Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5203_Библиотеки_им_академика_М_И_Перельмана.pdf
130
W. Jing et al.
symptomatic. Interestingly, there were no signicant demographic differences
between the symptomatic and asymptomatic HA groups, except for the number of
coadministered medications. VPA treatment duration, dosage, and serum levels did
not signicantly differ between the two groups. However, patients using risperidone
alongside VPA had signicantly higher VPA levels, which correlated with blood
ammonia levels and symptomatic HA.A recent paper by Dong Won Kwack etal.
[253] highlighted that the total dosage of ASMs and the use of topiramate were
independent predictors of hyperammonemia in epilepsy patients treated with
VPA.Levocarnitine is the preferred therapeutic agent for hyperammonemia associated with VPA toxicity. Pagali etal. [254] presented a case of a 20-year-old woman
who intentionally overdosed on VPA, demonstrating a recurrence of hyperammonemia and symptoms after discontinuing levocarnitine supplementation. The authors
recommended at least 72h of levocarnitine treatment and an additional 24h of
monitoring to prevent hyperammonemia recurrence post-discontinuation. Another
case presented in the literature involved a 56-year-old man who developed hyperammonemia after intentionally overdosing on VPA and was treated with leucovorin.
In severe refractory cases, intermittent hemodialysis may be utilized, and recent
studies advocate the use of carbapenem antibiotics, particularly meropenem, for
treatment [255].
Dyskinesia
Dyskinesia, including tremor and Parkinson’s disease symptoms, are recognized
adverse effects of VPA.Tremor typically presents as postural tremor, and there is no
denitive correlation between VPA dosage and tremor occurrence. Lan etal. [256]
conducted a study on the risk factors associated with VPA-induced tremor and
reported that female sex, a family history of tremor, a daily dose of VPA exceeding
1000mg, and a therapy duration exceeding 24months were associated with VPAinduced tremor. However, the relationship between the development of resting
tremors and other symptoms of Parkinson’s disease in patients taking VPA remains
unexplored. In a study evaluating 125 patients treated with VPA for epilepsy or
migraine headaches using the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS), 11.2% of the patients exhibited resting tremors, with signicantly greater
FTM-TRS scores than did the controls (p<0.001). However, only one patient was
diagnosed with Parkinson’s disease, suggesting possible VPA-induced Parkinson’s
disease or exacerbation of motor features of Parkinson’s disease by VPA.The incidence of Parkinson’s syndrome in this cohort study was 1.6%, which contrasts with
a previously reported pooled incidence of 3%. The occurrence of resting tremors in
11.2% of VPA-treated patients was linked to VPA-induced tremor rather than to the
presence of Parkinson’s disease [257].
VPA is associated with various other movement disorders. Rissardo etal. [258]
evaluated the clinico-epidemiological features, pathophysiological mechanisms,
and treatment of VPA-related movement disorders (MDs). Among the 362 subjects
with MD secondary to VPA across 138 publications, the identied MDs included
Parkinson’s syndrome (252 cases), myoclonus (54 cases), dystonia (17 cases),
2 Antiseizure Medications
131
dyskinesia (16 cases), stuttering (4 cases), tics (3 cases), and inability to sit still (1
case). Discontinuation of VPA treatment was the most common management
approach, with an 80.61% full recovery rate. Additionally, there has been a case
report of VPA-induced reversible lateralized manual dexterity in a 24-year-old
woman who was diagnosed with Rasmussen’s encephalitis at the age of 6. She
developed persistent left-sided hemiparesis at the age of 11years after the addition
of VPA to CBZ and phenobarbital treatment, and motor cessation was observed the
day after VPA cessation [259].
Others
Yıldız etal. [260] investigated the potential cardiac effects of both low-dose (LD)
and high-dose (HD) VPA treatment in seizure-free rats. These ndings revealed a
dose-dependent increase in caspase-3 staining intensity, accompanied by a notable
reduction in connexin 43 and troponin T staining intensity in the VPA-treated group.
Biochemically, high-dose VPA administration led to a signicant increase in malondialdehyde (MDA) levels within myocardial tissues. These observations underscore the potential risk of cardiovascular complications associated with VPA
treatment. In addition, Liang etal. [261] examined the risk of all-cause mortality
and mortality specically from heart failure (HF) in individuals receiving a combination of VPA and LEV/LTG.Their analysis conrmed that VPA treatment was
linked to higher rates of both all-cause mortality and mortality attributable to heart
failure.
Moreover, VPA has been implicated in renal injury. Anguissola et al. [262]
reviewed the literature and identied 28 case reports documenting the cases of 48
epileptic patients who had used VPA for 7months or longer and exhibited features
consistent with signicant renal tubular injury. These manifestations included hypophosphatemia, urinary glucose, proteinuria, metabolic acidosis, hyperuricemia,
renal tubular proteinuria, hypokalemia, and hypocalcemia. Biopsies from six
patients revealed altered proximal renal tubular cells accompanied by large, malformed mitochondria. Notably, mild or asymptomatic renal injury was described in
eight patients. Isolated renal tubular proteinuria, primarily of N-acetyl-β-
aminoglucosidase, was frequently observed in 285 subjects who had taken VPA for
7months or more. Thus, valproic acid may induce signicant tubular injury, often
associated with proximal tubular mitochondrial toxicity; prolonged treatment, typically exceeding 7months, is commonly linked to asymptomatic or less symptomatic tubular injury. Additionally, VPA has been implicated in lung injury through
oxidative stress mechanisms [263].
The long-term administration of VPA has been linked to acute pancreatitis, a
potentially life-threatening condition. Monica C M Bischof etal. [264] conducted
an extensive literature review on VPA-induced acute pancreatitis, highlighting its
unpredictable onset and high fatality rate.
Although the effects of sodium phenytoin on oral health have been extensively
studied, information regarding the impact of VPA remains scarce. A study noted a
44% correlation between VPA and gingival hyperplasia, emphasizing the need for
132
W. Jing et al.
dentists treating epilepsy patients to consider the potential for VPA-induced gingival overgrowth [265]. In addition, VPA has been specically associated with an
elevated risk of urinary tract infections [266]. Coagulation disorders are among
the most commonly reported adverse effects of VPA, with platelet dysfunction
being predominant [267]. Pediatric patients are particularly susceptible to VPAinduced hematotoxicity due to their increased risk of leukemia. Riahi-Zanjani
etal. [268] conducted a systematic literature review, identifying 36 relevant articles involving 1381 pediatric patients, which revealed that VPA therapy can lead
to severe hematologic toxicity, including neutropenia, thrombocytopenia, and
myelosuppression, even at therapeutic doses. Discontinuation of VPA or dose
reduction typically results in complete resolution of hematologic impairment
within 2weeks. The authors stressed the importance of monitoring hematological
parameters during VPA treatment and suggested that combining VPA with antioxidants may mitigate hematologic side effects by targeting potential mechanistic
pathways.
Drug-induced lupus erythematosus (DILE) constitutes 10–15% of systemic
lupus erythematosus (SLE) cases and can be caused by more than 100 drugs. The
clinical and serologic manifestations of DILE vary widely depending on the drug,
often leading to its oversight in clinical practice. In June 2021, Papadopoulou etal.
[269] searched for VPA-induced DILE cases in the PubMed and Embase databases
and identied 15 articles meeting the inclusion criteria. While SLE predominantly
affects women, VPA-induced lupus appears to be more prevalent in men. Half of the
patients developed DILE within the initial 3months of VPA treatment, while four
patients experienced DILE onset between 1 and 5years after commencing VPA
therapy. The presentation of lupus was generally mild, with polyarthritis, pleural
effusion, or pericarditis being the most common manifestations. Notably, one
patient exhibited Rowell syndrome, a rare variant of lupus erythematosus characterized by erythema multiforme and sporadic antinuclear antibodies (ANAs).
Involvement of the central nervous system, kidneys, or skin was minimal or absent,
although seven patients displayed cytopenia. Immunological assessments revealed
positive ANAs in the majority of patients (86.7%), with ve patients testing positive
for antihistone antibodies, three for anti-dsDNA antibodies, and two showing hypocomplementemia. Despite the rapid resolution of clinical symptoms upon discontinuation of VPA, serologic abnormalities persisted for up to 18 months.
Corticosteroids were administered to eight patients during VPA cessation. The
authors underscored the association between VPA and DILE, urging clinicians to be
vigilant to ensure optimal patient outcomes. Although some potential pathophysiologic mechanisms have been proposed, further research is needed for a comprehensive understanding of the syndrome.
Additionally, a few cases of drug reaction eosinophilia and systemic syndrome
(DRESS), characterized by cutaneous symptoms, fever, eosinophilia, thrombocytopenia, and multiorgan involvement, have been linked to VPA [270]. Furthermore,
VPA-associated Fanconi syndrome (FS), though rare, should be considered in epilepsy patients, particularly if the patient has severe psychomotor disorders, uses
feeding devices, and receives ASM treatment other than VPA [271].
2 Antiseizure Medications
133
Summary
Since its introduction as an antiseizure medication (ASM), VPA has been subjected
to more than 50years of experimental research and clinical use, establishing it as
one of the most potent ASMs available. Its remarkable efcacy extends beyond
neurological disorders, demonstrating promising therapeutic benets in various
other elds. This broad potential warrants continued investigation and exploration,
not only within the realm of neurology but also across diverse medical domains.
2.1.1.7 Phenytoin Sodium
Drug Characteristics
[Chemical name] 5,5-Diphenylhydantoin sodium salt
[Chemical structure]
[Molecular formula] C15H11N2NaO2
[Molecular weight] 274.25
[Indications] This drug can be used for the treatment of generalized tonic–clonic
seizures, focal seizures, and status epilepticus and for the prevention and treatment
of epileptic seizures during and after neurosurgery.
[Specication] Phenytoin sodium tablets (mostly tablets): 50 mg; 100 mg.
Phenytoin sodium for injection: 0.1g; 0.25g.
[Dosage]
Typical dosages for adults usually start at 100mg (1 tablet) twice daily, increasing
gradually to 250–300mg/day over 1–3weeks. The total daily dose is usually divided
into three equal doses, with a maximum of 300mg/dose or 500mg/day. However,
personalized dosing should consider individual patient characteristics and pharmacokinetic proles. Once seizure control is achieved and steady blood drug levels are
reached, long-acting (controlled release) formulations may be used once daily. In
cases of frequent seizures, an initial dose of 12–15mg/kg body weight, divided into
134
W. Jing et al.
two to three doses every 6h, may be administered. Starting from the following day,
100mg (or 1.5–2 mg/kg body weight) may be given three times daily until the
appropriate dosage is established.
Regarding children, VPA should generally be avoided in infants and young children due to challenges in monitoring side effects. If necessary, the initial dose is
typically 5mg/kg/day, divided into two to three doses, with adjustments made as
necessary. The maximum daily dose is 250 mg. Maintenance dosages typically
range from 4 to 8mg/kg or, according to body surface area, do not exceed 250mg/
m2, with consideration given to monitoring blood concentrations.
[Adverse reactions]
Gingival hyperplasia is common, with a high incidence in children. If hyperplasia is
severe, surgical removal may be needed.
Adverse intestinal effects include nausea, vomiting, constipation, epigastric
pain, dysphagia, loss of taste, anorexia, and weight loss.
Adverse central nervous system reactions include confusion, ataxia, blurred
vision, diplopia, toxic amblyopia, vertigo, headache, insomnia, transient nervousness, tremor, ataxia, chorea, dystonia, slurred speech and confusion, transient neurosis, chorea, dystonia, tremor, and asterixis.
Hematopoietic system adverse reactions include granulocytopenia or thrombocytopenia, aplastic anemia, and megaloblastic anemia.
Adverse skin reactions include allergic reactions, common rashes with high
fever, and rare severe skin reactions, such as exfoliative dermatitis and erosive erythema multiforme.
Adverse reactions of the rheumatic immune system include systemic lupus erythematosus and fatal hepatic necrosis.
Adverse reactions to the lymphatic system include Hodgkin’s disease.
Long-term use in children can cause rickets or bone abnormalities, and use by
pregnant women can occasionally cause teratogenesis.
In addition, phenytoin has also been reported to increase blood sugar and
cause cancer.
Clinical Applications andBasic Research
Historical Evolution ofPhenytoin Sodium
Heinrich Biltz rst synthesized phenytoin in 1908, initially believing it to possess
analgesic and sedative properties, without recognizing its potential as an antiepileptic medication. It was not until 1936 when American doctor H.Houston Merrit and
chemist Tracy Putnam rst utilized phenytoin sodium for treating epilepsy, observing its inhibitory effects on seizures in patients. This discovery identied phenytoin
as a signicant drug for epilepsy treatment. In 1946, L.S.Goodman conducted further research on the anticonvulsant properties of phenytoin sodium [272]. B
Bashinski proposed the use of phenytoin sodium for treating epilepsy in children
[273]. In 1949, J.P. McGovern described phenytoin poisoning [274]. In 1950, R D
2 Antiseizure Medications
135
Sweet et al. investigated a xed skin rash caused by phenytoin [275]. In 1981,
C.E.Pfeie and colleagues described the solubility of phenytoin in three different
intravenous injection solutions. Their study concluded that 0.9% sodium chloride
and lactated Ringer’s solution were suitable for intravenous administration of phenytoin [276]. In 2020, Yi Kang discovered that phenytoin improves gingival broblast aging and is related to autophagy [277].
Adverse Reactions ofPhenytoin Sodium
M Kathiravan etal. [278] conducted a cross-sectional study aiming to address anemia induced by long-term phenytoin treatment in epilepsy patients. They categorized epilepsy patients into groups of cases (duration >2 years) and controls
(<1year) based on the duration of phenytoin treatment. The study revealed that the
levels of folic acid and vitamin B12 were signicantly lower in the case group than
in the control group. This suggests that prolonged use of phenytoin may signicantly affect the concentrations of folic acid and vitamin B12in epilepsy patients.
Y Han etal. [83] performed a systematic review and comprehensive evaluation
of thyroid hormone levels in epilepsy patients and controls receiving monotherapy.
They assessed the long-term effects of oral ASMs on thyroid hormone levels in
epilepsy patients. The ndings indicated that patients with treated chronic epilepsy
are at a greater risk of developing thyroid dysfunction, such as subclinical or clinical
hypothyroidism, than the general population. CBZ and phenytoin treatment were
found to decrease T4 levels and have little effect on TSH secretion, making them the
drugs most strongly associated with reduced T4 and T3 levels.
Sangeetha etal. [279] conducted a cross-sectional study to assess atherogenic
risk factors in young Indian adult epilepsy patients treated with phenytoin. They
categorized subjects into three groups: healthy controls, newly diagnosed epilepsy
patients, and epilepsy patients treated with phenytoin for more than 6months. This
study revealed that compared to healthy controls, newly diagnosed epilepsy patients
exhibited alterations in indicators related to dyslipidemia, oxidative stress, and lowgrade inammation (hsCRP). These changes were further exacerbated in epilepsy
patients after 6months of phenytoin treatment.
C Morán-Mariños etal. [280] conducted a systematic literature review on cases
of drug reaction eosinophilia and systemic symptoms (DRESS) syndrome induced
by phenytoin and explored the characteristics of patients with this syndrome.
DRESS syndrome is a severe adverse skin reaction caused by sensitivity to drugs,
including phenytoin. The review identied 40 cases of DRESS syndrome, with all
patients presenting with a rash, 50% with lymphadenopathy, and 30% with facial
edema. The liver and respiratory tract were the most commonly affected organs, and
eosinophilia was a prevalent feature. Given the severity and high mortality rate of
DRESS syndrome, the authors emphasized the importance of monitoring for
adverse effects of ASMs.
M Sáenz-Farret etal. [81] conducted a comprehensive review aiming to elucidate the intricate relationship between movement disorders and ASMs. They
explored various combinations of 15 movement disorders (excluding ataxia) and
136
W. Jing et al.
24 ASMs, aiming to describe treatable movement disorders, those exacerbated or
induced by ASMs, and the complex interaction mechanisms and risk factors
involved. The relationship between ASMs and movement disorders is multifaceted. Although ASMs are commonly employed to alleviate tremor, myoclonus,
and restless leg syndrome, they can also act as potential triggers for iatrogenic
movement disorders, notably Parkinson’s disease and tremor. The ASMs that
worsen or induce movement disorders include phenytoin. The pathophysiology of
phenytoin-induced choreoathetosis is incompletely understood but has been
attributed to defects in basal ganglia neurotransmitters. Phenytoin inhibits dopamine uptake in the brain, leading to an increase in homovanillic acid in cerebrospinal uid, suggesting heightened dopaminergic activity. However, phenytoin
treatment may exacerbate Parkinson’s disease and tardive dyskinesia, potentially
by antagonizing specic dopamine receptor subtypes, thereby potentiating dyskinesia induced by dopamine blockers. Both epileptic and nonepileptic myoclonus
have been reported in patients taking phenytoin. Asterixis, a common movement
disorder associated with phenytoin use, is frequently observed in patients receiving intravenous phenytoin treatment with transiently elevated drug concentrations. Additionally, generalized athetosis, choreoathetosis, and isolated athetosis
may occur, particularly at toxic phenytoin concentrations. In summary, the therapeutic or toxic effects of a drug on motor symptoms can vary depending on factors
such as dosage, individual variability, concurrent medication use, and other less
understood conditions.
A case report described a 53-year-old woman with recurrent acute ataxia [281].
Although the patient had a history of epilepsy, she had been seizure-free for more
than a decade. Complete cranial MRI revealed no evident signs of phenytoininduced ataxia. Remarkably, her symptoms swiftly ameliorated upon reduction of
phenytoin dosage, and no recurrence was noted during the 1-year follow-up period.
This nding underscores the importance of considering potential adverse drug
effects when patients with epilepsy treated with phenytoin present with ataxia.
A Asadi-Pooya A etal. [282] conducted a systematic review of the literature to
comprehensively delineate the cosmetic adverse effects associated with ASMs,
focusing particularly on alopecia, hirsutism, acne, and gingival hyperplasia. The
most robust evidence for such effects is linked to phenytoin use, which is implicated
in causing gingival hyperplasia, hirsutism, and acne, and valproic acid, which is
associated with alopecia and hirsutism. Phenytoin-induced gingival hyperplasia is
inuenced by various factors, including genetic predisposition, activation of collagenase, inammation and immune changes induced by plaque, and stimulation of
growth factors. Maintaining good oral hygiene is crucial for preventing gingival
hyperplasia, and patients receiving antiepileptic therapy should prioritize oral
health. Some studies suggest that folic acid supplementation may mitigate
phenytoin- related gingival hyperplasia, although this remains a topic of debate.
Jana Heidemann [266] investigated the correlation between anticonvulsant drug
usage and the risk of urinary tract infections through a case–control study. By
matching controls without urinary tract infections with patients with urinary tract
infections based on sex, age, and codiagnosis, the study revealed that phenytoin,
2 Antiseizure Medications
137
primidone, carbamazepine, and valproic acid use were associated with an elevated
risk of urinary tract infections.
Research by Erika Minowa [283] demonstrated that phenytoin use induces an
increase in the intracellular calcium concentration ([Ca2+]i) by impeding calcium
efux in human gingival broblasts. Furthermore, phenytoin use was found to augment the small calcium response triggered by low-concentration ATP or histamine
stimulation by inhibiting calcium efux. These ndings suggest that phenytoin may
contribute to drug-induced gingival overgrowth by interacting with inammatory
bioactive substances in the gingiva.
Matteo Candeloro [41] retrospectively analyzed patient data from 2011 to 2020
to investigate the incidence of thromboembolic events in individuals treated with
CBZ or phenytoin in combination with oral anticoagulants. The study revealed a
greater occurrence of thromboembolism in patients treated with anticoagulants
combined with CBZ or phenytoin than in those not taking ASMs. Thrombotic and
bleeding event rates were similar among patients receiving treatment with direct
oral anticoagulants (DOACs) or vitamin K antagonists.
Phenytoin Sodium fortheTreatment ofRefractory andSuperrefractory Status
Epilepticus
Status epilepticus is a common neurological emergency in children. Rapid treatment is necessary because neuronal death and damage are suspected to be related to
the duration of epileptic seizures.
A Klowak J etal. [284] conducted a study to assess the effectiveness and safety
of levetiracetam compared to those of phenytoin or fosphenytoin in treating
benzodiazepine- refractory status epilepticus in children. Phenytoin is associated
with adverse reactions such as hypotension and cardiac arrhythmias, particularly
with rapid infusion, and it has a narrow therapeutic window with signicant drug
interactions. Despite being commonly recommended as a second-line treatment for
status epilepticus, this recommendation is based on low-quality evidence, including
observational studies and expert opinions. The authors found evidence suggesting
that levetiracetam is as effective as phenytoin or fosphenytoin in children with
benzodiazepine- refractory status epilepticus. Given their similar efcacy, clinicians
and guideline developers should consider the differing safety proles when choosing between levetiracetam and phenytoin or fosphenytoin.
According to P Jain etal. [95], intravenous phenytoin or phenobarbital administration has traditionally been the preferred treatment for benzodiazepine-resistant status epilepticus. However, the adverse effects of phenytoin, including
cardiac arrhythmias, hypotension, extravasation, and purple glove syndrome, as
well as limitations on the infusion rate, restrict its use. Based on low-quality evidence, the primary outcome was that phenobarbital was signicantly better than
phenytoin in children and signicantly better than valproate in adults in regard to
adverse effects. Levetiracetam is similar to phenytoin or fosphenytoin regarding
adverse effects. Mortality rates were comparable between interventions. For intubation in children, phenobarbital is considered safer than phenytoin, levetiracetam
138
W. Jing et al.
is safer than phenytoin, and valproate is superior to both phenobarbital and phenytoin regarding safety, with less cardiovascular instability than phenytoin.
Phenobarbital and high- dose levetiracetam were signicantly more effective than
phenytoin in halting seizures within 60min. Ultimately, drug selection should
take into consideration effectiveness, safety concerns, availability, cost, and systemic comorbidities.
Application ofPhenytoin Sodium inSpecial Populations withEpilepsy
Status epilepticus poses a critical medical emergency with considerable risks to
morbidity and mortality. Liver and renal dysfunction can signicantly impact
the pharmacokinetics of drugs used in its treatment. Phenytoin is often employed
as a second-line therapy after benzodiazepines. G Mastroianni et al. [285]
reported that severe liver damage can reduce phenytoin clearance, leading to an
increased risk of toxic plasma concentrations. However, there are no specic
dosage adjustments recommended for patients with mild to severe hepatic disease. Caution should be exercised when using phenytoin in these patients, with
frequent monitoring of serum levels advised to mitigate the risk of toxicity.
Additionally, phenytoin should be used cautiously in patients with hepatic failure due to its potential for toxicity. In patients with renal disease, it is recommended that lorazepam be administered during the prehospital and early
in-hospital stages of status epilepticus and switch to phenytoin when status epilepticus is conrmed. Phenytoin is considered safe for use in individuals with
kidney disease.
Status epilepticus during pregnancy poses a life-threatening medical emergency
for both the mother and fetus. Managing status epilepticus during pregnancy is challenging due to pregnancy-related pharmacokinetic changes and fetal risks associated with antiepileptic and narcotic drugs. Currently, there is no standardized
treatment protocol for status epilepticus during pregnancy, and existing evidence is
primarily derived from case reports and small case series. The literature on status
epilepticus during pregnancy suggests that benzodiazepines are the preferred rstline treatment, with levetiracetam and phenytoin being the most suitable secondline options [188].
In a single-blinded case–control study conducted by Mahmoud Mohammadi
etal. [286], it was observed that phenytoin and levetiracetam had efcacy rates of
83.3% and 86.7%, respectively, in treating neonatal epilepsy, with no statistically
signicant difference between the two groups. Adverse effects were comparable
between the phenytoin and levetiracetam groups, indicating the safety and practicality of both drugs in managing neonatal epilepsy. Veronica Alix [287] conducted a
retrospective observational cohort study comparing the acute and long-term efcacy
of fosphenytoin and phenobarbital as rst-line ASMs for neonatal epilepsy. Although
there were no differences in acute outcomes between the two groups, signicantly
fewer infants in the fosphenytoin group exhibited moderate to severe neurodevelopmental delays at the 18- and 24-month assessments. This suggests that fosphenytoin
may have the potential to signicantly enhance neurodevelopmental outcomes in
2 Antiseizure Medications
139
neonates aged 18–24months compared to phenobarbital. In a systematic review by
Rui Shi etal. [288], which assessed the effectiveness and safety of levetiracetam and
phenytoin as second-line drugs for treating convulsive status epilepticus in children
through meta-analysis, levetiracetam was found to be more effective than phenytoin
in treating convulsive status epilepticus, with no increase in incidence of adverse
reactions. This highlights levetiracetam as a favorable option for managing convulsive status epilepticus in children due to its efcacy and safety prole compared to
those of phenytoin.
The Efcacy andSafety ofPhenytoin Sodium astheFirst Choice
fortheTreatment ofEpilepsy
I Guidotti etal. [289] conducted a comprehensive literature review spanning
40years from 1983 to 2022, focusing on studies describing human regeneration through multichannel video electroencephalography in the treatment of
pediatric patients with epileptic seizures. One study compared phenobarbital
and phenytoin as first- and second-line treatments and reported that both controlled less than 50% of neonatal seizures. Although phenytoin, or its prodrug
fosphenytoin, has been traditionally utilized as a first- or second-line ASM for
neonatal seizures due to its effects on voltage-dependent sodium channels,
published data do not clearly establish its superiority over phenobarbital.
Although phenytoin or its precursor fosphenytoin, which acts on voltagedependent sodium channels, has traditionally been used as a first- or secondline antiepileptic for neonatal seizures, published data have not definitively
confirmed its superiority over phenobarbital. However, phenytoin use poses
several risks, including the potential for arrhythmias and hypotension, a narrow therapeutic range due to its nonlinear pharmacokinetics, a short half-life
necessitating plasma level monitoring, poor intestinal bioavailability, and
interactions with various antibiotics and other epilepsy medications, rendering it potentially unsafe.
J Dell’Aquila etal. [290] reviewed multiple clinical studies comparing the effectiveness of phenytoin and levetiracetam in suppressing seizure activity. Although
phenytoin has been a historical mainstay in epilepsy treatment and a second-line
option for status epilepticus, its use has declined due to signicant side effects,
including sedation, hirsutism, gingival hyperplasia, and various other adverse
effects. Intravenous phenytoin administration is associated with additional complications, such as hypotension, cardiac arrhythmias, and skin necrosis. Moreover, its
narrow therapeutic index and complex pharmacokinetics necessitate careful dose
monitoring to prevent toxicity and minimize drug interactions. In contrast, levetiracetam, a second-generation ASM, offers advantages such as fewer adverse reactions, a reduced need for dose monitoring, fewer drug interactions, faster attainment
of therapeutic levels, and a wider therapeutic index. Although there was no signicant difference in the efcacy of phenytoin or levetiracetam for treating status epilepticus, the incidence of adverse effects of levetiracetam was signicantly lower
than that of phenytoin.