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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5851_Библиотеки_им_академика_М_И_Перельмана.pdf
476
M. Trammel et al.
Additionally, metabolism can occur by hepatic conjugation and mitochondrial
β-oxidation. Common inducers that increase clearance and decrease steady-state
concentrations include phenobarbital (PHB), phenytoin (PHT), primidone, carbamazepine (CBZ), and topiramate (TPM). Inhibitors of metabolism that slow clearance
and increase the steady-state concentrations of ASMs include valproic acid (VPA)
and non-ASMs such as omeprazole, verapamil, macrolide antibiotics, paroxetine,
ketoconazole, and sulfamethoxazole [20]. Of ASMs, levetiracetam (LEV) has the
fewest DDIs.
ASM elimination, expressed as the biological half-life, is the time required for
the drug’s serum concentration to decrease by 50% after absorption and distribution. Half-life is commonly most affected by renal function, and dose adjustment is
often necessary with kidney impairment and renal replacement therapy. Metabolism
and clearance can be dependent on concomitant medications, hepatic function, and,
as is the case of PHT, nonlinearity at baseline.
Additionally, there are patient factors that may play a role in the pharmacokinetics of medications. The pharmacist considers several patient-specic issues when
choosing medications, routes of administration, and clearance. These include
changes in drug metabolism and clearance in the setting of preexisting or evolving
kidney injury or hepatic failure, shock, hypotension, hyperthermia, or pregnancy;
gastrointestinal absorption and gut motility; and changes in nutritional status (e.g.,
albumin and protein intake), total body weight, or body water that may impact the Vd.
Other key concepts when treating patients with SE include tapering of ASMs,
especially in the setting of an infusion that has been administered at anesthetic
doses. Both BZPs and barbiturates can have withdrawal symptoms of anxiety, restlessness, insomnia, irritability, confusion, nausea, vomiting, tremor, muscle stiffness, seizure, psychosis, and autonomic changes such as hypertension, tachycardia,
and diaphoresis.
18.4 Therapeutic Drug Monitoring
seizures, which requires continuous electroencephalography unless the patient
awakens to baseline state), a best practice guideline was established for therapeutic drug monitoring (TDM) of ASM levels for key reasons: (1) to identify a target
therapeutic concentration after titrating to clinical effectiveness since the cause of
a change in drug response in the future may be identied by a level that varies
from this target; (2) to evaluate for medication toxicity, especially when the therapeutic index (TI), i.e., the margin between the therapeutic dose and toxic dose, is
narrow; (3) to assess compliance, especially in patients with uncontrolled or
breakthrough seizures; (4) to guide dosage adjustment when pharmacokinetics
may vary (e.g., metabolic changes, concomitant medications, pregnancy); and (5)
to guide dose adjustment with medications with dose-dependent pharmacokinetics, e.g., PHT [21].
18 Status Epilepticus andRefractory Status Epilepticus
477
TI is dened as ED50/TD50, or the ratio of the drug concentration at which the
drug is therapeutic or effective for 50% of patients (ED50) to the concentration that
is toxic to 50% of patients (TD50) [22]. Older-generation ASMs such as PHT have
a narrow TI with complicated pharmacokinetics and a high potential for DDIs.
Although newer ASMs are less likely to have these concerns, TDM of newer ASMs
in a real-world study showed clinical benet in seizure reduction and decreases in
side effects [23].
Since albumin levels may uctuate widely during the hospital course of a critically ill patient, TDM is especially helpful when ASMs are signicantly protein
bound, e.g., PHT and VPA. In this situation, free levels might be helpful, although
unless obtained on-site; delays in results can render the information less relevant in
an ICU setting. When concomitant medications are administered, TDM can potentially assist the clinician in atypical dosing that may be necessary, although reference ranges can be misleading. The references are based on statistics of when the
majority of patients experienced optimal response and may not be relevant to the
index patient.
The optimal timing to draw a medication level is when the ASM has reached a
steady state, typically 4–5 half-lives after starting treatment or a dose adjustment.
ASMs with long half-lives do not require a trough level; however, ASMs with midor short half-lives (<12h) may experience more uctuation with inconsistent antiseizure efcacy, and a trough obtained just before a “steady-state” dosage
administration might be useful (e.g., LEV, VPA, or TPM) (Table18.2).
Table 18.2 Target therapeutic index (TI) for selected ASMs
Drug Established target TI
Carbamazepine
Clobazam
Phenobarbital
Phenytoin
a
(CBZ) 4–11μg/mL
a
(CLO) 0.03–0.3μg/mL
a
(PHB) 10–40μg/mL
a
(PHT) Total: 10–20μg/mL
Free: 1–2μg/mL
Valproic acid
a
(VPA) 50–100μg/mL
Drug Potential or suggested TI
Levetiracetam
Brivaracetam
Ganaxolone
Lacosamide
Lamotrigine
Perampanel
Topiramate
a
[21]
b
[24]
c
[25]
b
(LEV) 10–40μg/mL
b
(BRV) 0.2–2μg/mL
c
(GX) 85–250ng/mL
b
(LCM) 3–10μg/mL
b
(LTG) 3–13μg/mL
b
(PMP) 0.1–1μg/mL
b
(TPM) 2–10μg/mL
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M. Trammel et al.
18.5 Adverse Drug Effects
Consideration of adverse drug effects (ADEs) includes (1) acute dose-related effects
that are typically rapidly reversible, e.g., sedation, fatigue, sodium levels, platelets,
and transaminases; (2) idiosyncratic ADEs that are less common but serious and
often dose dependent, such as Stevens-Johnson syndrome and toxic epidermal
necrolysis; and (3) cumulative toxicity, which is less likely a concern in SE when
initiating ASM, as this typically requires a prolonged exposure over several months
to years.
18.6 Management Strategies forTermination ofSE
In a study of patients with generalized convulsive status, successful termination
with rst-line treatment with GABAergic medications such as lorazepam, PHB, or
diazepam (DZP) with PHT varied between 64.9%, 58.2%, and 55%, respectively;
however, the response rates for a second-line agent were 7.0% and 2.3% for thirdline agents [26]. Thus, 35–45% of patients with SE fail rst-line therapy, and rapid
escalation may help prevent RSE and improve outcomes [27].
When considering termination of SE, two major strategies include (1) enhancement of inhibitory processes and (2) opposition of excitatory processes. Initial
immediate termination focuses on a fast-acting BZP to activate the GABAA receptor
that allows negatively charged chloride cellular inux with neuronal inhibition.
Subsequent second- and third-line therapy continues to attempt to leverage
GABAergic inhibition through GABA receptors, GABA transaminase, or GABAsynthesizing enzyme glutamate decarboxylase. Additional strategies include (1)
modulation of excitatory processes through decreases in the glutaminergic excitatory activity (i.e., NMDA or AMPA glutamate receptors); (2) modulation of synaptic vesicles, i.e., synaptic vesicle glycoprotein 2A (SV2A); and (3) direct or
indirect action on voltage-gated sodium, calcium, or potassium ion channels by
modication of the synthesis, metabolism, or function of neurotransmitters and
receptors. SE termination often requires multiple mediations utilizing different targets of action.
18.6.1 Guidelines forSE Termination
Various guidelines have been created to address strategies for the termination of SE
[28, 29]. The guidelines universally discuss the initial use of a fast-acting BZP, followed by second-line parenteral medications. The Established Status Epilepticus
Treatment Trial (ESETT) of 384 patients with SE refractory to BZP showed equivalent efcacy of seizure termination in patients randomized to an infusion over
18 Status Epilepticus andRefractory Status Epilepticus
479
10min of (1) LEV 60mg/kg, maximum dose of 4500mg; (2) valproate 40mg/kg,
maximum dose of 3000 mg; or (3) fosphenytoin 20 mg/kg, maximum dose of
1500mg [30]. There were no signicant differences in hypotension, intubation, or
death. As such, these agents are the most frequently utilized second-line ASMs in
SE.The primary outcome of cessation of SE and improvement in the level of consciousness at 60min occurred in 47% of patients treated with LEV, 46% with VPA,
and 45% with fosphenytoin. However, 10.7–11.2% of patients had recurrent seizures or RSE.
The most recent SE guideline published in 2020 addresses refractory convulsive
SE and evaluates the strength of evidence for the efcacy of eight parenteral ASMs
as a third-line treatment [27]. For RSE, administration of parenteral medications
often requires anesthetic/sedating doses that require endotracheal intubation. While
administering parenteral agents to terminate seizures, enteral agents are often added
with the eventual goal to wean parenteral medications but with adequate anti- seizure
effect to prevent seizure/SE recurrence.
18.7 Anti-seizure Medications
18.7.1 Available Parenteral Preparations
18.7.1.1 Benzodiazepines: GABAA Receptor Activation
BZPs are positive allosteric modulators of postsynaptic GABAA receptors, which
are ligand-gated chloride channels. BZPs bind to the α+/𝛾− subunit interface of the
GABAA receptor, increasing the afnity of GABA binding to receptors. This
increases the frequency of opening of the chloride channels, leading to membrane
hyperpolarization with subsequent inhibition of neuronal activity. Other positive
modulators that bind to different sites on the GABA
receptor include barbiturates,
A
alcohol, propofol (PRO), etomidate, and volatile anesthetics such as isourane
[31–33].
The lipophilic property of each of the BZPs often drives the bedside therapeutic
choice. DZP, the most lipophilic, has fast CNS penetration but rapid redistribution,
causing a short-acting anti-seizure effect. DZP may therefore be the ideal agent in a
patient undergoing epilepsy monitoring in preparation for potential resection of an
epileptogenic focus, as it can terminate a seizure to prevent SE but allow another
seizure to occur, facilitating the localization of the nidus for resection. However, in
most patients with SE, a longer-acting agent, such as lorazepam, is preferable to
allow secondary administration of a longer-acting ASM to prevent further seizures
when the BZP effect clears.
The SE guidelines universally address the essential initial step in the acute setting to terminate seizures as quickly as possible given the synaptic changes and
the loss of GABAergic responsiveness following prolonged seizures. Rectal DZP
is useful in an outpatient setting but with less ease of use and rapidity than an
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M. Trammel et al.
intramuscular (IM) or IV route. As noted above, DZP is less utilized as an IV rstline therapy due to its lipophilic properties conferring a shorter effective half-life
for seizure termination compared to lorazepam. The RAMPART trial in the prehospital setting demonstrated that administration of IV lorazepam had faster termination of seizures than IM midazolam (MDZ) when IV access is already
established. However, when IV access is not yet obtained, the time to effective
cessation of seizures is faster with IM MDZ when compared with IV lorazepam
[28, 29, 34].
Secondary effects of BZPs and other GABAergic agents such as PRO and barbiturates include a decrease in cerebral metabolic rate and cerebral blood ow [35].
Systemic effects include hypotension and respiratory depression inuenced by dosage, rate of administration, and concomitant medications. Acute reversal with umazenil, a 1,4-imidazobenzodiazepine competitive antagonist at the BZP-binding
site on the GABAA receptor, is not recommended in patients with SE, as seizures
may be further potentiated [36]. Instead, hemodynamic and mechanical ventilatory
support should be initiated accordingly if cardiac or respiratory ADEs occur.
Infusion/Anesthetic Dosing ofBZP asaThird-Line Therapy
When seizures persist despite the administration of both rst-line GABAergic treatment and a second-line therapy (e.g., LEV, VPA, and/or fosphenytoin), i.e., RSE,
the guidelines recommend a third-line strategy of a parenteral infusion of an ASM
with anesthetic properties to terminate seizures. Continuous EEG monitoring to
detect NCSz/NCSE is essential. Current guidelines target seizure cessation, or alternatively, a burst-suppression pattern [27, 28], although anecdotally, achieving a
burst suppression pattern does not necessarily prevent break-through ictal activity
(i.e. seizures) and close continuous EEG monitoring is essential.
Lorazepam, while an excellent rst-line IV ASM, is not an ideal option for a
continuous infusion due to a diluent, propylene glycol (1,2-propanediol). Propylene
glycol is metabolized by alcohol dehydrogenase in the liver to lactaldehyde and
then by aldehyde dehydrogenase to lactate, acetate, and pyruvate, causing both a
severe anion gap metabolic acidosis and an osmolar gap [37]. Missing the diagnosis
of an unexplained anion gap acidosis, typically associated with an osmolar gap, may
lead to progressive hypotension and acute kidney injury due to acute tubular necrosis [38]. Propylene toxicity can also occur when administering high-dose injections
or infusions of diazepam or pentobarbital (PTB).
MDZ is water soluble at lower pH and does not require propylene glycol to
maintain stability as an infusion. MDZ infusions are well tolerated and require
higher doses on average to reach therapeutic efcacy for seizure cessation when
compared to doses needed for sedative effects. MDZ has excellent CNS penetration
due to its lipophilicity and is 94–98% protein bound. Agents, e.g., aspirin, that compete for the site where MDZ binds to albumin may enhance the action of MDZ [39].
The therapeutic effect of MDZ is complex due to metabolism by hepatic and intestinal CYP3A4 to its active metabolite, 1′-hydroxymidazolam, followed by
18
tatus Epilepticus andRefractory Status Epilepticus
S
481
glucuronidation and renal excretion. As expected, inhibitors of CYP3A4 activity
such as erythromycin, diltiazem, verapamil, and azole antifungals can prolong the
effect of MDZ.Although prolonged use of MDZ infusions induces hepatic CYP3A
activity, the half-life of MDZ can increase due to a rise in its Vd and an increase in
its free fraction [40]. Importantly, for patients with SE, other ASMs are often coadministered and can affect the action of MDZ.
It is essential to recall the potential for withdrawal complications when an MDZ
infusion is used for a prolonged period and at high doses. Adding a long-acting
enteral BZP such as clonazepam or clobazam may increase the safety of weaning a
parenteral infusion (Table18.3).
18.7.1.2 Other GABAergic Therapies
In addition to MDZ, other parenteral medications, such as barbiturates and PRO,
can be utilized to terminate seizures.
Barbiturates: GABAergic
First used in 1912, phenobarbital (PHB) was predated by the rst documented
ASM, potassium bromide, which was isolated from the Mediterranean Sea in 1826
[43]. Barbiturates bind to the β-subunit of the GABAA receptor to increase the duration of the opening of the chloride channel without altering the channel conductance
or opening frequency. This increase in the mean open duration results in neuronal
hyperpolarization and inhibition. However, at higher plasma concentrations
(>50μM), such as those achieved with PTB infusions, barbiturates directly open
GABAA receptors in the absence of GABA [44]. Barbiturates also reduce AMPA/
kainate receptor-mediated signals resulting in decreasing glutamate excitatory postsynaptic currents [45]. Studies show that barbiturates decrease cerebral metabolic
rate and cerebral blood ow in animals and brain-injured humans, which can also
decrease intracranial hypertension in a low cerebral compliance state [46, 47].
Table 18.3 Benzodiazepines for seizure termination [27, 41, 42]
Drug Pros Cons
Lorazepam Optimal choice for IV bolus
administration
Midazolam Optimal choice agent for IM
administration and IV
infusion at anesthetic
dosages
Diazepam Rectal route available Rapid redistribution with a short duration of action.
IV intravenous, IM intramuscular
Dilute 1:1 with saline due to high viscosity. IV
product contains propylene glycol. Not
recommended for infusion
Rapid redistribution (short duration of action), renal
and hepatic dysfunction can result in accumulation
of active metabolites. IV product contains propylene
glycol, but infusion does not
IV product contains propylene glycol
482
M. Trammel et al.
Phenobarbital
Phenobarbital (PHB), albeit the oldest ASM still in use, is no longer a treatment of
choice for seizures because of sedation and signicant DDIs but may be considered
as a bridge to weaning from a long-term PTB infusion. PHB is approximately 50%
protein bound with an estimated Vd of 0.6L/kg [48]. It is metabolized in the liver
primarily by CYP2C9, with minor metabolism by CYP2C19 and CYP2E1, and
approximately 25% is excreted unchanged in the urine. It has a long half-life of
100–160h in adults. In children, metabolism is increased with a reported half-life
of 103h in term infants and 67h in infants 4weeks of age [49].
PHB is a potent inducer of hepatic enzymes and can speed the metabolism of
other hepatically cleared medications, thereby decreasing their efcacy [50].
However, the metabolism and clearance of PHB can be inhibited with subsequent
PHB accumulation by felbamate, oxcarbazepine, PHT, and VPA [51–53]. PHB
ADEs are similar to all barbiturates: lethargy and somnolence are major complaints.
Infusion/Anesthetic Dosing ofBarbiturates asaThird-Line Therapy
Pentobarbital Infusion
Pentobarbital (PTB) is 45–75% protein-bound, metabolized by hydroxylation to an
inactive metabolite with urinary excretions after glucuronidation. PTB is a potent
inducer of hepatic enzymes such as CYP2A6. It is moderately lipophilic and readily
crosses the blood-brain barrier. The IV solution has a pH of 9.5 and requires a propylene glycol diluent, which makes it incompatible with many other IV medications
and requires monitoring for osmolar or anion gap acidosis at higher doses. Given its
lipophilicity and hepatic metabolism, elimination is biphasic. The rst phase is
about 4h and may require additional loading boluses to reach a steady-state plasma
concentration; the second phase is 35–50h and can be longer depending on drug
accumulation in adipose and muscle [54].
PTB ADEs frequently include hypotension due to peripheral and splanchnic
blood vessel dilation [55] and are accentuated with rapid administration. More complicated ADEs typically appear with high doses of PTB. Effects on the brainstem
include cardiorespiratory depression [56], progressive loss of cough reex, shivering response, corneal reexes, and eventually pupillary dilation. Systemically,
higher levels of PTB can correspond to loss of tracheal epithelium ciliary motility
[57], ileus [58], and suppression of the immunological response to infection by
inhibiting lymphocytic activation and inhibiting phagocytosis by leukocytes [59].
Thiopental
Infusion
Thiopental (THP) is less frequently utilized than PTB for SE.Although it is typically considered a short-acting anesthetic, it is more lipophilic than PTB, and as a
result, it rapidly redistributes to the muscle and fat with an initial half-time of
18 Status Epilepticus andRefractory Status Epilepticus
483
15min. The secondary half-life of THP is approximately 7h due to a high Vd secondary to its lipophilicity [60]; thus, long-term thiopental infusions can result in
elimination half-lives ranging from 18 to 36h [61], and its use can be complicated
by prolonged emergence from sedation once an infusion is stopped.
Propofol Infusion: GABAergic
Propofol (PRO) is an alkylphenol that acts as a GABA
receptor agonist that acti-
A
vates the ꞵ-1 subunit of the chloride channel in the receptor increasing the duration
of channel opening. PRO also inuences presynaptic GABAergic transmission
through GABA uptake and GABA release [62]. When utilized for SE cessation,
weaning of PRO has been associated with seizure recurrence; therefore, additional
ASM therapies may be necessary before decreasing or stopping the PRO infusion [63].
PRO is highly lipid-soluble with poor water solubility and is formulated in a lipid
emulsion of 10% soybean oil, 2.25% glycerol, and 1.2% lecithin from puried egg
phosphatide. It must be used with caution in patients with egg yolk allergies or
patients with disorders of fat metabolism. The risk for infection is high; therefore,
vials and tubing must be changed every 12h. PRO is more than 95% protein-bound
and highly lipophilic with a quick onset of action. It is primarily metabolized to
inactive metabolites through hepatic glucuronidation and excreted in urine, although
extrahepatic sites such as the lungs are responsible for the biotransformation of
PRO to an inactive metabolite [64].
Like other GABAergic anesthetics, PRO decreases cerebral metabolic rate and
cerebral blood ow. PRO can be associated with profound hypotension due to a
decrease in cardiac β-adrenoceptor responsiveness [65] and peripheral vasodilation
due to inhibition of sympathetic vasoconstriction [66] with decreased cerebral perfusion pressure unless caution is taken during administration. PRO is classically
associated with respiratory depression and hypertriglyceridemia; therefore, adjustment of enteral or parenteral nutrition may be necessary to avoid overfeeding the
patient when administered at high dosages [67]. A rare but potentially life-threatening complication of PRO includes propofol-related infusion syndrome (PRIS).
PRIS is characterized by opisthotonos, muscle rigidity, choreoathetoid movements,
myoclonus, seizures, hyperthermia, hyperkalemia, and metabolic and lactic acidosis due to direct mitochondrial respiratory chain inhibition or impaired mitochondrial fatty acid metabolism. When untreated, patients can progress to rhabdomyolysis,
acute kidney injury, transaminitis, hypotension, and arrhythmias, including ventricular tachycardia and brillation, or bradycardia leading to asystole/cardiac failure.
First reported in children, it has also been found in adults, typically with higher dose
(>5mg/kg/h) infusions lasting more than 48h [68].
484
M. Trammel et al.
18.7.1.3 Second-Line Non-anesthetic ASMs
Phenytoin andFosphenytoin: Sodium Channel Blocker
Phenytoin (PHT), synthesized as a barbiturate derivative in 1908 and rst used as an
ASM in 1937, is the second oldest ASM still in clinical use. Fosphenytoin (fosPHT)
is a phosphorylated ester prodrug of PHT that was rst approved in 1996. The IV
solution of PHT has poor water solubility, and its diluents include propylene glycol
and alcohol adjusted to a pH of 12. FosPHT has a pH of 8.6–9.0 that enhances the
solubility and safety if an infusion extravasates and in the hemodynamic tolerance
to rapid infusion. FosPHT is more frequently utilized in clinical practice due to its
safety prole and is rapidly metabolized to PHT by red blood cell and liver phosphatases in a 1:1 conversion to PHT.
PHT binds to the neuronal inner cytoplasmic membrane at the inner vestibule of
the pore of the voltage-gated sodium channel in its inactive state. This action prolongs the neuronal refractory period and stabilizes the neuronal membrane [69, 70].
PHT may also inhibit postsynaptic voltage-gated calcium channels [71, 72]. PHT is
90–95% protein bound, and active free levels are increased by hypoalbuminemia or
displacement by other medications, such as VPA. Its Vd increases with the dose
from 0.52 to 0.78L/kg. PHT is metabolized primarily hepatically via CYP2C9 and
CYP2C19 enzymes to an active metabolite that is excreted in the urine. The metabolite is saturable, which results in a nonlinear dose-serum concentration relation.
PHT demonstrates rst-order kinetics at low plasma levels, but at therapeutic levels
and saturable hepatic metabolism, it shifts to zero-order kinetics with large changes
in plasma levels with small dose adjustments. It reaches peak plasma concentration
in about 30min.
PHT signicantly induces hepatic enzymes and affects levels of PHB, CBZ, felbamate, oxcarbazepine, TPM, omeprazole, MDZ, uoxetine, amiodarone, digoxin,
cyclosporine, estrogens, progestogens, voriconazole, uconazole, and itraconazole [73].
Short-term toxic side effects include nystagmus, loss of smooth extraocular pursuit, diplopia, ataxia, skin rash, or fever. Long-term use can be complicated by gingival hyperplasia, calvarial hyperostosis, hirsutism, peripheral neuropathy,
cerebellar atrophy, and vitamin D and B12 deciency [74].
When transitioning from parenteral dosing to enteral administration, it is important to recognize that only the PHT sodium salt extended-release oral formulation
can be given once a day, while other formulations in suspension, chewable tablets,
or IV should be dosed at least twice or three times per day.
Valproic Acid: GABAergic, Sodium, andCalcium Channel Activity
Valproic acid (VPA) is a simple 8-carbon branched-chain fatty (carboxylic) acid
derived from valeric acid that is different from most ASMs that are heterocyclic
nitrogen-containing compounds. VPA is typically well-tolerated as a rapid infusion,
18 Status Epilepticus andRefractory Status Epilepticus
485
although it does have signicant DDIs [53, 75]. VPA has multiple mechanisms of
action, including attenuation of voltage-gated sodium ion channels by blocking the
neuronal entry of sodium; inhibition of GABA transaminase, which blocks GABA
degradation; increasing GABA synthesis by increasing the expression and activity
of glutamic acid decarboxylase; modulation of calcium channels and NMDA receptors; and inhibition of histone deacetylase, which affects gene regulation associated
with synaptic transmission, neurogenesis, inammation, and neuronal plasticity [76].
VPA is 90% protein-bound, with saturable binding at higher therapeutic levels
resulting in higher free VPA levels. The Vd of VPA is 0.15–0.22L/kg. VPA undergoes extensive hepatic biotransformation by mitochondrial β-oxidation, microsomal
hydroxylation, glucuronidation, and other conjugation reactions with excretion of
its multiple metabolites in the urine. Less than 3% is excreted unchanged in the
urine. As a fatty acid, VPA is a substrate for fatty acid β-oxidation, which takes
place primarily in mitochondria. VPA-induced impairment of mitochondrial function and fatty acid metabolism is likely the cause of its signicant ADEs [77]. VPA
has a well-identied risk for hyperammonemia due to the interference of the conversion of ammonia to urea and is contraindicated in children and adults with known or
suspected mitochondrial disorders or disorders of fatty acid metabolism or risk for
hyperammonemia. Given the effect of VPA on the carnitine shuttle that results in the
depletion of carnitine stores during long-term or high-dose therapy, co- administration
of -carnitine may prevent VPA hepatotoxicity and hyperammonemia [78]. VPA
has a black box warning for hepatotoxicity, pancreatitis, and teratogenicity due to
the 1–2% risk for neural tube defects, e.g., spina bida, if used during the rst trimester of pregnancy. Other side effects include tremor, somnolence, weight-gain,
nausea, vomiting, and thrombocytopenia [79].
The co-administration of ASMs that induce hepatic enzymes such as CBZ, barbiturates, or PHT will accelerate VPA metabolism and require an increase in dosages. Conversely, VPA competes with PHT and BZPs for serum protein-binding
sites, and concomitant administration raises the free concentration of VPA [80].
Free levels of VPA may be helpful when ASM co-administration is necessary; however, results are often delayed and not clinically relevant in an emergent setting due
to off-site testing.
Unlike most ASMs that induce hepatic enzymes, increasing clearance and
decreasing plasma levels, VPA is well known to inhibit enzymatic metabolism and
increase plasma levels of ASMs such as PHB, PHT, CBZ, and lamotrigine (LTG)
[19, 81]. Thus, the unpredictable relationship between VPA and other medications
often makes it a challenging medication in complicated patients.
Levetiracetam: Synaptic Vesicle Protein 2A Binding
Levetiracetam (LEV) is a pyrrolidinone that was rst approved in 1999, and the IV
preparation in 2006. Unlike most ASMs, its primary mechanism of action is not
through inhibitory or excitatory neurotransmitter receptor activity but a novel