EPILEPSY -IEPILEPSY -I

Department of PharmacologyDepartment of Pharmacology

College of PharmacyCollege of Pharmacy

King Saud UniversityKing Saud University

Definitions Definitions

• Epilepsy: Epilepsy: is a chronic neurological disorderis a chronic neurological disorder of brain function of brain function characterized by a periodic recurrent, and unpredictable characterized by a periodic recurrent, and unpredictable occurrence of unprovoked seizures .occurrence of unprovoked seizures .

• Seizure: Seizure: transient alteration of behavior due to disordered and transient alteration of behavior due to disordered and rhythmic firing of population of brain neurons.rhythmic firing of population of brain neurons.

• These seizures are usually distressful and often incapacitating.These seizures are usually distressful and often incapacitating.• Seizures occur when there is abnormal, excessive, Seizures occur when there is abnormal, excessive,

synchronized firing of neurons. Can be local or generalizedsynchronized firing of neurons. Can be local or generalized

• Convulsion:Convulsion: The major motor manifestations of a seizure The major motor manifestations of a seizure (rhythmic jerking of the limbs)(rhythmic jerking of the limbs)

Etiology

is usually unknown (>70%). Seizures are signs of underlying neurological disturbances

Etiology or First Cause• Birth and perinatal injuries

• Vascular insults

• Head trauma

• Congenital malformations

• Metabolic disturbances (serum Na+, glucose, Ca2+, urea)

• Drugs or alcohol (including withdrawal from barbiturate, CNS

depressants)

• Neoplasia (tumors)

• Infection or fever

• Genetic ( >25 single gene mutations identified)

Pathophysiology of EpilepsyPathophysiology of Epilepsy

High frequency discharge of impulses by interconnected High frequency discharge of impulses by interconnected cerebral neurons cerebral neurons

Starts locally then spread Starts locally then spread

Enhancement of excitatory transmissionEnhancement of excitatory transmission

Reduction of inhibitory transmissionReduction of inhibitory transmission

Symptoms of EpilepsySymptoms of Epilepsy

Convulsion (motor cortex involvement)Convulsion (motor cortex involvement)

Peripheral autonomic discharge (hypothalamus involvement )Peripheral autonomic discharge (hypothalamus involvement )

Loss of consciousness (reticular formation involvement)Loss of consciousness (reticular formation involvement) Others, staring, , jerking movements of the arms and legs and Others, staring, , jerking movements of the arms and legs and

amnesiaamnesia

Diagnostic ToolsElectroencephalogram (EEG)

The most important tool for diagnosis epilepsyMeasures brain wavesShould be performed with 24 hours of seizureRepeated EEGs are often required

Computerized Tomography (CT) ScansUsually the first test ordered for first-time seizures

Magnetic Resonance Imaging (MRI)Strongly recommended for children with first-time seizuresAlso for seizures associated with significant mental or motor problemsMay help to determine if the disorder can be treated with surgery

EEGEEG

Figure 1. Electroencephalograph (EEG) records in epilepsy

Distinguishing between seizure types is important because different types of seizure may have different causes, prognoses and treatments.

Seizure typesClassified into two broad categories

organized according to the source of the seizure within the brain:

Partial (localized to one region of the

brain)

Generalized (distributed throughout the brain).

Types of EpilepsyTypes of Epilepsy

Partial seizures• Simple partial seizures: These seizures begin from a small area

in your brain and don't result in loss of consciousness (20-60”)

• Complex partial seizures: These seizures also begin from a small area of your brain. They alter consciousness and usually cause memory loss (amnesia) and nonpurposeful movements, such as repeated hand rubbing, lip smacking (30”-2 min.)

• Secondary generalized seizures (partial seizures with secondary generalization): These seizures occur when simple or complex seizures spread to involve your entire brain (1-2 min.)

Types of Epilepsy; cont.Types of Epilepsy; cont.

Generalized seizuresGeneralized seizures• Absence (petit mal seizures): These seizures are

characterized by sudden loss of consciousness, staring, & stopping of body activities (<30”)

• Myoclonic seizures: These seizures usually appear as sudden jerks of arms and legs

• Atonic seizures: Also known as drop attacks, these seizures cause sudden collapse or fall down. After a few seconds, consciousness is regained

• Generalized tonic-clonic (grand mal seizures): They're characterized by a loss of consciousness, sustained muscles contraction followed by periods of muscle relaxation

Types of Epilepsy; cont.

Status epilepticus: Characterized by convulsions without cessation (lasting greater than Characterized by convulsions without cessation (lasting greater than

30 minutes)30 minutes)

• Mortality: 5 -15% • Causes: hyponatremia, pyridoxine deficiency, abrupt

withdrawal of anticonvulsants or fever

Animal Models of Epilepsy

Genetic strains that show epilepsy-like characteristics

Transgenic mouse strains Local cortical damage Convulsant drugs (pentylenetetrazol) Kindling model Kainate model

Kindling

Repeated low-level electrical stimulation to some brain sites in animals can lead to permanent increases in seizure susceptibility

In other words, a permanent decrease in seizure "threshold.”

Amygdala and parahippocampal regions are particularly susceptible

Chemical stimulation may cause this too (repeated exposure to pesticides can induce seizures in humans)

Changes in anatomy and cell morphology (loss of critical components in the neural circuit)

Nature of epilepsy

Epilepsy affects about 0.5% of the population. The characteristic event is the seizure, which is often associated with convulsions but may occur in many other forms. The seizure is caused by an asynchronous high-frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain. In absence seizures, the discharge is regular and oscillatory. Partial sizures affect localised brain regions, and the attack may involve mainly motor, sensory or behavioural phenomena. Unconsciousness occurs when the reticular formation is involved. Generalised seizures affect the whole brain. Two common forms of epilepsy are the tonic-clonic fit (grand mal) and the absence seizure (petit mal). Status epilepticus is a life-threatening condition in which seizure activity is uninterrupted.

Many animal models have been devised, including electrically and chemically induced generalised seizures, production of local chemical damage and kindling. These provide good prediction of antiepileptic drug effects in humans. The neurochemical basis of the abnormal discharge is not well understood. It may be associated with enhanced excitatory amino acid transmission, impaired inhibitory transmission, or abnormal electrical properties of the affected cells. Several Several susceptibility genes, mainly encoding neuronal ion susceptibility genes, mainly encoding neuronal ion channels, have been identified.channels, have been identified.. Repeated epileptic discharge can cause neuronal death (excitotoxicity). Current drug therapy is effective in 70-80% of patients.

Excitotoxicity and oxidative stress

Excitatory amino acids (e.g. glutamate) can cause neuronal death. Excitotoxicity is associated mainly with activation of NMDA receptors, but other types of excitatory amino acid receptors also contribute. Excitotoxicity results from a sustained rise in intracellular Ca2+ concentration (Ca2+ overload). Excitotoxicity can occur under pathological conditions (e.g. cerebral ischaemia, epilepsy) in which excessive glutamate release occurs. It can also occur when chemicals such as kainic acid are administered.

Raised intracellular Ca2+ causes cell death by various mechanisms, including

1.activation of proteases, 2.formation of free radicals, 3. and lipid peroxidation. 4.Formation of nitric oxide and

arachidonic acid are also involved.

Raised Raised [[Ca2+]i affects many processes, the Ca2+]i affects many processes, the chief ones relevant to neurotoxicity beingchief ones relevant to neurotoxicity being

1.1. increased glutamate release increased glutamate release 2.2. activation of proteases (calpains) and lipases, causing activation of proteases (calpains) and lipases, causing

membrane damage membrane damage 3.3. activation of nitric oxide synthase; while low activation of nitric oxide synthase; while low

concentrations of nitric oxide are neuroprotective, concentrations of nitric oxide are neuroprotective, high concentrations in the presence of reactive oxygen high concentrations in the presence of reactive oxygen species generate peroxynitrite and hydroxyl free species generate peroxynitrite and hydroxyl free radicals, which damage many important biomolecules, radicals, which damage many important biomolecules, including membrane lipids, proteins and DNA including membrane lipids, proteins and DNA

4.4. increased arachidonic acid release, which increases increased arachidonic acid release, which increases free radical production and also inhibits glutamate free radical production and also inhibits glutamate uptake (site 6). uptake (site 6).

Various mechanisms act normally to protect neurons against excitotoxicity, the main ones being :

1.Ca2+ transport systems,

2.mitochondrial function and

3.the production of free radical scavengers

Oxidative stress

Oxidative stress refers to conditions (e.g. hypoxia) in which the protective mechanisms are compromised, reactive oxygen species accumulate, and neurons become more susceptible to excitotoxic damage.

Excitotoxicity due to environmental chemicals may contribute to some neurodegenerative disorders.

Measures designed to reduce excitotoxicity include the use of 1.glutamate antagonists,

2. calcium channel-blocking drugs

3.free radical scavengers;

none are yet proven for clinical use.

Mechanism of action of antiepileptic drugs

Current antiepileptic drugs are thought to act mainly by three main mechanisms: – reducing electrical excitability of cell membranes,

mainly through use-dependent block of sodium channels

– enhancing GABA-mediated synaptic inhibition; this may be achieved by an enhanced postsynaptic action of GABA, by inhibiting GABA transaminase, or by drugs with direct GABA agonist properties

– inhibiting T-type calcium channels (important in controlling absence seizures).

Newer drugs act by other mechanisms yet to be elucidated.

Drugs that block glutamate receptors are effective in animal models but are unsuitable for clinical

PhenytoinPhenytoin

Mechanism of action:Mechanism of action:– acts mainly by use-dependent block of sodium

channels thus it blocks sustained high frequency repetitive firing of action potentials

- Membrane stabilization

– effective in many forms of epilepsy, but not absence seizures

– metabolism shows saturation kinetics, therefore plasma concentration can vary widely; monitoring is therefore needed

–drug interactions are common

–main unwanted effects are confusion, gum hyperplasia, skin rashes, anemia, teratogenesis

–widely used in treatment of epilepsy; also used as antidysrhythmic agent

Phenytoin Indications

1. Generalized tonic-clonic (grand mal) and complex partial (psychomotor, temporal lobe) seizure

2. Prevention and treatment of seizures occurring during or following neurosurgery

3. Trigeminal neuralgia and migraine4. Ventricular tachycardia, paroxysmal

supraventricular tachycardia and arrhythmias associated with digitalis glycoside toxicity

5. Rheumatoid arthritis and discoid lupus erythematosus

Phenytoin Side EffectsPhenytoin Side Effects• CNS: nystagmus, ataxia uncoordinated muscle or eye uncoordinated muscle or eye

movementmovement mental confusion, dizziness, insomnia , Cognitive impairment

• Immunologic: rashes and systemic lupus erythematosus• GI system: Nausea, vomiting, constipation, toxic hepatitis

and liver damage• Connective tissues: gingival hyperplasia, coarsening of the

facial features, and hypertrichosis Hirsutism,, gingivial Hirsutism,, gingivial hyperplasiahyperplasia

• Blood: thrombocytopenia, leukopenia, granulocytopenia and megaloblastic anemia

• Bone: osteomalacia

Precautions & ContraindicationsPrecautions & Contraindications

Precautions:Precautions:

Impaired liver function Impaired liver function

Elderly patientsElderly patients

HyperglycemiaHyperglycemia

OsteomalaciaOsteomalacia

Contraindications:Contraindications:

hypersensitivy to phenytoin or other hydantoinshypersensitivy to phenytoin or other hydantoins

PharmacokineticsPharmacokinetics• Absorption: oral & slow

• Metabolism: By the hepatic mixed function oxidase system

• Excretion: Urine (5% as unchanged drug); as glucuronides)

• Half-life elimination: Approximately 24 hours.

• High protein binding

• Enzyme inducer.

Drug interactionsDrug interactions

• Alcohol intake, amiodarone, chloramphenicol, Alcohol intake, amiodarone, chloramphenicol, diazepam, H2-antagonists, isoniazid diazepam, H2-antagonists, isoniazid →→ increase increase phenytoin levelphenytoin level

• Phenylbutazone, salicylates, succinimides, Phenylbutazone, salicylates, succinimides, sulfonamides sulfonamides →→ increase phenytoin level increase phenytoin level

• Carbamazepine and sucralfate Carbamazepine and sucralfate →→ decrease phenytoin decrease phenytoin levellevel

• Corticosteroids, warfarin, digitoxin, doxycycline, Corticosteroids, warfarin, digitoxin, doxycycline, estrogens, furosemide, oral contraceptives, quinidine, estrogens, furosemide, oral contraceptives, quinidine, rifampin, theophylline, vitamin D rifampin, theophylline, vitamin D →→ phenytoin phenytoin decreases their level decreases their level

ValproateValproate Mechanism of action:1. Enhancement of GABA action2. Weak inhibition of GABA transaminase, 3.Blocks voltage-dependent sodium channels4.T-type Ca2+ channel blockade

Indications:• Treatment of absence, myoclonic partial, and

tonic-clonic seizure• Migraine prophylaxis• Bipolar disorder

Adverse EffectsAdverse Effects

relatively few unwanted effects• GI side effects: nausea, vomiting and anorexiaGI side effects: nausea, vomiting and anorexia• CNS: ataxia, tremors, sedation, CNS: ataxia, tremors, sedation, • Rashes and alopeciaRashes and alopecia• Elevates liver enzymes; hepatitis (rarely) Elevates liver enzymes; hepatitis (rarely) • Acute pancreatitisAcute pancreatitis• HyperammoniaHyperammonia

baldness, teratogenicity, liver damage (rare, but serious). The most serious side effect is hepatotoxicity

Precautions & ContraindicationsPrecautions & Contraindications

Precautions:Precautions:• Hepatic Dysfunction Hepatic Dysfunction • Pancreatitis Pancreatitis • Blood disordersBlood disorders• Thrombocytopenia Thrombocytopenia

Contraindications:Contraindications:• Active liver diseaseActive liver disease• Hypersensitivity to valproateHypersensitivity to valproate• Family history of severe hepatic dysfunctionFamily history of severe hepatic dysfunction

PharmacokineticsPharmacokinetics

• Metabolism: hepatic via glucuronide conjugation Metabolism: hepatic via glucuronide conjugation and mitochondrial beta-oxidationand mitochondrial beta-oxidation

• Half-life elimination:adults(9-16 hrs)Half-life elimination:adults(9-16 hrs)• Children(4-14hrs)Children(4-14hrs)• Excretion: urineExcretion: urine• Protein binding: 80%to90%Protein binding: 80%to90%• Valproate is hepatic enzyme inhibitor Valproate is hepatic enzyme inhibitor

Drug interactionsDrug interactions

• Valproate inhibits metabolism of phenobarbital, Valproate inhibits metabolism of phenobarbital, lamotrigine, lorazepam & phenytoinlamotrigine, lorazepam & phenytoin

• Valproate is displaced by aspirin from plasma Valproate is displaced by aspirin from plasma proteinprotein

• Plasma conc. Of valproate reduced by Plasma conc. Of valproate reduced by carbamazepinecarbamazepine

• The concomitant use of valproic acid and The concomitant use of valproic acid and clonazepam may induce absence status in patients clonazepam may induce absence status in patients with a history of absence type seizureswith a history of absence type seizures

• Cholestyramine reduces absorption of valproateCholestyramine reduces absorption of valproate

Carbamazepine:

derivative of tricyclic antidepressants NaNa++ channel inactivation channel inactivationsimilar profile to that of phenytoin but with fewer unwanted effects effective in most forms of epilepsy (except absence seizures); particularly effective in psychomotor epilepsy; also useful in trigeminal neuralgia strong inducing agent, therefore many drug interactions low incidence of unwanted effects, principally sedation, ataxia, mental disturbances, water retention.

Carbamazepine is a powerful inducer of Carbamazepine is a powerful inducer of hepatic microsomal enzymes, and thus hepatic microsomal enzymes, and thus accelerates the metabolism of many other accelerates the metabolism of many other drugs, such as phenytoin , oral drugs, such as phenytoin , oral contraceptives, warfarin and corticosteroids. contraceptives, warfarin and corticosteroids. In general, it is inadvisable to combine it with In general, it is inadvisable to combine it with other antiepileptic drugs. Ozcarbazepine, other antiepileptic drugs. Ozcarbazepine, introduced recently, is a prodrug that is introduced recently, is a prodrug that is metabolised to a compound closely metabolised to a compound closely resembling carbamazepine , with similar resembling carbamazepine , with similar actions but less tendency to induce drug-actions but less tendency to induce drug-metabolising enzymesmetabolising enzymes. .

Ethosuximide:

the main drug used to treat absence seizures; may exacerbate other forms

acts by blocking T-type calcium channels

relatively few unwanted effects, mainly nausea and anorexia.

Secondary drugs include:

phenobarbital: highly sedative

various benzodiazepines (e.g. clonazepam ); diazepam used in treating status epilepticus.

Diazepam , given intravenously or rectally, is used to Diazepam , given intravenously or rectally, is used to treat treat status epilepticusstatus epilepticus, a life-threatening condition , a life-threatening condition in which epileptic seizures occur almost without a in which epileptic seizures occur almost without a break. Its advantage in this situation is that it acts break. Its advantage in this situation is that it acts very rapidly compared with other antiepileptic drugs. very rapidly compared with other antiepileptic drugs. With most benzodiazepines, the sedative effect is With most benzodiazepines, the sedative effect is too pronounced for them to be used for maintenance too pronounced for them to be used for maintenance therapy.therapy. Clonazepam and the related compound clobazam Clonazepam and the related compound clobazam are claimed to be relatively selective as antiepileptic are claimed to be relatively selective as antiepileptic drugs. Sedation is the main side effect of these drugs. Sedation is the main side effect of these compounds, and an added problem may be the compounds, and an added problem may be the withdrawal syndrome, which results in an withdrawal syndrome, which results in an exacerbation of seizures if the drug is stopped exacerbation of seizures if the drug is stopped abruptly abruptly

Newer agents that are becoming widely used because of their improved side effect profile include vigabatrin, lamotrigine , felbamate , gabapentin , pregabalin , tiagabine, topiramate and zonisamide