Hundie Tesfaye 1; E. Eva Klapková 1; Alena Tesfayeová 2; Vladimír Komárek 2
Department of Clinical Biochemistry and Pathobiochemistry, Division of Clinical Pharmacology, University Hospital, Motol, nd Faculty of Medicine, Charles University, Prague, Czech Republic
1; Department of Paediatric Neurology, University Hospital, Motol, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
Čas. Lék. čes. 2011; 150: 451-456
Epilepsy is a serious health disorder affecting both paediatric and adult population worldwide. Due to difficulties in identifying its aetiology, initial management is often guided by empiric therapy measures. Symptomatic control requires the use of antiepileptic drugs (AEDs), many of which have the potential for adverse drug interactions. Children are especially susceptible to drug interactions and frequently exhibit atypical adverse events, which may require special care.
Aim. To demonstrate a case of a 15 year old girl suffering from refractory epilepsy with underlying focal cortical dysplasia (FCD), whose seizure deterioration was most probably associated with drug-drug interactions between prescribed common antiepileptic drugs, namely valproic acid, phenobarbital or the prodrug primidon and carbamazepine.
Key words: focal cortical dysplasia, refractory epilepsy drug, drug interaction.
Epilepsy is a common
disorder approximately affecting 0.5–2% of the population
worldwide. Approximately one-third of cases are resistant to drug
treatment although the mechanisms underlying this drug resistance are
not well understood (1). In a recent review, Reynolds and Rodin
(2) brought attention to the history of clinical concepts of epilepsy
and its classification, especially in the last 100 years. Throughout
its recorded history, epilepsy has always been defined by its most
dramatic symptoms, like falling, motor activity or loss of
consciousness, but separation from other causes of the same
paroxysmal symptoms has always proved challenging. A recent
paper by Meencke (3) also describes the history of the clinical
neuropathology of epilepsy in the last hundred years, from microscopy
to molecular neuropathology, mainly focusing on the concepts of
hippocampal sclerosis and causes or consequence of seizures, as well
as the concept of developmental disturbances in respect to general
epileptogenicity. Clinical neuropathology remains an important
discipline in the future of epileptology and brain research
especially in the area of molecular genetics, whereas, neuropathology
may help to understand the stages of epileptogenesis and factors
responsible for the progressive nature of the disease. Despite
remarkable progress, the aetiology of the syndrome is often difficult
to confirm. Focal cortical dysplasia (FCD) is a congenital
abnormality where the neurons in an area of the brain fail to migrate
in the proper formation in utero. It is one of the most common causes
of intractable epilepsy in children and is a frequent cause of
epilepsy in adults. FCD is associated with enlarged cells known as
balloon cells for their large elliptical shape, displaced nucleus,
and lack of dendrites or axons. It is hypothesized that balloon cells
and dysplastic neurons contribute to seizures in patients with
cortical dysplasia. Refractory epilepsy with underlying focal
cortical dysplasia is usually resistant to drug treatment in
approximately one-third of cases, but the mechanisms underlying this
drug resistance are not understood. Previous studies in human
epilepsy have shown that multidrug resistance (MDR-1) or multidrug
resistance associated protein (MRP-1) may also be overexpressed in
brain tissue (glia and neurones), which do not normally express these
proteins.Thus in pathologies causing refractory epilepsy, the
presence of overexpressed resistance proteins in lesional dysplastic
neurones may lower the interstitial concentration of AEDs in the
vicinity of the epileptogenic pathology leading to drug resistant
As drug monotherapy rarely controls the disease, multi-drug
approaches are common practice, especially in paediatric age groups.
Symptomatic control requires the prophylactic use of antiepileptic
drugs (AEDs), many of which have the potential for adverse drug
interactions with other coprescribed medication. Drug-drug
interactions are reported to give rise to adverse drug reactions
(ADRs) in at least 6% of subjects with epilepsy (4). Children are
especially susceptible to drug interactions and frequently exhibit
atypical adverse events, which may require hospitalization or result
in death (5). In primary care, 3.0% of children on chronic
antiepileptic therapy are co-prescribed therapeutic agents, which
could give rise to clinically serious drug-drug interactions (6).
Within a 36 year period 331 children aged < 17 years died
following suspected ADRs in the United Kingdom. AED therapy was
associated with 65 of these deaths, and sodium valproate alone with
31 deaths. Even the ‘safer’ second-generation AEDs were involved
in 20 fatal cases and have been identified as the most important
cause of drug-related childhood death (7). In the present case we
describe possible drug-drug interactions which may be responsible for
clinical deterioration in a patient with refractory epilepsy.
A female paediatic patient
was on long term follow-up and general care for refractory epilepsy.
No familial history association was reported with the diagnosis. Her
epilepsy was classified as multi-drug resistant, where all available
AEDs including combinations of new generation drugs failed to fully
control the entity. Further investigation led to the diagnosis of FCD
IIb Lsin. indicating surgery (stereotactic resection) as the most
appropriate treatment. Post sugery, no significant long term
improvement was observed, instead, hemianopsia and praparesis l.dx.
has been observed as complication. Maintenance dose of AEDs was
continued, but with poor control yet, where vagus nerve stimulation
(VNS) has been provided in addtion to AEDs therapy. AEDs levels just
four months before deterioration were within conventional therapeutic
ranges (Table 1. first row), whereas phenobarbital levels during the
clinical deterioration were within toxic ranges despite the rest of
the AEDs being within therapeutic margins. Once upon admission her
state had deteriorated and VPA was added to thre AEDs (PRM, PB i.v.,
CBZ) and this led to further deterioration. The main clinical
manifestations potentially linked to ADRs were alteration of
consciousness, halucination and delerium. AED levels revealed
significantly high PB levels (Fig. 1.) despite significant reduction
of the dose from intially 300 mg/day to only 100 mg/day during the
Drug-drug interactions at any
level (both pharmacokinetic and pharmacodynamic) represent a major
challenge in multi-drug treatment of epilepsy. Valproic acid is
a minor substrate of CYP2A6, 2B6, 2C8/9, 2C19, 2E1. It weakly
inhibits CYP2C8/9, 2C19, 2D6 and 3A4; whereas it induces CYP2A6. In
the present case of concomitantly used drugs, phenobarbial and
carbamazepine are inducers, but the inhibitory effect of valproate
may be significant as demonstrated by evident cumulation of
phenobarbital blood levels (Fig. 2). Valproic acid may increase,
decrease, or have no effect on carbamazepine levels; but may increase
serum concentrations of carbamazepine – epoxide (active metabolite)
by inducing the metabolism of parent drug (carbamazepine). VPA can
displace the protein binding of CBZ. VPA also inhibits microsomal
epoxide hydrolase (mEH), the enzyme responsible for the breakdown of
epoxide into inactive
metabolites. Valproic acid appears to inhibit the metabolism of
phenobarbital; thus increasing its overall effect. (Cave: PB
intoxication after adding PB/PRM to VPA, as a late effect).
Phenobarbital/primidone, and carbamazepine may produce enzyme
inducing effects that can lower the half-life of VPA thus leading to
therapeutic failure. Although the mechanism is unknown, it should be
considered that phenobarbital levels increase when valproic acid is
given concomitantly, enhancing its sedative effects. It is well
documented that carbamazepine serum concentrations may be elevated
when valproic acid is added to the treatment regimen. This is largely
due to an increase in carbamazepine epoxide levels. Phenobarbital,
primidone, and carbamazepine may produce enzyme inducing effects that
can temporarily lower the half-life of valproic acid. The mechanism
of action of carbamazepine and its derivatives is relatively well
understood i.e, voltage-gated sodium channels are the molecular pores
that allow brain cells (neurons) to generate action potentials, the
electrical events that allow neurons to communicate
over long distances.
After the sodium channels open, to start the action potential, they
inactivate, essentially closing the channel. Carbamazepine stabilizes
the inactivated state of sodium channels, meaning that fewer of these
channels are available to open, making brain cells less excitable.
Epileptic children exposed to oxidative stress and conventional
antiepileptic drugs change the oxidative/antioxidative balance.
Recently, Aycicek et al. confirmed the effects of carbamazepine,
valproic acid and phenobarbital on the oxidative and antioxidative
balance in epileptic children (8).
Common symptoms of AED overdose
include coma, deep sleep, motor restlessness, and visual
hallucinations, where supportive treatment is necessary. Valproic
acid is usually well tolerated but has been associated with some side
effects. Several cases of VPA induced non-hepatic hyperammonemic
encephalopathy in subjects treated by VPA alone and other concomitant
AED have been reported in the medical literature (9).
Valproate-induced hyperammonemic encephalopathy is an unusual
complication which may occur just after the beginning or during
treatment. It is characterized by vomiting, drowsiness, lethargy and
progressive impairment of consciousness, focal neurologic signs,
cognitive slowing and increased seizure frequency. This is a poorly
studied side effect independent of the drugs hepatotoxic action. The
increase in serum ammonium level is due to several mechanisms,
although the most important one appears to be the inhibition of
carbamoylphosphate synthetase-I, the enzyme that begins the urea
cycle. Hyperammonemia leads to an increase in the glutamine level in
the brain, which produces astrocyte swelling and cerebral edema.
Polytherapy with several drugs, such as phenobarbital, seems to
contribute to the problem (10). Valproic acid-induced hyperammonemic
encephalopathy may occur in people with normal liver function,
despite normal doses and serum levels of VPA (11). Our patient also
had significant hyperamonemia cca 109 μmol/L
(normal range 14-55 μmol/L)
which was gradually reversible. Carbamazepine may aggravate juvenile
myoclonic epilepsy and has also been linked to serious adverse
cognitive effects, including EEG slowing and cell apoptosis. These
adverse effects have been said to be associated with the formation of
CBZ metabolites. The problem of biounequivalence and/or therapeutic
unequivalence may be demonstrated by toxicity or therapeutic failure
in association with replacement of different generic products. Such
a problem was first observed in Australia, when an outbreak of
phenytoin intoxication occurred among epileptic patients (12, 13) as
a result of single excipient change from calcium sulphate
to lactose by the drug
manufacturer. The consequence was a substantial increase in
bioavailability and an increase of phenytoin serum concentrations by
80 to 100%. Patients presented with a typical clinical picture
of phenytoin intoxication with ataxia, double vision and periods of
vomiting, where a complete remission in all patients was
achieved when the original excipient was restored (14). Similar cases
have been reported, of patients, who had seizure frequency increase
after they were switched to generic drug associated with significant
drug level changes (15). In a recently published cases of
breakthrough seizures, brand to generic substitution was blamed as
the main cause (16). In Denmark, several patients who complained of
adverse effects when switched to generic lamotrigine underwent
hospitalization with blood levels assessed every 3 hours. One patient
had a fall, a skull fracture, and an epidural hematoma
after the switch and had elevated levels during testing that were
consistent with toxicity while taking the generic drug. Another
patient had status epilepticus and lower levels on the generic and
a third patient had ataxia within the first hour of taking the
generic associated with a higher Cmax
(17). Two Canadian studies (18, 19) demonstrated that switchback
rates from generic to brand are 5 to 10 times higher for AEDs than
other classes of medications and significantly higher numbers of
outpatient visits and mean length of hospital stays occurred in
people taking generic AEDs compared with those taking brand name
drug. In 2007, US case – controlled database analysis of healthcare
for 12- to 64-year-olds with epilepsy and AED formulation changes,
indicated 81% greater odds of an AED formulation switch relative to
the controls (20). Carbamazepine, phenobarbital, and valproic acid
are among commonly used antiepileptic drugs that show complicated
pharmacokinetic behavior. Immunoassays are used routinely to monitor
these drugs, and assay specificity is important to obtain accurate
results. Frank et al. (21) reported molar cross-reactivity of
carbamazepine-10,11-epoxide of 12% in carbamazepine determination by
immunoassay, indicating that high performance liquid chromatography
(HPLC) may be useful for monitoring patients. This may be
particularly relevant for those patients exhibiting symptoms of
carbamazepine toxicity, whose serum carbamazepine concentration is
within the therapeutic range but who may be producing significant
levels of the active epoxide metabolite. Unfortunately we did not
have access to this assay at the time of case manifestation. Matos et
al. (22) reported cases in which false-positive antidepressive drug
levels led to the diagnosis of carbamazepine intoxication. Dasgupta
et al. (23) observed significant interference of carbamazepine with
the FPIA method. Besides problems relating to interindividual and
intra-individual variation and ideosyncratic undesired effects,
shortcomings due to bioequivalence and/or therapeutic equivalence
problems may also be a challenge associated with the
introduction of different generic products (13–14). For the
determination of bioequivalence, the so-called rule of inclusion is
used, meaning that the 90% confidence intervals (CIs) for the new
preparation should be within the limits: for AUC 80–125%. Proof of
bioequivalence between reference
preparations of antiepileptic drugs does not mean that they are
freely interchangeable. Generic formulations with proven
bioequivalence to branded preparations can be used, for example, at
the beginning of treatment or in poorly controlled patients with
serum concentrations in the mid range. However, it has been
demonstrated that the usual rules for bioequivalence and the range of
acceptability for preparations of carbamazepine are problematic (23).
Beside the pharmacokinetic variability, interaction at
a pharmacodynamic level is also possible due to some
similarities in mechanism of actions. The available data indicate
that the anticonvulsant efficacy of these AEDs is mainly due to the
inhibition of sodium channel activity (24). Similar targets or
mechanism of action and other conditions affecting pharmacokinetic
and toxicodynamic processes may be significant in terms of drug-drug
interactions. The mechanism of action of valproic acid is not clearly
defined; however, effects of the drug may be related at least in part
to increased brain concentrations of the inhibitory neurotransmitter
GABA, probably through inhibition of catabolic enzymes of GABA. Thus,
valproate may cause increased availability of GABA, an inhibitory
neurotransmitter, to brain neurones or may enhance or mimic its
action at postsynaptic receptor sites. Animal studies have shown that
valproic acid inhibits GABA transferase and succinic aldehyde
dehydrogenase, enzymes which are important for GABA catabolism,
whereas results of a study indicate the drug inhibits neuronal
activity by increasing potassium conductance (25). In a study of
88 paediatric patients receiving sodium valproate monotherapy, side
effects were noted in 71 patients. Although average doses in these
patients were significantly higher than in the 17 patients with no
side effects, no difference in plasma concentration were noted (26).
In clinical practice, serum level monitoring of anticonvulsant drugs
is usually adequate. When there is an alteration in the binding of
the anticonvulsant drug to the plasma proteins, however, the
relationship between the serum concentration and therapeutic efficacy
or toxicity becomes difficult to interpret. Behavioural alterations,
digestive disorders, and neurological changes are the common side
effects observed and can occur with combinations such as
non-steroidal anti-inflammatory drugs (NSAIDs), phenytoin,
carbamazepine and valproic acid, or when albumin levels are low.
A failure to rely on serum free levels of the anti-convulsant
under these circumstances can easily result in poor clinical
decisions. The technique of serum free level measurement and
illustrative examples of specific cases are provided to document the
usefulness of this invaluable laboratory test (27). The relationship
between dose and total valproate concentration is nonlinear, i.e.
concentration does not increase proportionally with dose, but
increases to a lesser extent at higher doses due to saturable
plasma protein binding. The kinetics of unbound drug are linear.
Symptoms of overdose include coma, deep sleep, motor restlessness,
and visual hallucinations. Valproic acid appears to inhibit the
metabolism of phenobarbital; thus increasing its effect.
Phenobarbital is a short-acting barbiturate with sedative,
hypnotic, and anticonvulsant properties. Time to peak, serum on oral
is 1–6 hours, whereas half-life elimination in children is 37–73
hours, with 20% to 50% excreted as unchanged drug in the urine. As is
the case with barbiturates in general, phenobarbital depresses the
sensory cortex, decrease motor activity, alter cerebellar function,
and produces drowsiness,
sedation, and hypnosis.
In high doses, it exhibits anticonvulsant activity and may produce
also dose-dependent respiratory
acid appears to inhibit the metabolism of phenobarbital, thus
increasing its effect. One must beware of phenobarbital intoxication
after adding PB/PRM to VPA, also as a late effect. Valproic acid
and valnoctamide both interact with carbamazepine, as they inhibit
microsomal epoxide hydrolase (mEH), the enzyme responsible for the
breakdown of carbamazepine-10,11 epoxide into inactive metabolites.
By inhibiting mEH, valproic acid and valnoctamide cause a buildup
of the active metabolite, prolonging the effects of carbamazepine and
delaying its excretion. In combinations with CBZ, VPA inhibits the
reduction of the metabolite CBZ-epoxide, thus leading to an overdose
of CBZ-epoxide, an interaction which happens more frequently when CBZ
is added to VPA than the other way round. Carbamazepine itself is
associated with a number of idiosyncratic adverse effects,
including skin rash, blood disorders and hepatitis, in 30–50% of
patients (28) These adverse effects have been associated with the
formation of CBZ metabolites (29–30). Therefore, therapeutic drug
monitoring (TDM) of CBZ metabolites also has important clinical
implications. In addition CBZ is also a well known enzyme
inducer up-regulating cytochrome P450 enzymes (31).
To enhance our understanding of
epilepsy as a disease, antiepileptic drugs (AEDs) PK/PD
principles, including drug interaction mechanisms, may allow more
effective use of these drugs. If a high potential for metabolic
drug-drug interactions exists between co-administered antiepileptic
drugs, undesired effects may occur unexpectedly at any time during
therapy. Carbamazepine, phenobarbital, and valproic acid are commonly
used antiepileptic drugs that show complicated pharmacokinetic
behavior. Therefore, dose adjustment based on clinical judgement
assisted by therapeutic drug monitoring may be of vital importance.
– adverse drug reactions
– antiepileptic drugs
– confidence intervals
– focal cortical dysplasia
– gamma aminobutyric acid
– high performance liquid chromatography
– multidrug resistance
– microsomal epoxide hydrolase
– non-steroidal anti-inflammatory drugs
– therapeutic drug monitoring
– vagus nerve stimulation
– valproic acid
The corresponding autor is
thankful to Dr. Gareth J. Veal from Newcastle University, UK,
for reviewing the manuscript not only language wise also for
Tesfaye, Ph.D. Ústav
klinické biochemie a patobiochemie 2. LF UK a FN
Motol V Úvalu
84, 150 06 Praha 5 e-mail:
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