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Phenytoin

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names/main trade names
   1.6 Main manufacturers and/or importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
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
         8.3.1.2 Urine
         8.3.1.3 Other biological specimens
      8.3.2 Arterial blood gas analysis
      8.3.3 Haematological 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
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive system
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat, local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from litterature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
12. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADRRESS(ES)
    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: 295-298C
                       (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 20C

               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 g / mL (40 to 80 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 g/mL (80
                       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 g/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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    12. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADRRESS(ES)

        Author:                 Prof.Dr.A.N.P.van Heijst
                                Baarnseweg 42 A
                                3735 MJ Bosch en Duin
                                The Netherlands
                                Tel. (31) 30 228 7178
                                Fax  (31) 30 225 1368
                                E-mail: 106072.2411@compuserve.com
                                December 1996.
    
        Reviewer:               MO Rambourg Schepens
                                Centre Anti-Poisons de Champagne Ardenne
                                Centre Hospitalier Universitaire
                                F-51092 Reims Cedex
                                France
                                E-mail: marie-odile.rambourg@wanadoo.fr
                                August 1997
    
        Peer review:            N Ben Salah, A Borges, J Gregan, M Mathieu
                                Nolf, L Murray (coordinator), MO Rambourg
                                Schepens
                                Rio, September 1997
    
        Finalization/Edition:   L Murray, MO Rambourg Schepens
                                November 1997
    



    See Also:
       Toxicological Abbreviations
       Phenytoin (IARC Summary & Evaluation, Volume 66, 1996)