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\def\RunningAuthor{Satish Kumar Sharma and Suruchi Singh}
\firstPage{7694}
\articleType{Review Article}
\receivedDate{20 Oct 2020}
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\title{\textbf{A Review on conceptual framework of Drug Side Effects and Pharmacoresistance in Epilepsy}}
\author{Satish~Kumar~Sharma\textsuperscript{*}\textsuperscript{1}, 
            Suruchi~Singh\textsuperscript{2}~\\[5pt]{\textsuperscript{1}Department of Pharmacology, Glocal School of Pharmacy, Glocal University, Mirzapur Pole, Saharanpur - 247121, Uttar Pradesh, India}~\\{\textsuperscript{2}Glocal School of Pharmacy, Glocal University, Mirzapur Pole, Saharanpur - 247121, Uttar Pradesh, India}}

\begin{abstract}
Epileptic seizures in the form of involuntary body movements have made patients' lives extremely difficult. There are mainly two types of seizures partial or focal seizure affect just one side of the brain and generalised seizures affect the whole brain of a person. The person suffers from neuro-sensory deregulation and consciousness loss, coupled with episodes of seizures. Different drug therapies have been used for epilepsy patients targeting neurotransmitters regulation mechanisms. The drug targets and mechanism of action in polytherapy remain ambiguous.  However, 6 out of 10 patients quit antiepileptic drug (AED) therapy due to side effects like depression, aggression and psychosis. Several behavioral side effects make them socially awkward, due to which patients cease to continue drug therapies. The combined effect of AED side effects and resorting therapies lead to recurrent seizures which further disturb the neurotransmission on account of every seizure episode. The present review describes epilepsy in terms of clinical treatments and associated side effects. The study provides a novel conceptual loop of correlation between AED polytherapy, side effects and Pharmacoresistance. This review creates caution for clinicians to think intricately before prescribing drugs for epilepsy and ensure communication of side effects. The review opens research prospectives for drug targets to break the conceptual loop for the Pharmacoresistance. Further, this paper enhances the understanding of epilepsy and improves diseases condition. 
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Anti-epileptic drugs,\newline AED Side effects,\newline Pharmacoresistance,\newline Recurrent seizures
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Satish~Kumar~Sharma~\\ Phone:\ ~\\  Email:\ satishdipsar55@gmail.com
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\section{Introduction}
Epilepsy is a common, fatal neurological disorder that causes unprovoked sensory disturbance and/or consciousness loss in the form of recurrent seizures. A person is considered to be epileptic when two or more seizures are experienced without any direct correlation with medical conditions such as fever or drug withdrawal symptoms \unskip~\citep{954896:20967186}. Among 50 million patients of epilepsy worldwide, there are around 10 million patients in India \unskip~\citep{954896:20967179}. Epilepsy causes uncontrolled body movements, temporary impaired awareness and consciousness loss that can cause injuries, psychological morbidities and progressive memory dysfunction \unskip~\citep{954896:20967178}. Hence, it is usually associated with disturbed quality of life in terms of health. 

The treatment of epileptic patients usually involves administration of anti-epileptic drugs (AEDs) in synergistic combinations to achieve freedom from seizures \unskip~\citep{954896:20967198}. AEDs target voltage-gated ion channels and neurotransmitter receptors \unskip~\citep{954896:20967200}. Aberrant body movements and loss of central nervous system connection in epileptic discharge occur due to defects in the functioning of ion channels. According to animal model studies on epilepsy, dendritic K\ensuremath{^{+}} channels and hyperpolarized T- type Ca\ensuremath{^{2+}} channels are major contributors to seizures \unskip~\citep{954896:20967189}. AEDs targeting Na\ensuremath{^{+}} channels have been found most effective against seizures as they stabilize the inactive state of Na\ensuremath{^{+}} channel and synaptic blockade prevents repeated firing of exons \unskip~\citep{954896:20967203}. Along with excitability in the central nervous system, voltage-gated ion channels also regulate the peripheral autonomic nervous system, cardiovascular system and digestive system. AEDs also regulate the hormonal system \unskip~\citep{954896:20967188}. Before selecting an ion-channel target, it is necessary to ensure tissue type in which it is expressed{\textemdash}voltage-gated ion channels in heart share close homology with those expressed in the brain. So, selected drugs should preferably target isoforms expressed in the brain over those expressed in the heart.

Subsequent research studies in molecular mechanisms of epilepsy suggest G-protein coupled receptors as potential targets for AEDs. The principal inhibitory neurotransmitter receptor gamma-aminobutyric acid (GABA) counterbalances neuronal excitation. GABA antagonists have been found to produce seizures, hence drugs that increase GABA expression have been potent anti-convulsants \unskip~\citep{954896:20967195}. Basically, AEDs regulate channels and receptors of the central nervous system to inhibit seizures. The present review describes epilepsy in terms of clinical treatments and associated side effects. The study provides a novel conceptual loop of correlation between AED polytherapy, side effects and Pharmacoresistance.

\textbf{Clinical pharmacoresistance in Epilepsy}

Obstinate epilepsy is marked by the occurrence of seizures so frequent that they pose compulsion for severe medication. Otherwise, there is a threat to patients' ability to live. However, frequent use of medications leads to adverse side effects \unskip~\citep{954896:20967201}. Clinically, severe medication often leads to partial or complete failure of the body's ability to respond to AEDs. The condition of failure to regulate seizures by first and/or second drug trials of AEDs at required doses is referred to as pharmacoresistance. In such cases, patients experience neuropsychological, psychiatric and social burden towards epilepsy treatment \unskip~\citep{954896:20967178,954896:20967199}. 

Researchers have proposed several mechanisms responsible for Pharmacoresistance epilepsy which have been hypothesised as two major aspects: pharmacokinetic transporter hypothesis and target hypothesis. According to the transporter hypothesis, overexpression of efflux transporters at the blood-brain barrier (BBB) causes limited penetration of AEDs to the brain \unskip~\citep{954896:20967207}. One of these efflux transporters includes ATP-dependent glycoprotein efflux system (P-gp) encoded by a family of multidrug-resistant genes MDR1 in humans \unskip~\citep{954896:20967180}. According to pre-clinical studies, absence of MDR1 gene subunit results in increased uptake of lipophilic drugs in the brain \unskip~\citep{954896:20967177}. Hence, active expression of these genes leads to transfer of some part of AEDs back to blood, thus inhibiting many drugs reaching brain parenchyma. Exposure to decreased concentration of AEDs or changed drugs distribution promotes resistance among target cells \unskip~\citep{954896:20967192}. 

Alternatively, the target hypothesis indicates alterations in target receptors of AEDs that results in insensitivity towards drug effects \unskip~\citep{954896:20967196}. Voltage-gated ion channels and neurotransmitter receptors are direct targets of AEDs. The drug-receptor binding is affected due to molecular changes in desired targets reducing drug sensitivity \unskip~\citep{954896:20967206}. These molecular changes are caused due to intrinsic polymorphism or acquired alterations occurred during disease process or frequent seizures. Thus, pharmacoresistance occurs when AEDs fail to inhibit Ca\ensuremath{^{2+}} or Na\ensuremath{^{+}} channels mediated neuronal excitation or to enhance downregulation of neuronal current mediated by GABA receptors \unskip~\citep{954896:20967196}. 

Another aspect of pharmacoresistance pathogenesis is related to temporal lobe epilepsy (TLE). The prevalent form of epilepsy is caused due to neurodegeneration in hippocampus regions of the brain \unskip~\citep{954896:20967184}. Pharmacoresistance associated with TLS is linked to dysregulated neurotransmission caused by glutamate and GABA receptors. During recurrent aggravated seizures, an increased level of glutamate causes a synaptic disturbance. The presynaptic regulation of glutamate release and postsynaptic current inhibition mediated by GABA receptors at dendritic layers is severely affected \unskip~\citep{954896:20967205}. In summary, variations in drug delivery, polymorphic changes in drug target and frequent dysregulation of neurotransmission in seizures are responsible for fatal pharmacoresistant epilepsy.

\textbf{The rational approach towards Epilepsy therapies}

Pharmacoresistance has rendered epilepsy treatments to be more complicated. The patients who fail to respond towards the first-line drug at optimum or maximum dose tolerance mostly turn out to have refractory epilepsy \unskip~\citep{954896:20967193}. It seems obvious to use a combination of drugs to control seizures. 

According to a study involving patients with recurrent seizures even after first-line monotherapy, when randomly selected for additional treatment with gabapentin or vigabatrin were found successful. 31\% (Gabapentin) and 39\% (Vigabatrin) of patients subjected to additional drug treatment were relieved of seizures \unskip~\citep{954896:20967187}. These results show revival of anticonvulsant potency of AEDs quite moderately for patients who already have tried a number of drugs. The polytherapy could be more effective among patients who have seizures continued after the first monotherapy. However, ambiguity persists related to studies depicting the synergistic effects of AEDs. 

It is difficult to correlate clinical observations to pharmacological mechanisms as action mechanisms of drug combination are not clearly understood. Anticonvulsant properties of carbamazepine and phenytoin which induce hepatic enzymes directly affect voltage-gated Na+ ion channels, whereas renally eliminated drugs like gabapentin, vigabatrin have an unknown mechanism of action \unskip~\citep{954896:20967202}. There could be several consequences of polytherapy, such as a new drug that can reduce the penetration level of other drugs and cause seizures. It can reduce effectiveness and can cause unexpected severe side effects. It is possible that these AEDs chemical combine inside the human body and promote pharmacoresistance.

\textbf{Side effects of antiepileptic drugs}

Most AEDs cause adverse side effects due to drug reactions. However, behavioural side effects such as aggression, psychosis, hyperactivity and restlessness are usually overlooked when the seizure-free condition is achieved. The first clinical AED {\textendash} potassium bromide {\textendash} has displayed psychiatric toxicities. Almost all AEDs cause some episodes of cognitive, psychiatric and behavioural side effects \unskip~\citep{954896:20967197,954896:20967185}. These side effects are observed due to non-specific target binding of AEDs. These side effects cause rapid deregulation of neurotransmission impulse causing rapid on and off the signal by neurotransmitters and receptors. Recurrence of such activities in the brain can lead to polymorphic mutations in receptors, which can develop resistance against AEDs (Figure~\ref{f-11d89efd9480}). AED side effects create rapid deregulation of neurotrans mission signals leading to polymorphic mutations in receptors. The mutated receptors escape from AED target and cause drug resistance. The ignored drug effects can pose more risk factors to social life quality than seizures frequency. Hence, clinical management is required for polytherapy and commercial drugs against epilepsy. 


\bgroup
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\caption{\boldmath {A connected conceptual loop of Anti epileptic drugs (AEDs)and their side effects in causing pharmacoresistant epilepsy. }}
\label{f-11d89efd9480}
\end{figure*}
\egroup

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\makeatother 
\caption{\boldmath {An identified problem of correlation between AED side effects and pharmacoresistance. }}
\label{f-7f286995ca9e}
\end{figure*}
\egroup
\textbf{Gabapentin}

Gabapentin, a structural analogue of GABA helps in increasing GABA synthesis and repairs GABA shutdown. It has low anticonvulsant potency and it is being used clinically at much higher doses than prescribed in pre-marketing studies. It is most effective as add-on treatment and less potent in monotherapy. According to a study involving five trials with 997 randomized patients, Gabapentin is efficient as add-on treatment of drug-resistant partial epilepsy \unskip~\citep{954896:20967181}. However, the drug is ineffective in the absence or myoclonic seizures and has adverse side effects such as coordination loss, double/blurred vision, unusual eye movements and tremors \unskip~\citep{954896:20967194}.

\textbf{Topiramate}

Topiramate accounts for being distinctive from general AEDs as it is derivative of naturally occurring monosaccharide D-fructose with sulfamate functionality. It targets voltage-gated Na\ensuremath{^{+}} and Ca\ensuremath{^{2+}} channels, GABA receptors and certain glutamate receptors \unskip~\citep{954896:20967182}. Patients with a long history of treatment with the drug have reported reverse cognitive effects and adverse side effects as major reasons for discontinuation of therapy \unskip~\citep{954896:20967204}. Topiramate has also been reported to cause drug-resistant partial epilepsy \unskip~\citep{954896:20967191}. Overall the exact cause of cognitive dysfunction in epilepsy is not known, but the drug treatment side effects can be one of the potential reasons. 

\textbf{Vigabatrin}

Vigabatrin is an analogue of GABA which binds irreversibly to GABA transaminase and prevents degradation of GABA \unskip~\citep{954896:20967193}. Thus, the drug helps to increase levels of GABA receptors to treat infantile spasms \unskip~\citep{954896:20967190}. However, Vigabatrin is the last chosen drug during treatment for focal epilepsy because it has been reported to cause irreversible visual defects in 30\% to 60\% patients. The effects are thought to be related to GABA mediated toxicity on retinal cells \unskip~\citep{954896:20967183}. The drug has also been reported to cause psychosis as side effects \unskip~\citep{954896:20967193}.

According to data collated by Thigpen \textit{et al}., the most commonly used AEDs have aggressive side effects on patients. Due to this, there is a huge economic and social burden on patients and their families \unskip~\citep{954896:20967186}. Hence, it is necessary that doctors should ensure communication of side effect possibilities to patients or caregivers. Knowledge of such behavioural changes and ways to tackle them can minimize their impact, leading to rapid therapeutic adjustments and less retraction in the middle of therapy. 

\textbf{Pharmacovigilance for AEDs side effects}

Epilepsy is a complex disorder with pharmacoresistance being linked to disease progression. The common treatment of the disease involves AED therapy and the mechanism of progressive drug resistance remains unknown. Etiologically, AEDs' cognitive and behavioural side effects can be linked to the regulation of impulse in the central nervous system. Myoclonic and absence seizures occur due to rapid impulse connections and failed regulation. 

These repetitive seizures associated with side effects can cause polymorphic changes in receptors which can be major contributors to pharmacoresistance. Recurrent seizures after drug therapies can be more dangerous than it seems. The complex functioning of brain and AED interaction targets, further disturbed by frequent seizures, can lead to an unbreakable loop of AED side effects and drug resistance. Hence there is a need to break the connectivity between AED side effects and pharmacoresistance, as shown in Figure~\ref{f-7f286995ca9e}, to achieve a completely seizure-free state in patients. The occurrence of multiple seizures as AED side effects can lead to altered drug targets which can possibly develop resistance from drugs, creating a correlation between AED side effects and drug resistance.
    
\section{Conclusion}
Despite several advances in drug treatments for epilepsy, patients have shown poor recovery along with recurrent seizures. These patients are usually subjected to synergistic combinations of AEDs with severe side effects without any significant reduction in seizure frequency. The drug targets and mechanism of action in polytherapy remain ambiguous. Most common side effects of AEDs include blacking out, psychosis, aggression and behavioral disorders which are results of non-systematic synaptic impulse in the brain. The frequent occurrence of these side effects and failure to control seizures can result in polymorphic mutations in receptors and drug targets. Consequently, severe side effects of AEDs can cause molecular changes in drug targets which can be a contributing factor to pharmacoresistant epilepsy. Hence, it is important to expand studies on AED side effects and their mechanistic relation towards drug resistance. It is likely that AED treatments lacking pharmacovigilance can worsen drug resistance in epilepsy patients. Therefore, the review suggests a correlation of AED side effects with pharmacoresistance which  can further enhance understanding of epilepsy and improve disease condition. 

\textbf{Funding Support}

The authors declare that they have no funding support for this study.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.
    

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