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Mégarbane B, Baud F
| Authors |
Keynote lecture: Poisoning induced coma: Toxicokinetic - toxicodynamic relationships. | Title |
XXII International Congress of the EAPCCT, Lisbon, Portugal, 22-25 May, 2002. Abstract in: J Toxicol Clin Toxicol 2002, 40(3), 256-8
| Source |
| Toxicokinetics, Neurotoxicity
| Index terms |
| Objectives: Pharmacokinetic Pharmacodynamic (PK
PD) relationships describe in the same individual the
quantitative relationships between the drug-induced
effect and the timely corresponding drug concentrations.
The value of PKPD relationships in clinical pharmacology
is now well recognized. Moreover, for a long
time, rough qualitative relationships have been described
between neurological presentation and plasma ethanol
concentration in acute alcohol ingestion or between
coma depth and psychotropic drug concentration in acute
poisonings. However, to date, precise quantitative
Toxicodynamic Toxicokinetic (TKTD) relationships
have not been extensively studied in medical toxicology
and their potential interest is still poorly investigated. In
fact, in toxicology, many difficulties may be encountered
in testing such relationships. The date of the ingestion,
and the exact ingested dose are generally unknown. To
be considered, the observed clinical effect has to be
reversible, strictly related to the toxicant and easily
measurable in clinical practice. Finally, determination of
the toxicant plasma concentrations has to be obtained by
routinely performed assays. In this review, Our aim is to
present the place of TKTD interactions in drug
involved coma.
Methods: We studied TKTD relation-ships
in meprobamate (MB) and phenobarbital (PB)
acute poisonings. Plasma concentrations were measured
using an enzymatic (PB) and a colorimetric assay (MB).
The depth of coma was assessed using the Glasgow
Coma Scale (GCS). Non-linear regression was used for
modeling TKTD relationships. We then discussed the
place of such relationships in the diagnosis, the prognosis
evaluation, the pathophysiology investigation and the
treatment decisions in drug-induced coma.
Results: TKTD relationships were studied in 6 acute PB and 7
acute MB poisonings (Figs. 1 and 2 - omitted in ToxiLit). Two patients
were previously treated with PB and 3 with MB. Mixed
drug poisoning was noted in all MB-poisoned patients
and in 2/6 PB poisoned ones. The GCS at the time of
hospital admission was 3 in the 6 PB poisoned patients
and the mean GCS was 4 ± 1 in the MB-poisoned
patients. The mean plasma PB concentration was
710.5 ± 281.9 mmol/l and MB concentration was
1054 ± 318 mmol/l. The TKTD relationships were
well fitted with the sigmoidal Emax model: the mean Hill
coefficients were 6.0 ± 1.9 and 6.9 ± 4.0 respectively in
PB and MB-poisoning and the mean C50 were
289.7 ± 97.1 mmol/l and 487.9 ± 318.8 mmol/l. A maximal
toxic effect (GCS of 3) was associated with a wide
range of plasma PB or MB concentrations, indicating
clearly the saturation of the drug receptors in these
situations of high doses ingestion. During the course of
poisoning, the relationships between the depth of coma
and the corresponding plasma concentrations were of
sigmoidal shape. The high values of the Hill coefficient
showed that a small decrease in plasma concentrations
near the C50 was associated with a dramatic improvement
in the level of consciousness. Two MB-poisoned patients
exhibited tolerance to the sedative effects of this drug.
In non-tolerant patients, the mean C50 was close to
the upper limit of the therapeutic plasma concentration
of MB given by our toxicological laboratory
(200 mmol/l). In the 6 PB-poisoned patients, the
mean C50 was approximately equal to 3-fold the upper
limit of the therapeutic plasma concentration of PB
(100 mmol/l). These TKTD relationships may help
diagnosis in the toxic coma, dealing with the comparison
of the severity of coma with the plasma concentration
currently used as a surrogate of the ingested dose. It
seems more pertinent to consider not only a single
concentration effect relationship determined on admis-sion,
but also a series of relationships, to take in account
the distribution phase of the toxicant. Analyzing blood
concentrations with respect of the delay elapsed since the
ingestion may also help predicting the time of awakening
and thus the evaluating the prognosis of coma. In PB and
MB poisonings, improvement of the level of conscious-ness
is rapid after a long period of profound coma,
depending on the patient tolerance. Quantifying the
dynamic tolerance in pretreated patients and under
standing the mechanisms contributing to toxicity in
overdoses may be afforded by the consideration of TK
TD relationships. Otherwise, ultimate evaluation of
antidotes modifying toxicokinetics (such as decreasing
the intoxicant bioavailability with activated charcoal or
promoting its elimination with hemodialysis) is based on
modifying toxicodynamic criteria and thus can be more
precisely appreciated with TKTD relationships. These
relationships show clearly that clinical improvement
resulting from a reduction of body burden of toxin
present in the body is dependent on the amount of toxin,
the slope of toxicity and the ratio of the amount of toxin
removed to the dose required to produce a toxic effect.
Conclusion: TKTD relationships describe and
quantify in the same individual the kinetics of
dynamic events. They can be helpful in the assessment
of the diagnosis, the prognosis and the treatment of
drug-induced coma.
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