Keywords
epilepsy - antiseizure medications (ASMs) - systemic illnesses - pharmacokinetics
- safety profiles
Introduction
Many people worldwide suffer from epilepsy, a common neurological condition. The Global
Burden of Disease Study from 2016 estimates that 39.3 million individuals in India
and 45.9 million people worldwide suffer from active epilepsy.[1] The main goal of treating epilepsy using antiseizure medications (ASMs) is to completely
control seizures while reducing adverse effects. Many ASMs have been developed over
time, and there are currently close to 30 in widespread use.[2] However, controlling seizures can be challenging, especially when ASM selection
is influenced by other comorbid medical disorders. The absorption, distribution, metabolism,
and excretion of ASMs are greatly impacted by several comorbidities, including cardiovascular
risk factors (such as type 2 diabetes, hypertension, dyslipidemia, and atrial fibrillation)
as well as hepatic and renal illnesses. Older ASMs often have high protein binding,
which requires careful therapeutic drug monitoring. In contrast, newer ASMs generally
have narrower therapeutic indices but offer better safety profiles. As a result, selecting
the appropriate ASMs with favorable safety profiles for patients with comorbidities
presents a significant challenge for neurologists.[3]
In this context, we provide an overview of ASMs used to treat epilepsy in people with
systemic diseases.
Materials and Methods
We did not perform a systematic literature search because this was a narrative review.
However, a search of the PubMed database was conducted using the following search
parameters: “anticonvulsant” and “antiepileptic drugs” along with the keywords “cardiovascular
disease,” “liver disease,” “kidney disease,” “porphyria,” “psychiatric disorder,”
“psychiatric disorder,” “cognitive impairment,” and “comorbid conditions” and the
outcomes were evaluated to make sure they were pertinent to the review's subject.
The analysis includes studies that addressed the use of antiseizure drugs in relation
to systemic disorders. Studies that did not address systemic illness or focus solely
on epilepsy without considering systemic factors were excluded. No date limitations
were applied to the searches. Once the articles were identified, a comprehensive review
of all the results was undertaken, and the findings and conclusions were aggregated
and summarized.
Cardiovascular Disease
Hepatic enzymes are known to be induced by older ASMs, including carbamazepine (CBZ),
phenytoin (PHT), and phenobarbital (PB), and this can be linked to vascular hazards.[4] Even at higher therapeutic concentrations (e.g., 20 μg/mL), PHT is often not linked
to the requirement for cardiac monitoring.[5] It is noteworthy, therefore, that a large prospective cohort study discovered that
24.1% of patients over 60 experienced hypotension when given PHT at a dose of 11 to
25 mg/kg (with an infusion rate of 50 mg/min). Additionally, another study reported
that administering 1000 mg of PHT over 2.5 minutes during a seizure caused hypotension
in 0 to 18% of patients, arrhythmia in 0 to 5%, and apnea in 0 to 2%.[6] The cardiovascular effects of PHT are primarily attributed to high infusion rates,
which lead to rapid distribution into body tissues. Factors such as metabolic disorders
and older age can affect the elimination of PHT from the body. According to studies,
people over 50 and those with cardiovascular conditions are thought to be safer with
an infusion rate of 25 mg/min.[7] Nonetheless, the prodrug fosphenytoin is regarded as safer compared with PHT, as
it has a lower incidence of hypotension and fewer tissue side effects.[8]
CBZ is known to have negative effects on heart rate and electrical conduction, including
causing dysfunction in the sinus node and atrioventricular (AV) node block, particularly
in patients with existing cardiac abnormalities.[9] According to earlier observations, even at therapeutic dosages of CBZ, bradycardia
and sinus rhythm tachycardia might occur.[10] In a separate study, it was found that CBZ overdose resulted in tachycardia, while
therapeutic or moderate doses were associated with bradycardia.[11] Furthermore, a recent study with 5,473 people in a general population found that
using CBZ is linked to a higher risk of sudden cardiac arrest, with a modified odds
ratio of 1.90.[12]
Valproate (VPA), a broad-spectrum antiepileptic medication, has a 1 to 5% chance of
causing hypertension, tachycardia, and palpitations. It is generally well tolerated,
even in cases of new-onset status epilepticus, with no significant cardiac side effects
reported.[13]
[14]
The newer antiepileptic medication, lacosamide (LCM), has demonstrated cardiac effects
when administered rapidly via intravenous dosing. It has been associated with first-degree
AV block in 22.4% of patients.[15] However, a recent study suggested that administering LCM at an infusion rate of
30 minutes is safer, showing no incidence of atrial fibrillation, bradycardia, or
atrial flutter. An isolated case of atrial premature complexes (n = 1), hypotension (n = 1), and first-degree AV block (n = 1) was documented in 38 patients.[16]
Lamotrigine (LTG) is generally considered safe compared with other antiepileptic medications.
The Food and Drug Administration of the United States (FDA) did, however, issue a
warning about its usage in patients with heart problems in 2021. Based on in vitro
data, this caution was issued because LTG may have poor cardiac sodium inhibitory
action, which could result in class IB antiarrhythmic effects.[17] Following the FDA warning, a systematic review indicated that LTG at therapeutic
doses is associated with mild QRS widening (not serious),[18] and LTG is not linked to an elevated risk of cardiac conduction abnormalities in
people without preexisting cardiac problems, nor does it increase the risk of mortality
in patients with such morbidities, according to another study with large cohorts.[19] In conclusion, LTG is regarded as a safe choice for treating epilepsy in those who
have cardiac issues. [Table 1] shows the metabolism of ASM with cardiac medications and precautions to be taken.
Table 1
Medications must be used carefully in those with heart disease
|
ASM
|
Cardiac drug
|
Interaction/Effect
|
|
PHT
|
Ticlopidine
|
Increases PHT level
|
|
Antiarrhythmic
|
Increases metabolism of antiarrhythmic
|
|
Amiodarone
|
Increases PHT levels
|
|
Beta-blockers
|
Increases B blocker metabolism
|
|
Dihydropyridine
|
Increases dihydropyridine metabolism
|
|
Losartan
|
PHT reduces active metabolite by 63%
|
|
Oral anticoagulants (OAC)
|
Reduces effects of OAC
|
|
OAC increases PHT levels
|
|
Diuretics
|
PHT reduces the diuretic response
|
|
Digoxin Statins
|
PHT reduces digoxin levels.
PHT stimulates statin metabolism
|
|
CBZ
|
Ticlopidine
|
Increases the level of CB2
|
|
Antiarrhythmic
|
Increases antiarrhythmic metabolism. Diltiazem/verapamil increase CB2 levels
|
|
Antihypertensive
|
Increases metabolism of beta-blockers
|
|
OAC
|
Reduces the effect of OAC
|
|
Diuretics
|
Use with caution to avoid hypernatremia
|
|
Statins
|
Stimulates the metabolism of statins
|
|
VPA
|
Salicylates
|
Increases the VPA's available percentage
|
|
Antihypertensive
|
Raises nimodipine levels by 50%
|
Abbreviations: ASM, antiseizure medication; CBZ, carbamazepine; PHT, phenytoin; VPA,
valproate.
Compared with a placebo, using eslicarbazepine acetate (ESL) was linked to a slightly
increased incidence of elevated total cholesterol, triglycerides, and low-density
lipoprotein levels. It is important for patients taking warfarin to have their international
normalized ratio monitored to ensure proper maintenance. As ESL operates as a sodium
channel blocker, there is a theoretical risk of arrhythmias in patients who have preexisting
heart rhythm disorders.[20]
Patients using cenobamate may experience over 20 minutes of QT shortening, with 31%
affected with a dose of 200 mg and 66% at 500 mg. Cenobamate should not be used to
treat people with inherited short QT syndrome. When cenobamate is taken with other
drugs that also reduce the QT interval, caution is advised. Additionally, cenobamate
is extensively metabolized, and its metabolism can be influenced by other drugs, while
it may also affect the metabolism of other medications.[21]
Studies have indicated that rufinamide treatment can lead to QT interval shortening.
However, there is currently no evidence linking its use to ventricular rhythm disturbances
or drug-induced sudden mortality. There is no known therapeutic danger associated
with the degree of QT slowing brought by the drug rufinamide. Rufinamide should not
be used to treat patients with familial short QT syndrome since they are more likely
to experience sudden cardiac arrest and ventricular arrhythmias, particularly with
ventricular fibrillation. Additionally, rufinamide should not be taken with any medications
that decrease the QT interval.[22]
Liver Disease
Neurologists find ASM especially difficult since sudden symptomatic seizures or seizures
might exacerbate the progression of hepatic disorders. ASMs' ability to bind to plasma
proteins can be impacted by several liver conditions, which raises the possibility
of toxicity.
Lorazepam is a safer option for patients with liver disease due to fewer drug interactions
and is suggested as the primary treatment for seizure control. Since the majority
of benzodiazepines are processed in the liver, hepatic illness can significantly impact
their metabolism. In particular, midazolam undergoes metabolism by cytochrome P450,
and its clearance is compromised during liver pathologies. As a result, these should
generally be avoided in patients with liver disease to prevent sedation and reduce
the risk of aggravating preexisting encephalopathy.[23]
VPA can follow an alternate metabolic pathway in individuals with liver disease, leading
to the production of toxic hepatotoxic metabolites and hyperammonemia.[24] Because of its unpredictable dynamics, PHT can accumulate to hazardous serum levels
in low albumin levels.[25] PB has an extended half-life in patients with liver cirrhosis (∼130 hours), which
can lead to drug accumulation.[25]
As such, avoid these medications in the treatment of epilepsy in individuals with
hepatic pathologies.
Levetiracetam (LEV) is the most important medication for treating epilepsy in individuals
with liver disease because only 2% of it is broken down by liver enzymes, resulting
in minimal drug interactions. Typically, no modification of the dosage is necessary
for mild to moderate liver disease. However, a 50% dosage reduction is advised in
situations of severe liver illness that are categorized as Child–Pugh class C.[26]
LCM is predominantly metabolized through particular pathways, although its byproducts
are inert, and currently, there is no evidence of medication interactions. Because
of its linear pharmacokinetics and modest protein binding (15%), it is a safer choice
for hepatic disease patients.[27]
Topiramate (TPM) is also considered safe for use in liver disease since only 20% is
broken down in the liver. In cases of severe hepatic disease, a 30% reduction in dosage
is advised. Additionally, gabapentin (GBP) and pregabalin (PGB) are commonly used
in clinical settings due to their negligible to minimal protein binding, which allows
for the safe management of seizures in individuals with hepatic disease.[28]
[29]
In summary, an appropriate ASM for individuals with hepatic disease should feature
less binding with the protein and minimal hepatic metabolism.[30]
A pharmacokinetic study involving adults with hepatic cirrhosis across grades A, B,
and C of Child–Pugh revealed a 50, 57, and 59% increase in brivaracetam (BRV) exposure,
respectively, compared with matched healthy controls. Because of this increased exposure,
dosage adjustments for BRV are recommended at all stages of liver damage.[31] No effects were observed in individuals with slight liver dysfunction (Child–Pugh
grade A) after administration of one dose of 200 mg cannabidiol. However, individuals
with moderate (Child–Pugh grade B) or severe (Child–Pugh grade C) liver disease experienced
an increase in the area under the curve of approximately 2.5 to 5.2 times high compared
with healthy volunteers with healthy liver. Due to this increased exposure, dose modifications
are necessary for individuals with moderate or severe liver disease; no dose modification
is required for those with mild liver disease.[32]
Cannabidiol causes a dose-dependent elevation in hepatic transaminases. The most pertinent
reason behind the discontinuation of cannabidiol in trials was an increase in transaminases.
In controlled research studies of Lennox–Gastaut syndrome or Dravet syndrome, the
alanine aminotransferase elevation incidence is greater than three times the upper
limit of normal (ULN) with 13% in cannabidiol-treated patients to 1% in placebo-treated
diseased individuals. Risk factors for elevated transaminases include concomitant
use of VPA or clobazam, baseline transaminase levels above the ULN, and high doses
of cannabidiol.[31]
Cenobamate is cautiously used in individuals with mild to moderate liver disease,
as a low-maintenance drug dose may be required (data are currently missing). The cenobamate
use is not suggested for individuals with severe liver dysfunction. Additionally,
cenobamate may rarely cause a dose-dependent increase in liver transaminases.[32]
Renal Disease
Chronic kidney disease (CKD) or renal impairment can have a major impact on how well
medications or their active metabolites are eliminated, which may result in toxicity.
A normal glomerular filtration rate (GFR) and some indication of renal impairment
are characteristics of CKD stage 1. A slight decline in GFR (60–89 mL/min per 1.73
m2) is indicative of stage 2 CKD. A GFR of 30 to 59 mL/min per 1.73 m2 is considered to be mild renal impairment in CKD stage 3. A GFR of 15 to 29 mL/min
per 1.73 m2 is referred to as CKD stage 4, which is regarded as significant renal impairment.
A GFR of less than 15 mL per minute per 1.73 m2 is known as CKD stage 5, and to maintain life at this point, dialysis or a kidney
transplant must be considered.[33]
LEV, GBP, PGB, LCM, and vigabatrin are among the ASMs that the kidneys partially remove.
The elimination half-life of these medications is extended in cases of decreased renal
clearance, which causes drug buildup in the body. For instance, GBP can accumulate
in individuals with renal impairment, resulting in sedation.[34] Additionally, when vigabatrin or LEV is used in individuals with renal issues, there
is a possibility of developing encephalopathy.[35]
LEV is primarily excreted from the body through the renal, with approximately 95%
of a given drug excreted while passing urine in healthy individuals. However, in individuals
with kidney problems, the elimination of LEV is prolonged, and its clearance depends
on the rate of creatinine clearance. The drug's half-life varies: it takes approximately
10 hours in cases of mild kidney failure and up to 24 hours in severe kidney failure.[25] Consequently, dosage adjustments are often necessary based on the severity of kidney
dysfunction. LEV is effectively taken out through hemodialysis, with roughly 50% of
the drug cleared within 4 hours of a dialysis session. Therefore, it is recommended
to administer an additional dose of 250 to 500 mg every 4 hours during dialysis.[25]
In individuals with renal damage, the accumulated uremic acid and hypoalbuminemia
decrease the binding of the protein to certain ASMs like PHT and VPA, which are normally
more than 90% protein-bound. This reduction in binding of the protein can elevate
the pharmacologically active fraction of these drugs, leading to more pronounced therapeutic
effects and side effects.[36] Renal replacement therapy (RRT) also affects the pharmacokinetics of ASMs. Both
hemodialysis and continuous RRT significantly influence the removal of ASMs, necessitating
adjustments in dosing or supplementation.[37] For patients receiving PHT, oxcarbazepine (OXC), CBZ, VPA, BRV, LTG, and LCM, no
dose reduction is required during maintenance hemodialysis. In contrast, PB, GBP,
TPM, vigabatrin, LEV, and ethosuximide (ETX) are largely removed during hemodialysis
and thus require supplementation.
In renal transplant patients, it is vital to manage drug interactions with immunosuppressant
medications to prevent organ rejection. Hepatic enzyme-inducing agents like PHT and
CBZ should be avoided to prevent failure of immunosuppressive therapy and to reduce
the risk of transplant rejection.
Based on how they are eliminated, ASMs can be divided into three major groups. medications
that are removed by a combination of renal and nonrenal pathways, pharmaceuticals
that are primarily eliminated by hepatic metabolism, and drugs that are excreted unchanged
by the kidneys or undergo minimal metabolism.[25] When used alone or in conjunction with medications that do not induce enzymes, the
medications in the first group include TPM, vigabatrin, PGB, and GBP. PHT, VPA, CBZ,
tiagabine (TGB), and rufinamide are among the medications that are primarily removed
through biotransformation. LEV, LCM, zonisamide (ZNS), primidone, phenobarbitone,
ezogabine/retigabine, OXC, eslicarbazepine, ETX, and felbamate are among the medications
in the intermediate group.[25] Patients who have liver or renal disease should use these medications with caution.
It is challenging to employ antiepileptic medications when hepatic or renal illness
is present, necessitating a thorough understanding of the pharmacokinetics of these
drugs. To improve clinical outcomes, more frequent serum concentration monitoring
and closer patient follow-up are required.[25] In individuals with combined liver and renal impairment, LEV, LTG, LCM, GBP, and
PGB can be used with dose adjustments.
CKD or renal impairment can have a major impact on how well medications or their active
metabolites are eliminated, which could be harmful. The GFR is used to classify the
stages of CKD: stage 1 denotes normal GFR with evidence of kidney damage; stage 2
denotes mild GFR reduction (60–89 mL/min per 1.73 m2); stage 3 denotes moderate impairment (30–59 mL/min per 1.73 m2); stage 4 denotes severe impairment (15–29 mL/min per 1.73 m2); and stage 5 (GFR < 15 mL/min per 1.73 m2) requires RRT, such as dialysis or transplantation, to maintain life.[33]
LEV, GBP, PGB, LCM, and vigabatrin are among the ASMs that are partially eliminated
by the kidneys. Drug buildup may result from a longer elimination half-life caused
by reduced renal clearance. For example, GBP accumulation in renal impairment can
lead to sedation,[34] while vigabatrin and LEV can cause encephalopathy.[35]
LEV is primarily excreted through renal, with approximately 95% of the given dose
eliminated through the urine in normal individuals.[25] Its half-life is prolonged from roughly 10 hours in mild renal failure to 24 hours
in severe cases due to the considerable slowdown in its clearance caused by renal
impairment. As a result, it is crucial to modify dosage according to creatinine clearance.
During hemodialysis, approximately 50% of LEV is removed within 4 hours, and supplemental
doses of 250 to 500 mg are recommended every 4 hours.[25]
Hypoalbuminemia and the accumulation of uremic acid in renal dysfunction reduce the
protein binding of highly protein-bound ASMs like PHT and VPA. This reduction leads
to increased free drug fractions and enhanced pharmacological effects. Additionally,
RRT further affects the pharmacokinetics of ASMs. For example, hemodialysis significantly
removes drugs such as GBP, TPM, vigabatrin, and LEV, necessitating supplemental dosing.
In contrast, patients taking PHT, CBZ, OXC, VPA, LTG, BRV, and LCM typically do not
require dose reductions during maintenance hemodialysis.[37]
In renal transplant patients, it is crucial to manage drug interactions with immunosuppressants
to prevent organ rejection. ASMs that induce the enzymes, such as PHT and CBZ, can
compromise efficacy with immunosuppressants and should be avoided. LTG, which is also
an enzyme inducer, requires careful consideration. On the other hand, LCM has the
advantage of having minimal impact on immunosuppressants and can be included in treatment
regimens.
ASMs can be categorized based on their elimination routes: those excreted unchanged
or minimally metabolized by the kidneys (e.g., GBP, PGB, vigabatrin, TPM), those predominantly
eliminated by hepatic metabolism, and those removed through both renal and nonrenal
routes (e.g., LEV, LCM, ZNS, PB, OXC, ETX).[25] Caution is warranted in cases of renal or hepatic impairment, requiring close monitoring
and serum concentration checks to optimize outcomes. For individuals with both kidney
and liver dysfunction, LEV, LTG, LCM, GBP, and PGB are preferable ensuring appropriate
dose adjustments. [Table 2] shows the recommended ASM in renal transplant patients.
Table 2
ASM in renal transplant patients
|
ASM
|
Category
|
Recommendations for renal transplant
|
|
PHT, CBZ
|
Older ASMs
|
Avoid due to enzyme induction
|
|
PHT, CBZ
|
Older ASMs
|
Avoid due to enzyme induction
|
|
VPA
|
Older ASM
|
Safe in renal transplant patients
|
|
LCM, LTG, LEV
|
Newer ASMs
|
Preferred due to minimal interaction with immunosuppressants
|
Abbreviations: ASM, antiseizure medication; CBZ, carbamazepine; LCM, lacosamide; LEV,
levetiracetam; LTG, lamotrigine; PHT, phenytoin; VPA, valproate.
Psychiatric Disorders
Psychiatric diseases are most common in individuals with epilepsy. The most frequent
include anxiety, depression, psychosis, personality changes, cognitive abnormalities,
and attention deficits. ASMs can have both sedative and excitatory effects. For example,
LTG acts as a mood stabilizer with antidepressant properties,[38] while LEV has been linked to aggressive behavior.[39] In contrast, PHT and VPA are associated with lower levels of irritability. Certain
antidepressants can also have proconvulsant effects. According to the FDA phase 2
and 3 clinical trials, clomipramine and bupropion are linked with a higher incidence
of seizures.[40] Additionally, amoxapine and maprotiline have been reported to pose an elevated seizure
risk at standard doses.[41]
The first-line ASMs, including CBZ, PHT, CBZ, and PB, are potent inducers of the enzymes.
As a result, they can reduce the serum concentrations of certain antidepressants,
such as tricyclic antidepressants as well as selective serotonin reuptake inhibitors
such as paroxetine and citalopram. To maintain therapeutic levels of these antidepressants,
a dose reduction of approximately 30% may be necessary. In contrast, VPA does not
exhibit such interactions with antidepressants.[42] The newer ASMs, including LTG, TGB, LEV, and ZNS, also do not have this effect.
The relationship between ASMs and suicidal behavior has raised concerns. In 2008,
a meta-analysis of 11 ASMs from a multicenter randomized controlled study highlighted
a potential link between suicide and these medications.[43] However, there is no conclusive evidence of the risk of suicidal behavior associated
with ASMs[44] and epilepsy.[45]
When treating individuals with epilepsy, it is significant to consider the adverse
effects of ASMs and antipsychotics. Weight gain is a significant concern with VPA
and CBZ. Fluoxetine is a preferred option because it is linked with a relatively smaller
increase in weight and has the additional benefit of enhancing alertness. However,
it can increase the plasma concentrations of CBZ and PHT, so monitoring serum levels
is necessary.
Additionally, hypernatremia should be considered when using serotonin and norepinephrine
reuptake inhibitors in combination with CBZ, OXC, and ESL. ASMs that have negative
psychotropic effects, such as benzodiazepines, barbiturates, TPM, LEV, and ZNS, should
be used with caution. In contrast, LTG, LCM, PGB, and GBP are known to have beneficial
effects. Psychiatric drugs and their effect on seizures are listed in [Table 3].
Table 3
Psychiatric medications and their level of seizure risk
|
Risk level
|
Severe risk
|
Medium risk
|
Mild risk
|
|
Psychiatric medications
|
Bupropion,
clomipramine, chlorpromazine, clozapine
|
Tricyclic antidepressants, venlafaxine, thioridazine, olanzapine, quetiapine
|
Fluoxetine
Sertraline
Paroxetine
Trazodone
Haloperidol Risperidone
|
In addition, ASMs may cause sexual dysfunction, which may lead to psychiatric consequences.
-
Enzyme-inducers, in high doses, can increase the sex hormone-binding globulin, lower
the free testosterone, and thereby reduce the libido and sexual function impairment.[46]
-
Other ASMs, including acetazolamide, benzodiazepines, and PGB, may cause sexual dysfunction
as well.
-
Sexual dysfunction is not common with ETX, GBP, LTG, LEV, TGB, VPA, and ZNS.[47]
When prescribing an ASM for a patient with epilepsy, preexisting psychiatric problems,
or learning disabilities, drug–drug interactions and side effects of ASM should be
taken into consideration ([Table 4]). The treating physician should consider which ASM might best help the patient maximize
seizure control and minimize psychiatric symptoms.
Table 4
Recommended antiseizure medications in patients with preexisting psychiatric, learning,
and behavioral problems
|
Preexisting psychopathology
|
Recommended antiseizure medications
|
|
Depression
|
Carbamazepine, lamotrigine
|
|
Mania
|
Valproate, carbamazepine, oxcarbazepine
|
|
Bipolar disorder
|
Valproate, carbamazepine, lamotrigine, oxcarbazepine
|
|
Aggression and agitation
|
Valproate, carbamazepine, phenytoin
|
|
Anxiety disorders
|
Pregabalin (generalized anxiety disorder), gabapentin
(social anxiety disorder)
|
|
Binge-eating disorder
|
Topiramate, zonisamide
|
|
Learning disability
|
Lamotrigine, levetiracetam
|
|
Attention-deficit hyperactivity disorder
|
Lamotrigine, carbamazepine, oxcarbazepine
|
Note: From Nadkarni and Devinsky,[48] Brodtkorb and Mula,[49] Schubert,[50] Schmitz,[51] Mula et al,[52] Tassone et al,[53] Kaufman,[54] Bialer,[55] Kimiskidis and Valeta,[56] and Kanner.[57]
Porphyria
A group of diseases known as porphyria is brought on by an aberrant buildup of porphyrins
and impacts the skin and nervous system. A reduction in neuronal activity, which can
result in seizures, is one outcome of this metabolic imbalance, which is frequently
characterized by hyponatremia, which can be brought on by digestive and kidney losses,
high water intake, and the impacts of the hormone antidiuretic. These metabolic abnormalities
may also be the cause of common symptoms during porphyric attacks, such as headaches,
cramping in the muscles, feeling nauseated, and altered awareness.[58]
Certain isoenzymes of cytochrome, specifically CYP2C9, CYP2C19, and CYP3A4, can be
activated by various ASMs such as CBZ, PHT, and PB. However, these medications worsen
or trigger attacks of acute intermittent porphyria. They accelerate the breakdown
of uroporphyrinogen decarboxylase and hydroxymethylbilane synthetase while altering
the feedback mechanism involved in heme biosynthesis. Current research regarding newer
ASMs only partially clarifies their potential role in precipitating porphyric attacks.[58]
Most ASMs induce porphyrias, enhancing liver metabolism and raising heme synthesis
in the liver.[59] Safer alternatives include GBP, LEV, and OXC, which have minimal effects on hepatic
enzymes and do not induce porphyric crises.[60]
[61] Acute porphyric attacks can be treated effectively with benzodiazepines, particularly
clonazepam. Intravenous magnesium has also been administered for status epilepticus,
although with a less favorable response.[62] Additionally, propofol has been utilized safely in cases of status epilepticus,
along with GBP and LEV for maintenance therapy.[63]
Epilepsy and Thyroid Disease
Epilepsy and Thyroid Disease
According to earlier research, there may not be a direct correlation between a patient's
thyroid hormone levels and epilepsy. However, using ASMs may cause certain abnormalities
in thyroid function. Numerous biological functions depend on thyroid gland hormones,
and insufficiency can exacerbate metabolic syndrome by impacting several body systems.
Therefore, it is crucial to thoroughly investigate thyroid hormone levels in epileptic
patients undergoing long-term therapy with ASMs.[64]
Prolonged use of ASMs has been linked to several metabolic, endocrine, and hormonal
abnormalities, as well as an increase in cardiovascular risks and incidents according
to research on epilepsy. Even when ASMs are given within therapeutic parameters, these
hazards may still materialize. Lipid abnormalities, hyperhomocysteinemia, being overweight
or obese, increased insulin resistance, diabetes type 2, hyperuricemia, and subclinical
thyroid dysfunction are a few of the dangers that are linked to this condition. Additionally,
long-term ASM users with persistent epilepsy may develop asymptomatic or subclinical
atherosclerosis disease, enlarged carotid arterial intima-media thickness, and perhaps
serious cerebrovascular and cardiovascular events.[65]
The chronic use of ASMs has notable effects on endocrine functions. Clinical studies
have indicated that medications such as CBZ, PHT, and VPA can alter normal thyroid
functions.[66] In one study involving 298 epilepsy patients, it was found that CBZ, TPM, and LEV
led to a significant decrease in free thyroxine levels.[67]
[Table 5] shows the advised use of ASMs in individuals with epilepsy and other comorbidities.
Table 5
ASM recommendations in individuals with epilepsy and other comorbidities[24]
|
Safe ASMs
|
Not recommended/To avoid ASMs
|
|
Cardiac disorders
|
LEV, LTG, TPM, VPA, ZNS. GBP
|
CBZ, OXC, PGB, PHT
|
|
Liver disorders
|
LEV, PGB, TPM. GBP, ZNS
|
BZD, CBZ, ESM, LTG PB, PHT, PRM, TGB, VPA,
|
|
Kidney disease
|
BZD, CBZ, ESM, PHT, TGB, VPA
|
GBP, LEV, LTG, OXC, PB, PGB, PRM, TPM, ZNS
|
|
Porphyria
|
LEV, OXC, PGB. GBP*
|
BZD, CBZ, LTG, PB, PHT, PRM, TGB, TPM, VPA, ZNS
|
|
Renal transplantation
|
BZD, LTG, VPA
|
ASM with renal excretion, enzyme-inducing ASM
|
|
Cognitive impairment
|
LTG, LCM, OXC, VPA. GBP
|
BZD, CBZ, LEV, PB, PHT, PRM, PGB, TPM, ZNS
|
|
Psychiatric disorders
|
LTG, OXC, VPA, GBP, PGB
|
LEV, PER, TPM, ZNS
|
|
Hypothyroidism
|
BZD, LEV, LTG, PGB, ZNS. GBP
|
CBZ, OXC, PB, PHT, PRM, TPM, VPA
|
Abbreviations: ASM, antiseizure medication; CBZ, carbamazepine; GBP, gabapentin; LCM,
lacosamide; LEV, levetiracetam; LTG, lamotrigine; OXC, oxcarbazepine; PB, phenobarbital;
PGB, pregabalin; PHT, phenytoin; TGB, tiagabine; TPM, topiramate; VPA, valproate;
ZNS, zonisamide.
Many patients with epilepsy also have comorbidities, which should be a significant
factor when selecting the most appropriate ASM. Although there is limited scientific
evidence regarding the management of epilepsy in individuals with associated diseases,
it is essential to evaluate the available data that supports the use of specific ASMs
for particular conditions. [Table 4] is a summary of the most recommended ASMs in each situation, as well as those that,
according to the best-known data, need to be avoided or are not as strongly advised.[24]
In conclusion, administering ASMs in the context of systemic illness requires a careful
and nuanced approach. The effects of ASMs extend beyond just controlling seizures;
they also impact various physiological systems. It is crucial to recognize and address
potential interactions, particularly when managing comorbid issues like psychiatric,
cardiovascular problems, kidney and liver disorders, endocrine disturbances, and porphyrias.
