
31
Question
  • What is the proportion of salicylate in the
    non-ionized (protonated) state compared with the
    ionized (non-protonated) state in urine with
  • pH 3.5 ?
  • pH 7.5 ?

32
Answer
  • pH 3.5
  • Protonated / nonprotonated 103.5-3.5
  • Salicylic acid / salicylate 100 1
  • Ratio 11
  • pH 7.5
  • Protonated / nonprotonated 103.5-7.5
  • Salicylic acid / salicylate 10-4
  • Ratio 110,000

33
Dose was 150 mg IV . . . Vd ?
34
Dose was 150 mg IV . . . Vd ?
Cp at t 0 7.5 mg/L
Vd dose / Cp 150 / 7.5 20 L
35
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36
Digoxin OD in a child
37
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38
Lithium
39
Elimination
Can you say haff-life?
40
Half-life the time it takes for the Cp to drop
in half
1 half-life
2 half-lives
41
No. of half-lives Increment Percent of
maximum 1 50 50 2 25 75 3 12.5 87.5 4 6.
25 93.75 5 3.125 96.875 6 1.5625 98.4375
42
Slope the proportion of drug elimination per
unit time (natural log graph)
K slope of
43
What is Clearance? (Cl)
VOLUME per unit TIME cleared of the drug
units mL/min or L/hr
44
Clearance calculation
  • If the reported Cl is 200 mL/min,
  • What is the Half-life?
  • How much drug is gone after 2 hours?

45
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

46
Now try again
  • Cl is 200 mL/min
  • Drug concentration is 1000 ng/mL

47
Cl x Cp 200 mL/min x 1000 ng/mL 200,000
ng/min 200 mcg/min 0.2
milligrams/minute !
48
What is the relationship between Cl and Vd?
Slope Cl Vd
0.693 Vd
t 1/2
Cl
49
First-order kinetics
a.k.a. concentration-dependent kinetics
Elimination is LINEAR when plotted on semi-log
graph
50
What happens in OD?
  • Saturation of normal routes of elimination ?
    zero-order kinetics

First-order Half-life 1
hour Hours Level 0000 60 0100 30 0200 15 0300
7.5
Zero-order Elim. 30 mg/L/hr Hours Level 0
000 210 0100 180 0200 150 0300 120
51
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52
Nonlinear kinetics
53
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54
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55
Km x dose rate
Css
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?
56
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

57
Clearance can be
  • Metabolic (ClM)
  • Renal (ClR)
  • Lungs (ClL)
  • etc (Cletc)
  • and even hemodialysis (ClHD) and other
    extracorporeal methods
  • Total Cl ClM ClR ClL Cletc ClHD

Intrinsic clearance (by the body)
58
Extracorporeal removal
ARTERY or VEIN
VEIN
Blood from patient
Return to patient
Hemodialysis
59
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

60
Hemodialysis Cl
Cout
Cin
Flow rates 250-350 mL/min (w/catheter) Extracti
on ratio Clearance Flow rate x
Extraction ratio
Cin Cout Cin
61
1000 - 340
Extraction ratio
2/3
1000
ClHD flow rate x ER 300 x 2/3 200 mL/min
62
Whats the half-life on HD?
0.693 Vd
t 1/2
Cl
0.693 x 40 L/kg x 100 kg / 12 L/hr
231 hours !
63
OK, whats really the half-life?
0.693 Vd
t 1/2
Need to use Cltotal not ClHD
Cl
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
64
Continuous Renal Replacement Therapy
(CVVH)
Cp
Cu
(or vein)
Rate of ultrafiltrate production up to 3
L/hr Clearance
x
Cultrafiltrate
Volume/time of ultrafiltrate
(CVVHD)
(or vein)
Cplasma
65
Beckmann U et al JTCT 2001 39393-7
66
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 adds 20-35 mL/min
  • But can be provided continuously
  • Volume cleared 50L/dayvs 36 L/day w/ 4 hours
    of HD
  • No rebound
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