IPCS INCHEM HomePhenytoin
Phenytoin
International Programme on Chemical Safety
Poisons Information Monograph 416
Pharmaceutical
1. NAME
1.1 Substance
Phenytoin
1.2 Group
(N03) Antiepileptics (N03A B02) Hydantoin derivatives
1.3 Synonyms
diphenylhydantoin; Fenitoina; Phenantoinum; Phenytoinum;
5,5-Diphenylhydantoin; 5,5-Diphenylimidazoline-2,4-dione
1.4 Identification numbers
1.4.1 CAS number
57-41-0
1.4.2 Other numbers
CAS number: phenytoin sodium: 630-93-3
ATC codes: N03AB52: phenytoin, combinations
1.5 Main brand names/main trade names
Dantoin, Dilantin, Diphenlyn, Phenyltoin, Divulsan,
Novo-diphenyl, Phentoin sodium, Denyl sodium, Dilantin
sodium, Diphentoin, Diphenylan sodium, Kessodanten,
Elsanutin, Phentoin, Di-Hydan, Phenhydan
1.6 Main manufacturers and/or importers
Carrion, Parke Davis
2. SUMMARY
2.1 Main risks and target organs
The intoxication usually manifests as mild central
nervous system effects. More severe manifestations may be
seen following massive overdose but fatalities are extremely
rare.
2.2 Summary of clinical effects
Onset of symptoms including lateral nystagmus, ataxia,
and drowsiness occurs within 1 to 2 hours after ingestion and
may persist for about 4 to 5 days.
In more severe cases, horizontal nystagmus, coarse tremor and
inability to walk may be observed.
In very severe poisoning, conciousness is impaired but coma
is rarely observed.
2.3 Diagnosis
Diagnosis of phenytoin poisoning is clinical and based
on history of overdose and/or access to phenytoin and the
presence of specific clinical features especially nystagmus,
dysarthria and ataxia. The diagnosis may be confirmed in the
laboratory by measurement of an elevated serum phenytoin
level but the levels do not always correlate precisely with
the clinical severity of the intoxication.
2.4 First aid measures and management principles
Careful supportive management, gut decontamination
measures and patience for 3 to 5 days almost always result in
a good clinical outcome.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Synthetic.
3.2 Chemical structure
Molecular formula: phenytoin: C15 H12 N2 O2
phenytoin sodium: C15 H11 N2 Na O2
Molecular weight: phenytoin: 252.3
phenytoin sodium: 274.3
Structural name(s): Phenytoin: 5,5-Diphenylhydantoin;
5,5-Diphenylimidazoline-2,4-dione.
3.3 Physical properties
3.3.1 Colour
White
3.3.2 State/Form
solid-crystalline
solid-powder
3.3.3 Description
Phenytoin:
Very slightly soluble in water, slightly soluble in
chloroform and ether, soluble 1 in 70 in alcohol.
Melting point: 295-298ーC
(Reynolds, 1996; Budavari, 1996).
Phenytoin sodium:
Phenytoin sodium (synonyms): Diphenin; Phenytoinum
Natricum; Soluble phenytoin
Slightly hygroscopic; on exposure to air it gradually
absorbs carbon dioxide with the liberation of
phenytoin.
Odourless, tasteless.
Soluble in water; the solution is turbid unless pH is
adjusted to 11,7
Soluble in alcohol
Practically insoluble in chloroform, in ether and in
methylene chloride.
Note on incompatibility: The mixing of phenytoin
sodium with other drugs or its addition to infusion
solutions is not recommended because precipitation may
occur (Reynolds, 1996).
3.4 Other characteristics
3.4.1 Shelf-life of the substance
5 years at 20ーC
3.4.2 Storage conditions
In airtight containers.
4. USES
4.1 Indications
4.1.1 Indications
4.1.2 Description
Anticonvulsant
Antiarrhythmic.
4.2 Therapeutic dosage
4.2.1 Adults
Anticonvulsant:
The dose should be individualised to optimise control
of convulsions. Measurement of plasma concentrations
is useful: 10 to 20 オg / mL (40 to 80 オmol/L) will
achieve good control in the majority of cases. A small
group of patients may require and will tolerate serum
phenytoin concentrations greater than 20 オg/mL (80
オmol/L) (Levine & Chang, 1990).
The suggested initial dose is 100 mg thrice daily
progressively increased at intervals of a few days to
a maximum of 600 mg daily.
Because it may take a week to establish therapeutic
plasma concentrations, an initial loading dose of 12
to 15 mg/kg body weight divided into 2 or 3 doses may
be given over about 6 hours and then followed by 100
mg thrice daily.
In the treatment of status epilepticus, a loading dose
of 10 to 15 mg/kg body weight of phenytoin sodium may
be given as slow intravenous injection (not more than
50 mg per minute) (Reynolds, 1996). Cardiac rhythm and
blood pressure should be continuously monitored during
the infusion.
Antiarrhythmic:
Phenytoin is occasionally used in the treatment of
cardiac arrhythmias, particularly those associated
with digitalis intoxication; it is of little or no use
in cardiac arrhythmias caused by acute or chronic
heart disease.
The usual dose is 3.5 to 5 mg/kg body weight
administered by slow intravenous injection at a rate
of not more than 50 mg per minute. This dose may be
repeated once if necessary (Reynolds, 1996). Cardiac
rhythm and blood pressure should be continuously
monitored during the infusion.
4.2.2 Children
Anticonvulsant:
Suggested initial dose is 5 mg/kg body weight daily in
2 or 3 divided doses. Suggested maintenance dose is 4
to 8 mg/kg body weight daily.
Status epilepticus: intravenous loading dose of from
10 to 20 mg/kg body-weight, at a rate not exceeding 1
to 3 mg/kg/mn. (Reynolds, 1996). Cardiac rhythm and
blood pressure should be continuously monitored during
the infusion.
Antiarrhythmic:
As for adults.
4.3 Contraindications
Acute intermittent porphyria, hypersensitivity.
Intravenous injection in patients with sino-atrial cardiac
block, second- or third degree atrio-ventricular block, sinus
bradycardia and Adam-Stokes syndrome. Caution is indicated in
patients with uremia, hypoalbuminaemia, liver function
disorders, and viral hepatitis (Informatorium Medicamentorum,
1995).
5. ROUTES OF EXPOSURE
5.1 Oral
Most common route
5.2 Inhalation
Not applicable
5.3 Dermal
Not applicable
5.4 Eye
Not applicable
5.5 Parenteral
Intravenously in status epilepticus.
5.6 Other
No data
6. KINETICS
6.1 Absorption by route of exposure
Phenytoin is slowly, but almost completely absorbed from
the gastro-intestinal tract; the rate of absorption is
variable and its bioavailability can differ markedly with
different pharmaceutical formulations. Large doses are more
slowly absorbed. In severe oral poisoning, gastro-intestinal
absorption may continue up to 60 hours (Wilder et al., 1973).
Administration of 100 mg orally to normal volunteers produced
two peaks at 2.5 to 3.5 and 10 to 12 hours (Robinson et al.,
1975).
6.2 Distribution by route of exposure
Phenytoin is widely distributed throughout the body and
is extensively (87 to 93%) bound to protein. The apparent
volume of distribution is about 0.5 to 0.8 L/kg (Gugler et
al., 1976; Hvidberg & Dam, 1976). Plasma binding is almost
exclusively to albumin; in individuals with normal plasma
albumin concentration and in absence of displacing agents,
phenytoin is about 90% plasma bound.
6.3 Biological half-life by route of exposure
Following oral administration of therapeutic doses,
phenytoin has a very variable, dose-dependent half-life. The
range for a therapeutic dose is from 8 to 60 hours with an
average of from 20 to 30 hours (Robinson et al., 1975;
Hvidberg & Dam, 1976). In overdose in adults the range is
from 24 to 230 hours (Holcomb et al., 1972; Gill et al.,
1978; Albertson et al., 1981).
6.4 Metabolism
Phenytoin is extensively metabolised in the liver to 5-
(4-hydroxyphenyl)-5 phenyl-hydantoin, which is inactive. This
para hydroxylation of phenytoin is carried out by cytochrome
P450 2C9 (Veronese et al., 1991, 1993). This enzyme also
hydroxylates tolbutamide (Doecke et al., 1991), and warfarin
(Rettie et al., 1992; Kaminski et al., 1993). This explains
the interaction with these substances.
The p-hydroxylated phenytoin is in turn conjugated to its
glucuronide. Phenytoin hydroxylation is capacity-limited
because of the saturable enzyme systems in the liver. At
therapeutic doses, metabolism is nonlinear (first-order
kinetics), while at toxic doses the metabolism is linear
(zero-order kinetics) (Ellenhorn & Barceloux, 1988; Reynolds,
1996).
The p-hydroxylated phenytoin can be oxidised to 3,4-
dihydroxyphenyl-phenylhydantoin, the catechol metabolite of
phenytoin, and further to the 3-O-methylated catechol
metabolite of phenytoin. These metabolites of phenytoin are
of possible toxicological interest (Edeki & Brase, 1995).
Phenytoin is more rapidly metabolised in children. (McEvoy,
1995)
The rate of metabolism appears to be subject to genetic
polymorphism (Reynolds, 1996).
Phenytoin undergoes entero-hepatic recycling (Reynolds,
1996).
6.5 Elimination by route of exposure
The total systemic clearance of phenytoin from plasma is
5.9 mL/minute/kg. (Gilman et al., 1990).
Phenytoin is mainly excreted in the urine as its hydroxylated
metabolite (23 to 70%), either free or in conjugated form
(5%). About 4% is excreted unchanged, in the urine and 5% in
the faeces. (Parker et al., 1970).
Small amounts are excreted in the milk.
7. PHARMACOLOGY AND TOXICOLOGY
7.1 Mode of action
7.1.1 Toxicodynamics
Phenytoin is eliminated mainly through para-
hydroxylation by a cytochrome P450 system. The
metabolic pathway is subject to saturable kinetics in
overdose, allowing accumulation of free phenytoin.
Even at therapeutic doses, accumulation of free
phenytoin is possible in: hypoalbuminaemia, chronic
renal failure, hepatic dysfunction, hereditary
insufficient para-hydroxylation (Kutt et al., 1964;
Vasko et al., 1980; de Wolff, 1983), and inhibition of
phenytoin metabolism by other drugs.
7.1.2 Pharmacodynamics
Phenytoin binds to specific site on voltage-
dependent sodium channels and is thought to exert its
anticonvulsant effect by suppressing the sustained
repetitive firing of neurons by inhibiting sodium flux
through these voltage dependent channels (Francis &
Burnham, 1992). Phenytoin stabilises membranes,
protecting the sodium pump in the brain and in the
heart. It limits the development of maximal convulsive
activity and reduces the spread of convulsive activity
from a discharging focus without influencing the focus
itself. (Reynolds, 1982, 1996)
Phenytoin has antiarrhythmic properties similar to
those of quinidine or procainamide. Although
phenytoin has minimal effect on the electrical
excitability of cardiac muscle, it decreases the force
of contraction, depresses pacemaker action and
improves atrioventricular conduction. It also prolongs
the effective refractory period relative to the action
potential duration (Mc Evoy, 1995).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Ingestion of 4,5 g has been reported
to produce transient coma. However, 25 g has
been tolerated without serious depression
(Gosselin et al., 1976).
7.2.1.2 Children
Fatal outcome has been reported in a
7-year-old who ingested 2 g (Gosselin et al.,
1976), in a 4 year old child who ingested
forty 50 mg tablets and in a 16 year old girl
who ingested an unknown amount (Laubscher,
1966).
7.2.2 Relevant animal data
Phenytoin has high acute toxicity:
LD50 (oral) mouse: 150 mg/kg
LD50 (intravenous) rat: 101 mg/kg
LD50 (intravenous) rabbit: 125 mg/kg
(Sax & Lewis, 1989; ANDIS, 1994).
7.2.3 Relevant in vitro data
Not relevant
7.3 Carcinogenicity
Malignancies, including neuroblastoma, in children whose
mothers were on phenytoin during pregnancy have been reported
(McEvoy, 1995).
7.4 Teratogenicity
Phenytoin is classed as a teratogen risk factor D
(Positive evidence of human fetal risk, but the benefits from
use in pregnant women may be acceptable despite the
risk).
The epileptic pregnant woman taking phenytoin, either alone
or in combination with other anticonvulsants, has a two to
three times greater risk of delivering a child with
congenital defects. It is not known if this increased risk is
due to antiepileptic drugs, the disease itself, genetic
factors, or a combination of these, although some evidence
indicates that drugs are the causative factor.
A recognisable pattern of malformations, known as the fetal
hydantoin syndrome has been described and includes
craniofacial and limb abnormalities, cleft lip, impaired
growth, and congenital heart defects. (Briggs, 1994).
7.5 Mutagenicity
No data available.
7.6 Interactions
Drug interactions with phenytoin are numerous. They may
be classified, according to mechanism, in the following
way:
Drugs displacing phenytoin plasma protein binding sites
Azapropazone (Geaney et al., 1983)
Diazoxide (Roe et al., 1975)
Heparin (Schulz et al., 1983)
Ibuprofen (Bachman et al., 1986)
Phenylbutazone (Lunde et al., 1970)
Salicylic acid (Lunde et al., 1970; Fraser et al., 1980;
Paxton, 1980; Leonard et al., 1981)
Sulfadimethoxine (Hansen et al., 1979)
Sulfafurazole (Lunde et al., 1970)
Sulfamethizole (Hansen et al., 1979; Lumholz et al.,
1975)
Sulfamethoxydiazine (Hansen et al., 1979)
Sulfamethoxypyridazine (Hansen et al., 1979)
Tolbutamide (Wesseling & Mols-Thurkow, 1975)
Valproic acid (Patsalos & Lascelles, 1977; Monks et al.,
1978; Dahlqvist et al., 1979; Bruni et al., 1980; Monks &
Richens, 1980; Perucca et al., 1980; Sanson et al., 1980)
Decreased total and unbound plasma phenytoin concentration
caused by increased metabolism
Folic acid (Viukari, 1968; Furlanot et al., 1978; Berg et
al., 1983)
Dexamethasone (Wong, 1985)
Phenobarbital (Cucinell et al., 1965; Kutt et al., 1969;
Browne et al., 1988a)
Diazepam (Vajda et al., 1971; Richens & Houghton, 1975)
Rifampicin (Kay et al., 1985)
Methadone (Tong et al., 1981)
Nitrofurantoin (Heipert & Pilz, 1978)
Oestrogens and progestagens
Increased unbound fraction of phenytoin secondary to reduced
intrinsic metabolism
Anticonvulsants:
Valproic acid (Patsalos & Lascelles, 1977; Wilder et al.,
1978; Bruni et al., 1980; Sanson et al., 1980; Perucca,
1984)
Carbamazepine (Hansen et al., 1971; Zielinski et al., 1985;
Browne et al., 1988b)
Sulthiame (Hansen et al., 1968; Houghton & Richens, 1974)
Clobazam (Zifkin et al., 1991)
Antithrombotics:
Coumarin derivatives (Skovsted et al., 1976; Panegyres &
Rischbieth, 1991; Abad-Santos et al., 1995)
Triclodine (Rindone et al., 1996)
Antituberculous drugs:
Isoniazid and PAS (Kutt et al., 1970; Walubo & Aboo,
1995)
H2 antagonists:
Cimetidine (Neuvonen et al., 1981; Levine et al., 1985;
Sambol et al., 1989)
Ranitidine (Bramhall & Levine, 1988)
Omeprazole (Gugler & Jensen, 1985)
Non-steroidal anti-inflammatory agents:
Azapropazone (Roberts et al., 1981; Geany et al., 1983)
Phenylbutazone (Andreasen et al., 1973; Neuvonen et al.,
1979)
Ibuprofen (Sandyk, 1982)
Antiinfective agents:
Metronidazole (Jensen & Gugler, 1985; Blyden et al.,
1988)
Chloramphenicol (Christensen & Skovsted, 1969; Ballek et al.,
1973; Cosh et al., 1987)
Antimycotics:
Miconazole (Rolan et al., 1983)
Fluconazole (Cadle et al., 1994)
Psychoactive drugs:
Fluoxetine (Jalil, 1992)
Risperidone (Sanderson, 1996)
Miscellaneous:
Amiodarone (Gore et al., 1984; Shackleford & Watson, 1987;
Ahmad, 1995)
Allopurinol (Yokochi et al., 1982)
Disulfiram
7.7 Main adverse effects
Anticonvulsant hypersensitivity syndrome is a
potentially fatal drug reaction with cutaneous and systemic
manifestations (incidence 1: 1000 to 1: 10.000). The findings
are:
Fever (90-100%)
Dermatological (90%): erythema, papulous rash. In some cases
erythroderma and even a lethal epidermal necrolysis has been
reported.
Lymphadenopathy (70%): lymphoma and depressed immunological
function have been reported.
Hepatitis (50-60%): hepatitis may develop in severe liver
failure and death.
Haematological (50%): leucocytosis with atypical lymphocytes,
eosinophilia, and agranulocytosis.
Connective tissues: coarsening of facial features, enlargment
of the lips, gingival hyperplasia, hypertrichosis, Peyronie's
disease.
(Physician's Desk Reference, 1995)
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biological analyses
8.1.1.3 Arterial blood gas analyses
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gs analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological Analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological analyses and their interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple qualitative test(s)
8.2.1.2 Advanced qualitative confirmation test(s)
8.2.1.3 Simple quantitative method(s)
8.2.1.4 Advanced quantitative method(s)
8.2.2 Test(s) for biological specimens
8.2.2.1 Simple qualitative test(s)
8.2.2.2 Advanced qualitative confirmation test(s)
8.2.2.3 Simple quantitative method(s)
8.2.2.4 Advanced quantitative method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analyses
8.3.1.1 Blood, plasma or serum
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.2 Urine
"Basic analyses"
"Dedicated analyses"
"Dedicated analyses"
Optional analyses"
8.3.1.3 Other biological specimens
8.3.2 Arterial blood gas analysis
Decrease of blood pH causes reduced protein
binding of phenytoin resulting in higher tissue
levels.
8.3.3 Haematological analyses
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.4 Other (unspecified) analyses
8.3.5 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Summary of the most essential biomedical and toxicological
analyses in acute poisoning and their interpretation
Interpretation of toxicological tests: total
phenytoin:
Serum concentration Signs and Symptoms
10 - 20 (g/mL) therapeutic range (Troupin 1984a, b)
20 - 30 (g/mL) horizontal nystagmus on lateral gaze,
ataxia, and drowsiness (Riker et al.
1978)
30 - 40 (g/mL) vertical nystagmus, slurred speech
ataxia, lurching gait, coarse tremors
50 - 70 (g/mL) fatalities recorded (Subik & Robinson
1982)
Interpretation of toxicological tests: free phenytoin
1.5 - 3.5 (g/mL) minor signs of intoxication (Wilson et
al. 1979)
> 5 (g/mL) toxic effects (Booker & Darcey 1973)
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Onset of symptoms and signs, principally
involving the central nervous system, occurs within
hours of acute overdose (Ellenhorn & Barceloux, 1988;
Curtis et al., 1989). These manifestations of toxicity
may last many days and, in general, correlate with
serum phenytoin concentrations. The earliest
manifestations of toxicity following overdose are
nystagmus on lateral gaze, ataxia and drowsiness. With
more severe intoxication, vertical nystagmus,
dysarthria, progressive ataxia to the point of
inability to walk, hyperreflexia and impaired level of
consciousness are observed. Coma and/or respiratory
depression is rarely observed and should prompt
consideration of an alternative diagnosis. Paradoxical
seizures have been reported in severe phenytoin
intoxication but are extremely rare (Stilman & Masdeu,
1985).
9.1.2 Inhalation
Not relevant
9.1.3 Skin exposure
Not relevant
9.1.4 Eye contact
Not relevant
9.1.5 Parenteral exposure
Fatalities have been reported following
intravenous administration of phenytoin to elderly
patients with cardiac arrhythmias (Gellerman &
Martinez, 1967; Unger & Sklaroff, 1967; Zoneraich et
al., 1976; Earnest et al., 1983).
These complications appear more likely when
intravenous phenytoin is administered at a rapid rate
(Earnest et al., 1983) and have been attributed to the
solvent propylene glycol rather than to the phenytoin
itself (Louis et al., 1967; Gross et al., 1979;
Randazzo et al., 1995). The risk of hypotension and
arrythmia is minimal when intravenous phenytoin is
used as an anticonvulsant and administered at the
recommended rate. In a series of 164 patients who
received intravenous phenytoin loading following
presentation with acute convulsions, the incidence of
hypotension was approximately 5%, and the incidence of
apnea and cardiac arrhythmias was 0% (Binder et al.,
1996).
9.1.6 Other
No data available
9.2 Chronic poisoning
9.2.1 Ingestion
The same as in acute poisoning.
9.2.2 Inhalation
Not relevant.
9.2.3 Skin exposure
Not relevant
9.2.4 Eye contact
Not relevant
9.2.5 Parenteral exposure
Not relevant
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Normally the clinical course is one of gradual
resolution of the signs and symptoms of intoxication leading
to complete recovery.
Death is rare after phenytoin overdose. It has been reported
in association with administration of intravenous phenytoin
for treatment of cardiac arrhythmias in elderly people
(Gellerman & Martinez, 1967; Unger & Sklaroff, 1967;
Zoneraich et al., 1976), and rarely from coma and hypotension
following oral overdose in children (see section 11 for
details).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Intravenous phenytoin has been reported to
cause depression of cardiac conduction, ventricular
fibrillation and heart block in elderly people treated
for cardiac arrhythmias (Gellerman & Martinez, 1967;
Unger & Sklaroff, 1967; Zoneraich et al., 1976).
Intravenous phenytoin is irritant and may cause
phlebitis (Jamerson et al., 1994).
9.4.2 Respiratory
No data available.
9.4.3 Neurological
9.4.3.1 CNS
Nystagmus, ataxia, dysarthria,
drowsiness, coarse resting tremor, ankle
clonus, brisk deep tendon reflexes. In severe
poisoning, the patient becomes obtund,
confused and disoriented. Coma and
respiratory depression are unusual.
9.4.3.2 Peripheral nervous system
No data available.
9.4.3.3 Autonomic nervous system
No data available
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
No data available.
9.4.5 Hepatic
A phenytoin hypersensitivity syndrome occurs
and is characterised by hepatitis. Overall mortality
rate when liver is involved is between 18% and 40%
(Harinasula & Zimmerman 1968; Dhar et al., 1974;
Parker & Shearer, 1979; Ting et al., 1982; Smythe &
Umstead, 1989; Howard et al., 1991,). The hepatitis is
usually anicteric (Pezzimenti & Hahn, 1970). Icterus
portends a poorer prognosis (Chaiken et al., 1950;
Dhar et al., 1974; Parker & Shearer, 1979).
Hepatomegaly with or without splenomegaly may be
present. The elevated hepatic transaminases, which may
be in the thousands of international units, can
continue to rise after phenytoin is discontinued (Ting
et al., 1982; Howard et al., 1991). Phenytoin-induced
chronic hepatitis has been reported (Roy et al.,
1993).
9.4.6 Urinary
9.4.6.1 Renal
No data available.
9.4.6.2 Other
No data available.
9.4.7 Endocrine and reproductive system
Phenytoin can induce hyperglycemia by
inhibiting the release of insulin (Belton et al.,
1965; Kizer et al., 1970; Levin et al., 1970; Holcomb
et al., 1972; Britton & Schwinghammer, 1980; Carter et
al., 1981). However, hypoglycemia has been reported in
a patient treated with phenytoin for 19 years who
ingested 20 g phenytoin together with 225 mg
zopiclone. This hypoglycemic episode was attributed to
phenytoin and may be due either to an escape from the
inhibitory effects of phenytoin on insulin secretion
or an increased sensitivity of the tissues to insulin
(Manto et al., 1996).
9.4.8 Dermatological
In the Anticonvulsant Hypersensitivity
Syndrome, the cutaneous eruption begins as a patchy
macular erythema that evolves into a dusky, pink-
red,confluent, papular rash that usually is pruritic.
The upper trunk, face, and upper extremities are
affected first, with later involvement of the lower
extremities. In some cases erythroderma ensues.
Patients have periorbital and facial edema (Vittirio &
Muglia, 1995).
Epidermal necrolysis (even lethal) has been reported
(Gately & Lam, 1979; Janinis et al., 1993; Hunt,
1995).
9.4.9 Eye, ear, nose, throat, local effects
No data available.
9.4.10 Haematological
A number of adverse haematological effects
have been reported. These are not observed following
acute overdose.
The haematological abnormalities reported include
leucocytosis with atypical lymphocytes, eosinophilia
(Ray-Chaudhuri et al., 1989), leucopenia (Choen &
Bovasso, 1973) and agranulocytosis (Tsan et al., 1976;
Rawanduzy et al., 1993).
The marrow toxicity of anticonvulsants, which may be
more likely when used in combination (e.g. primidone),
is recognised. There may be three mechanisms of
toxicity. Firstly, primidone and phenytoin both cause
folate deficiency and a megaloblastic anaemia.
Secondly, an immune mechanism with a phenytoin-
dependent antigranulocyte antibody may cause
leucopenia, which resolves on discontinuing therapy.
Finally, phenytoin may cause a direct toxic effect
with pancytopenia and agranulocytosis (Laurenson et
al., 1994).
Subnormal serum-folate concentrations were found in
patients with chronic epilepsy treated with phenytoin
(Horwitz et al., 1968; Maxwell et al., 1972). It was
suggested that folate deficiency resulted from
accelerated metabolism of folate consequent upon
induction of liver enzymes by
anticonvulsants.
9.4.11 Immunological
It seems likely that an aetiological
relationship exists between phenytoin treatment and
lymphoma. There is evidence of depressed immunological
function in patients given phenytoin (Brandt & Nilson,
1976; Rodriguez-Garcia et al., 1991; Ishizaka et al.,
1992; Kondo et al., 1994; Abbondazo et al.,
1995).
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
No data available.
9.4.12.2 Fluid and electrolyte disturbances
No data available
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
Anticonvulsant hypersensitivity syndrome is a
potentially fatal drug reaction with cutaneous and
systemic manifestations (incidence one in 1000 to one
in 10 000 exposures) to the arene oxide producing
anticonvulsants: phenytoin, carbamazepine, and
phenobarbital sodium. The features include fever
(90-100%), rash (90%), lympheadenopathy (70%),
periorbital or facial edema (25%), hepatitis (50-60%),
haematologic abnormalities (50%), myalgia, arthralgia
(21%) and pharyngitis (10%). The reaction may be
genetically determined (Vittorio & Muglia,
1995).
9.4.14 Other clinical effects
Not relevant.
9.5 Other
Connective tissues: coarsening of facial features,
enlargment of the lips, gingival hyperplasia, hypertrichosis,
Peyronie's disease (Dahlloef et al., 1991; Hassell & Hefti,
1991; Bredfeldt, 1992; Natelli, 1992; Thomason et al., 1992;
Seymour, 1993; Tigaran, 1994; McLoughlin et al., 1995; Perlik
et al., 1995).
9.6 Summary
10. MANAGEMENT
10.1 General principles
Toxicity is rarely fatal and is treated by the
institution of general supportive care and the
discontinuation of phenytoin.
10.2 Life supportive procedures and symptomatic/specific treatment
Make a proper assessment of airway, breathing,
circulation and neurological status of the patient.
Maintain a clear airway.
Administer oxygen if indicated.
Open and maintain an intravenous route. Administer
intravenous fluids.
Monitor vital signs. It is not necessary to monitor the
cardiac rhythm except in very severe cases.
10.3 Decontamination
Administer activated charcoal following acute overdose
(not necessary for cases of chronic toxicity).
10.4 Elimination
Forced diuresis, haemodialysis and haemoperfusion are
all ineffective (Jacobsen et al., 1986).
10.5 Antidote treatment
10.5.1 Adults
Not applicable.
10.5.2 Children
Not applicable.
10.6 Management discussion
No data available.
11. ILLUSTRATIVE CASES
11.1 Case reports from litterature
A 70-year old man with chronic lung disease for many
years and angina pectoris for six months was admitted to the
hospital because of increasing congestive heart failure
despite digoxin and diuretic therapy. On admission the
patient manifested evidence of some left-sided congestive
heart failure wih tricuspid regurgitation. The ECG revealed
regular sinus rhythm. The patient responded well to bed rest,
oxygen, antibiotics, bronchodilators, and expectorants.
Maintenance dose of digoxin was continued. Two days after
admission, he suddenly experienced pulmonary edema and atrial
flutter with a ventricular response of 150. Phenytoin 250 mg,
was given intravenously over a period of three minutes. The
atrial flutter persisted, but with a high degree of atrio-
ventricular block, followed by asystole three minutes after
the completion of phenytoin. All attempts at resuscitation
failed (Unger & Sklaroff, 1967).
A 4 year-old girl was well until midway through the afternoon
when her parents noted that her behaviour was abnormal. The
next day, it was learned that she had accidentally ingested
forty 50-mg tablets of phenytoin which has been prescribed
for an older sister. The patient was hyperactive and ataxic.
She appeared to have particular difficulty in keeping her
head erect. Her pupils were miotic. Shortly thereafter she
complained of epigastric pain and generalized pruritus. She
had delusions and was difficult to manage. Her temperature
was normal. Her condition changed little until that evening
when she became progressively lethargic and was thereupon
admitted to the hospital. The ataxia worsened, the patient
became gradually less responsive, and her pupils were
alternately miotic and dilated. By the following morning she
was semicomatose. Several times that day and the following
day, she vomited small mounts of pink material. The patient
repeatedly opened her eyes and appeared to be afraid and then
lapsed back into general unresponsiveness. Shortly after, the
blood pressure became unrecordable. At 80 hours after the
onset of symptoms there was an irreversible brain damage. A
blood sample, drawn 24 hours after the onset of symptoms,
revealed a phenytoin level of 94 mg/L (Laubscher, 1966).
A 15-year-old boy ingested 19,5 g phenytoin sodium (15 g
verifiable, equivalent to 392 mg/kg body weight)
approximately four hours before emergency department
presentation. He demonstrated the following signs: vomiting,
obtundation responsive only to painful stimuli, reactive to
light midposition pupils, brisk deep tendon reflexes,
choreoathetoid movements, and irregular and shallow
respirations. Treatment included nasotracheal intubation,
gastric lavage, and activated charcoal. His clinical
condition improved over the 7 following days, with periods of
combativeness and agitation requiring the administration of
diazepam, and responsiveness only to pain, alternately. The
patient demonstrated no hypotension or cardiac arrhythmia.
Peak phenytoin plasma level was 100,8 徃/mL. (Mellick et al.,
1989).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
No data available
12.2 Other
No data available
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