Antiepleptic Drugs And Treatmentof Eplipsy

Hanan Fathy

• Depolarising Na+ and Ca++ ionic current shifts are activated by glutamate receptors. • Repolarising K+ currents are mediated by GABA receptors. • Hyperpolarisation is mediated by GABAa receptors creating an influx of Cl- => inhibition of impulse generation.

• A transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. • Commonly generated in cortex and hippocampus, may also be subcortical

Na K

Ca

• Abnormal electrical discharge in the brain. • Coordinated activity among neurons depends on a controlled balance between excitation and inhibition. • Any local imbalance will lead to a seizure. • Imbalances occur between glutamate-mediated excitatory neurotransmission and gamma-aminobutyric acid (GABA) mediated inhibitory neurotransmission. • Generalised epilepsy is characterised by disruption of large scale neuro-networks in the higher centres.

What causes the seizure? • Hyperexcitability in a critical mass of neurons • Hypersynchony • Propagation – Normal pathways – Pathologic pathways

What causes neuronal hyperexcitability? • Changes in ion channels • Changes in receptors

Resting membrane potential

3

-70 mV

2

Action Potential

Na Channels • Essential for depolarization during action potential • Blocking fast channel inactivation leads to increased excitability – Induces paroxysmal depolarization shifts – Increasing synchrony

K Channels • Important for post-excitatory membrane repolarization • M current controls sub-threshold membrane excitability • K Channel blockade produces epileptiform discharges in vitro • M current defect identified in benign neonatal familial convulsions

Ca Channels • Different types of channels (T, N, L, P, Q) • Ca currents contribute to the paroxysmal depolarization shift • May be responsible for long-term structural changes affecting excitability and synaptic efficacy • Participate in cytotoxicity • Activation of T-type channels is thought to underlie the abnormal thalamocortical rhythmicity associated with 3-Hz spike-and-wave in absence

What causes neuronal hyperexcitability? • Changes in ion channels • Changes in receptors – Excitatory amino acid receptors – GABA-A receptor

Excitatory amino acid (EAA) receptors

• EAA: glutamate and aspartate • Two main receptor types: AMPA/kainate and NMDA

NMDA receptor • Sustains long-lasting depolarization events • NMDA agonists induce epilepsies in animals • Structural changes have been seen in surgical specimens • Involved in long term potentiation

GABA receptors • Activation leads to membrane hyperpolarization via inflow of Cl and outflow K • Decreased neuronal firing

Cellular and Synaptic Mechanisms of Epileptic Seizures

(From Brody et al., 1996)

Other possible causes

• Inherited mutations of proteins involved in the ion channels • Reduction in the activity of homeostatic ATPase pumps within neuron cell membranes

• • • • • •

Lifestyle pharmacotherapy surgery; ablative surgery: deep brain stimulation vagal nerve stimulation ketogenic diet

Basis of Pharmacological Rx Most anti-epileptic agents act either by blockade of depolarisation channels (Na+ and Ca++) OR Enhancing the activity of GABA (neurotransmission inhibition)

SEIZURE INHIBITING DRUGS • Seizures can arise from removal of GABA induced inhibition when GABA levels drop. • Most GABA is eventually converted to succinate by GABA aminotransferase • A GABA aminotransferase inhibitor, Na dipropylacetate, is widely used as anti convulsant. • GABA is most commonly found in local circuit interneurons • Drugs that acts as agonists or modulators for postsynaptic GABA reseptors, such as BARBITURATES, are also used to treat eplipsy.

Treatment of Epilepsies Goals: • Block repetitive neuronal firing. • Block synchronization of neuronal discharges. • Block propagation of seizure. Minimize side effects with the simplest drug regimen. MONOTHERAPY IS RECOMMENDED IN MOST CASES

Treatment of Epilepsies Strategies: •

Modification of ion conductances.

•

Increase inhibitory (GABAergic) transmission.

•

Decrease excitatory (glutamatergic) activity.

Targets • Excitation (aim to reduce) – Ionic-inward Na+, Ca++ currents – Neurotransmitter: glutamate • Inhibition (aim to increase) – Ionic-inward CI-, outward K+ currents – Neurotransmitter: GABA

• Remove by surgery, if focus is well-defined and if drugs do not work well.

• A drug which decreases the frequency and/or severity of seizures in people with epilepsy • Treats the symptom of seizures, not the underlying epileptic condition • Goal—maximize quality of life by minimizing seizures and adverse drug effects

STAGED APPROACH TO EPILEPSY MANAGEMENT

• Tolerability and long-term safety are the most important factors in choosing the first drug. • If the first AED is poorly tolerated at low dosage an alternative should be chosen. • If the first AED does not completely abolish seizures – combination therapy may be tried. • Work-up for epilepsy surgery should be considered after failure of two well-tolerated AED’s. • If needed, subsequent combinations of two or at most three AED’s may be effective

Treatment of Epilepsies •

AEDs: 1st generation

• • • •

Benzodiazepines and barbiturates Carbamazepine and phenytoin Ethosuximide Valproic acid

•

AEDs: 2nd generation

• • • • • • • • • •

Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Pregabalin Tiagabine Topiramate Zonisamide All share a common problem: “Start low, go slow”

Standard pharmacological targets • • • •

Sodium channels Calcium channels GABA receptors: chloride channels Glutamate receptors: NMDA, AMPA/KAINATE

Classification of Anticonvulsants Action on Ion Channels

Enhance GABA Transmission

Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid Ca++: Ethosuximide Valproic acid

Benzodiazepines (diazepam, clonazepam) Barbiturates (phenobarbital) Valproic acid Gabapentin Vigabatrin Topiramate Felbamate

Na+: For general tonic-clonic and partial seizures Ca++: For Absence seizures

Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence

Inhibit EAA Transmission Felbamate Topiramate

Phenytoin Na1+

I

Na1+

I

GABA reuptake

GAT-1 transports GABA into neurons and GAT-2,3 into glia, to help clear the synaptic cleft. Driving force is from ion gradients across membrane. Tiagabine (gabatril) blocks reuptake and increases extracellular GABA levels.

Cl-

Cl-

Barbiturate GABA Cl-

Cl-

Cl-

GABA

Benzodiazepines and Barbiturates • Enhance inhibitory neurotransmission by modulating the GABA-A receptor complex • Barbiturates increase the duration that the channel is open • BZDs increase the opening frequency

Carbamazepine and Phenytoin • Block post-tetanic potentiation • Limit sustained repetitive firing in neurons in culture • Inhibit voltage-gated Na channels • Oxcarbazepine is similar

Ethosuximide • Reduces low-threshold T-type calcium currents in thalamic neurons thought to underlie the abnormal thalamocortical rhythmicity associated with 3-Hz spike-andwave in absence • May also have Na effects

Valproic Acid • Extremely broad spectrum likely related to multiple mechanisms of action. • Block sustained repetitive firing of mouse neurons in culture • Effects on voltage-gated Na channels • Reduces T-type Ca currents • Elevates whole brain GABA levels • Potentiates GABA responses

Felbamate • Broad spectrum • Multiple mechanisms: – Na channels – Enhance GABA-mediated Cl currents – Blocks NMDA evoked currents, may have neuroprotective qualities – Use limited by hematologic and hepatic toxicities

Gabapentin • Designed to mimic the steric conformation of GABA, but does not seem to function this way • Interacts with Na and Ca channels • May increase GABA in certain brain regions • Pregabalin probably similar mechanism

Lamotrigine • Broad spectrum • Acts at voltage dependent Na channel • Inhibits sustained repetitive firing in cultured neurons • Interacts with N and P type voltage gated calcium channels

Levetiracetam • Mechanism unclear • May modulate high-voltage Ca currents • May prolong hyperpolarization associated with GABA-mediated neurotransmission

Topiramate • • • • •

Broad spectrum Has effects against Na and Ca currents Antagonistic to AMPA/kainate receptor Also may enhance GABA-evoked Cl currents Carbonic anhydrase inhibition altering bicarbonate homeostasis

Zonisamide • • • •

Broad spectrum Na T-type Ca GABA-A

Oxcarbazepine – Blocks voltage-dependent sodium channels at high firing frequencies – Exerts effect on K+ channels

Pregabalin – Increases neuronal GABA – Increase in glutamic acid decarboxylase – Decrease in neuronal calcium currents by binding of alpha 2 delta subunit of the voltage gated calcium channel

The Future – Other Treatments

• Brain stimulation • Deep Brain Stimulation • Focus Stimulation • Vagal stimulation already useful • Seizure prediction to guide when to medicate/stimulate • More precise brain surgery • Stem cells: release adenosine, GABA, NPY • Gene therapy: GABA release, more (effective) receptors

Treatment of first seizure • Patient should know following statistics: – 4% of population to age 74 will have an unprovoked seizure of some sort • With normal EEG, risk of 2nd seizure in 2 years is 24% • With abnormal EEG, risk of 2nd seizure in 2 years is 50% (generally 1.5-3 fold increased risk) • Symptomatic seizures with abnormal EEG carry a 65% risk of 2nd seizure • Risk of seizure after 2nd seizure is 70-80%

Current Treatment Options

Partial

Generalized

Simple Complex Secondarily generalized

Tonicclonic

Tonic

Myoclonic Atonic Infantile Absence spasms

CBZ, PHT, PB, GBP, VGB

ACTH, VGB

VPA, LTG, TOP (FBM), LEV

ESX

Partial Onset Seizures • With secondary generalization – First-line drugs are carbamazepine and phenytoin (equally effective) – Valproate, phenobarbital, and primidone are also usually effective

• Without generalization – Phenytoin and carbamazepine may be slightly more effective

• Phenytoin and carbamazepine can be used together (but both are enzyme inducers)

Partial Onset Seizures—New Drugs • Adjunctive (add-on) therapy where monotherapy does not completely stop seizures—newer drugs felbamate, gabapentin,

lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide

• Lamotrigine, oxcarbazepine, felbamate approved for monotherapy where phenytoin and carbamazepine have failed. • Topirimate can effective against refractory partial seizures.

Generalized Onset Seizures • Tonic-clonic, myoclonic, and absence seizures— first line drug is usually valproate

• Phenytoin and carbamazepine are effective on tonicclonic seizures but not other types of generalized seizures • Valproate and ethoxysuximide are equally effective in children with absence seizures, but only valproate protects against the tonic-clonic seizures that sometimes develop. Rare risk of hepatoxicity with valproate—should not be used in children under 2.

Generalized Onset Seizures • Clonazepam, phenobarbital, or primidone can be useful against generalized seizures, but may have greater sedative effects than other AEDs • Tolerance develops to clonazepam, so that it may lose its effectiveness after ~6 months • Carbamazepine may exacerbate absence and myoclonic, underscoring the importance of appropriate seizure classification • Lamotrigine, topiramate, and zonisamide are effective against tonic-clonic, absence, and tonic seizures

Infantile spasms Infantile spasms are an epileptic syndrome and not a seizure type. The attacks although sometimes fragmentary are most often bilateral and are included, for pragmatic purposes with the generalized seizures Characterized by recurrent myoclonic jerks with sudden flexion or extension of the body and limbs; the form of infantile spasms are, however, quite heterogeneous. 90% have their first attack before the age of 1 year. Most patients are mentally retarded, presumably from the same cause of the spasms. The cause is unknown. Infections, kernicterus, tuberous sclerosis and hypoglycemia have all been implicated.

INFANTILE SPASMS Drugs of choice: Corticotropin or Corticosteroids Zonisamide Alternatives: Clonazepam Vigabatrin Phenobarbital

Classifying Side Effects of AEDs • Adverse – Dose-related (usually neurotoxicity)

• Acute (titration-related; transient vs persistent) • Chronic – Idiosyncratic

• Allergic (mild; severe, possibly life-threatening) • Non-allergic – Chronic

• Effects on organs or tissues • Neurotoxicity (including cognitive) – Teratogenicity

• “Beneficial”

Some Less Common Side Effects of Newer AEDs • Clobazam – Weight gain – Impotence • Vigabatrin – Hair loss – visual field constriction • Gabapentin – Myoclonus – Choreoathetosis

• Lamotrigine – Insomnia

• Topiramate – Kidney stones (< 1.5%) – Especially with family history, males, dehydration

Serious Side Effects of New Antiepileptic Drugs • Vigabatrin – Psychosis: 2 - 4% – Peripheral retinal degeneration: ? 1/3 (rarely symptomatic)

• Lamotrigine – Severe skin reactions (e.g. Stevens-Johnson)

• 1/100 children • 1/300 - 1/1,000 adults • Felbamate – Aplastic anemia: 1/2,000 - 1/5,000 – Hepatic failure: 1/5,000 - 1/10,000

GENERAL ASPECTS OF PROGNOSIS

FOUR GROUPS • Benign epilepsies – (20-30%) in which remission occurs after a few years and treatment can often be avoided (e.g. BECTS, Benign Occipital) • Pharmacosensitive – seizure control is easy and spontaneous remission occurs after a few years (e.g. childhood absence) • Pharmacodependent – drug treatment will control seizures but no spontaneous remission occurs (e.g. JME) 4. Pharmacoresistant (refractory) – poor prognosis

ANTI EPILEPTIC DRUGS - THERAPY

• Among 470 epileptic patients about 47% responded to their first AED • 13% responded to a second AED • 4% responded to a third monotherapy • Only 35 were controlled with 2 AED’s • About 30% are “pharmacoresistant” = refractory epilepsy Brodie, Neurology 2002

Refractory Epilepsy 30% of epilepsy patients are resistant to treatment with multiple AEDs - Occurs even though AEDs used on the same person have different mechanisms P-glycoprotein involvement is an attractive hypothesis – Is there an association with polymorphism and drug resistance in epilepsy?

Hypothesis • An insufficient amount of drug is crossing the BBB for therapeutic levels to be reached • Polymorphisms of pharmacokinetic and pharmacodynamic processes (especially transporters) is a popular explanation

P-glycoprotein • Pgp and multidrug-resistanceassociated proteins (MRPs) - found in apical membrane of BBB capillary endothelial cells

-

- Defense mechanism to protect the brain from xenobiotics • Expression of P-glycoprotein is increased in seizure foci of experimental animals - Association of transport protein overexpression with acute seizure activity • Some AEDs considered to be substrates of Pgp and MRPs

Multidrug transporter hypothesis

• Refractory epilepsy result from localized transporter overexpression at BBB • Resistance can occur even if mechanism of drugs are different

What can be done? Surgery • Identify epileptogenic zone using structural magnetic resonance imaging in lesional epilepsy • Intraaxial structural abnormality may indicate site of seizure onset • Resection identified area

Limitations • Invasive • In some patients, cannot identify epileptic brain tissue accurately (nonlesional partial epilepsy) • Risk of damaging healthy brain

What can be done? Ketogenic diet • Effective against different types of seizures • It is a high-fat diet (4:1 lipid:nonlipid ratio) which induces ketosis • Used to treat intractable pediatric epilepsy • Mechanism not known

Ketosis • Excessive amount of ketone bodies found in normal blood and interstitial fluids • Ketone bodies replace glucose as substrate of metabolism

Ketogenic Diet

• An alternative for intractable epilepsy not amenable to surgery since 1920’s • Fasting for seizure control has been suggested since biblical times

Ketogenic Diet – Possible Mechanisms

• Acidosis • Water balance and dehydration • Direct action of acetoacetate or hydroxybutyrate • Changing energy sources of the brain from glucose to ketones

Energy Metabolism • BBB function disrupted during seizures • Suggested decreased transport of glucose by GLUT1 • Decreased uptake of glucose in epileptic foci (hypometabolic) • Ionic homeostasis harder to maintain • KD increases energy reserve • Better maintenance of ionic homeostasis

Ketogenic diet-clinical use

• Absence • Symptomatic myoclonic • Lennox-Gaustaut Sy At Johns Hopkins: “The Ketogenic diet is considered for all children who have intractable seizures of any type and from any cause who have not responded to a variety of regimens”.

Ketogenic Diet

• Classic: Ratio of Ketogenic to antiketogenic is 4 : 1 fat (protein + carbohydrates) - The diet allows 1 gr of protein/kg body weight daily - Restriction of fluids - Vitamins supplement

Ketogenic Diet - efficacy

• 1/3 – complete seizure control • 1/3 – greater than 50% seizure improvement • 1/3 – no improvement • 2/3 – one drug reduced • 10% - all drugs discontinued

Ketogenic Diet –Side effects

• Renal stones • Hyperuricemia • Acidosis • Hypocalcemia • Eating problems • Secondary carnitine deficiency

ANTIEPILEPTIC DRUG INTERACTIONS

With other antiepileptic Drugs: - Carbamazepine with phenytoin Increased metabolism of carbamazepine phenobarbital Increased metabolism of epoxide. - Phenytoin with primidone

Increased conversion to phenobarbital.

- Valproic acid with clonazepam May precipitate nonconvulsive status epilepticus phenobarbital Decrease metabolism, increase toxicity. phenytoin Displacement from binding, increase toxicity.

ANTIEPILEPTIC DRUG INTERACTIONS

With other drugs: antibiotics anticoagulants cimetidine isoniazid oral contraceptives salicylates theophyline

 phenytoin, phenobarb, carb. phenytoin and phenobarb met. displaces pheny, v.a. and BDZs  toxicity of phenytoin antiepileptics  metabolism. displaces phenytoin and v.a. carb and phenytoin may effect.