Clinical Pharmacology of Modern Antiepileptic Drugs

Reddy: Clinical Pharmacology of Modern Antiepileptic Drugs 3875 International Journal of Pharmaceutical Sciences and Nanotechnology Review Article Clinical Pharmacology of Modern Antiepileptic Drugs Prof. D. Samba Reddy, RPh, PhD, FAAPS, FAAAS, FAES Professor & NIH CounterACT Investigator, Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center, College of Medicine, Bryan, Texas 77807, USA. Received July 25, 2017; accepted August 20, 2017 Volume 10 Issue 6 November December 2017 MS ID: IJPSN-07-25-17-REDDY ABSTRACT This article describes current antiepileptic drugs (AEDs) that are available for treatment of epilepsy. Epilepsy is characterized by repeated occurrence of seizures. Epileptic seizures are classified into focal and generalized types. Around two-dozen AEDs are available for treating epilepsy. AEDs act on diverse molecular targets to selectively modify the abnormal excitability of neurons by reducing the focal seizure discharges or preventing spread of excitation. AEDs suppress seizures by blocking the voltage-gated sodium channels (phenytoin, carbamazepine, valproate, lamotrigine, oxcarbazepine, topiramate), voltage-activated calcium channels (ethosuximide, gabapentin), potentiation of GABA inhibition (barbiturates, benzodiazepines, tiagabine), and reduction of glutamate excitation (felbamate, parampanel). Carbamazepine, phenytoin, and valproate are the first-line agents for partial seizures and generalized tonic-clonic seizures. Ethosuximide is the drug of choice for absence seizures. AEDs are orally-active and show unique pharmacokinetic features. Some AEDs cause enzyme induction and hence produce drug-drug interactions. Newer AEDs such as gabapentin, levetiracetam, tiagabine, and pregabalin do not cause enzyme induction. Despite many advances in epilepsy research, nearly 30% of people with epilepsy have drug-resistant or intractable seizures. Presently, there is no cure for epilepsy. Thus, newer and better AEDs that can better prevent refractory seizures and modify the disease are needed for curing epilepsy. KEYWORDS: Epilepsy; Seizure; Phenytoin; Carbamazepine; Valproate; Ethosuximide; Levetiracetam. Introduction Epilepsy is a chronic disorder characterized by recurrent unprovoked seizures. A seizure is an abnormal electrical discharge in the brain that causes alteration in consciousness, sensation, and/or behavior. When the risk of spontaneous seizures is sufficiently high, generally after two witnessed spontaneous seizures, the patient is diagnosed with epilepsy. Epilepsy affects about 3 million people in the United States and approximately 65 million people worldwide (Jacobs et al., 2009; Reddy, 2013; Hesdorffer et al., 2013). It is the fourth most common neurological disorder in the US after migraine, stroke, and Alzheimer s disease (Hesdorffer et al., 2013). Epilepsy affects people of all ages and both genders. Every year, nearly 150,000 new cases of epilepsy are diagnosed in the United States (Hesdorffer et al., 2013). Despite advances in technology and treatment, epilepsy still remains a huge economic burden, with an estimated health care cost of $2.7 billion per year (Vivas et al., 2012). Epilepsy may develop because of an abnormality in brain wiring, an imbalance in inhibitory and excitatory neurotransmitters, or some combination of these factors. Many different mechanisms (e.g., ion channels and neurotransmitters) can cause neuronal hyperexcitability and lead to the development of seizures. Imbalances between excitatory (glutamate) and inhibitory (GABA) neurotransmitters, as well as excessive acetylcholine, norepinephrine, and serotonin levels, may also be involved in seizures. Primary epilepsy (~50%) is idiopathic. In secondary epilepsy (~50%), referred to as acquired epilepsy, seizures may result from a variety of conditions including trauma, anoxia, metabolic imbalances, tumors, encephalitis, drug withdrawal, or neurotoxicity. The most common risk factors for secondary epilepsy are birth injury, cerebrovascular disease, brain tumors, alcohol withdrawal, traumatic head injuries, developmental cortical malformations, genetic inheritance, and infections of the central nervous system (Reddy and Volkmer, 2017). There are antiepileptic drugs (AEDs) available for the treatment of epilepsy. They act on diverse molecular targets to selectively modify the excitability of neurons by reducing the focal seizure discharges or preventing spread of excitation (Table 2). Despite many advances in epilepsy research, nearly 30% of people with epilepsy have intractable seizures that do not respond to even the best available AEDs. There is a significant need for drugs that prevent the development of epilepsy ( antiepileptogenic agents ) or alter its natural course to delay the appearance or severity of epileptic seizures ( disease-modifying agents ) (Jacobs et al., 2001; Clossen and Reddy, 2017; Younus and Reddy, 2017a). During the past decade, there has been growing research emphasis on the prevention of epileptogenesis 3875

3876 Int J Pharm Sci Nanotech Vol 10; Issue 6 November December 2017 and attempts to transition lead discoveries into FDA licensed therapies to cure epilepsy (Jacobs et al., 2009; Simonato et al., 2012). The Institute of Medicine (IOM) released a consensus report in 2012 on public health dimensions of the epilepsies, focusing on promoting health and understanding epilepsy (Austin et al., 2012; Hesdorffer et al., 2013). In the report, Epilepsy Across the Spectrum: Promoting Health and Understanding, there are 13 recommendations for future work in the field of epilepsy including a key recommendation to develop drugs for the prevention of epilepsy. History and Definitions Seizures have been described as early as 1600 BC. In 500 BC, ancient Babylonians accurately described several features of epilepsy. People often thought epilepsy was caused by demons, and those with the disorder were viewed with fear and suspicion. During the course of history, there have been many drugs used to treat the symptoms of what we now call epilepsy. Bromide was used as an antiepileptic in the 19 th and 20th centuries despite the toxic side effects. Barbituric acid first used as an antiepileptic in the early 1900s. Phenytoin was used beginning in the 1930s, based on the efficacy seen in the animal studies of Merrit & Putnam. A breakthrough was finally made with the discovery of GABA ( -aminobutyric acid) as an inhibitory neurotransmitter in the middle of the 20th century. Since then, much effort has focused on this pathway as a treatment for epilepsy, including several newer antiepileptic drugs being discovered and marketed. We now know that epilepsy is not a single disease state, but is a collective designation for a group of central nervous system (CNS) disorders. The International League Against Epilepsy (ILAE) described a formal definition of epilepsy : a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures (ILAE, 1981; Berg et al., 2010). A more general definition, recommend also by the ILAE is: a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. A single seizure does not result in a diagnosis of epilepsy. A diagnosis requires the occurrence of recurrent (two or more) epileptic seizures, unprovoked by any immediate identified cause. Complicating the diagnosis, and ultimate treatment, is the fact that in this spectrum disorder, there are different types of seizures, which lead to different types of epilepsy diagnosis. Diagnosis of Epilepsy Epilepsy diagnosis is made if more than two unprovoked seizures occur. EEG (electroencephalogram) and MRI (magnetic resonance imaging) are used to confirm electrographic (epileptiform discharges) and morphological abnormalities (hippocampal atrophy or mesial temporal sclerosis), respectively. History and biochemical profile are very helpful for diagnosis and treatment decisions. Seizures are classified into partial (focal) seizures or generalized seizures. Each category can then be further subdivided. In some patients, both types of seizures may be experienced. Partial, or focal, seizures (60% of all epilepsies) begin in a certain section of the brain and may be different for different people. The involved sites can include cortical areas, frontal lobe, and temporal lobe. Generally, partial seizures cause disturbances in motor function, sensory perception, autonomic function, and behavior. Sensory symptoms include paresthesias, abnormal tastes or smells, flashing lights, and hearing changes. Automatisms, or repetitive movements (chewing, swallowing, or sucking), can be described in some patients. A number of patients experience an aura or warning symptoms minutes to hours before a seizure of this type. In patients with partial seizures, the brain region involved will be used to further define the type of epileptic diagnosis and potentially effect treatment options. Generalized seizures (40% of all epilepsies) involve both hemispheres of the brain (Duncan et al., 2006). A variety of generalized seizures have been identified. The list includes absence, tonic, clonic, myoclonic, atonic, tonic-clonic, or even secondary seizures. Typically, bilateral motor symptoms are experienced. In 2014, the ILAE provided a revised definition of epilepsy. Epilepsy diagnosis is made when at least two unprovoked (or reflex) seizures occurring greater than 24 hours apart or one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years. Epilepsy is considered resolved for individuals who had an agedependent epilepsy syndrome but are now past the applicable age or those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years. Pathophysiology of Epilepsy The mechanisms underlying development of epilepsy are not very well understood. The term epileptogenesis is used to describe the complex plastic changes in the brain that, following a precipitating insult or injury, convert a normal brain into a brain debilitated by recurrent seizures (Sutula, 2004; Reddy, 2009; Dudek and Staley, 2011; Pitkänen and Lukasiuk, 2011). Neuronal injury and neuroinflammation have been proposed to play a central role in the overall pathogenesis of acquired epilepsy. The most common current hypothesis about epileptogenesis suggests that there are three stages (Figure 1). The first stage requires an initial precipitating event. This is followed by the second stage which is a latent period that a can last a varied amount of time. The third stage is the chronic period in which the patient suffers from spontaneous seizures. Epileptogenesis is a slow process, as it takes several months for spontaneous seizures to appear (Dudek and Staley, 2011; Reddy, 2011). The time required to reach stage 3 represents a window of opportunity for testing interventions in people at high risk for epilepsy (Rao et al., 2006; Reddy and Mohan, 2011; Reddy, 2013).

Reddy: Clinical Pharmacology of Modern Antiepileptic Drugs 3877 assessed in the brain (Figure 2). Experimental field and intracellular recordings in isolated tissue sample provide a detailed neurophysiological abnormalities underlying in epileptic regions. Paroxysmal depolarization shift (PDS) is an intracellular correlate of an interictal (an ictal event occurs during a seizure) spike on surface EEGs. The PDS is an abnormal prolonged depolarization with repetitive spiking characteristic of neurons in epileptic cortical zones that are reflected as interictal discharges in the EEG. Fig. 1. Pathophysiology of epilepsy (epileptogenesis). Epileptogenesis is the process whereby a normal brain becomes progressively epileptic because of precipitating injury or risk factors such as brain injury, stroke, brain infections or prolonged seizures. Epilepsy development can be described in three stages: (1) the initial injury (epileptogenic trigger); (2) the latent period (silent period with no seizure activity); and (3) chronic period with spontaneous recurrent seizures. Although the precise mechanisms underlying spatial and temporal events remain unclear, epileptogenesis may involve an interaction of acute and delayed anatomical, molecular, and physiological events that are both complex and multifaceted. The initial precipitating factor activates diverse signaling events, such as inflammation, oxidation, apoptosis, neurogenesis and synaptic plasticity, which eventually lead to structural and functional changes in neurons. These changes are eventually manifested as abnormal hyper-excitability and spontaneous seizures. The general neuronal mechanism underlying occurrence of epileptic seizures is illustrated in Figure 2. Studies in animal models have provided improved understanding of the neurophysiological basis of epileptic seizures (Simonato et al., 2012; O'Dell et al., 2012). Experimental field and intracellular recordings in isolated brain sections provide a detailed description of neurophysiological abnormalities underlying epileptic regions. This knowledge has guided some standard diagnostic tools and endpoints. In epilepsy patients, spontaneous seizures arise from hyperexcitable and hypersynchronous neuronal networks and it likely involves both cortical and several key subcortical structures. The EEG is the primary tool with which both normal and abnormal electrical activity is Fig. 2. Potential cellular and synaptic mechanisms of epileptic seizures. A seizure can be divided into three phases: (1) focal epileptogenesis (initiation), (2) synchronization of the surrounding neurons, and (3) propagation of the seizure discharge to other areas of the brain. Arrows indicate where each of the mechanisms on the left participates in the three phases involved in seizure generation. Electrophysiological activity in a single neuron during an epileptic seizure is complex and can be described by d the paroxysmal depolarization shift (PDS). The PDS consists of a large depolarization of the neuronal membrane associated with a burst of action potentials. In most cortical neurons, the PDS is generated by a large excitatory synaptic current that can be enhanced by activation of voltage-regulated intrinsic membrane currents. The interictal spike is a sharp waveform recorded in the EEG of patients with epilepsy; it is asymptomatic (no behavioral correlate) but the location of the interictal spike helps localize the brain region from which seizures originate. Classification of Seizures Epileptic seizures are classified according to the International League Against Epilepsy (ILAE) classification scheme (Table 1). The previous classification divides seizures into focal (partial) or generalized (bilateral) seizures. Each of these classifications is even further subdivided, as explained below. TABLE 1 Classification and characteristics of epileptic seizures. Convulsive Features Partial Simple Confined to specific muscle groups and specific sensory disturbances, depends on local of focus Complex Confused and/or inappropriate behavior Generalized Absence Abrupt, brief loss of consciousness, some eyelid blinking Loss of Consciousness Usual Duration Postictal Confusion EEG During Seizures No 5 10 sec No Normal or focal spikes Yes 5 sec 2 min Yes Temporal or frontal focal activity spreading to one or both hemispheres Yes 5-20 sec No Generalized 3-H synchronized spike and wave discharge TABLE 1 Contd

3878 Int J Pharm Sci Nanotech Vol 10; Issue 6 November December 2017 Convulsive Features Tonic-Clonic Tonic contraction of entire musculature, followed by clonic contractions (clonic jerks) Myoclonic Isolated muscular contractions, or clonic jerks of arms and shoulders Atonic Loss of postural tone resulting in falling or dropping to floor Loss of Consciousness Usual Duration Postictal Confusion EEG During Seizures Yes 1-2 min Yes Generalized high amplitude spikes Yes (partial) Usually single events but may cluster No Generalized bursts of multiple spikes No 1-2 sec No Generalized irregular spikes, polyspike or spike and wave discharges Partial Seizures (a) Simple partial seizures: Simple partial seizures are characterized by a localized onset of excessive neuronal discharge referred to as the focus. Because only part of the brain is involved in seizure activity, there is almost always no impairment of consciousness. Depending upon the cortical brain area involved, the seizure may be limited to a single limb or muscle group. Behavioral signs include both sensory and motor manifestations. Some signs categorized as sensory are: hallucinations or illusions affecting touch, vision, hearing, smell and taste. A person may see lights, hear buzzing sounds, or feel tingling or numbness. Signs that are categorized as motor include a change in muscle activity in one part of the body without loss of consciousness. This includes convulsive movements and jerking. (b) Complex partial seizures: For this type of seizure, which is also referred to as temporal lobe epilepsy (TLE), the focus is located in the temporal lobe (limbic epilepsy). The person performs automatic movements called automatisms (picking at clothes, walking aimlessly, picking up things, mumbling, lip smacking). Seizures last between 30 seconds and 3 minutes, and are followed by a state of confusion and short-term memory loss. There is usually impairment of consciousness, amnesia, and postictal confusion. TLE is also the most common form of drug-refractory epilepsy. Atrophy of mesial temporal structures is well known to be associated with TLE and hippocampal sclerosis is the most frequent abnormality in this form of epilepsy. An aura is a sensation(s) felt by the patient immediately preceding an epileptic seizure. It is an unusual smell, sensory illusion, déjà vu familiar feeling, etc. This is a focal phenomenon that warns the patient of the impending attack. Auras represent anything the brain is capable of manifesting, and the sensation will be dependent upon the area of the brain affected. For example, if the focus is in the limbic area, the sign will be psychic (déjà vu); in the amygdala it could be alterations of smell; in the motor cortex, a twitching hand; in the sensory cortex, a tingling foot; in the occipital lobe, a visual phenomenon. (c) Partial seizures secondarily generalized: Partial seizures can progress to become generalized seizures (secondary generalized). This type of seizure is characterized by a loss of, or impaired, consciousness and convulsive movements. A sensory or motor aura may precede the seizure. An aura may be felt as a tingling or movement of a limb, which can spread throughout the body (generalized seizure). A secondary generalized seizure may be difficult to distinguish from a generalized tonic-clonic seizure. Generalized Seizures (a) Absence seizures (Petit Mal): are characterized by a brief loss of consciousness, and generally occurs in childhood. A generalized 3-Hz synchronized spike and wave discharge are evident in the EEG. It is not associated with an aura. A typical absence seizure is observed as a freeze or blank staring. Absence seizures are generalized from the beginning involving the entire cortex. In most cases, the attack may involve clonic movements, ranging from blinking eyelids to a jerking of the entire body. This seizure lasts less than 1 minute. (b) Tonic-clonic seizures (Grand Mal): seizures begins with a sudden loss of consciousness, maximal tonic spasm of all body musculature, followed by clonic jerking, postictal depression. The sequential steps of a grand mal seizures involves: (i) Tonic phase (30 seconds)-- body becomes rigid and falls; (ii) Clonic phase (2-3 minutes)-- body experiences rhythmic jerks, followed by relaxation; and (iii) Postictal state (10 minutes)-- body becomes limp, and the person remains unresponsive. In some patients, the seizure is preceded by a prodrome - a feeling of tenseness or depression well before the seizure (several hours). Immediately prior to the seizure, the patient may experience an aura, a warning signs and symptoms including altered sensations and deja vu feelings. (c) Myoclonic seizures are single or multiple myoclonic jerks of the neck and shoulder flexor muscles (no loss of consciousness). They are rare and often associated with permanent neurologic damage. Myoclonic seizures do not respond well to drug therapy. (d) Atonic seizures (Drop Attacks) are characterized by sudden loss of postural tone with sagging of the head or falling (brief loss of consciousness).

Reddy: Clinical Pharmacology of Modern Antiepileptic Drugs 3879 Atonic seizures do not respond well to drug therapy. Epileptic syndromes refer to a cluster of symptoms frequently occurring together and include seizure types, etiology, age of onset, and other factors. More than 40 distinct epileptic syndromes have been identified within the partial and generalized epilepsies. Revised Classification of Epileptic Seizures (2017) The ILAE has recently revised the classification of seizures (10). It is believed that these changes will help make diagnosing and classifying seizures more accurate and easier. Separating seizures into different types helps guide further testing, treatment, and prognosis or outlook. Using a common language for seizure classification also makes it easier to communicate among clinicians caring for people with epilepsy and doing research on epilepsy. The old classifications worked for many years but did not capture many types of seizures. This new version is thought be more complete. The 2017 classification uses awareness as a surrogate marker of consciousness. The new basic classification is a simple version of the major categories of seizures (Figure 3). The new basic seizure classification is based on 3 key features: (1) Where seizures begin in the brain; (2) Level of awareness during a seizure; and (3) Other features of seizures. The first step is to separate seizures by how they begin in the brain. The type of seizure onset is important because it affects choice of seizure medication, possibilities for epilepsy surgery, outlook, and possible causes. Fig. 3. ILAE 2017 classification of seizures types basic version. (i) Focal onset seizures: Previously called partial seizures, these start in an area or network of cells on one side of the brain. In this new basic system, seizure behaviors are separated into groups that involve movement, such as focal motor seizure (some type of movement occurs during the event), focal non-motor seizure (other symptoms that occur first, such as changes in sensation, emotions, thinking, or experiences). It is also possible for a focal aware or impaired awareness seizure to be sub-classified as motor or non-motor onset. (ii) Generalized onset seizures: Previously called primary generalized, these engage or involve networks on both sides of the brain at the onset. Seizures that start in both sides of the brain, called generalized onset, can be motor or nonmotor. Generalized motor seizure or the generalized tonic-clonic seizure term is still used to describe seizures with stiffening (tonic) and jerking (clonic). This represent the grand mal. Generalized non-motor seizure include primarily absence seizures ( petit mal ). These seizures involve brief changes in awareness, staring, and some may have automatic or repeated movements like lip smacking. A focal to bilateral seizure is a seizure that starts in one side or part of the brain and spreads to both sides has been called secondary generalized seizures. Now the term generalized refers only to the start of a seizure. The new term for secondary generalized seizure would be a focal to bilateral seizure. (iii) Unknown onset seizures: If the onset of a seizure is not known, the seizure falls into the unknown onset category. Later on, the seizures type can be changed if the beginning of a person s seizures becomes clear. When the beginning of a seizure is unknown, this classification still gives a way to describe whether the features are motor or nonmotor. Status Epilepticus Status epilepticus (SE) is characterized by continuous seizures or repeated seizures without regaining consciousness for 5 minutes or more (Delgado-Escueta et al., 1983; DeLorenzo et al., 1992). SE is a lifethreatening emergency, if untreated, can lead to brain damage and death (Delgado-Escueta et al., 1983; DeLorenzo et al., 1992; Reddy and Kuruba, 2013). Since it is a life-threatening emergency with a mortality rate of about 25%, therapy should begin with fast-acting drugs. The pathophysiology of status epilepticus (SE) is not clearly understood but excess excitatory (glutamate) neurotransmission and loss of normal inhibitory (GABA) neurotransmission are thought to be the most likely mechanisms. The first-line therapies of choice are intravenous benzodiazepines (e.g. lorazepam and diazepam), which potentiate the inhibitory responses mediated by GABA-A receptors (Brophy et al., 2012). The standard treatment is often IV diazepam/lorazepam; followed by phenytoin/phenobarbital. Intravenous benzodiazepines are usually effective in terminating status attacks and providing short-term control. For prolonged therapy, intravenous phenytoin is usually used because it is highly effective and less sedating than benzodiazepines or phenobarbital. Fosphenytoin is a safer, water-soluble prodrug form of phenytoin that is used intravenously. In cases of severe cases or refractory SE, the general anesthetic agent propofol is used.

3880 Int J Pharm Sci Nanotech Vol 10; Issue 6 November December 2017 Success rates of benzodiazepines for SE cessation range from 60% to 90%.In a recent major study, an evaluation of IM (intramuscular) midazolam vs. IV (intravenous) lorazepam found similar adverse profiles and recurrent seizure rates (Silbergleit et al., 2012). However, the IM midazolam group had a statistically significant improvement (73% vs. 63%) in seizurecessation rates upon emergency department arrival and in the proportion of subjects admitted to the intensive care unit. Thus, IM midazolam is as safe and effective as IV lorazepam in the management of prehospital SE. The efficacy of benzodiazepines dramatically decreases with increasing durations of SE (Mayer et al., 2002). In some cases of SE, there is a complete loss of the therapeutic efficacy of benzodiazepines and more drastic second-line (phenytoin and fosphenytoin) and third-line therapies (propofol or phenobarbital) must be employed, but are not always successful (Wheless and Treiman, 2008). These pharmacoresistant forms of SE are termed refractory SE. Refractory SE, which occurs in up to 40% of all patients with SE, remains a challenge for management because of poor prognosis. In general, refractory SE is treated with coma induction using anesthetics (Stecker et al., 1998). Therefore, novel lifesaving anticonvulsants are needed with improved profile for effective suppression of SE and neuroprotection. BOX 1 Differences between AEDs and anesthetic actions on sodium channels. Antiepileptic drugs (AEDs) work quite differently than anesthetics in modulating sodium channels. Voltage-gated sodium channels are responsible for the rising phase of action potentials. The sodium channel protein senses the depolarization and, within a few hundred microseconds, undergoes a conformational change that converts the channel from its closed (resting) non-conducting state to the open conducting state that permits sodium flux. Within a few milliseconds, the channel inactivates, terminating the flow of sodium ions. Brain sodium channels can rapidly cycle through the resting, open and inactivated states, allowing neurons to fire high-frequency trains of action potentials, as is required for normal brain function and for the expression of epileptic activity. The AEDs like phenytoin and carbamazepine block high-frequency repetitive spike firing, which is believed to occur during the spread of seizure activity, without affecting ordinary ongoing neural activity. It is that they preferentially affect channels such that they prolong the inactivation of Na + channels, by a slowing of the rate of recovery of channels from inactivation, thus delaying repolarization, mostly in a voltageand use-dependent fashion. This accounts for their ability to protect against seizures without causing a generalized impairment of brain function (unlike anesthetics). These properties are explained by preferential binding of the drugs to inactivated conformations of the channel. General Pharmacology of Antiepileptic Drugs Background and General Principles Around two-dozen antiepileptic drugs (AEDs) classified as first (standard), second (newer), and third (recent) generation agents are available for treating epilepsy (Table 2) (Mattson et al., 1985; McNamara, 2006; Chadwick et al., 1998; Marson et al., 2007ab; Schachter, 2007). Current drug therapy is designed to inhibit seizures, but none effectively prevent or cure the disorder. The goal of the therapy is to eliminate seizures without interfering with normal function of the CNS; the adverse effects on the CNS result in side effects that impair the patient s quality of life. Treatment begins with a single drug, increasing the dosage gradually until seizures are controlled or adverse effects become unacceptable. If seizures are not controlled with the first drug tried, substitution of a second drug is tried, and so on, until an effective drug or combination of drugs is discovered (Broadie and Kwan, 2002; Gluaser et al., 2006; Rogers and Cavazos, 2005; Diaz et al., 2008; French and Pedley, 2008). The overall efficacy of many AEDs has mixed results. Roughly 70% of patients can live seizure-free lives with the proper clinical treatment. In 30-50% of patients, tolerable side effects are associated with treatment; however, drug substitution is required in 15-30% of cases. Therefore, despite many advances in epilepsy therapy, nearly 30% of people with epilepsy have intractable seizures that do not respond to even the best available treatment. Unfortunately, if adequate drug treatment is not established in the first 2 years, the complications and co-morbidity are extensive: depression, cognitive impairment, seizure-related injury, and an increased mortality rate. After at least 2 years of seizure-free period, AEDs may be withdrawn. The patient must adhere to a regimen of tapering down the dose until no drug is required. Relapse is seen in 20-40% of patients. It is important to remember that drug therapy is individualized, patient by patient. Guidelines are available from the ILAE and American Academy of Neurology but they serve only as starting points for physicians. Selection of the most appropriate AED is based on a number of important considerations including seizure or epilepsy type, age, gender, comorbidities, potential adverse effects, and drug interactions (Stringer, 1998). Mechanisms of Action The general mechanism of action (MOA) of AEDS include: 1) reducing the discharge rate of neurons in the focus ( minimize initiation ) and 2) preventing the spread of excitation from the focus to other brain areas ( block spreading ). These MOAs are due to binding of drug on one or more target molecules in the brain (Table 3). The targets include ion channels, neurotransmitter transporters, and neurotransmitter metabolic enzymes (Rogawski and Loscher, 2004; White and Rho, 2010). The ultimate goal is to modify the bursting properties of neurons and reduce synchronization in neuronal ensembles (Figure 2). However, as with some other drugs, specificity for the targets is not always discrete and this causes the side effects. Based on their efficacy against different seizure types of epileptic syndromes, AEDs are classified as broadspectrum or narrow-spectrum agents. Broad-spectrum agents are effective for many different types of seizures. Narrow-spectrum agents are effective for only specific types of seizures. Table 2 summarizes which drugs currently on the market fall into each category.

Reddy: Clinical Pharmacology of Modern Antiepileptic Drugs 3881 TABLE 2 Summary of antiepileptic drugs. Year Approved AED Mechanism of Action Clinical Efficacy Adult Daily Dose Therapeutic Level ( g/ml) First (standard) Generation: 1968 Carbamazepine (Tegregol) Na + channel blockade Broad spectrum* 400-800 mg 4-12 1997 Clonazepam Allosteric modulation of GABA-A Absence/myoclonic, LGS 1.5-8 mg receptor 1963 Diazepam Allosteric modulation of GABA-A Status epilepticus 1-2 mg receptor 1960 Ethosuximide (Zarontin) T-type Ca 2+ channel blocker Absence seizures 750-1250 mg 40-100 1912 Phenobarbital Allosteric modulation of GABA-A Broad spectrum 60-150 mg 15-45 receptor 1953 Phenytoin (Dilantin) Inhibition of voltage-gated Na + channels Broad spectrum 200-400 mg 10-20 1974 Primidone Allosteric modulation of GABA-A Partial/generalized 750-1250 mg receptor 1983 Valproate (Depakene) GABA synthesis and Na + channel Broad spectrum 750-2000 mg 40-100 blockade Second (newer) Generation: 1993 Felbamate (Felbatol) Na +, Ca 2+ and NMDA blockade Partial/generalized 2400-3600 mg 32-137 2004 Fosphenytoin Prodrug of phenytoin Status epilepticus IV infusion 1993 Gabapentin (Neurontin) GABA turnover and Ca 2+ channel Partial (add-on) 1800-3600 mg 12-20 inhibition 1994 Lamotrigine (Lamictal) Na + channel blockade Broad spectrum 100-500 mg 3-14 1999 Levetiracetam (Keppra) Binds to SV2 synaptic vesicle Partial/generalized 1000-3000 mg 10-40 protein 2000 Oxcarbazepine (Trileptal) Na + and Ca 2+ channel blockade Partial/generalized 900-2400 mg 3-40 2005 Pregabalin (Lyrica) GABA turnover and Ca 2+ channel Partial (add-on) 150-300 mg inhibition 1997 Tiagabine (Gabitril) Blockade of GABA uptake Partial (add-on) 16-36 mg 1996 Topiramate (Topamax) Increases GABA and inhibits Broad spectrum 100-400 mg 5-25 Ca 2+ channels 2000 Zonisamide (Zonegran) Na + and Ca 2+ channel blockade Partial/generalized 100-200 mg 10-40 Third (recent) Generation: 2008 Lacosamide (Vimpat) 2008 Rufinamide (Banzel) 2011 Ezogabine (Potiga) Also, retigabine 212 Perampanel (Fycompa) 2013 Eslicarbazepine (Aptiom) 2016 Brevacetaram (Briviact) Na + channel blockade Na + channel blockade Activation of voltage-gated K + channels Glutamate AMPA receptor antagonist Inhibition of voltage-gated Na + channels Binds to SV2 synaptic vesicle protein Lennox Gastaut Syndrome (LGS) Lennox Gastaut Syndrome Resistant partial/ focal seizures Partial/ focal seizures Partial/ focal seizures Partial seizures 200-400 mg 3200 mg 600-1200 4-12 mg 200-800 mg 50-200 mg Others: 2005 Diazepam (Diastat) GABA-A receptor modulator Acute seizures 5-20 mg Rectal gel 2011 Clobazam (Onfi) GABA-A receptor modulator Lennox Gastaut 20-40 mg Syndrome 2013 Vigabatrin (Sabril) GABA metabolism 3000 mg *Broad spectrum = partial, generalized and other seizure types; List does not include all derivatives or salts. Pharmacokinetics of AEDs Many AEDs have complex pharmacokinetic features. AEDs are orally active, plasma protein bound, and exhibit a long half-life. They compete for protein binding with other drugs resulting in drug-drug interactions. AEDs are metabolized by the hepatic microsomal enzyme system; some drugs can induce these enzymes and thus can enhance metabolism of other drugs. This results in competition for metabolism and consequently serious drug interactions in polypharmacy. This is a key issue in the therapeutic management of epilepsy. It is often difficult to predict the pharmacokinetics of AEDs; thus, therapeutic monitoring of their serum levels is vital for the overall effective management of epilepsy therapy. AEDs can be grouped into enzyme-inducing and enzymenon-inducing types (Table 4). Some AEDs are available as parenteral or injectable products (benzodiazepines, phenytoin and levetiracetam). Diazepam is available as rectal gel (Diastat) that may help terminate seizures activity (febrile seizures) in children.

3882 Int J Pharm Sci Nanotech Vol 10; Issue 6 November December 2017 TABLE 3 Molecular classification of antiepileptic drugs. Mechanism Blockage of voltage-gated sodium channels Enhancement of GABA inhibition Blockage of low-threshold (T-type) Ca 2+ channels Reduction of glutamate excitation Binding to SV2 synaptic vesicle protein Drug Phenytoin Fosphenytoin Carbamazepine Valproate Lamotrigine Oxcarbazepine Phenobarbital Primidone Diazepam Lorazepam Clonazepam Tiagabine Valproate Ethosuximide Gabapentin Valproate Felbamate Gabapentin Parampanel Levetiracetam Briveracetam TABLE 4 List of antiepileptic drugs (AEDs) that do and do not induce hepatic enzymes. Enzyme-inducing AEDs Carbamazepine (Tegretol) Felbamate (Felbatol) Oxcarbazepine (Trileptal) Phenobarbital (Luminal) Phenytoin (Dilantin) Primidone (Mysoline) Topiramate (Topamax) Lamotrigine (Lamictal)* Eslicarbazepine (Aptiom) Rufinamide (Banzel) Clobazam (Onfi) Perampanel (Fycompa) Enzyme non-inducing AEDs Clonazepam (Rivotril) Ethosuximide (Zarontin) Gabapentin (Neurontin) Levetiracetam (Keppra) Pregabalin (Lyrica) Tiagabine (Gabitril) Valproate (Depakote) Vigabatrin (Sabril) Zonisamide (Zonegran) Brivaracetam (Briviact)** *weak enzyme inducer; **weak enzyme inhibitor Undesired Side Effects and Therapeutic Monitoring AEDs can cause various undesired side effects, and this is an important factor to consider when selecting therapy. Treatment of epilepsy is long-term, and patient compliance is critical for treatment success. Considering the importance of drug tolerability is a major issue and should not be minimized (McNamara, 2006; Meador, 2006; Diaz et al., 2008). Although most AEDs can cause common CNS side effects (e.g., dizziness and drowsiness), some AEDs are more tolerable compared to others. In general, newer agents like gabapentin and levetiracetam appear to have the least effects on cognition. A recognized problem associated with discontinuation of AEDs too abruptly is the increased incidence of suicide (Patorno et al., 2010; Arana et al., 2010). The FDA released a report (FDA, 2008) that stated that the increased risk of suicidal behavior in patients taking most AEDs was 0.43% vs. 0.22% in a placebo group. Due to the potential risk, a black box warning has been added to the labeling of all AEDs, and distribution of medication guides is required. In addition, if a therapy is to be discontinued, it must be accomplished in a tapering down-dose manner. Due to the wide range of type and severity of possible side effects, it is very important for physicians to know the concentrations of drug by monitoring blood concentrations. This allows for proper seizure control while minimizing adverse effects (Pitsalos et al., 2008; Reddy, 2010). Established drug levels for various AEDs should be primarily viewed as reference ranges and not therapeutic levels (see Table 2). A blood concentration that falls below the reference range is likely to result in loss of response, while a concentration that falls above the reference range can result in toxicity. These reference ranges serve merely as a guide, and each patient will have an individualized therapeutic level. Other Therapeutic Issues with AEDs As previously mentioned, AEDs may interact with other drugs including oral contraceptives. Enzymeinducing AEDs such as carbamazepine, phenytoin, primidone, and phenobarbital and, to a lesser extent, felbamate, topiramate, oxcarbazepine, eslicarbazepine, ralfinamide, clobazam and perampanel, may decrease serum concentrations of estrogens and/or progestins, possibly resulting in contraceptive failure (Reddy, 2010; 2017). Perampanel and lamotrigine have decreased levels of levonorgestrel. Levetiracetam, gabapentin, lacosamide, pregabalin, zonisamide, and valproate do not affect serum concentrations of oral contraceptives. Oral contraceptives can reduce lamotrigine concentrations, which then transiently increase if the contraceptive includes a week of inactive tablets. Prolonged use of antiepileptic drugs, particularly those that result in enzyme induction (phenytoin, carbamazepine, phenobarbital, primidone), may increase the risk of osteoporosis. Valproate, which does not induce hepatic enzymes, has been associated with decreases in bone mineral density. Generic versions of many AEDs are now available. In general, a generic drug offers a lower-cost alternative that is roughly bioequivalent (pharmacokinetic parameters within 80-125%) to the brand-name drug. A meta-analysis of randomized controlled trials comparing use of brand-name and generic forms of phenytoin, carbamazepine, and valproate found no difference in seizure control (Kesselheim et al., 2010; 2013; Privitera et al., 2016). However, variation in the appearance of generics between manufacturers may also increase the risk of nonadherence. If it often suggested that prescription refills should be filled from the same generic manufacturer.

Reddy: Clinical Pharmacology of Modern Antiepileptic Drugs 3883 Clinical Pharmacology of Selected AEDs Hydantoins: Phenytoin (Dilantin); Ethotoin (Peganone); Fosphenytoin (Cerebyx) Clinical indication: This class is a broad-spectrum drug intended to treat generalized tonic/clonic (grand mal) seizures, partial seizures, or status epilepticus. These drugs may exacerbate absence seizures. BOX 2 Phenytoin non-linear pharmacokinetics. The three key features of phenytoin pharmacokinetics are: protein binding (>90%), atypical elimination kinetics, and metabolism by CYPs, all three strikingly impact on its elimination kinetics. (i) (ii) (iii) Because phenytoin is highly bound to serum proteins, variations in the fraction of phenytoin that is bound (by drugs that compete for binding) strikingly affect the absolute amount of free drug, which in turn determines its metabolism/elimination kinetics. Phenytoin s overall metabolism is nonlinear. The nonlinear pharmacokinetics of phenytoin represents a highly complicating factor. Because the rate at which phenytoin is metabolized (hydroxylation to parahydroxyphenyl-derivative) is dose dependent, elimination can follow both first and zeroorder processes, depending on the concentration range. That is, elimination rate is non-linear as a function of its concentration. Elimination kinetics shift from first-order to zero-order at moderate to high dose levels that result in elevated plasma levels. At low plasma levels (perhaps lower than 10-20 g/ml therapeutic range), it follows a first-order elimination, so the rate of elimination is proportional to the concentration (its level in plasma decreases exponentially with time, with typical t1/2). At high plasma levels that are relatively enzyme-saturating (perhaps within or exceeding therapeutic levels), it follows a zero-order elimination, so the rate of elimination is constant due to capacity limited metabolism (its levels in plasma decrease in a linear fashion over time, like ethanol). However, the gears keep shifting depending upon the free concentration due to many factors over the course of treatment. A mathematical model with Michaelis-Menten elimination can predict the pharmacokinetics of phenytoin. Finally, the metabolism of phenytoin (by CYP2C9/10) is enhanced in the presence of inducers of microsomal enzymes (e.g., phenobarbital) and inhibited by inhibitors (e.g., cimetidine), which in turn affects the free concentrations. Such drug interactions could add further complication to its elimination kinetics. Mechanism of action: These drugs limit the development of spontaneous seizure activity and reduce the spread of the seizure. The effect is mediated by slowing the rate of recovery of voltage-gated sodium channels from inactivation, thus delaying repolarization and reducing excitability. This action is both voltage- and usedependent (Fig. 4). Pharmacokinetics: Phenytoin is highly fat soluble, highly protein bound (98%), readily absorbed from the GI tract, and metabolized in the liver by CYP2C9/10 so should be used with caution in patients with liver disease. It also induces CYP2C/3A families. Oral bioavailability is variable due to first-pass metabolism which is nonlinear and follows zero-order kinetics. Thus, a relatively small change in dosage can produce a marked change in blood levels. The metabolism of phenytoin is enhanced in the presence of inducers of liver metabolism (e.g., phenobarbital) and inhibited other drugs (e.g., cimetidine). Valproic acid lowers phenytoin plasma levels because it displaces phenytoin it from plasma protein binding sites and increases availability for metabolism. The half-life is 24 hours. Fig. 4. Mechanism of action of AEDs (phenytoin, valproate, and carbamazepine) acting on voltage-gated sodium channels. This class of drugs prolong the inactivation of the Na + channels, thereby reducing the ability of neurons to discharge high frequency firing. The channel opens for Na + influx when both (A) activation gate and (I) inactivation gate opens. Adverse effects: The class is known to cause gingival hyperplasia (20-40% of patients, especially children), coarsening of facial features, hirsutism, skin rash, mental confusion, altered vitamin D and calcium metabolism, dizziness, ataxia (inability to coordinate voluntary movement), nystagmus (involuntary movement of eye), diplopia (double vision). There are also teratogenic effects: cleft palate, congenital heart disease, slowed growth, and mental retardation ( fetal hydantoin syndrome ). This class is contraindicated for sinus bradycardia and SA block and has a Black Box Warning of cardiovascular risk when administered with rapid infusion. Barbiturates : Phenobarbital (Luminal); Primidone (Mysoline) Clinical indication: This class is comprised of broadspectrum drugs intended to treat generalized tonic/clonic (grand mal) seizures, partial seizures, or status epilepticus. These drugs may exacerbate absence seizures. Although commonly used in children, major undesired side effects are sedation and cognitive impairment. Mechanism of action: This class acts by suppressing seizure activity, elevating the seizure threshold, and limiting the spread from a focus through a combination of mechanisms. This includes having a binding site on the GABA-A receptors. They are positive allosteric modulators of GABA-A receptors (enhance GABA-mediated inhibition) (Fig. 5). At high concentrations, they can directly open GABA-A receptor chloride channels and, barbiturates reduce the excitatory effects of glutamate. Pharmacokinetics: This class of drugs are potent inducers of enzymes (CYP2C; 3A & UGT, uridine diphosphate-glucuronosyltransferase) as 40-60% is plasma protein bound. The drugs are metabolized by hepatic microsomal enzymes (mainly by CYP2C9). In general, the half-life is 90 hours.

3884 Int J Pharm Sci Nanotech Vol 10; Issue 6 November December 2017 Phenobarbital Diazepam Valproate Tiagabine Fig. 5. Mechanism of action of AEDs (barbiturates, benzodiazepines, tiagabine) acting on GABA inhibition and GABA-A receptor complex. Barbiturates such as phenobarbital act at specific sites and potentiate the GABA inhibition by increasing the frequency and duration of channel opening. Benzodiazepines such as diazepam and clonazepam act at specific sites and potentiate the GABA inhibition by increasing the frequency of channel opening. Tiagabine increases synaptic levels of GABA by inhibiting the reuptake transporter in neurons and glial cells. Valproate is thought to affect GABA metabolism, but exact mechanism is not clear (Figure adapted from Reddy, 2014). Adverse effects: These include sedation, ataxia, impaired cognitive function, withdrawal seizures, osteomalacia (softening of the bone due to deficiency of vitamin D and calcium). There is paradoxical hyperactivity in some children, and agitation and confusion in some elderly patients. In general, these drugs are suspected teratogens. It should be noted that Primidone can be used in some patients who are hypersensitive to barbiturates. 85% of primidone activity is due to metabolism to phenobarbital. Its activity is considerably less then phenobarbital, and toxic levels may be reached before full control of seizures is achieved. It is often used in combination with other drugs, namely phenytoin and carbamazepine. Succinamides: Ethosuximide (Zarontin) Clinical indication: This drug is the primary choice for the treatment of absence seizures. It is sometimes use, but not highly effective, in the treatment of tonicclonic seizures. Mechanism of action: This class inhibits low threshold voltage-dependent (T-type) calcium channel currents, especially in thalamic neurons that act as pacemakers to generate rhythmic cortical discharges (3- Hz SWDs). Pharmacokinetics: These drugs are not plasma protein bound, but are metabolized by hepatic microsomal enzymes (does not induce these enzymes). The half-life is 40-50 hours. Adverse Effects: These include nausea and vomiting (onset of treatment) and are suspected teratogens, most notably in combination with barbiturates. Iminostilbenes: Carbamazepine (Tegretol; Carbatrol) Clinical indication: This class is a broad-spectrum drug intended to treat generalized tonic/clonic (grand mal) seizures, partial seizures, or status epilepticus. It is the treatment of choice for partial seizures in pediatric patients. In regard to efficacy, it is similar to phenytoin for focal and major motor seizures and has the least cognitive impairment. Mechanism of action: This class of drugs inhibit voltage-gated sodium channels (Fig. 5) and may also be partial agonists at adenosine A2A and/or A2B receptors, and antagonists at A1 adenosine receptors. Pharmacokinetics: These drugs are metabolized to an epoxide that is as active as the parent compound by CYP3A4. They induce hepatic microsomal enzymes CYP2C, CYP3A and UGT and are 80% plasma protein bound. The half-life is 10-15 hours. Adverse effects: These drugs may cause diplopia, ataxia and a rare but frequently fatal aplastic anemia (idiosyncratic). In addition, they are suspected teratogens. They can cause liver toxicity and are contraindicated with MAO inhibitor use within 2 weeks. They have a Black Box Warning for causing aplastic anemia/ agranulocytosis. Benzodiazepines: Clonazepam (Klonopin), Diazepam (Diastat, Valium), Lorazepam (Ativan); Clorazepate (Tranxene) Clinical indication: This class is used as an adjunct treatment for absence seizures, myoclonic seizures, and atonic seizures. Diazepam, lorazepam, and clorazepate are used for status epilepticus and as adjuncts for other anticonvulsants. In addition, rectal administration of diazepam gel is approved for intermittent use in adults as treatment of increased seizure activity while taking other AEDs and in children help terminate febrile seizures and reduce emergency room visits. A rectal diazepam gel is available for home management of seizures in children and adults (O Dell et al., 2005). Mechanism of action: The drugs in this class are positive allosteric modulators of GABA-A receptors (Fig. 5). They enhance the action of the inhibitory neurotransmitter GABA by acting upon specific benzodiazepine sites located on the GABA-A receptor channel. Pharmacokinetics Oral pills, IM and IV formulations Adverse Effects: The use of these drugs is limited due to sedation and tolerance. They can also cause respiratory depression and bronchial hypersecretion. If used in combination with sodium valproate, they are suspected teratogens. Carboxylic Acids: Valproic Acid (Depakene), Divalproex Sodium (Depakote) Clinical indication: These are broad-spectrum AEDs used to treat absence seizures, tonic-clonic seizures, myoclonic seizures, and partial seizures. Mechanism of action: The exact MOA is unknown. The drugs do inhibit metabolism of GABA via down regulation of GAT-1 and -3 GABA transporter proteins. They also prolong recovery of sodium channel inactivation (Fig. 6) and cause some reduction of low threshold (Ttype) calcium currents.