1) Sodium valproate is currently the first choice treatment for generalized epilepsy. It prevents high-frequency neuronal firing by modulating gamma-aminobutyric acid (GABA) and sodium ion concentrations in the brain. 2) Phenobarbital was historically one of the first treatments for epilepsy. It reduces seizure risk by enhancing the effects of the inhibitory neurotransmitter GABA in the brain. 3) Both drugs have been shown to effectively control seizures and reduce recurrence in clinical trials and animal studies, though they can cause side effects like sedation, vomiting, and liver toxicity.

1. Secondary Effects that can alleviate other disease
•Sedative-HypnoticEffects.
•AnxietyRelief
•Prevents withdrawal symptoms from other barbiturate medications
Epilepsy: An overview of treatments and common therapeutic drugs
Irtaza Tahir and TamanaYousof
Aetiology
Pathophysiology
The pathophysiology of Epilepsy is based on two factors:
1) High-frequency bursts of action potentials
•Bursting activity: prolonged depolarization due to the decreased inhibition or influx of extracellular Ca2+, leads to the opening of voltage-dependent Na+ channels, influx of Na+, and generation of repetitive action potentials.
2) Hyper synchronization of a neuronal population (which is the synchronized bursts from a group of neurons and is related to the “spike discharge” seen on an EEG)
High frequency bursts from hyper synchronized neuronal populations lead to paroxysmal depolarizing shift.
Seizure propagation, occurs when there is sufficient activation to recruit surrounding neurons. This leads to a loss of surround inhibition and spread of seizure activity into contiguous areas via local cortical connections, and to more distant areas via long association pathways such as the corpus callosum.
Figure 1: Basic elements of a seizure generating network. Including: (A) Modulation of Neurotransmitter concentrations in the synaptic cleft (B) Role of (lack of) inhibition in seizure generating networks (C) Positive feedback mechanism in thalamo-cortical seizure generation (D) Spike wave complexes created by seizure. Adapted from: Moshe, S. et al. (2014). Epilepsy: new advances. The Lancet. Published Online.
Two Common Drug Therapeutics
Epidemiology
Worldwide around 50 million people have Epilepsy:
•About 0.4 –1.3% of the general population has active epilepsy
•About 0.6 –1.5% of individuals in the population have epilepsy over their lifespan
The incidence of epilepsy varies worldwide according to age (higher at infancy, youth and old age) and geography (higher in rural areas and developing countries)) (WHO, 2014). 30 –40 % of Epileptics have Generalized Onset Epilepsy.
Risk Factors
Exacerbating and Triggering Factors
•Lack of Magnesium
•Oxidative Stress and Mitochondrial Dysfunction
•Missed medication
•Lack of sleep or disrupted sleep
•Psychological stress
•Poor eating habits and nutritional deficiencies
•The menstrual cycle or hormonal changes
•Flashing lights or patterns
References
Brian, R.H., Foote, S.E., & Wallis, W.E. (1978). Sodium valproate(Epilim) in epilepsy: a trial. N. Z. Med. J. , 88)626): 479-82.
Czapinski, P., Blaszczyk, B. & Czuczwar, S. (2005) Mechanisms of Action of Antiepileptic Drugs. Current Topics in Medicinal Chemistry, 5, 3-14
Epilepsy. WHO. 2012. Retrieved from http://www.who.int/mediacentre/factsheets/fs999/en/ at Nov 16 2014.
Farwell, J., Lee, Y.J., Hirtz, D., Sulzbacher, S., Ellenberg, J. & Nelson, K. (1990) Phenobarbital for Febrile Seizures-Effects on Intelligence and on Seizure Recurrence. The New England Journal of Medicine
Health Concerns: Epilepsy. Life Extension: Foundation for Longer Life. Retrieved from http://www.lef.org/protocols/neurological/epilepsy/page-01 on November 21, 2014
Leach, J.P.& O’Dwyer, R. (2011) Epilepsy Simplified. TFM Publishing Ltd.
Losher, W. (1998). Valproate: A reappraisal of its pharmacodynamics properties and mechanisms of action. Progress in Neurobiology, 58, 31-59.
Malamiri, R.A., Ghaempanah, M., Khosroshahi, N., Nickkhah, A., & Ashrafi, M.R. (2012). Efficacy and safety of intravenous sodium valproate versus phenobarbital in controlling convulsive status epilepticusand acute prolonged convulsive seizures in children: A randomisedtrial. EuJ. Paed. Neuro.,16, 536-541
Mclean, M.J., & MacDonald R.L. (1986). Sodium vaiproate, but not ethosuximide, produces use-and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. The Hournalof Pharmacology and experimental Therapeutics, 237(3), 1001-1011.
Menhardi, H. 1999 The Epilepsies Part I. Handbook of Clinical Neurology: volume 72
Moshe, S. et al. (2014). Epilepsy: new advances. The Lancet. Published Online.
Perucca, E. (2002). Pharmacological and therapeutic properties of valproate. CNS Drugs, 16(10), 695-714.
Phenobarbital. Drug Bank. Retrieved from http://www.drugbank.ca/drugs/db01174 on November 21, 2014
Phenobarbital. RxList: The Internet Drug Index. Retrieved from http://www.rxlist.com/phenobarbital-drug/side-effects-interactions.htm on November 21, 2014
Schobben,F., Kleikn, E., & Vree, T.B. Therapeutic monitoring of vaproicacid. Therapeutic Drug Monitoring, 2, 61-71.
What are the Risk Factors. Epilepsy foundation. Retrieved from http://www.epilepsy.com/learn/epilepsy-101/what-are-risk-factors on November 21, 2014Zivanovic, D., Stanojlovic, O., Susic, V. & Stojanovic, J. (2004) The effects of phenytoin and phenobarbital on seizures induced by imipenem/cilastatinin rats. Actaneurol. Belg104, 20-26
Sodium Valproate
The Current First Choice Treatment for Generalized Epilepsy
Rationale for Treatment
Sodium Valproate is used to prevent high frequency repetitive firing in the brain of epileptic individuals. It does so by modulating the concentrations and efficacy of γ-amino butyric acid (GABA) and sodium ions and thus inhibits post-synaptic activation of neurons.
Mechanisms for Drug Action
Currently, the mechanism of Sodium Valproate is not completely understood. However, research indicates that it has many functions and that it increases GABA levels in the Midbrain and Spinal fluid by:
•Activation of Glutamic Acid Decarboxylase (an enzyme involved with GABA synthesis) in the Midbrain
•Increasing GABA release and promoting binding to receptors
•Decreasing GABA uptake by microglial cells and the presynaptic neuron through down-regulation of GABA Transporters
•Inhibiting GABA Transaminase, which normally functions in neurons and microglia to metabolize up-taken GABA into Succinic Semialdehyde
Studies have also shown that it impacts ion channels using its characteristics as a fatty acid to influence the biophysical properties of the membrane surrounding voltage-gated sodium channels and preventing sodium influx.
Evidence of Effectiveness
Secondary Effects that can alleviate other diseases
Drug
Doses (mg/day)
Primary Mechanismof Action
Adverse Side Effects
Lamotrigine
100-300
Inactivation of Voltage Dependent Sodium Channels
0.1% PatientsCan Develop a Life Threatening Skin Rash
Levetiracatem
1000-3000
Inhibits Presynaptic CalciumChannel Activation
>10% Patients Develop a Psychiatric Reaction
Table 1: Two modern drug therapeutics for Generalized Epilepsy. Adapted from: http://www.epilepsy.com/learn/treating-seizures-and-epilepsy/seizure-and-epilepsy- medicines/seizure-medication-list
PhenoBarbital
A First Generation Treatment for Epilepsy
Rationale for Treatment
Phenobarbital suppresses seizures by decreasing repetitive firing and enhancing inhibition bybinding to inhibitory γ-amino butyric acid (GABA) receptors, and modulates chloride currents through receptor channels. It also inhibits glutamate induced depolarization.
Mechanisms for Drug Action
Phenobarbital acts on GABAA receptors, increasing synaptic inhibition. This elevates the seizure threshold and reduces the spread of seizure activity from a seizure focus. Phenobarbital does this via:
•Increasing the affinity of GABA to its recognition sites within the GABAA receptor complex
•Binding directly to the GABA chloride channel leading to increased influx of chloride anions and thus hyperpolarization
It also functions to reduce the effects of excitatory amino acid neurotransmitters such as glutamate.
Evidence of Effectiveness
Suggested Treatment
Graph 7and 8:
(TOP)The prevalence of Epilepsy in developed countries. Epilepsy is more common in children and the elderly.
(RIGHT)Worldwide prevalence and geographical variation in life time and active epilepsy.
Adapted from Savage, N. (2014). Epidemiology: The complexities of epilepsy. Nature 511, S2-S3.
Human trials and animal models suggest strong efficacy:
•Murine model: Ceased Spontaneous Repetitive Firing in 90% of neurons
•Human Trial: 75% of individuals achieved significant levels of relief without major side effects
Figure 3: Risk factors that increase the probability of acquiring generalized epilepsy.
Adapted from: http://www.healthline.com/ hlcmsresource/images/topic_centers/Epilepsy/epilepsy-stats/Epilepsy- RiskFactors_01.jpg
Graph 3: Increasing concentration of NaVPdecreases the proportion of mice neurons undergoing spontaneous repetitive firing.
Figure 2: Oscilloscope tracings from mice neurons comparing spontaneous synaptic activity in control mice and those receiving 30 μM NaVP. Adapted from Mclean, 1986.
Side Effects
•Nausea, vomiting and indigestion
•Postural tremor
•Body weight gain
•Pancreatitis and liver toxicity
•Severe teratogenesis
Drug Interactions
NaVPinteracts with 702 drugs, including:
Acetaminophen:
•Loss of coordination, suicidal thoughts & other nervous system and mental effects
Aspirin
•Decreases metabolism of NaVP
Sodium Benzoate:
•Weak Pulse, Low body temperature
•Bulimia
•Anorexia Nervosa
•Bipolar disorder
•Schizophrenia
•Mania
•Anxiety
•Migraine
•PTSD
•Impulse Control
27
23
3
7
0
5
10
15
20
25
30
35
Valproate (n=30)
Phenobarbital (n=30)
Number of Patients
Response to Treatment
Less than 20 mins
No Control
4
12
23
11
0
5
10
15
20
25
30
Valproate (n=27)
Phenobarbital (n=23)
Number of Patients
Recurrence of Seizure within 24 Hrs
Yes
No
3
3
1
17
4
1
0
5
10
15
20
Lethargy and Sedation
Vomiting
Hypotension
Respiratoy Depression
Adverse Effects
Phenobarbital Group (n=30)
Valproate Group (n=30)
Graph 4: The response to treatment with Valproate and Phenobarbital of patients with Generalized Epilepsy. Adapted from: Malamiri, 2012.
Graph 5: A comparison of recurrence of seizures within 24 Hours after taking Valproate vs. Phenobarbital. Adapted from: Malamiri, 2012.
Graph 6: Clinically significant adverse effects in patients taking Valproate vs. Phenobarbital. Adapted from: Malamiri, 2012.
Genetic12%
Vascular13%
Congenital Malformations8%
Neurodegenerative Disorder10%
Hippocampal Sclerosis5%
Neooplasm5%
Trauma5%
Childhood Epilepsy Syndrome5%
Toxic/Metabolic Disorder5%
Single Gene Disorder2%
Unknown Cause30%
CAUSES OF EPILEPSY
Graph 2: Probability of Remaining Free of Seizures from the time of the index seizure when the drug was first received. Adapted from: Farwell, 1990.
Side Effects
•Neurotoxicity: Sedation, Behavior, Cognition, Mood
•Connective tissue disorders: Dupuytren’scontracture, Frozen shoulder, Folate deficiency (zhang, 2011)
Drug Interactions
Phenobarbital interacts has known interactions with 1032 drugs, including:
CNS depressants:
•Such as other sedatives or hypnotics, antihistamines, tranquilizers, or alcohol, may produce additive depressant effects.
Estradiol, estrone, progesterone:
•Increases metabolism of the above hormones. Thus, it decreases the effectiveness of contraceptives.
Anticoagulants:
•Phenobarbital lowers the plasma levels of dicumaroland causes a decrease in anticoagulant activity as measured by the prothrombintime
Human trials and animal models suggest strong efficacy:
•Murine Model: Decreased animal deaths from epilepsy, and increased the time to lethal outcome and seizure severity
•Human model: Increased the probability of being seizure free up to 1000 days after initial treatment relative to placebo
From the data, above we conclude that using valproate would be the most efficacious treatment for generalized epilepsy. However, it may be beneficial to use phenobarbital or other anti-epileptic drugs for patients who are pregnant or are hypersensitive to valproate.
Graph 1: The Various causes of Epilepsy. Adapted from: Leach, 2011.