Clinical Pharmacokinetics 6: 161-192 (1981)

0312-5963/81/0005-0161/$08.00/0
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Pharmacokinetics of Drug Overdose

Jon Rosenberg, Neal L. Benowitz and Susan Pond

Clinical Pharmacology Unit of the Medical Service, San Francisco General Hospital Medical
Center, and Departments of Medicine and Psychiatry, University of California, San Francisco,
California

Summary Pharmacokinetics of drugs taken in overdose may differ from those observed following
therapeutic doses. Differences are due both to dose-dependent changes and to effects of drugs or
pathophysiological consequences of the overdose on kinetics. Dose-dependent changes in rate
and extent of absorption, bioavailability (saturation of first-pass metabolism), distribution
(saturation of protein binding sites) and metabolism are discussed. Gastrointestinal motility is
affected both by specific drug actions, such as delayed gastric emptying by anticholinergic
drugs, and by general nervous system depression caused by many drugs. Drug-induced cir-
culatory insufficiency may retard tissue distribution and reduce clearance. Disturbances in
blood and urine pH may alter distribution and clearance of weak acids and bases. Drug-in-
duced renal or hepatiC failure can significantly decrease clearance. Hypothermia is a common
complication of drug overdose and might retard distribution and also reduce clearance.
The data concerning pharmacokinetics during overdose are usually incomplete and difficult
to interpret. Doses and times of ingestion are uncertain, duration of blood and urine sampling is
often inadequate to distinguish absorption from distribution and elimination phases, active
metabolites are not measured, protein binding is not determined and clinical features of
patients not adequately described. We have, however, reviewed available data for salicylate,
paracetamol (acetaminophen), barbiturates, ethchlorvynol, glutethimide, chloral hydrate, tri-
cyclic antidepressants, lithium, phenytoin, ethanol, theophylline, digoxin, amphetamine and
phencyclidine.

An understanding of the pharmacokinetics of selection of methods to accelerate drug removal or

drugs taken in overdose could contribute to rational
medical management of many patients admitted to
hospitals each year after suicidal or accidental drug
ingestions. For example, blood concentration data
might be used to predict the time course of coma or
other pharmacological or toxic effects. Similarly,
pharmacokinetic data may facilitate evaluation and
allow decisions to treat patients prophylactically for
anticipated toxicity. The published data on phar-
macokinetics after an overdose are often difficult to
interpret for the following reasons: dose and time of
drug ingestion are rarely known reliably; a prolonged
absorption phase and relatively brief period of blood
sampling in most patients make it difficult to dis-
 Pharmacokinetics of Drug Overdose
tinguish continuing absorption from elimination; the
identity, amounts, and concentrations of other drugs
ingested are often not known or stated; and the pre-
sence and potential effects of specific organ toxicities
or disease states and their physiological effects on
pharmacokinetics are commonly not evaluated. These
factors may account for the often poor correlation be-
tween the clinical findings in overdose patients and
the blood concentrations of ingested drugs. Other fac-
tors could also contribute to this poor correlation
such as differences among subjects in their responses
to various drug concentrations in blood or tissue.
However, careful studies of the time course of blood
concentrations of drugs during overdose, identifica-
tion and quantitation of active metabolites, measure-
ment of protein binding, and more careful recording
of clinical findings may allow better correlation of
these findings with pharmacokinetic data.
The pharmacokinetics of most drugs taken in
overdose are often assumed to be similar to those ob-
served after therapeutic doses, but may differ consi-
derably. Evidence that such differences occur and
possible mechanisms for the differences are subjects
of this review. Initial discussion will centre around
the phases of drug absorption, distribution, and
elimination and the ways that these processes may be
altered after drug overdose. The second part of the
review deals with specific drugs for which there are
reasonable data about the pharmacokinetics after an
overdose.
1. Effects of Overdose on Pharmacokinetic
Processes
1.1 Dose-dependent Kinetics
J . J. J Absorption and Bioavailability
The small intestine is the principal site of drug ab-
sorption. In general, the rate of drug absorption de-
pends on the rate of dissolution of the drug and the
rate of gastric emptying, which may determine transit
time into the small intestine (Rowland, 1978). The
eventual amount of drug absorbed depends primarily
162
on drug solubility and the amount of time the drug
remains in the small intestine.
An overdose of a drug commonly delays its ab-
sorption, which may in turn delay the onset or peak
intensity of the drug's action. Mechanisms respons-
ible for delayed drug absorption include formation of
a poorly soluble mass of drug, and a decrease in gas-
trointestinal motility, the latter which will be dis-
cussed later (section 1.2. J). On occasion, bezoar for-
mation has necessitated operative removal of the drug
mass, either because of continuing drug absorption or
because of mechanical obstruction (Schwartz~ i 976).
Theoretically, the percentage of drug reaching the
systemic circulation after an overdose may be greater
than after a therapeutic dose. This may occur because
of saturation of presystemic or first-pass metabolism
of a drug that normally exhibits significant first-pass
metabolism. Such drugs will include many of the nar-
cotic analgesics, tricyclic antidepressants, phenothia-
zines and ~-adrenoceptor antagonists. Even within
the therapeutic dosage range, propranolol (Walle et
aI., 1978) appears to display dose-dependent increases
in bioavailability.
Individual examples in which drug absorption ap-
pears to be altered because of ingestion of an overdose
are discussed in the section on specific drugs. How-
ever, even when reported, data on drug absorption in
overdose patients are difficult to evaluate because of
unreliable histories of the quantities of the drug in-
gested and because of intervening measures such as
emesis, lavage, or administration of charcoal or
cathartics.
J . J.2 Distribution
Drug distribution depends on route of administra-
tion, plasma and tissue protein binding, blood flow,
diffusion rate, and extent of partitioning to tissues
(Rowland, 1978). An alteration in drug distribution
with increasing drug concentration can have impor-
tant implications after an overdose. Even when the
plasma concentration of drug is within the thera-
peutic range, such drugs as salicylate, phenylbutazone
(Aarbakke, 1978), naproxen (Runkel et al., 1976),
and disopyramide (Cunningham et al., 1977) may
 Pharmacokinetics of Drug Overdose
saturate plasma protein binding sites. Therefore, as
blood concentration increases, the fraction of the drug
that is unbound also increases. It is likely, although
not well studied, that these and other drugs, par-
ticularly those that are highly protein-bound, will
similarly saturate plasma protein binding sites and be
proportionately less bound after an overdose. Assum-
ing no change in the drug binding to tissues, the
volume of distribution of a drug then increases.
Because of variability in protein binding among sub-
jects, it may be difficult to relate total blood con-
centration of drug to clinical effects. The concentra-
tion of free drug might be more closely related to
clinical effects.
Estimations of drug clearance based on total blood
or plasma concentration of drug may be complicated
by the presence of concentration-dependent protein
binding. For example, for a drug whose clearance of
unbound drug is constant, a concentration-dependent
decrease in protein binding will result in a relative
decrease in total blood concentration. Therefore,
clearance calculated from total blood concentration of
drug would increase.
In the absence of changes in distribution, changes
in plasma concentration of drug usually reflect
changes in the amount of drug in the body. However,
in the presence of concentration-dependent protein
binding, changes in plasma concentration of drug
may be disproportionate to changes in the amount of
drug in the body, because distribution changes with
concentration. Estimation of drug half-life becomes
less informative in the presence of dose-dependent
protein binding. Half-life depends both on volume of
distribution and clearance, and reported differences in
half-life in overdose patients may reflect an alteration
in one or both of these parameters.
Usually, the rate of diffusion into tissues is rapid
relative to the rates of its absorption and elimination.
Therefore, clinical effects of the drug parallel the rate
at which the drug enters the systemic circulation.
However, diffusion of a drug into tissues may be slow
and result in a significant lag time between peak
blood concentrations of drug and peak clinical mani-
festations. One drug with these characteristics is
163
lithium, which will be discussed in detail later. Also
discussed later will be the effect of haemodynamic,
acid-base, and other pathophysiological phenomena
on distribution of drug into tissues after drug over-
dose.
1.1.3 Elimination
Generally, processes in pharmacokinetics are
assumed to be first-order, so that the rate of elimina-
tion of the drug is directly proportional to the drug
concentration in the plasma. The proportionality fac-
tor for the elimination process is clearance, which is
the parameter that relates the elimination rate to con-
centration of the drug. However, as virtually all drug
metabolism and secretory pathways involve enzyme-
catalysed or carrier-mediated systems, the capacity of
these systems may limit the rate of metabolism or
elimination. This has been shown after usual doses of
ethanol (Lundquist and Wolthers, 1958) and after
therapeutic doses of salicylate (Levy et al., 1972) and
phenytoin (Arnold and Gerber, 1970). If biotransfor-
mation or elimination proceeds via a single pathway,
then the rate of elimination may be described by the
Michaelis-Menten equation (Levy et al., 1972;
Wagner, 1971):
-dC Vm·C
(Eq. 1)
dt Km + C
where - dC/dt is the rate of decline of drug con-
centration, C; V m is the theoretical maximum rate
when the enzyme or carrier is saturated; and Km is
the Michaelis constant. Km reflects the affinity of the
enzyme or carrier protein for the substrate.
For low plasma concentrations (C« Km),
elimination proceeds as a first-order process because
equation 1 reduces to:
-dC Vm·C
(Eq.2)
dt Km
Increasing doses and, thereby, increasing plasma
concentrations of drug, will ultimately lead to a con-
centration-dependent elimination rate. Once C is
 Pharmacokinetics of Drug Overdose 164

much greater than Km, elimination proceeds as a
zero-order process as indicated:
-dC
- - = Vm (Eq. 3)
dt
In this case, elimination occurs at a constant rate
and the elimination is independent of drug concentra-
tion. The time courses of elimination of 3 different
doses of salicylate (fig. 1) illustrate the 3 general
kinetic situations. Elimination of the lowest dose
follows first-order kinetics. Conversely, the highest
dose yields initial concentrations considerably abOVe
Km so that the concentration of drug declines initially
at a constant rate. The time required for the initial
concentration of drug to decrease by 50 % is depen-
dent on concentration and increases as concentration
increases.
Mechanisms of apparent saturation at sites of drug
metabolism or excretion may differ for different
drugs. Possible mechanisms include simple saturation
concentration-dependent kinetics exhibited by these
drugs is that the relative contribution of methods of
extracorporeal drug removal to total body clearance
would increase as the drug concentration increases.
This is so because endogenous drug clearance would
decrease as drug concentration increased. Further-
more, as already mentioned, drug action may be
greatly prolonged because of an associated prolonged
drug 'half-life'. A further implication of concentra-
tion-dependent kinetics would be that the area under
the plasma concentration-time curve after an oral
dose may increase uisproportionately whh increasing
dose. At sufficiently high dosage levels, the area
would be proportional to the square of the dose rather
4000-

I ...·...·....
of the enzyme or carrier, inhibition of enzyme activity 2000L
by the drug, decrease in enzyme affinity or activity
-
due to a metabolic product of the drug, exhaustion of E100000 ' ..
co factors required for enzyme activity, and partial in- E 1 . . .·, .".
activation or destruction of enzyme or carrier. The
latter is illustrated by the self-catalysed destruction by
~
.~
500 -
I .".\ "'-"
., '. - Beginning of
first-order kinetics

drugs of the cytochrome P-450 haem, the terminal

electron acceptor in the hepatic microsomal mono- :1 2°O'?1' 0\ \.. ~,,,
"i • '/ \.

; ':1
oxygenase system (DeMatteis, 1970; Ivanetich et a!., .y

1978). Destruction is probably due to a metabolite

formed from the parent drug by metabolism in the ~~, ~,;~e".,
mono-oxygenase system. Some of the commonly

I- t .b- t~/?l- , t - , - , -~
used barbiturates have been shown to destroy P-450 <t: 20- It)

in this way (Levin et al., 1972). •

The drugs that have actually been demonstrated to ,-,-,
4 8 12 16 20 24 28
exhibit concentration-dependent pharmacokinetics in Time (h)
the overdosed patient include chloral hydrate/
trichloroethanol (Stalker et aI., 1978), ethchlorvynol
(Benowitz et aI., 1980), some barbiturates (Forrest et Fig. 1. Dose-dependency of salicylate elimination kinetics
a!., 1974; Prescott et al., 1973), theophylline (Kadlec in 1 subject.
Amount unexcreted estimated from initial dose minus
et aI., 1978), paracetamol/acetaminophen (Slattery
cumulative urinary excretion of salicylate and metabolites.
and Levy, 1979), and perhaps glutethimide (Maher, Vertical arrows indicate time after excretion at which 50% of
1970). These drugs are discussed in more detail in dose has been eliminated (from Levy: J. Pharm. Sci. 54: 959,
later sections of this review. One implication of the 1965; reproduced by permission of author and editor).
 Pharmacokinetics of Drug Overdose
than to the dose itself (Gibaldi and Perrier, 1975).
Furthermore, the area under the curve after ad-
ministration of a fixed dose of the drug showing con-
centration-dependent elimination may also vary with
the rate of absorption. The area under the plasma
concentration-time curve would be in this case larger
the more rapidly the dose is absorbed.
Finally, under certain circumstances, drug elim-
ination may appear to be first-order but drug half-life
may increase with increasing dose. This may occur
either because of drug elimination by parallel
capacity-limited and first-order processes, or because
of inhibition of metabolism of the parent drug by a
product (Gibaldi and Perrier, 1975).
1.2 Pathophysiology of Drug Overdose
1.2.1 Gastrointestinal Motility
Many drugs taken in overdose decrease gastroin-
testinal motility (Nimmo, 1976). The list includes
drugs with specific anticholinergic activity, those that
directly affect gastrointestinal smooth muscle, and
those that generally depress autonomic nervous
system activity. Conversely, the organophosphate in-
secticides and drugs used to treat myasthenia gravis
that inhibit acetylcholinesterase may result in
enhanced gastrointestinal motility.
A decrease in gastrointestinal motility may both
decrease the rate and increase the amount of drug ab-
sorbed, or lead to prolonged, erratic, and delayed ab-
sorption. If a drug is poorly water-soluble, a decrease
in gastrointestinal motility may increase the eventual
amount of drug absorbed because of the length of
time that the drug has to dissolve. Rate of dissolution
is often the limiting factor in drug absorption,
especially of poorly water-soluble drugs such as
digoxin and phenytoin. It is not surprising, therefore,
that many patients continue to manifest drug toxicity
many days after a single ingestion of a drug,
presumably because of persistence of the drug in the
small intestine with continuing absorption. Thus, the
use of lavage and administration of activated charcoal
may be indicated for as long as 12 to 24 hours after
165
an overdose. Furthermore, although not definitely
proven to be effective in drug overdose, cathartics,
because of their effect in increasing gastrointestinal
motility, could decrease absorption of poorly soluble
drugs. Finally, one drug may alter the absorption of
another, and toxicity of a drug taken in a mixed over-
dose might thus be altered by the second drug. For ex-
ample, after therapeutic doses of propoxyphene, the
absorption of concurrently ingested paracetamol
(acetaminophen) is slowed (Nimmo et a1., 1979). Pro-
bably propoxyphene delays gastric emptying and
hence delivery of paracetamol to the small intestine.
Theoretically, decreasing the rate of absorption of
paracetamol may mitigate against some of the
hepatotoxic effects of the paracetamol that are related
in part to the rate of generation of a toxic metabolite.
1.2.2 Cardiovascular and Pulmonary Function
Drug overdose is often complicated by com-
promised cardiovascular and pulmonary function
that can in turn influence drug kinetics (Benowitz and
Meister, 1976; Benowitz et al., 1979). Most com-
monly, overdose patients develop hypotension due to
a decrease in cardiac output and/ or vascular resis-
tance. After a severe overdose of drugs such as tri-
cyclic antidepressants, frank cardiogenic Shock may
develop. However, drug overdosed patients may not
exhibit the increased activity of the sympathetic ner-
vous system which usually occurs in patients with
hypotension due to primary myocardial depression.
Rather, the drugs may suppress sympathetic nervous
system activity which in part accounts for the
decreased vascular resistance that accompanies many
drug overdoses. Occasionally, anticholinergic or sym-
pathomimetic drug overdose may lead to hyperten-
sion with or without increased cardiac output.
Furthermore, noncardiogenic pulmonary oedema fre-
quently accompanies severe drug overdose, such as
with narcotics and salicylates. The oedema may
worsen hypoxaemia and acidosis and add to the
drug's depressant effect on the cardiovascular system.
Each of these pathophysiological changes may
alter pharmacokinetics. However, often the precise
effects cannot be examined easily in overdose patients
 Pharmacokinetics of Drug Overdose
because of the rapidly changing clinical status.
Therefore, we might consider the effects of more
stable altered haemodynamic states, such as cardiac
failure, on pharmacokinetics (Benowitz and Meister,
1976). Cardiac failure substantially decreases the
volume of distribution and clearance of some drugs.
A decrease in cardiac output decreases perfusion of
organs, such as skeletal muscle, that show major up-
take of drugs. Conversely, autonomic reflex adjust-
ments direct a greater fraction of cardiac output and
hence drug to critical organs such as brain and heart.
Reduced hepatic and renal blood flow and! Oi tiSSUe
hypoxia also decrease hepatic and renal drug
clearance. Thus, in the overdose patient with a low
cardiac output, we would predict that blood con-
centrations would be higher and more persistent than
expected from the dose, due both to diminished tissue
distribution and drug clearance.
1.2.3 Acid-base Disturbances
Alterations in acid-base balance, whether drug-in-
duced or not, may alter drug pharmacokinetics and
toxicity. For example, blood pH may alter distribu-
tion of drug into organs such as the brain, as illus-
trated by salicylate. A small decrease in blood pH
below 7.4 can result in a large increase in the propor-
tion of salicylate that is non-ionised and available to
diffuse into the brain. Both in salicylate-intoxicated
animals (Hill, 1973) and in patients (Gabow et aI.,
1978), salicylate toxicity correlates with extent of
acidaemia. Waddell and Butler (\957) demonstrated
in dogs that lowering blood pH increased brain levels
and anaesthetic effects of phenobarbitone. Acid-base
status has also been reported to affect the course of
tricyclic antidepressant overdose (Brown, I 976a). In
experimental animals and in tricyclic antidepressant
drug-overdosed patients, cardiac arrhythmias have
been reported to be reduced by administration of
alkali to maintain blood pH equal to or greater than
7.4 (Brown, I 976a,b). Some investigators recom-
mend infusion of sodium bicarbonate until patients
become alkalaemic up to a pH of 7.5. However, why
an alkaline pH should mitigate against the toxicity of
tricyclic antidepressants is unclear. The mechanism
166
may not be based on the effect of alkalaemia on the
partitioning of drug between drug and the myocar-
dium.
Alteration of urinary pH by a pathophysiological
process or by therapeutic intervention may alter renal
clearance of some drugs. If renal clearance can be in-
creased to a sufficient fraction of total body clearance
to alter pharmacokinetics, then an alteration of urin-
ary pH can be used as a therapeutic intervention to
hasten drug elimination after an overdose. The renal
clearance of saJicylate is increased in an alkaline
urine. and in uverdused patient" the eiirnination ha!f-
life can be shortened significantly (Morgan and Polak,
197 \). Similarly, alkalinisation of the urine increases
the renal clearance of phenobarbitone significantly
(Waddell and Butler, 1957; Hadden et ai., 1969). The
renal elimination of the basic drug amphetamine IS
sensitive to changes in urinary pH. Clearance in-
creases and plasma half-life decreases with urine
acidification (Davis et ai., 197 \). Patients with
amphetamine psychosis treated by acidifying the
urine had shorter half-lives of amphetamine and
shorter duration of symptoms than those treated with
alkalinising the urine (Anggard et aI., 1973). In con-
trast, the contribution of renal clearance to the total
body clearance of phencyclidine is unknown, and the
role of urinary acidification as proposed by Aronow
et al. (I 978) for the treatment of patients overdosed
with phencyclidine is uncertain.
1.2.4 Renal Function
Although a significant percentage of cases of acute
renal failure is reported to be caused by nephrotoxins
(Maher, 1976), drug overdose per se is not often com-
plicated by acute renal failure. The substances most
often implicated are drugs with nephrotoxicity at ap-
proximately therapeutic levels (e.g. antibiotics such as
aminoglycosides) or unusual poisons (e.g. ethylene
glycol, carbon tetrachloride, inorganic mercury,
Amanita phalloides mushroom). Renal failure may be
induced through a variety of mechanisms, which we
will review briefly. Pharmacokinetics in renal disease
were recently reviewed by Levy (I977) and in this
journal by Fabre and colleagues (Fabre and Balant,
 Pharmacokinetics of Drug Overdose
1976; Fabre et a!., 1980) and will not be discussed
here.
Drugs producing acute proximal tubular necrosis
include antibiotics, particularly aminoglycosides,
halogenated hydrocarbon solvents such as carbon
tetrachloride and tetrachloroethylene, metals includ-
ing mercury, arsenic and iron, mushrooms and
various snake venoms (Maher, 1976). Paracetamol
overdose may result in acute hepatic necrosis as well
as acute renal failure, but the former usually pre-
dominates (Rumack and Matthew, 1975).
The deposition of crystals may lead to intrarenal
tubular obstruction and tubular necrosis. Most
patients surviving the acute toxicity of ethylene glycol
poisoning develop renal failure typical of acute tubu-
lar necrosis (Parry and Wallach, 1974). It has been
assumed that oxalate crystal deposition in the renal
tubules causes acute tubular necrosis, although this
has been questioned recently. Ethylene glycol itself is
relatively non-toxic, so it appears that metabolism is
necessary for nephrotoxicity. The first step in its
metabolism to oxalate is mediated by alcohol de-
hydrogenase. Administration of ethanol, which com-
petes for this enzyme, decreases the rate of metabolite
production and may be of value in prevention of acute
tubular necrosis (Parry and Wallach, 1974). Ethanol
should be started within 4 to 6 hours of ingestion,
because ethylene glycol is metabolised rapidly and has
a short half-life (3 hours in non-human primates [Par-
ry and Wallach, 1974]).
A number of drugs are associated with rhab-
domyolysis, myoglobinuria, and acute renal failure.
These include stimulant drugs such as amphetamines
or phencyclidine, narcotics, sedatives, and drugs that
produce seizures such as tricyclic antidepressants
(Cogen et a!., 1978; Eneas et a!., 1979; Komer et aI.,
1976). Treatment of myoglobinuria should be a con-
sideration in the treatment of overdose with these
drugs. The necrotising angiitis reported to be associ-
ated with intravenous stimulant abuse may also cause
acute renal failure (Citron et a!., 1970). Although
rhabdomyolysis and acute renal failure have been
reported occasionally in heroin users, a chronic
sclerosing glomerulonephritis is the more common
167
renal complication in these patients (Cunningham et
a!., 1980). Snake and spider venoms can produce
renal failure because of haemolysis, haemoglobinuria,
and shock (Russell et aI., 1975).
Although abrupt decreases in renal function have
been associated with the administration of aspirin and
other prostaglandin inhibitors (Kimberly et a!.,
1978), acute renal failure is uncommon in patients
with salicylate overdose. However, evidence of neph-
rotoxicity such as celluria and proteinuria is usually
observed (Temple, 1978).
Accidental or suicidal ingestion of inorganic mer-
curic salts frequently causes acute renal failure due to
proximal tubular necrosis (Maher, 1976). Renal func-
tion is particularly important with respect to treat-
ment of mercury poisoning because the chelating an-
tidote, dimercaprol (BAL), is eliminated by the kidney
and may accumulate with renal failure. Accumula-
tion of BAL or the mercury-BAL complex may be
nephrotoxic as well (Maher, 1976). Renal insufficien-
cy was a common complication of lithium overdose
in one series of patients (Schou et ai., 1968), as dis-
cussed in section 2.5, although acute renal failure se-
condary to lithium intoxication has been infrequently
reported (Lavender et aI., 1973). Because the
clearance of lithium is primarily renal, renal failure
may alter the course of lithium intoxication.
1.2.5 Hepatic Function
Single doses of a few drugs or toxins may lead to
acute hepatic necrosis. Important examples include
paracetamol (Proudfoot and Wright, 1970), iron
(Gleason et a!., 1979) and Amanita phal/oides
mushrooms (Becker et a!., 1976). The presence of
acute or pre-existing chronic liver disease in an over-
dosed patient has obvious pharmacokinetic implica-
tions for many drugs. However, precise details of the
alterations in pharmacokinetics by liver disease will
not be discussed here because of the many reviews
and reports already available (Schenker et a!., 1975;
Blaschke, 1977). In contrast, chronic ingestion of
drugs such as barbiturates or phenytoin may enhance
the metabolism of other drugs by the hepatic micro-
somal mono-oxygenase system. Enhanced metabol-
 Pharmacokinetics of Drug Overdose
ism of a second drug may be important if the drug is
metabolised to toxic intermediates. An example
would be the combination of hepatic microsomal
enzyme-inducing drugs and paracetamol. In animals,
phenobarbitone increases the production of the toxic
metabolite of paracetamol and hence hepatic necrosis
(Mitchell et aI., 1973). A retrospective study of
patients with paracetamol overdose suggested greater
susceptibility to the hepatotoxic effects of paracetamol
in patients taking anticonvulsant medication (Wright
and Prescott, 1973).
Apart from direct hep~Tic injury or lIiterlltion of
drug-metabolising enzymes, drug pharmacokinetics
may be altered by a reduction in hepatic blood flow.
Most often, hepatic blood flow will be reduced
because of the hypotension associated with many
drug overdoses. In turn, reduced hepatic blood flow
may decrease systemic clearance and presystemic
elimination of drugs that undergo extensive first-pass
biotransformation in the liver. Thus, the bio-
availability of these drugs may be greater than antici-
pated leading to higher blood concentrations of drug
than expected. Drugs that may exhibit this type of
pharmacokinetic behaviour include lignocaine (lido-
caine), some ~-adrenoceptor antagonists, opiate anal-
gesics, and the tricyclic antidepressants. The relation-
ships between drug kinetics and hepatic blood flow
have been reviewed recently by George (1979) and
the pharmacokinetics of drugs in abnormal haemo-
dynamic states by Benowitz and Meister (1976).
J.2.6 Hypothermia
Hypothermia, or a body temperature below 35°C,
is a common complication of drug overdose. Mechan-
isms include decreased heat production, increased
heat loss, and exposure to low temperature (Popovic
and Popovic, 1974). Sedative-hypnotic and narcotic
drugs may decrease metabolic rate. Hypothermia
after overdose with these drugs reflects diminished
heat production. These drugs also increase heat loss
by inhibiting shivering. Even in therapeutic doses,
phenothiazines produce poikilothermia, which,
coupled with exposure to a cool environment, may
result in hypothermia. Drugs can also produce hy-
168
pothermia by causing peripheral vasodilatation, a
phenomenon observed after most types of sedative-
hypnotic overdose and after ingestion of sym-
patholytic and cholinomimetic drugs.
Hypothermia could alter drug disposition. Blood
flow to and motility of the gastrointestinal tract are
reduced by hypothermia, but effects on drug absorp-
tion have not been studied. Hypothermia is associated
with haemodynamic changes that could affect drug
distribution. Most studies have been performed dur-
ing external cooling or hypothermic cardiopulmonary
bypass and not dmine drl1e-indl1ce(i hypothermia.
These two types of hypothermia may lead to signifi-
cantly different haemodynamic changes, particularly
in regard to sympathetic nervous system activity. For
example, immersion of human volunteers in water at
10°C is associated with an approximately 3-fold in-
crease in plasma noradrenaline (norepinephrine) con-
centration and a similar increase in metabolic rate
(Johnson et aI., 1977). In contrast, an overdose of
sedative-hypnotic or narcotic drugs decreases meta-
bolic rate and probably does not increase peripheral
vascular resistance to the same extent as external
cooling (Shubin and Weil, 1965).
In various animal studies, external cooling
resulted in increased total peripheral resistance and
decreased regional blood flow, in particular to brain
and kidney (Black et aI., 1976; Popovic and Popovic,
1974). Heart rate and cardiac output decreased in pro-
portion to the decrease in myocardial oxygen con-
sumption. There are few studies of drug distribution
during hypothermia. McAllister et al. (1979) com-
pared the kinetics of propranolol in anaesthetised
dogs maintained at 37°C to those maintained at 26°C
using a cold water bath. The apparent volume of dis-
tribution (Vd~) was reduced by more than 3-fold by
hypothermia, presumably as a result of peripheral
vasoconstriction. In an accompanying study of
patients on chronic oral propranolol therapy undergo-
ing coronary artery bypass surgery using hypother-
mic cardiopulmonary bypass, plasma propranolol
concentrations, corrected for haemodilution, rose
slightly during hypothermia. The investigators at-
tributed this change to a decrease in volume of dis-
 Pharmacokinetics of Drug Overdose
tribution, but because plasma volume was not
measured after cooling, the validity of the haemodilu-
tion correction is open to quest~on. Nurmand et al.
(\965) reported decreased distribution of thiopentone
(thiopental), but not amylobarbitone (amobarbital),
into fatty tissue during hypothermia and unchanged
distribution of both drugs into other organs.
Hypothermia may decrease the clearance of drugs,
particularly by liver metabolism, as blood flow to the
liver is decreased as cardiac output decreases.
Furthermore, intrahepatic distribution of blood may
also be altered, and the metabolic rate of hepatic cells,
as reflected by oxygen uptake, diminished by hy-
pothermia (Krarup and Larsen, 1972). The rates of
metabolism of many drugs by hepatic microsomes
are slowed as temperatures are decreased below 37°C
(Fuhrman et aI., 1944; Kaiser et aI., 1968; McAllister
et aI., 1978; Rink et aI., 1956). Studies in vivo
demonstrated that the clearance of propranolol in
dogs cooled to 26°C is reduced to 50 % of that at
37°C. Similarly, a fall in body temperature of I to
2°C in cats is associated with a 26 % decrease in rate
of elimination of ethanol (Krarup and Larsen, 1972).
Renal drug clearance may be altered by hypother-
mia. The activity of energy requiring metabolic pro-
cesses such as active tubular reabsorption and secre-
tion may be reduced (Black et aI., 1976; Popovic and
Popovic, 1974). Renal blood flow and glomerular
filtration rate decrease as cardiac output decreases.
Thus, clearance of drugs that are filtered or secreted
may decrease. In contrast, clearance of drugs that are
actively reabsorbed may increase. However, we know
of no studies of the effects of hypothermia on drug
elimination by the kidney.
A number of investigators have reported altered
effects of drugs during hypothermia but have not
measured the concentrations of the drugs. For exam-
ple, hypothermia prolonged the sleeping time of mice
after anaesthetic doses of pentobarbitone (Fuhrman,
1946). In hypothermic dogs, the pressor responses to
adrenaline (epinephrine), noradrenaline (norepineph-
rine) and angiotensin were delayed in onset,
diminished in magnitude, but prolonged in duration
(Rubenstein, 1961). Hypothermia decreased the
169
effects of digoxin on the heart; the amount of digoxin
necessary to produce ventricular fibrillation in hy-
pothermic dogs (24 to 28°C) was twice that in nor-
mothermic dogs (Beyda et aI., 1961). It is of interest
that digitalis drugs may reverse the effects of hy-
pothermia on cardiac conduction (Nahum and
Phillips, 1959). The magnitude and duration of action
of suxamethonium (succinylcholine) increased in cats
whose body temperatures were lowered from 36 to
30°C (Wislicki, 1960). This may be due at least in
part to a decrease in the rate of hydrolysis of suxa-
methonium by plasma cholinesterase.
In summary, hypothermia may result in altera-
tions of the disposition and pharmacodynamics of
drugs, either taken in overdose or administered in
therapeutic doses to hypothermic patients. These po-
tential alterations should be considered in the treat-
ment of these patients.
2. Pharmacokinetics of Specffic Drugs
During Overdose
2.1 Salicylate
Salicylate overdose was one of the first and best
characterised examples of the clinical application of
pharmacokinetics to the diagnosis and treatment of
drug overdose. A concise review of the pharmaco-
kinetics of salicylate was published recently (Levy,
1978). Salicylate disposition is dependent on the con-
centration of salicylate in the blood and on urine pH,
with large intersubject variability.
Absorption of salicylates in therapeutic doses is
usually rapid and complete in less than I hour. Large
single doses of aspirin may delay gastric emptying
and dissolution of drug by irritating the gastric
mucosa, resulting in rising salicylate concentrations
for as long as 24 hours after ingestion (Levy, 1978).
Hydrolysis of acetylsalicylic acid in the plasma to
salicylate is rapid with a plasma half-life of IS to 20
minutes (Rowland et aI., 1972).
Protein binding of salicylate is dose-dependent. At
low plasma concentrations (e.g. below 80)Jg/ml) in
 Pharmacokinetics of Drug Overdose 170

normal subjects, approximately 94 % of salicylate is The tissue distribution of salicylate is also pH de-
bound to albumin (Borga et al., 1976). Protein bind- pendent. Salicylic acid has a pKa of approximately
ing decreases with increasing plasma concentration of 3.0. Because only a small percentage (0.004%) of
salicylate, decreasing plasma concentration of salicylate is not ionised at pH 7.4, small changes in
albumin, and uraemia (Borg a et al., 1976; Ekstrand pH result in large changes in the proportion of drug
et al., 1979; Lowenthal et al., 1974; Yacobi and Levy, that is not ionised and enters tissue. The correlation
1977). There is also large intersubject variability, between arterial bicarbonate and partition of salicyl-
some of which may be genetically determined. Figure ate into the cerebrospinal fluid of infants with salicyl-
2 shows estimations of the increasing volume of dis- ate intoxication is shown in figure 3. Hill (I 973)
tribution with increasing dose in patients with sali- demonstrated the increase in toxicity of salicylate
cylate overdose. As protein binding decreases, sali- with acidaemia and the protective effect of
cyiate distrihution io the hrain, a key target organ in aikaiaemia. The ciinicai significance and TherapeUTic
salicylate toxicity (Hil~, 1973), probably increases. implications of salicylate overdose kinetics were re-
cently reviewed by Temple (J 978) and Done (J 978).
Both respiratory alkalosis and metabolic acidosis are
complications of salicylate overdose. Evaluation of
patients requires knowledge of both concentrations of
salicylate in plasma and arterial pH. Patients with
0.4 alkalaemia often do well with supportive care,
whereas patients with acidaemia should be treated
]>
.-
13
with bicarbonate or, if necessary, haemodialysis .
---
...J •
12
Gabow et al. (I978) recently observed a correlation
';;' 0.3 between incidence of acidaemia and presence of
o
·s.0 neurological symptoms in salicylate intoxicated
·c
1ii adults.
iJ
'0 The elimination of salicylate also varies with dose
~ 0.2 and urinary pH. The dose-dependency of the 2 quan-
:::J
'0
>
titatively most important metabolic pathways has
1: been demonstrated at therapeutic concentrations of
~
~ salicylate. The renal clearance of salicylate is depen-
~0.1 dent on urinary pH. With increasing blood con-
centrations of salicylate, the elimination of salicylate
by the kidney assumes increasing importance. Altera-
tion of urinary pH with antacid therapy has been
100 200 300 shown to alter salicylate levels significantly in
Dose (as salicylic acid) [mg /kg} patients taking antirheumatic doses of aspirin (Levy
and Leonards, 1971; Levy et aI., 1975). The renal ex-
cretion of salicylate is quantitatively more important
Fig. 2. Increasing volume of distribution with increasing after an overdose than after therapeutic doses.
salicylate dose. Alkalinisation of the urine is usually recommended in
• - Accidental intoxication (arrow indicating under-estima-
salicylate overdosed patients (Done, 1978; Temple,
tion of dose due to delay in urine collection); • - chronic in-
toxication; 0 - healthy adult male (from Levy and Yaffe: Ped.
1978). Various treatment regimens have been studied
54: 7813, 1974; reproduced by permission of author and edi- by Lawson et al. (1969) and Morgan and Polak
tor). (J 97 1). In the latter study, there was a 4-fold increase
 Pharmacokinetics of Drug Overdose 171

2.2 Paracetamol (acetaminophen)

15 The popularity of paracetamol has increased

• rapidly over the past 20 years. Overdosage of the

--
::; drug is now well documented and has caused many
C"
LU deaths. The predominant complication of overdosage
S is hepatic necrosis and failure, although renal, pan-
~.,<: 10
•• creatic, and cardiac complications also may be ob-
0
.0
lii • • served (Prescott and Wright, 1973; Proudfoot and
u
:c Wright, 1970; Rumack and Matthew, 1975;
(ij
:::l
• Williams and Davis, 1977).
t)
« 5 •• r = +0.90
intercept = 1.26
Paracetamol is absorbed rapidly after therapeutic
slope = 2.84 doses but may be absorbed more slowly as the dose
•
• increases. Rawlins and coworkers (1977) demon-
strated that plasma concentrations of paracetamol
reach a maximum at 0.5 to I hour after dosing with
2 3 4 5 500mg and 1000mg, respectively, but continue to
Serum/CSF salicylate ratio rise for 2 hours after a 2000mg dose. Oral
bioavailability was incomplete at all dose levels,
presumably due to first-pass metabolism, and was
Fig. 3. Influence of acid-base status (expressed as actual significantly less after 500mg (63 %) than after
serum bicarbonate concentration) on entry of salicylate into I OOOmg (89 %) or 2000mg (87 %). Precise estimates
the CNS (expressed as serum to CSF salicylate concentration
of the percentage of dose absorbed after an overdose
ratio) in 10 infants with salicylate overdose (from Buchanan
and Rabinowitz: J. Ped. 84: 391, 1974; reproduced by permis-
of paracetamol are not available because of the
sion of author and editor). unreliable histories of the amount of drug ingested by
overdosed patients and because of either spontaneous
or induced vomiting after the drug has been taken.
in renal clearance of salicylate for each rise of I unit Despite this, indirect estimates of the dose of
in urine pH. Thus, renal clearance of salicylate in- paracetamol ingested indicate that the mean dose ab-
creased from 16 to 64ml! min as urine pH increased sorbed is higher in patients with liver damage than in
from 6.5 to 7.5. The renal clearance of salicylate also those without, although individual susceptibility to
increased with increasing urine flow, an effect that liver damage varies widely (Prescott and Wright,
diminished as urine pH rose (Morgan and Polak, 1973). As little as 6.2g produced a severe hepatic
197 J). lesion in I patient, whereas 15.3g did not produce
Because of saturable metabolism and increasing liver damage in another.
volume of distribution, the apparent plasma half-life The probable mechanism of paracetamol hepato-
of salicylate increases with increasing dosage. The toxicity has been elucidated primarily by Mitchell and
time for plasma concentrations of salicylate to coworkers (1974). A small fraction of paracetamol is
decrease by one-half averages 2.5 hours after 0.3g, in- metabolised by hepatic microsomal enzymes to N-hy-
creases to 5 to 7 hours after I g, and may be as long as droxyparacetamol. This, in turn, is converted to a
24 hours after an overdose. Because renal clearance of reactive metabolite, which is primarily conjugated to
salicylate is a major determinant of elimination in the glutathione and excreted as mercapturic acid. How-
overdosed patient, the half-life will vary with the ever, the reactive metabolite can also bind covalently
urine pH (fig. 4). to liver cell proteins if hepatic levels of glutathione
 Pharmacokinetics of Drug Overdose 172

x
28

24

20

16
£
~ t2 l- ..........
I
:t::
~
III ~.
lii
Q)
8 x ~
>- I •
<> • I
~
(/) 4 ••
•
6.0 6.5 7.0 7.5 8.0
Urine pH

Fig. 4. Influence of urine pH on salicylate half-life during mannitol-lactate (x) and acetazolamide-bicarbonate (.) treatment
(from Morgan and Polak: elin. Sci. 41: 475, 1971; reproduced by permission of author and editor).

have been depleted to 30 % or less of normal values
(Mitchell et aI., 1973). The binding to liver cell pro-
teins causes the hepatic damage. Individual suscep-
tibility to paracetamol hepatotoxicity probably relates
in part to the amount of reactive metabolites gener-
ated, which in turn may depend on the state of
enzyme induction in the individual (for example, by
alcohol, sedatives, or anticonvulsants). Protein mal-
nutrition may deplete hepatic levels of glutathione
and thus also increase susceptibility to liver cell
necrosis.
The metabolic profile and disposition kinetics of
paracetamol are dose-dependent (Davis et aI., I 976;
Slattery and Levy, 1979). The compound is elimi-
nated from the body primarily by formation of
glucuronide and sulphate conjugates, both of which
are saturable biotransformation pathways. A small
fraction ofthe drug is excreted unchanged in the urine
and, as mentioned, a small fraction is metabolised to
N-hydroxyparacetamol. The elimination half-life of
paracetamol is prolonged in overdosed patients, par-
ticularly when it is associated with hepatic injury
(fig. 5). Prescott et al. (J 97 1) measured plasma con-
centrations of paracetamol at 2 points in time, 8
hours apart, in patients who did and did not develop
liver damage, as well as in normal subjects after
therapeutic doses. The plasma concentrations at 4 and
12 hours were higher in patients with liver damage
than in those without. Furthermore, the plasma
paracetamol half-life in the 17 patients with liver
damage was more than twice as long 0.6 ± 0.8
hours) than in the 13 patients without liver damage
(2.9 ± 0.3 hours) and more than 3 times as long as
the half-life in 17 normal subjects (2.0 ± 0.1 hours).
The prolonged half-life could reflect effects of early
hepatic injury and, in fact, has been suggested to be a
predictor of the development of clinical liver damage.
However, enzyme saturation or limited availability of
 Pharmacokinetics of Drug Overdose 173

glucuronic acid or sulphate could also explain the
prolonged half-life at high paracetamol concentra-
tions. N-Acetylcysteine has been used successfully in
preventing or decreasing hepatic damage and increas-
ing survival after paracetamol poisoning (Prescott et
a\., 1977). This drug may act as a scavenger for the
hepatotoxic metabolite of paracetamol, thus prevent-
ing binding of the metabolite to liver proteins
(Rumack and Peterson, 1978). In addition, N-acetyl-
cysteine could increase the capacity of the sulphate
conjugation pathway by acting as a sulphate source
(Slattery and Levy, 1979).
2.3 Sedative-Hypnotics
2.3.1 Barbiturates
Despite the extensive literature available on bar-
biturates, surprisingly little has been published on the
pharmacokinetic behaviour of these drugs in over-
dosed patients. This may be because of poor correla-
tion between blood concentration and pharmacologi-
cal effects and the now recognised inappropriateness
of tabulating 'toxic' and 'lethal' plasma or blood con-
centrations of drugs. These tabulations are grossly in-
accurate because of the problems, particularly after
ingestion of large single doses, of delayed onset of
pharmacological effects, complex concentration-effect
relationships, and tolerance (Prescott et aI., 1973).
However, some generalisations about the phar-
macokinetics of barbiturates can be made (Breimer,
1974; Harvey, 1975) and may help in the treatment
of barbiturate overdose.
The historical classification of the barbiturates into
long, intermediate, short, and ultrashort acting
categories is based upon the duration of action of a
single dose of each barbiturate in rabbits. However,
the duration of action is determined by dose, rate of
distribution, and elimination, and does not neces-
sarily correlate with terminal elimination phase half-

1000
- - Uver damage
- - - - No liver damage
300

15
E
a;'"
<J 30
~
"'-
~E
E~ 10
"'-
'" ::L
e.g
al"~
Cl~ 3
i~
-5 8
:58 32 36
4 8 12 16 20 24 28
Hours after overdose

Fig. 5. Paracetamol elimination in patients with and without liver damage (from Prescott et al.: Lancet 1; 519. 1971;
reproduced by permission of author and editor).
 Pharmacokinetics of Drug Overdose 174

life. For example, the average half-life of drugs

classified as intermediate acting barbiturates varies
from 3 to 7 hours for hexabarbitone to 34 to 42
hours for butobarbitone. The onset and termination 40
of drug effect are determined by the physicochemical
properties of barbiturates that affect both distribution
and elimination. There are major differences in these
properties between the short and long acting barbitur- 30

ates. The short acting barbiturates are lipid-soluble

and rapidly achieve high levels in the brain. Thus, the
onset of action is within minutes and this fact makes c
'E 20
-.&_-.. .
thionpntonp"- l1<:pflli "n"p<:thpti(' ""pnt Rprli<:trihlltion 1::::-
..s
~&&&~t'_&.~~&.- -~-.-. ~.&_~.- -o-·-~· -----~.--- ---~--
/

of thiopentone from the central nervous system to a>

0
other parts of the body is primarily responsible for <:
e
the termination of its anaesthetic effect. The slower '"
Q)
U 10
rate of elimination probably determines the duration
of residual pharmacological action. The longer acting
barbiturates are less lipid-soluble, may take longer to
produce their effect, and depend more on drug
elimination than redistribution for termination of 2 4 6
effect. Urine flow (ml/min)

In addition to their higher lipid solubility, the

shorter acting barbiturates are more highly protein-
bound (35 to 65 %) than their longer acting counter-
parts (Harvey, 1975). They are eliminated primarily
by hepatic metabolism and most of the metabolites
are inactive. Little unchanged drug appears in the
urine. These weak acids are mostly non-ionised at
physiological urine pH and are reabsorbed by the
renal tubule. Renal excretion may be increased
slightly, although insignificantly, by forced diuresis
and is not affected by alkalinisation of the urine (Had-
den et al., 1969). Long acting barbiturates, such as
phenobarbitone, are less protein-bound and have
lower pKas than the shorter acting drugs. Their lower
lipid solubility is associated with a smaller volume of
distribution. They are metabolised more slowly by
the liver and a greater fraction of unchanged drug is
excreted by the kidney. At least for phenobarbitone,
forced diuresis and alkalinisation of the urine increase
renal clearance. The contributions of urine pH and
flow to renal clearance of phenobarbitone are
demonstrated in figure 6. In overdosed patients,
forced alkaline diuresis may increase the renal
Fig. 6. Influence of urine flow and pH on phenobarbitone
renal clearance in dogs.
Ll - urine pH 7.8-8.0; 0 - urine pH below 7.0. Diuresis
was induced by oral water, intravenous mercaptomerin or in-
travenous sodium sulphate itrom Waddell and Butler: J. Clin.
Invest. 36: 1217, 1957, reproduced by permission of author
and editor).
clearance of phenobarbitone to values as high as
l7ml/ min (Hadden et al., 1969). This adds signifi-
cantly to the usual renal clearance of phenobarbitone
which is approximately I to 3ml/ min under physio-
logical conditions of urinary flow and pH. However,
forced diuresis incurs the risk of pulmonary oedema
(Goodman et al., 1976).
After therapeutic doses, most of a barbiturate dose
is absorbed within an hour; therefore, drug removal
by emesis or lavage should be attempted early. How-
ever, because delayed gastric emptying may lead to
protracted absorption, gastric lavage and administra-
tion of charcoal should still be given to patients who
have ingested barbiturates 4 to 8 hours earlier.
 Pharmacokinetics of Drug Overdose
Some data are available on barbiturate elimination
and half-life after drug overdose. The terminal half-
life of many of the intermediate acting barbiturates in
overdosed patients is shorter than the half-lives
measured in normal persons after therapeutic doses
(Prescott et aI., 1973). Furthermore, Martin et al.
(J 979) found that the mean serum half-life of
phenobarbitone in chronic sedative-hypnotic abusers
is 57.5 ± 4.9 hours versus 86.3 hours in normal
volunteers. Prescott and coworkers (J 973) and For-
rest et al. (J 974) also demonstrated that in some over-
dosed patients the rate of elimination of the ingested
barbiturate increased as the plasma concentration of
drug decreased. They proposed that acute barbiturate
ingestion induces microsomal enzyme activity, lead-
ing to an increased rate of barbiturate elimination. An
alternative explanation for these observations could
be that high levels of barbiturates exhibit capacity-
limited kinetics (Sumner et aI., 1975). It has also been
suggested that high concentrations of barbiturates
result in destruction of cytochrome P-450 haem
(Levin et al., 1972), as discussed previously (section
1.1.3 ).
There is recent evidence that phenobarbitone un-
dergoes enterohepatic or enteroenteric recirculation,
and that this cycle can be interrupted by administra-
tion of large multiple doses of activated charcoal.
Neuvonen and coworkers (J 980) administered char-
coal, I I 8g in 5 divided doses after administration of
phenobarbitone, and observed a shortening of the
half-life from 110 to 20 hours. The half-lives of car-
bamazepine, phenylbutazone and dapsone were also
shortened following administration of charcoal.
Charcoal was effective in increasing the elimination
of dapsone in 2 overdosed patients. Overdoses of
other drugs with long half-lives and possible entero-
hepatic recirculation, such as phenytoin, might be
similarly affected. This is an important area for future
investigation.
2.3.2 Ethchlorvynol
Ethchlorvynol overdose, although relatively un-
common, is associated with prolonged coma and
substantial morbidity (Teehan et aI., 1970). Mean
175
protein binding of ethchlorvynol in normal subjects is
62 % and does not vary over a 4-fold increase in con-
centration of ethchlorvynol in plasma (Benowitz et
aI., 1980). The ratio of ethchlorvynol concentrations
in cerebrospinal fluid and plasma, which probably
reflects partitioning of unbound drug, has been
reported to be 0.42, which is consistent with the pro-
tein binding data (Teehan et a!., 1970). After haemo-
perfusion in I patient, the plasma levels of ethchlor-
vynol rose significantly and peaked 6 hours after the
end of haemoperfusion (Benowitz et aI., 1980). This
reflects the high tissue affinity and slow redistribution
of ethchlorvynol from tissues to plasma.
After a therapeutic dose of ethchlorvynol, the
plasma concentration-time curve is biexponential,
with an average terminal half-life of 24 hours and a
clearance from 120 to 140ml/ min (Cummins et aI.,
1971). Half-lives of ethchlorvynol in overdosed
patients have been reported to be substantially longer
than those observed after a single therapeutic dose.
Teehan and coworkers (J 970) reported estimated
half-lives in 4 patients overdosed with ethchlorvynol
ranging from 21 to 105 hours with an average of 72
hours. We observed in I patient, that at high con-
centrations of ethchlorvynol in plasma, elimination
approached zero order (Benowitz et aI., 1980). The
observed rate of elimination was 30mg/L/day, cor-
responding to 1.6g/day in our patient. The plasma
concentrations of ethchlorvynol reported by Tozer et
al. (J 974) also showed that in the posthaemodialysis
period the decline of plasma concentrations was
linear, at a rate of 24.8mg/L/day. Log-linear decline
of ethchlorvynol concentrations after an overdose has
also been described (Ogilvie et aI., 1966); however,
the drug was measured by an assay that measured
ethchlorvynol and metabolites. Renal clearance of
ethchlorvynol is small and makes an inconsequential
contribution to overall drug removal (Cummins et aI.,
1971; Gibson and Wright, 1972; Westervelt, 1966).
2.3.3 Glutethimide
Acute glutethimide intoxication may be in-
distinguishable from that produced by overdosage
with other sedative-hypnotic drugs. However, the
 Pharmacokinetics of Drug Overdose
clinical course can be complicated by an as yet unex-
plained cyclic variation in the depth of coma (Maher
et al., 1962). Possible explanations include delayed
and intermittent absorption of glutethimide and
enterohepatic recirculation of glutethimide and/ or of
active metabolites. Glutethimide is extensively meta-
bolised and is excreted primarily in the urine as
glucuronidated metabolites. 4-Hydroxyglutethimide
(4-0HG) is active, and in mice produces a sedative
effect equal to or greater than the parent compound
(Ambre and Fischer, 1974). After therapeutic doses
of gillthetimicil\ seciation correiaTes weii with pia<;ma
concentrations of glutethimide, and the metabolite (4-
OHG) does not contribute significantly to the effect of
glutethimide (Crow et al., 1977). However, although
the data are somewhat conflicting, plasma levels of
glutethimide do not correlate or only correlate
roughly with the degree of depression of the central
nervous system in patients who have taken an over-
dose of glutethimide (Chazan and Garella, 1971;
Wright and Roscoe, 1970). Hansen and coworkers
(1975) demonstrated that 4-0HG accumulates in the
plasma of patients who have ingested an overdose of
glutethimide. In 1 patient, they found that coma
deepened despite a decreasing plasma level of
glutethimide, but the 4-0HG levels were increasing at
that time; the patient's clinical state correlated best
with the sum of the concentrations of both
glutethimide and 4-0HG in the plasma.
Apart from the accumulation of the active meta-
bolite, the long duration of coma induced by an over-
dose of glutethimide has been attributed to delayed
drug absorption or to saturation of biotransformation
pathways (Maher et ai., 1962; McDonald et al., 1963;
Schreiner et al., 1958). The mean half-life in normal
persons is 11.6 hours (Curry et al., 1971). The half-
life in 1 patient reported by Hansen et al. (1975) who
had taken an overdose was 10 hours. Maher (1970)
reported a mean half-life in 37 intoxicated patients of
40.1 ± 5.5 hours. These estimations were only
based on paired serum concentrations of glute-
thimide, but probably do reflect some saturation of
the biotransformation pathways of glutethimide at
higher drug concentrations.
176
2.3.4 Chloral Hydrate
Blood concentrations of chloral hydrate or its
metabolites are rarely reported in patients intoxicated
with this drug. Chloral hydrate is rapidly reduced by
alcohol dehydrogenase to trichloroethanol, the active
agent. Trichloroethanol is glucuronidated and the
conjugate is excreted by the kidneys. The half-life of
trichloroethanol in normal subjects is 8.2 to 13.6
hours, the half-life in I overdose patient was 35
hours at the highest concentration of trichloroethanol
and decreased as plasma concentration declined
(Staiker eT ai., i'ln).
2.4 Tricyclic Antidepressants
Compared with most other drugs, the mortality
from overdosage with tricyclic antidepressant (TCA)
drugs is high. A review of toxicological features in
106 severely or fatally intoxicated patients, with dis-
cussion of pharmacokinetic aspects, was published by
Bickel (I 975). Pharmacokinetic considerations are
important in understanding the time course of the
onset of the signs and symptoms and of the duration
of the potential toxicity. These issues have practical
consequences because continuous cardiac monitoring,
usually in an intensive care unit, is advisable as long
as there is evidence for or a probability of significant
intoxication.
The tricyclic antidepressants (TCAs) are strongly
anticholinergic and therefore depress gastrointestinal
motility. This may alter the rate of TCA absorption.
In therapeutic doses, TeAs have been shown to delay
the absorption of other drugs (Consolo et al., 1970;
Morgan et al., 1975). Time of peak concentrations
after therapeutic doses of various TCAs range from 3
to 12 hours. Little data are available concerning the
effects of larger doses of TCAs on their own absorp-
tion. In an overdosed patient in whom data were ob-
tained, peak concentrations cif nortriptyline occurred
17 hours after ingestion, which is consistent with
delayed absorption (Sjoqvist et ai., 1972). Evaluation
of a potentially serious TCA overdose must include
assessment of gastrointestinal activity.
 Pharmacokinetics of Drug Overdose
Once absorbed, TeAs are extensively bound to
body tissues. As a consequence, blood concentrations
are quite low and only a tiny proportion of the total
dose is available for elimination by metabolism, urin-
ary excretion or extracorporeal techniques. High con-
centrations of TeAs have been detected in body
tissues as long as 8 days after ingestion (Bickel,
1975).
The time course of TCAs in the blood after an
overdose has been examined in a few patients (Spiker
and Biggs, 1976). Data from 3 of 4 patients after
amitriptyline overdose showed half-lives of 60.3,
73.5, and 81.4 hours, which are considerably longer
than the apparent normal half-life range of 16 to 24
hours (Hollister, 1978). The half-life in the fourth
patient was 25.3 hours. In 2 patients with des-
ipramine overdose, the terminal half-lives were 26.3
and 26.5 hours and are at the upper limit of the nor-
mal range. Raw data were not published in most
cases, so we cannot assess whether or not the ter-
minal decline phase included continued slow absorp-
tion. In addition, the range of half-lives after thera-
peutic doses is quite wide (Hollister, 1978). For these
reasons, it is difficult to know if the elimination half-
lives in overdosed patients are significantly different
from those observed after therapeutic doses. Of in-
terest is a pregnant patient who ingested an overdose
of nortriptyline. She had a normal half-life of nortrip-
tyline of 17 hours, but the child, born the day after
the overdose, had a prolonged half-life of 56 hours
(Sjoqvist et ai., 1972).
Many questions remain in interpreting blood con-
centrations of TeAs after an overdose. It is well
known that tertiary TCAs such as amitriptyline and
imipramine, are demethylated to active secondary
TCAs, nortriptyline and desipramine. Total (tertiary
plus secondary) TeA concentrations in severely in-
toxicated patients are usually greater than 1)lg/ ml
(Petit et al., 1977). The ratio of plasma concentrations
of parent to demethylated TeA is higher with acute
overdose compared with therapeutic overdosing, and
might be useful in differentiating these circumstances
(Bailey et al., 1978). Recent data suggest that some of
the hydroxylated metabolites of TCAs may also be ac-
177
tive Oandhyala et al., 1977; Potter et al., 197 9a, b).
Thus, a full understanding of the relationship be-
tween the pharmacokinetics and the pharmaco-
dynamics of TeAs in the overdosed patients requires
measurement of concentrations of parent drugs and
active metabolites and quantitative assessment of
their relative activity.
2.5 Lithium
Appreciation of the pharmacokinetics of lithium
may result in better understanding of the course of
lithium toxicity and offers the possibility of early
diagnosis and treatment of severe overdose. The clini-
cal pharmacokinetics of lithium were reviewed re-
cently (Amidsen, 1977). Pharmacokinetic features of
particular relevance to the overdose situation are the
narrow therapeutic range of concentrations of lithium
in blood, the dependence of renal clearance of lithium
on sodium balance, and the slow rate of transfer of
15.0
10
5
eNS
E Admission depression
~ + +
~ 1~~~--~~~~~~--~~~
Days
Fig. 7. Serum lithium concentrations in a patient following
acute overdose (from Achong et al.: Canad. Med. Ass. J. 112:
868, 1975; reproduced by permission of author and editor).
 Pharmacokinetics of Drug Overdose
lithium in and out of tissues. A common cause of
lithium intoxication during chronic treatment is a
change in the patient's sodium balance, usually in-
duced by diuretic therapy, a change in diet, or gastro-
intestinal disease with vomiting or diarrhoea.
The absorption of an overdose of lithium may be
prolonged, perhaps due to the formation of relatively
insoluble aggregates of the lithium salt. In 1 patient,
the maximum plasma concentration of lithium occur-
red 45 hours after ingestion of a massive dose of
lithium carbonate (Achong et aI., 1975) [fig. 7]. The
onset of toxicity wao;; aiso deiayed in this patient,
resulting in failure to appreciate the severity of the
overdose.
The clinical course of a patient after lithium over-
dose is influenced by the distribution kinetics of
lithium. In particular, the delay in onset and pro-
longed course of neurotoxicity of lithium may be ex-
plained by the slow rate of transfer of lithium into
and out of the brain. The predominant toxicity of
lithium is neurological and is presumably related to
the concentration of lithium in the brain. In patients
who become intoxicated during the course of chronic
administration of lithium, severity of intoxication
correlates well with serum concentrations of lithium
(Schou et aI., 1968). In these patients, altered mental
status, seizures and coma are most often associated
with serum concentrations above 2.0mEq/L. Studies
in rats show that at steady -state, brain: serum
lithium concentration ratios are approximately 1.0,
whereas cerebrospinal fluid: serum ratios are ap-
proximately 0.4 (Wraae, 1978). Elimination of
lithium from the brain (into the CSF) may occur at a
slower rate than from serum (into urine), as seen in
figure 8 (Frazer et al., 1973), so that recovery of these
patients is usually later than that predicted from a fall
in the serum concentration of lithium (Schou et aI.,
1968).
In contrast, in patients who become intoxicated
after a single acute overdose, severity of intoxication
does not correlate well with serum concentrations of
lithium. This is due at least in part to the slow dis-
tribution of lithium from the blood into the brain. In
rats, maximal concentration of lithium in brain oc-
178
curs from 8 to 24 hours after an intraperitoneal dose
(Frazer et aI., 1973; Wraae, 1978). Figure 8 shows
the time course of lithium in serum and brain from 1
study. This long distribution time may explain why
patients, after an acute lithium overdose, may be
asymptomatic despite serum concentrations of lith-
ium of 4mEq/L or greater (Achong et aI., 1975).
Studies in rats show that erythrocyte concentra-
tions of lithium more closely approximate those of
brain than do serum levels (Frazer et aI., 1973).
Measurement of the concentration of lithium in red
biood ceUs (R HeI, or R He : serum nlTios, hllS been
suggested as a means of monitoring both therapeutic
and toxic responses (Elizur et aI., 1972). This might
prove to be most useful in patients after an acute
overdose, but to our knowledge no such data have
been published. Elizur et aI. (1972) reponed
RBC : plasma lithium concentration ratios in a series
of patients receiving lithium on a chronic basis. One
patient demonstrated neurotoxicity despite a normal
plasma concentration of lithium. This patient's
RBC : plasma lithium concentration ratio was higher
than that for all other patients, which is consistent
with the hypothesis that the RBC lithium concentra-
tion is a better predictor of neurological effects than
the plasma lithium concentration.
In patients with normal renal function, the renal
clearance oflithium ranges from 10 to 40ml/ min and
the plasma terminal half-life from 20 to 50 hours
(Amdisen, 1977). In overdosed patients, the elimina-
tion half-life may be prolonged to 30-100 hours,
presumably due to decreased renal clearance of
lithium (Schou et aI., 1968). This may, in turn, be due
to a consequence of lithium-induced nephrotoxicity
(Amdisen, 1977). Therefore, once patients become in-
toxicated, the course may be prolonged both by slow
intrinsic clearance of lithium from the brain and
decreased renal clearance of the drug.
In summary, patients who manifest signs of lith-
ium overdose who have been taking the drug chronic-
ally must be distinguished from those who have taken
a single acute overdose. In the former, toxicity should
be anticipated at an earlier time and at a lower serum
concentration of lithium. In the latter, prolonged ab-
 Pharmacokinetics of Drug Overdose 179

3.25 3.25

3.00 Plasma 3.00

RBC
2.75 2.75
Brain

2.50 2.50

2.25 2.25

2.00 2.00
/~\ 1.75
,
1.75 \
\

1.50 \
, 1.50
\
,
,,
1.25 1.25
]>
.......
.B' 100
-I.. , \

1.00
0
E
"", , ~~
....... 0.75 ,. .' " 0.75
'},
....J

w
C'
"... " i
EE 0.50 " .........
,
~
f····· ..... ..... 0.50
.... '''I
................~
:::l
:i:
:S 0.25 0.25

2 8 16 2 8 16 24
a. Time (h) b.

Fig. 8. Distribution of lithium in plasma, red blood cell and brain.

Rats were given intraperitoneal injection of lithium chloride (a) 2mEq/kg or (b) 4mEq/kg. Each mean value represents the four
determinations. each bar the SEM (from Frazer et al.: J. Psychiat. Res. 10: l. 1973; reproduced by permission of author and edi·
tor).

sorption and slow distribution of the drug into the
brain combine to delay or prevent the onset of tox·
icity. Serial determinations of serum levels of lithium
may be necessary to predict the course of overdose.
A major therapeutic decision involves the use of
dialysis. Haemodialysis increases lithium clearance
by 30 to 1OOml/ min, and peritoneal dialysis provides
a lithium clearance of 13 to 15ml/ min; these tech-
niques may more than double endogenous lithium
clearance and halve the elimination rate (Amdisen
and Skjoldborg, 1969; von Hartitzsch et al., 1972;
Wilson et al., 1971). Accelerated removal of lithium
would be most effective if performed before lithium
enters the brain. Once neurotoxicity is evident,
removal of lithium from the blood may be of less
benefit because of its slow transfer out of the brain.
Both death (Achong et al., 1975) and permanent
neurological damage (von Hartitzsch et al., 1972)
 Pharmacokinetics of Drug Overdose
have been reported in patients exposed to toxic levels
of lithium for 2 days or more before dialysis was in-
itiated. Dialysis techniques might be applied earlier to
patients known to be taking lithium chronically who
have signs of severe intoxication on admission.
Restoration and maintenance of adequate body
sodium will optimise the renal clearance of lithium.
Although increasing sodium intake and excretion
above this rate may increase the clearance of lithium
slightly, there is no evidence that forced diuresis sig-
nificantly increases lithium excretion or favourably
influences the course of overdose (Thomsen and
Schou, 1968).
2.6 Phenytoin
Overdose with phenytoin is relatively common.
Patients often remain intoxicated for a prolonged
period of time, primarily due to the dose-dependent
elimination kinetics of phenytoin. A recent review of
the pharmacokinetics of phenytoin is available
(Richens, 1979). Phenytoin is poorly water-soluble
and decreases gastrointestinal motility, thus resulting
in prolonged absorption after ingestion of a large
single dose. Peak plasma concentrations of phenytoin
occur between 24 and 48 hours after an overdose
(Holcomb et al., 1972; Pruitt et aI., 1975; Wilder et
aI., 1973; Wilson et aI., 1979) compared with 3 to 12
hours after therapeutic doses (Richens, 1979).
Approximately 92 % of phenytoin is bound to
plasma protein, and binding is decreased in patients
with uraemia, and perhaps acidaemia (Pruitt et al.,
1975). Although the binding of phenytoin to albumin
in vitro does not vary with the phenytoin concentra-
tion (Pruitt et al., 1975), the possibility of concen-
tration-dependent protein binding of phenytoin in
the overdosed patient has not been assessed ade-
quately.
In 2 overdose cases, plasma and CSF phenytoin
concentrations were measured simultaneously; the
resultant ratios were lower than expected, and the
degree of intoxication seemed out of proportion to the
plasma concentrations of phenytoin (Wilder et aI.,
180
1973; Wilson et al., 1979). As the CSF concentration
would be expected to be directly proportional to the
free phenytoin plasma concentration, these data sug-
gest that protein binding might have been decreased
in these patients.
Because of dose-dependent elimination, actual
plasma half-lives of phenytoin cannot be calculated.
However, the time for the plasma concentration of
phenytoin to decrease by half has been estimated in
intoxicated patients and is usually greater than 60
hours (Holcomb et aI., 1972; Wilder, 1973) and can
be up to 9.6 days (Gill et ai., ! ~ I ~,I and 1.1. days
(Wilson et aI., 1979), although prolonged absorption
and distribution probably contribute to this.
2.7 Ethanol
Ethanol is a common concomitant ingestion in
many overdose cases, and is the primary intoxicant in
some cases, mostly in children and non-tolerant
adults. A single ingestion of a large amount of
ethanol results in delayed gastric emptying, probably
as a result of gastric irritation. Consequently, absorp-
tion may be delayed, and toxicity may occur at a
variable time after ingestion. The prediction of peak
plasma concentrations of ethanol based upon dose
and apparent volume of distribution is useful in the
management of ethanol ingestion in children. For ex-
ample, consider a child ingesting 20ml of a commer-
cial product containing 90 % ethanol by weight, a
maximum dose of 18g of ethanol. Using an apparent
volume of distribution of 0.6L/kg, the estimated
maximum plasma concentration of ethanol 1 to 2
hours after ingestion is 1OOmg/ dl. This level is con-
sistent with moderate intoxication, but does not indi-
cate more serious consequences. The child might be
discharged after a short period of observation. This
example illustrates the point that only small volumes
of ethanol are necessary to produce intoxication in a
small child, and that pharmacokinetic calculations
may assist in predicting the degree of intoxication. A
similar use of the volume of distribution to calculate
a loading dose of ethanol in the treatment of metha-
 Pharmacokinetics of Drug Overdose
nol and ethylene glycol intoxication is discussed
below.
The elimination of ethanol is generally considered
to follow zero-order kinetics. When studied carefully,
however, the rate of disappearance of ethanol appears
to follow Michaelis-Menten kinetics, and the effect of
concentration on elimination rates can, for the most
part, be predicted by the Michaelis-Menten equation
as described in section 1.1.3, equation I. As ethanol
concentrations increase, the rate of disappearance
continues to increase. However, as Vm is ap-
proached, the increases become smaller, giving the
appearance of a fixed- or zero-order elimination rate.
For example, assume that for a particular individual
the Vm equals 7Smg/kg/h and km equals
13.8mg/dl(McCoy et aI., 1979; Vestaletal., 1977;
Wilkinson et aI., 1976): at blood concentrations of
ethanol of 10, SO, 100, and SOOmg/ dl, the rate of dis-
appearance, V, will be 31.S, S8.8, 6S.9 and
72.8mg/kg/h, respectively.
First-order elimination processes, which are of
minor importance at lower concentrations, may also
contribute to ethanol elimination in the overdosed
patient. Feinman and coworkers (I978) suggested
that the microsomal ethanol oxidising system
becomes important at higher concentrations of
ethanol. It has also been suggested, although not
demonstrated, that renal excretion can contribute sig-
nificantly to total elimination during the overdosed
period (Hammond et aI., 1973). Because ethanol dis-
tributes into total body water, ethanol concentrations
in urine are the same as those in blood, and renal
clearance approximates urine flow. Assuming a flow
of 100ml/hour, with a steady blood concentration of
ethanol of 100 or 500mg/ dl, the rate of the renal
ethanol elimination would be 100mg or SOOmg/
hour, respectively. Compared with the body's
usual metabolic capacity of about 7g/houdor greater
during the overdose period), renal excretion at normal
urine flow plays a minor role in total elimination.
However, during a forced diuresis of 1000mi of
urine/hour in a patient with a blood ethanol con-
centration of SOOmg/ dl, Sg/hour might be elimi-
nated by the kidney. Such a diuresis might contribute
181
significantly to the overall elimination rate, but is not
clinically recommended.
We know of only a few cases in which blood con-
centrations of alcohol have been characterised after an
overdose. In I patient, the decline of blood concentra-
tions of ethanol from 780 to 200mg/dl appeared
to be first-order with a half-life of about 200min
(Hammond et al., 1973). In another case, however,
with a peak blood concentration of ethanol of
63Smg/dl, elimination appeared to be zero-order
with a rate of 34mg/dl/hour (Lindblad and Olsson,
1976).
An additional use of ethanol pharmacokinetics for
overdosed patients is in the treatment of methanol
and ethylene glycol poisoning. The toxic metabolites
of these compounds account for most of the mor-
bidity and mortality resulting from their ingestion
(McMartin et aI., 1980; Parry and Wallach, 1974).
These metabolites are generated by the alcohol
dehydrogenase enzyme system. Ethanol has a greater
affinity for alcohol dehydrogenase than methanol and
ethylene glycol. At blood concentrations of ethanol of
100 to 200mg/ dl, much of the metabolism of
methanol and ethylene glycol is inhibited, so that the
less toxic parent compounds may be eliminated by the
kidney and by haemodialysis. The loading dose of
ethanol is determined by the volume of distribution,
while the maintenance dose is determined by the
elimination rate, which is dependent on both V m and
km (equation I). Assuming an average volume of dis-
tribution of 0.6L1kg, a loading dose of 0.6g/kg will
result in an average blood concentration of ethanol of
100mg/dl.
As reviewed recently by McCoy et aI. (I 979),
maintenance doses will depend on whether patients
are chronic drinkers (Vm = 7Smg/kg/h for
non-drinkers and 17Smg/kg/h for drinkers) and
may need to be adjusted for ethanol losses due to
haemodialysis. Thus, to maintain a blood ethanol
concentration of I OOmg/ dl, a non-drinker would re-
quire 66mg/kg/h and a drinker IS4mg/kg/h.
Assuming ethanol clearance of 120ml/min by
dialysis, an extra 7.2g ethanol/h would be necessary
to compensate for dialysis losses.
 Pharmacokinetics of Drug Overdose 182

2.8 Theophylline phylline were infused intravenously to 20 children

Theophylline intoxication most commonly occurs
during therapeutic administration primarily due to
disease-induced alterations in its kinetics. However,
theophylline overdose due to suicidal or accidental
ingestion is not uncommon. Good correlation has
been reported between serum concentrations of
theophylline and therapeutic (Mitenko and Ogilvie,
1973) and toxic effects (Jacobs et aI., 1976; Zwillich
et aI., 1975). Major morbidity and mortality occur as
a re.~mit of neurotoxicity. Zwiiiich et aL (j 975)
with asthma. Differences in steady-state serum con-
centrations were higher than those predicted from the
dose differences. The daily dose was increased by
50 % in 1 child, but the serum concentration of
theophylline increased by more than 300 % and
seizures developed. Few data are available on over-
dose kinetics. Kadlec et ai. (1978) reported a peak
serum concentration of theophylline of 102.4J.1g/ ml
in a 17-month old child and biphasic first-
order elimination curve in which serum levels
_________ "vpr
rlp{'iinptl ..... _a _'~fl h,,"r.,
_...... _." w,th
~ ........... "_ ..h"lf~l;fp
a_.... "r 1 'J_.'V'h .hr
A&&_ ............ ... ",
....... ,
.&~_

reported that 8 patients with seizures had serum con-
centrations of theophylline ranging from 25~g/ ml to
70~g/ml, with a mean of 53J.1g/ml compared with
the recommended therapeutic concentrations of 10 to
20J.lg/ml.
The kinetics of theophylline in children may be
dose-dependent, as suggested by Weinberger and
Ginchansky (1977). Two different doses of theo-
followed by a decline over the next 12 hours with a
half-life of 5.4 hours (fig. 9). Vaucher et al. (1977)
reported 2 children, ages 15 and 5 months, who had
monophasic first-order elimination (half-lives of 8.5
and 9 hours) at peak serum concentrations of
theophylline of 65 and 141 J.lg/ ml, respectively. A
possible explanation for this discrepancy is that
Vaucher used a spectrophotometric assay for theo-

tl/2 = 12.6h
100
kg = O.057h- 1
80
60 Lethargy T •
Vomiting .·t.
40 Haematemesis Seizure •
t
CSF
20

tl/2 = 5.4h
10 kg = O.128h- 1
8
6

TIme (h)

Fig. 9. Serum and CSF theophylline concentration in a 17-month-old child following acute theophylline overdose (from Kadlec
et al.: Ann. Allergy 41: 337, 1978; reproduced by permission of author and editor).
 Pharmacokinetics of Drug Overdose
phylline, which may have also measured metabolites,
whereas Kadlec et al. used a specific high perfor-
mance liquid chromatographic assay.
2.9 Digoxin
Digoxin overdose occurs in 2 contexts: the
chronic, usually gradual, situation, and the acute
overdose situation. The first, and by far the most
common form of overdose, occurs in a patient taking
digoxin chronically for treatment of arrhythmias or
cardiac failure. Both cardiac disease and increasing
age are associated with reduced creatinine clearance
and decreased renal and total clearance of digoxin.
When renal function becomes markedly reduced,
tissue binding decreases with a decrease in the volume
of distribution (Reuning et aI., 1973). Another in-
creasingly recognised cause of digoxin intoxication is
coadministration of quinidine, which increases the
serum concentration of digoxin by reducing both
clearance and extracardiac tissue binding of digoxin
(Bigger, 1979).
Less common is suicidal or accidental overdose of
a single large dose of digoxin. We reviewed 10 such
cases in which pharmacokinetic data were obtained
(Ahlmark, 1976; Bertler et aI., 1973; Hobson and
Zettner, 1973; Rumack et aI., 1974; Smith and
Willerson, 1971): 5 patients had cardiac diseases, and
5 were initially healthy. Two of the patients with car-
diac disease, who were the eldest at 67 and 78 years
of age, had reduced renal function (creatinine
clearance 49 and 40ml/min, respectively), whereas
the rest of the cardiac patients had normal renal func-
tion. The patients with cardiac disease and reduced
renal function had the longest serum half-lives of
digoxin at 36 and 60 hours, respectively, whereas in
the other overdosed patients, ages 2112 months to 65
years of age, the calculated serum half-lives of digoxin
ranged from 6 to 33 hours.
When an adequate number of blood samples were
obtained, the shape of the plotted decline of digoxin
concentration over time after acute overdose was
usually not simply logarithmic. In I case the half-life
183
was initially longer (43 hours) compared with the ter-
minal portion (J 5 hours) (Hobson and Zettner, 1973).
It is likely that this pattern results from delayed and
continuing gastrointestinal absorption. On the other
hand, several patients exhibited early half-lives of
drug that were shorter than terminal half-lives
(Ahlmark, 1976; Bertler et aI., 1973; Smith and
Willerson, 1971). It is likely that the early short half-
life represents continuing tissue distribution. At
therapeutic doses, the distribution half-life is usually
about 5 hours, so that distribution is essentially com-
plete by 24 hours (Reuning et aI., 1973). Conceivably,
tissue uptake is slower during the overdose so that the
tissue uptake phase, which is still faster than the rate
of elimination, is observed for several days. In many
of these patients, the reported half-lives after overdose
were somewhat shorter than the half-lives reported
after therapeutic doses of digoxin. In most, the short
half-lives are probably a function of sampling over
too short a time interval, thereby including the dis-
tribution phase. However, in I case, the terminal
half-life of IS hours did appear to be unusually short
(Hobson and Zettner, 1973). Whether this short half-
life is a function of the pathophysiology of the over-
dose or merely represents normal interindividual
variability could only have been experimentally ex-
amined by performing postrecovery pharmacokinetic
studies.
2.10 Narcotics
Although narcotic overdoses are relatively com-
mon, little is known of the pharmacokinetics of
opiate drugs in the acutely overdosed patient. Of most
relevance is the biological half-life of the administered
opiate, because of the relatively short half-life of the
competitive narcotic antagonist naloxone. Naloxone
has a plasma half-life of approximately 90 minutes
and an even shorter biological half-life (Fishman et
aI., 1973). After therapeutic doses, the half-lives of
most narcotics are longer than 90 minutes (Berko-
witz, 1976). Therefore, repetitive injections or con-
tinuous intravenous infusions of naloxone may be
 Pharmacokinetics of Drug Overdose
necessary to achieve the desired reversal of opiate
effects in overdosed patients.
2.10.1 Heroin and Morphine
The most commonly abused narcotic, heroin
(diamorphine), is rapidly metabolised to morphine,
which has a plasma half-life of approximately 2 hours
(Spector and Vessell, I 972). Weare not aware of any
pharmacokinetic studies in overdosed patients.
Morphine is a weak base and the occurrence of respir-
atory acidosis due to overdose may influence the dis-
tribution of morphine. Finck et ai. (i 9771 measured
the volume of distribution and brain concentration of
morphine in dogs with blood at normal pH (7 AI) and
in those with respiratory acidosis (pH 7.15). They
hypothesised that the decrease in systemic pH would
result in a decrease in non-ionised morphine from 23
to 14 %. Although the observed volume of distribu-
tion was smaller in the acidaemic dogs, the brain con-
centration of morphine actually increased, possibly
due to increases in cerebral blood flow secondary to
hypercapnia. Because 10% or less of morphine is ex-
creted unchanged in urine (Berkowitz, 1976), changes
in urinary pH do not substantially affect total
morphine clearance.
2.10.2 Methadone
From 5 to 22 % of a dose of methadone, which is
also a weak base, may be excreted unchanged into
alkaline and acid urine, respectively (Baselt and
Casarett, I 972). Spontaneous changes in urine pH
result in 3-fold differences in renal clearance of
methadone in methadone-maintained patients studied
by Bellward et aI. (1977). Since methadone has a long
half-life, often > 24h, a continuous infusion of nalo-
xone (0.04mg/mO may be necessary to antagonise
methadone effects over the course of the overdose.
2.10.3 Codeine
Codeine (methylmorphine) is in part metabolised
to morphine. The metabolism may be dose-depen-
dent, as suggested by the observation that maximum
rates of urinary excretion of codeine and metabolites,
measured during intravenous infusions, were similar
184
in doses of 30mg/hour and 60mg/hour (Nomof et
aI., 1977). Blood concentrations of codeine in 1
patient after an intravenous overdose decreased only
slightly over the first 48 hours, followed by a more
rapid fall with a half-life of approximately 6 hours
(Huffman and Ferguson, 1975). Shock and hepatic
damage during this patient's early course may have
contributed to the initial slow rate of disappearance of
codeine. The normal elimination half-life of codeine is
2.4 to 2.9 hours (Findlay et aI., 1978).
2.jO.4 Propoxyphene
Propoxyphene overdose is increasing in incidence
and is distinguished from most other narcotic over-
doses by the occurrence of seizures (Schou et aI.,
1978). A major metabolite, norpropoxyphene, is car-
diotoxic and its effects are not antagonised by nalox-
one (Nickander and Smits, 1973). In normal subjects,
the plasma half-life of propoxyphene is 8 to 24 hours
whereas that of norpropoxyphene is 18 to 36 hours
(Gram et al., 1979; Wolen et aI., 1975). Therefore,
norpropoxyphene accumulates in chronic users
(Baselt et aI., 1975). The use of hyperventilation for
management of cardiac toxicity due to propoxyphene
overdose has been proposed by Schou et aI. (J 978).
The authors reported that 5 patients with severe pro-
poxyphene intoxication who were treated with hyper-
ventilation had higher maximum serum levels of pro-
poxyphene and norpropoxyphene, and had longer
plasma half-lives of propoxyphene (mean of 30.5
hours) than 6 less severely overdosed patients who
were treated conservatively (J 7.9 hours). Because
plasma levels of drug and metabolite were determined
only after induction of respiratory alkalosis, it is not
possible to distinguish between concentration-depen-
dent and pH-dependent effects on the disposition of
propoxyphene in these patients.
2.11 Stimulants
(Amphetamine and Phencyclidine)
Although the use of amphetamines is apparently
decreasing, that of phencyclidine is increasing and
 Pharmacokinetics of Drug Overdose
r~sults in considerable morbidity and mortality.
Because both drugs are weak bases, their distribution
and renal elimination may be affected by pH.
The renal elimination of amphetamine is sensitive
to changes in urinary pH. Approximately 60 % of an
intravenously administered dose of amphetamine is
excreted unchanged into acid urine, whereas less than
20 % is usually excreted into alkaline urine (Davis et
aI., 1971). However, amphetamine is also metabol-
ised, primarily deaminated but also hydroxylated, to
potentially toxic metabolites. Davis et ai. (1971)
demonstrated a shorter plasma half-life of am-
phetamine with acid urine (8 to 10.5 hours) than with
alkaline urine (16 to 31 hours). Anggard et al. (1973)
acidified the urine of 3 patients and alkalinised the
urine of 4 patients with amphetamine psychosis. The
plasma half-life of amphetamine in the 3 with acid
urine was 7 to 14 hours, and the symptoms cleared
rapidly. The plasma half-life of the 4 with alkaline
urine was 19 to 34 hours, and psychosis was
prolonged. As a consequence of decreased renal
elimination of amphetamine, the formation of basic
polar metabolites increases; these metabolites may be
active and contribute to toxicity. Although these
results provide a rationale for acidifying the urine of
patients with amphetamine psychosis, its use has not
been studied in patients with acute amphetamine
overdose. In such cases, morbidity is related to the
acute cardiovascular effects of the drug rather than to
the time course of persistence of the drug in the body.
Acute amphetamine and phencyclidine overdose has
been associated with rhabdomylosis and excretion of
myoglobin in urine (Cogen et al., 1978). It has been
postulated that in acid urine a greater amount of fer-
rihemate dissociates from the globin of myoglobin,
resulting in more nephrotoxicity (Eneas et al., 1979).
The risks of urine acidification in the presence of
myoglobinuria may outweigh the potential benefits
(Barton et al., 1980).
An interesting aspect of amphetamine toxicity of
uncertain clinical significance is the triphasic lethal
dose curve obtained in mice (James and Franklin,
1978). The lethality of amphetamine in mice in-
creased up to 40mg/kg, decreased between 40 and
185
60mg/kg, and then increased again so that mortality
at 1OOmg/kg equalled that at 40mg/kg. Pretreatment
with inhibitors of hepatic oxidative metabolism
abolished the triphasic response curve. This observa-
tion supports the suggestion that metabolites of
amphetamine may contribute to its toxicity.
The issue of manipulation of acid-base status in
the treatment of phencyclidine (PCP) intoxication is
important, controversial, and requires further in-
vestigation. We know of no published studies of the
pharmacokinetics of PCP in man. Plasma concentra-
tions of PCP after intravenous administration have
been studied in dogs and monkeys, but neither renal
clearance nor the effect of pH on drug distribution
was reported (Wilson and Domino, 1978). Thus, the
relevant data are confined to overdosed patients in
whom the doses are unknown. However, a few con-
clusions can be made from these studies. Urinary
acidification clearly increases the renal clearance of
PCP (Aronow et ai., 1978; Domino and Wilson,
1977; Done et ai., 1977; Done et ai., 1978). Gastric
acidification increases the partitioning of phen-
cyclidine into gastric contents (Done et al., 1978).
After the recommendations of these authors, urinary
acidification and gastric suction have been used
widely in the treatment of phencyclidine overdose
(Rappolt et ai., 1979). However, the contribution of
techniques that increase renal or gastric clearance to
total body clearance is uncertain and may, in fact, be
small. In the few cases in which the time course of
serum concentrations of phencyclidine was reported,
the concentrations did not appear to be substantially
altered by these techniques (Done et aI., 1978). It is
difficult to evaluate the improvement in clinical status
after treatment because all patients reported were so
treated (Aronow et ai., 1978).
In 1 patient, phencyclidine concentrations in
serum and CSF were determined sequentially at vary-
ing serum pHs (Done et ai., 1978). At pH 7.4, the
CSF : serum ratio was 140: 66ng/ ml, or approx-
imately 2: 1; at pH 7.2, this ratio was 8: SOng/ml,
or approximately 1 : 6. An immediate improvement
in unspecified central nervous system effects was
reported. These investigators recommended mainte-
 Pharmacokinetics of Drug Overdose
nance of serum pH at approximately 7.3 during ad-
ministration of acid to effect urinary acidification.
This is a potentially hazardous procedure (Barton et
aI., 1980), and its ultimate benefit to the outcome of
the patient remains to be documented.
3. Design a/Clinical Studies
In reviewing clinical studies of the pharmaco-
kinetics of drug overdose, a number of problems
thai make resuiis difficuii io evaiuate were noted. We
offer the following suggestions for future studies:
1. Frequent blood sampling in the first few days
and continued blood sampling over the entire course
of recovery after overdose may permit better charac-
terisation of absorption and terminal elimination
kinetics.
2. Measuring concentrations of both ingested
drug and known or potentially active metabolites and
relating these concentrations to quantitative measures
of neurological depression or other clinical observa-
tions may suggest relationships which could later be
analysed by covariant analyses.
3. Measuring the concentrations of several drugs
over the course of an overdose may be necessary to
explain clinical observations when multiple drugs
have been ingested.
4. Measurement of protein binding in the drug-
overdosed patient may demonstrate that with 'higher-
than-therapeutic' blood concentrations or in the pre-
sence of other drugs andlor physiological distur-
bances such as acidaemia, hypo- or hyperthermia,
free drug concentrations differ from that expected
from data obtained in normal subjects.
5. For overdoses such as with lithium where
serious toxicity can occur long after peak blood con-
centrations, studying the relationship between blood
concentrations measured early in the course of over-
dose and outcome, may provide a rational basis for
interventions such as haemodialysis before serious
toxicity is manifest.
6. Manipulations designed to accelerate drug
removal, such as repeated administration of charcoal,
186
urinary acidification or alkalinisation, haemoperfu-
sion or haemodialysis should be preceded and
followed by adequate periods of blood concentration
measurement in order to assess quantitative removal
beyond that attributable to endogenous processes and
to detect possible late rebound of drug concentrations.
Direct measurement of drug in faeces, urine, haemo-
perfusion cartridge or dialysate solutions, as ap-
propriate, are also most useful.
A ckn()wiedgement.~
Preparation of this review was supported in part by
research grants DAO 1696 and DA02453 from the United
States National Institutes of Health.
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