Antiseizure Drugs

By

S. Bohlooli, PhD

SEIZURE DISORDERS

• Seizures are self sustained (but self-limiting) episodes of neural hyperactivity.

• - During a seizure some neurons of the brain begin to fire in massive synchronized bursts (a paroxysmal high-frequency, or synchronous low‑frequency, high voltage electrical discharge).

• .- Convulsive seizures, the most common form of attacks, begin with tonic or clonic jerking of all extremities with loss of consciousness.

Etiology- Hyperpyrexia (acute infections, heat stroke, etc)- CNS infections (meningitis, encephalitis, AIDS, brain abscess,

neurosyphilis, rabies, falciparum malaria, toxoplasmosis, etc)- Expanding brain lesions (neoplasm, intracranial hematoma, etc)- Brain defects (congenital, developmental)- Cerebral trauma (skull fractures, birth injury, etc)- Cerebral hypoxia (Adams-Stokes syndrome, anesthesia, carotid sinus

hypersensitivity, CO poisoning, etc)- Cerebral edema (hypertensive encephalopathy, etc) - Cerebral infarct or hemorrhage- Metabolic disturbances (hypoglycemia, hypoparathyroidism, etc)- Toxic agents (cocaine, antihistamines, tricyclic antidepressant,

salicylates, xanthines, atropine-like drugs, etc; lead, solvents, insecticides, etc.)

- Abstinence syndrome (alcohol, barbiturates, etc)- Anaphylaxis

EPILEPSY

DefinitionEpilepsy is a chronic recurrent disorder of cerebral function characterized by spontaneous, sudden brief attack of altered consciousness, motor activity, sensory phenomena or inappropriate behavior. The disorder is always associated with abnormalities in the EEG.

Pathogenesis

- A portion of dysfunctional tissue in the brain discharges synchronously in response to endogenous or exogenous stimuli.

- The spread of the discharge to other parts of the brain results in convulsive phenomena.

- In primary generalized epilepsy the seizures are generalized from the outset, beginning as a diffuse synchronous discharge affecting all cerebral areas simultaneously.

- Seizures themselves do not equal epilepsy. Given a sufficient stimulus even a normal brain can discharge in a diffusely synchronous fashion and produce a seizure.

This chronic low seizure threshold may result from several mechanisms including:

a) changes in intrinsic voltage-dependent membrane current.

b) attenuation or loss of pre and/or postsynaptic inhibition (mainly due to a genetic or postpathologic hypofunction of GABA neurons).

c) increased effectiveness of excitatory synapses (mainly due to a genetic or postpathologic hyperfunction of N-methyl-D-aspartate and glutamate neurons).

CLASSIFICATION OF EPILEPTIC SEIZURES

PARTIAL SEIZURES (focal, local)Simple partial seizures (focal cortical)- Specific motor, sensory, autonomic, or psychomotor focal phenomena

without loss of consciousness (the symptom of each seizure type is often an index of the site of brain dysfunction)

Complex partial seizures (psychomotor, temporal lobe)- Stereotyped purposive movements and bizarre behavior accompanied

by, mental distortion, complex sensory hallucinations, disturbed consciousness and strong emotional responses.

Partial seizures secondary generalized- These seizures begin locally bur they rapidly spread throughout the

entire brain (loss of consciousness is usually immediate).

GENERALIZED SEIZURES

Generalized tonic-clonic seizures (grand mal)- Unconsciousness with dramatic tonic-clonic convulsions, followed by

a period of confusion and exhaustion.Absence seizures (petit mal)- Brief period (10-30 sec) of unconsciousness, with eye or muscle

fluttering at a rate of 3/sec, and with or without loss of muscle tone.Atonic (akinetic) seizures- Brief periods of complete loss of postural tone with sagging of the

head or falling.Myoclonic seizures - Isolated myoclonic jerks that may reoccur for several minutes.Infantile spasms (West's syndrome)- Very brief (5-10 sec) sudden flexion of the arms, forward flexion of the

trunk, and extension of the legs. The syndrome is accompanied by a progressive mental retardation.

ANTISEIZURE DRUGS

• The inhibition of seizure activity in the CNS is accomplished without major disturbances in the normal electrical activity.

• In fact antiseizure drugs inhibit sustained, high-frequency, repetitive firing much more effectively than low-frequency, non-repetitive firing.

• Antiseizure drugs do not cure epilepsy; they just suppress seizures on a temporary basis. Therefore most patients must take them daily for life.

• Antiseizure drugs frequently cause adverse effects that are usually mild. However most antiseizure drugs may cause occasionally life‑threatening adverse reactions.

The mechanisms of action of antiseizure drugs are still not well understood but have been found to

concern mainly:

a) voltage-operated ion channels

b) inhibitory and excitatory synaptic functions

Chemical class Generic name Trade name

Hydantoins PhenytoinMephenytoinEthotoin

Dilantin, etcMesantoinPeganone

Iminostilbenes CarbamazepineOxcarbazepine

Tegretol

Barbiturates andDesoxybarbiturates

PhenobarbitalMephobarbitalMethabarbitalPrimidone

Luminal, etcMebaralGemonilMysoline

Valproates Valproic acidSodium valproate

DepakeneDepakote

Succinimides EthosuximidePhensuximideMethsuximide

ZarontinMilontinCelontin

Oxazolidinediones TrimethadioneParamethadione

TridioneParadione

Benzodiazepines DiazepamLorazepamClonazepamClorazepate

Valium, etcAtivanKlonopinTransene

GABA-ergic drugs GabapentinVigabatrinTiagabine

NeurontinSabrilGabitril

Others AcetazolamideFelbamateLamotrigineTopiramate

DiamoxFelbatolLamictalTopamax

PHENYTOIN PHARMACODYNAMICS

Mechanism of action- Frequency-dependent and voltage-dependent blockade of

inactivated Na+ channels (likely the main mechanism).- Blockade of post-tetanic potentiation.- Blockade of Ca++ channels (after high doses)- Alteration of synaptic concentrations of many neurotransmitters (after

high doses).Effects- Prevention of the spread of excitation from seizure focus (the

excessive discharge of the neurons of the focus is not prevented and therefore aura and EEG alterations are not eliminated)

- Cerebellar-vestibular stimulation (with high doses)[the drug is not a general CNS depressant and can cause excitation in

several brain neurons]- Analgesic effect in some type of neuropathic pain.

Chemical strucutre

PHENYTOIN PHARMACOKINETICS

ABSORPTION- Oral bioavailability: » 90% (absorption speed depends on

pharmaceutical preparation)- Oral Tmax: 3-12 hours. DISTRIBUTION- Bound in plasma: » 90%- Vd (70 Kg): » 45 L - Concentration in the cerebrospinal fluid is equal the unbound

concentration in plasma BIOTRANSFORMATION- 98% by the liver (biotransformation rate is low). EXCRETION- < 2% by the kidney. Total Clearance: concentration-dependent Half-life: concentration-dependent plasma concentrations < 10 mcg/mL: 6-24 hours plasma concentrations > 10 mcg/mL: 48-72 hours

PHENYTOIN INTERACTIONSPC of phenytoinare increased by:

PC of phenytoinare decreased by:

Phenytoin decreases PC of:

Chloramphenicol(2)Cimetidine (2)Warfarin (2)Isoniazid (2)Estrogens (2)Sulfonamides (3)Phenylbutazone (3)Valproic acid (2)(3)Fluoxetin (2)

Alcohol (1)Carbamazepine (1)Barbiturates (1)(4)Rifampin (1)

Quinidine (1)Estrogens (1)Corticosteroids(1)Methadone (1)Levodopa (1)Carbamazepine (1)Theophylline (1)Vit D (1)

PC = plasma concentrations(1) = stimulation of metabolism (induction of P-450 system)(2) = inhibition of metabolism(3) = displacement from plasma proteins(4) = inhibition of intestinal absorption

PHENYTOIN TOXICITY (1)

Central nervous system- Nystagmus (frequent), diplopia, ataxia, dyskinesia,

vertigo, tremor, hyperreflexia, blurring of vision.- Hyperactivity, nervousness, silliness.- Sedation, drowsiness (rare)- Peripheral neuropathy (7-30% of patients treated for long

time) - Phenytoin encephalopathy (with high drug plasma levels).

It may include abnormal facial and arm movements, staggering, mental confusion, delirium, hallucinations, increased frequency of seizures.

Cardiovascular system- Cardiovascular collapse, cardiac arrhythmias (when

administered IV for emergency treatment)

PHENYTOIN TOXICITY (2)

Gastrointestinal system- Anorexia, nausea and vomiting, epigastric pain.- Gum hyperplasia (30-40% of patients)- Cholestatic jaundice- Acute hepatic necrosis (very rare)Endocrine system- Hyperglycemia (blockade of insulin secretion)- Osteomalacia (due to increased metabolism of vit D and reduced

intestinal Ca++ absorption)Hematopoietic system- Megaloblastic anemia (rare)- Thrombocytopenia, leukopenia, pancytopenia (rare)- Agranulocytosis, aplastic anemia (very rare)- Hypoprothrombinemia (increased metabolism of vit K)- Limphoadenopathy, pseudolymphoma- Malignant lymphoma (?), Hodgkin's disease (?)

Other systems- Skin hyperpigmentation, hirsutism (mainly in women)- Coarsening of facial features (in children)- Nephritis, myopathy (rare)Allergic skin reactions- Skin rashes, erythema multiforme - Exfoliative dermatitis, Stevens-Jonson syndrome, lupoid

syndrome (very rare)Pregnancy- Risk of malformations increases 2-3 fold- A "fetal hydantoin syndrome" (cleft lip, cleft palate,

congenital heart disease, slowed growth and mental deficiency) has been described.

PHENYTOIN TOXICITY (3)

PHENYTOIN: THERAPEUTIC USES

THERAPEUTIC USESEpilepsy- It is a drug of choice for all form of epilepsy of cortical origin

(generalized tonic-clonic seizures, simple and complex partial seizures, etc) and for the emergency treatment of status epilepticus.

- Absence, myoclonic and akinetic seizures often may worsen in patients treated with phenytoin.

Trigeminal and related neuralgias- Carbamazepine remain the preferred agent for these

conditions but phenytoin is the second choice drug and can achieve good results.

Cardiac arrhythmias- Rarely used, except in arrhythmias due to digitalis toxicity.

PHENYTOIN: CONTRAINDICATIONS

- Absence seizures, myoclonic seizures, atonic seizures- Cardiac disease (A-V block, sinus bradycardia, cardiac failure)- Serious hepatic disease- Diabetes mellitus- Leukopenia, thrombocytopenia, lymphadenopathy, lymphomas- Porphyria (acute intermittent, variegata)- Pregnancy

RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENYTOIN AND THERAPEUTIC AND ADVERSE EFFECTS

Plasma levels (mcg/mL)

Therapeutic effects

Adverse effects

8-15 Complete (or partial) control of attacks in most patients

Negligible

20-29 As above Nystagmus, vertigo, blurring of vision

30-39 As above Ataxia and other symptoms of overdose toxicity

> 40 None Lethargy, stupor

CARBAMAZEPINE PHARMACODYNAMICS

Chemistry - A tricyclic compound closely related to tricyclic antidepressants- Its spatial conformation however is very similar to that of phenytoin.Mechanism of action- Frequency-dependent and voltage-dependent blockade of inactivated Na+

channels.- Decreased synaptic transmission (after high doses)Effects- Prevention of the spread of excitation from seizure focus (the excessive

discharge of the neurons of the focus is not prevented and therefore aura and EEG alterations are not eliminated)

- Cerebellar-vestibular stimulation (with high doses)[the drug is not a general CNS depressant and can cause excitation in several

brain neurons]- Analgesic effect in some type of neuropathic pain.- Antidiuretic effect (likely due to enhancement of ADH action on the kidney).- Mild antimuscarinic effects.- Strong induction of hepatic microsomal enzymes

Chemical structure

CARBAMAZEPINE PHARMACOKINETICS

ABSORPTION- Oral bioavailability: » 90%- Oral Tmax: 6-8 hours. DISTRIBUTION- Bound in plasma: » 75%- Vd (70 Kg): » 80 L - Concentration in the cerebrospinal fluid is equal to unbound

concentration in plasma BIOTRANSFORMATION- 99% by the liver (biotransformation rate is slow) EXCRETION -1% By the kidneyTotal Clearance: » 90 mL/min(70 Kg) Half-life: acute administration » 36 hours chronic administration » 20 hours

CARBAMAZEPINE INTERACTIONS

PC of carbamazepineis increased by:

PC of carbamazepineis decreased by:

Carbamazepine decreases PC of:

Verapamil(2)Warfarin (2)Isoniazid (2)Erythromycin (2)Valproic acid (2)Fluoxetin (2)

Carbamazepine (1)Barbiturates (1)Phenytoin (1)

Haloperidol (1)Theophylline (1)Estrogens (1)Warfarin (1)Corticosteroids(1)Primidone (1)Ethosuximide (1)Valproic acid (1)Clonazepam (1)Tricyclic antidepressants(1)

PC = plasma concentration(1) = stimulation of metabolism (induction of P-450 system)(2) = inhibition of metabolism

CARBAMAZEPINE TOXICITY

Central nervous system- Diplopia, ataxia, vertigo, headache, blurring of vision (common, dose-

related).- Sedation, drowsiness (after high doses).- Confusion, agitation, hallucinations (after high doses).- Increased frequency of seizures (rare).Cardiovascular system- Cardiac arrhythmias.- Worsening of coronary disease (rare).- Heart failure, after long treatments (rare).Gastrointestinal system- Anorexia, nausea and vomiting, abdominal pain.- Xerostomia, constipation.Cholestatic hepatitis (very rare).Urinary system- Water retention and hyponatremia, after long treatments.

Hematopoietic system- Megaloblastic anemia.- Thrombocytopenia, leukopenia (2% of patients).- Pancytopenia, agranulocytosis, aplastic anemia (very rare).Other systems- Osteomalacia (after long treatments).Allergic skin reactions- Skin rashes, urticaria, photosensitivity.- Exfoliative dermatitis, Stevens-Johnson syndrome, lupoid syndrome

(very rare).Pregnancy- The risk of malformations (craniofacial defects, fingernail hypoplasia,

delay of development) increases 2-3 fold if the drug is given during pregnancy.

CARBAMAZEPINE TOXICITY

THERAPEUTIC USESEpilepsy- It is the first choice drug for partial seizures and for generalized tonic-

clonic seizures.- In complex partial seizures carbamazepine prevents the attacks in 60-

65% of patients.- The antiepileptic effect can undergo tolerance in 10-20% of patients.- Absence, myoclonic and akinetic seizures often may worsen in

patients treated with carbamazepine.Trigeminal and related neuralgias.Carbamazepine is the first choice drug for trigeminal neuralgia (result

are good in 70% of patients). In refractory cases the addition of phenytoin can be useful.

Bipolar affective disorder- As an alternative to lithium for the therapy of acute mania and the

prophylactic treatment of bipolar disorder.Diabetes insipidus - Rarely used to treat pituitary diabetes insipidus. The drug is not

effective in nephrogenic diabetes insipidus, which indicates that functional V2 receptors are required for the antidiuretic effect.

CONTRAINDICATIONS AND PRECAUTIONS- Absence seizures, myoclonic seizures, atonic seizures- Cardiac disease (A-V block, sinus bradycardia, cardiac failure, myocardial infarction))- Serious hepatic disease- Alcoholism- Blood dyscrasias - SIADH- Pregnancy

PHENOBARBITAL PHARMACODYNAMICS

Chemistry- The drug belongs to the barbiturate class. Its three dimensional

conformation however is very similar to that of phenytoin.Mechanism of action- Enhancement of GABA-mediated inhibition (the opening of Cl- channels is prolonged by facilitating GABA action)- Direct opening of Cl- channels (after high doses).- Reduction of glutamate-mediated excitation (blockade of AMPA receptors).- Blockade of Na+ and Ca++ channels (at high doses)Effects- Suppression of the excessive discharge of the seizure focus - Prevention of the spread of excitation from seizure focus.- All other effects of the barbiturate class.

PHENOBARBITAL PHARMACOKINETICS

ABSORPTION- Oral bioavailability: 100%- Oral Tmax: 4-12 hours.(absorption rate depends on food and on pharmaceutical preparation) DISTRIBUTION- Bound in plasma: » 50%- Vd (70 Kg): » 40 L - Bound and free drug concentrations in brain are equal to those in

plasma BIOTRANSFORMATION- 75% by the liver (biotransformation rate is low) EXCRETION- By the kidney: 25% (acid urine) up to 75% (in alkaline urine) Total Clearance: » 4.5 mL/min(70 Kg) Half-life: adults: » 100 hours children: » 50 hours

BARBITURATE INTERACTIONS

PC of barbituratesare

Barbiturates decreases PC of:

increased by:Valproic acid (2)decreased by: Barbiturates (1)

Phenytoin (1) (3)Carbamazepine (1)Theophylline (1)Estrogens (1)Warfarin (1) (3)Corticosteroids (1)Quinidine (1)Propranolol (1)Calcium channel blockers (1)

PC = plasma concentrations(1) = stimulation of metabolism(2) = inhibition of metabolism(3) = inhibition of intestinal absorption

BARBITURATE TOXICITY

Central nervous system- Sedation, lassitude, drowsiness (the most frequent complains),

impairment of fine motor skills- Agitation and confusion (especially in aged people)- Nystagmus, diplopia, vertigo, ataxia (after high doses)- Paradoxical excitement (especially in children)- Muscular hypotonia, dysmetria, decreased cutaneous reflectivity,

tremor, foot clonus, Babinski's sign (after long treatment with high doses)

- Drug dependence (not with phenobarbital)Gastrointestinal system- Nausea and vomiting, abdominal pain, diarrhea.Respiratory system- Respiratory depression (after high doses)- Coughing, laryngospasm (after iv injection)

Hematopoietic system- Megaloblastic anemia (rare)- Hypoprothrombinemia- Leukopenia, thrombocytopenia, pancytopenia (rare)- Agranulocytosis, aplastic anemia (very rare)Other systems- Osteomalacia (after long treatments).- Attack of acute porphyria (in porphyremic patients)Allergic reactions- Asthma, angioneurotic edema, fever.- Skin rashes, urticaria, eczematous or bullous dermatitis.- Exfoliative dermatitis, Stevens-Jonson syndrome, lupoid syndrome

(very rare).Pregnancy- The risk of malformations increases 2-3 fold if barbiturates are given

during pregnancy.- Hemorrhage in the newborn

BARBITURATE TOXICITY

THERAPEUTIC USESEpilepsy- It is a second choice drug for simple partial seizures, for

generalized tonic-clonic seizures and for status epilepticus.

- Absence, myoclonic and akinetic seizures often may worsen in patients treated with phenobarbital.

Febrile convulsions in children- Sometime still used for the long-term prophylaxis in risk

children (that is children who have their first seizure before 18 month of age, who have significant neurological abnormalities, etc).

- Today, uncertainties regarding the efficacy of prophylaxis, combined with substantial side effects of the drug in children, strongly argue against its use.

Neonatal hyperbilirubinemia- Used to induce microsomal enzymes that conjugate

bilirubin.

CONTRAINDICATION AND PRECAUTIONS

- Absence seizures, myoclonic seizures, atonic seizures

- Porphyria (acute intermittent, variegata)

- Previous history of serious allergic reactions to barbiturates

- Serious respiratory or liver diseases

- Patients with severe pain

- Pregnancy

RELATIONSHIPS BETWEEN PLASMA CONCENTRATION OF PHENOBARBITAL AND THERAPEUTIC AND ADVERSE EFFECTS

Plasma levels (mcg/mL)

Therapeutic effects

Adverse effects

15 Minimum concentrations for febrile convulsions

Negligible

10-35 Control of grand mal or simple partial seizures

Sedation ,ataxia and nystagmus can appear but generally undergo tolerance

35-50 As above Overt symptoms of overdose toxicity

> 60 None Coma

PRIMIDONE PHARMACOLOGY

Chemistry- A desoxybarbiturate very similar to phenobarbital.Pharmacodynamics- Mechanism of action and effects are similar to those of phenobarbital

(the drug however has an anticonvulsant action independent of its conversion to active metabolites).

Pharmacokinetics- Oral bioavailability: 100% ; oral Tmax: » 3 hours.- Converted in liver into two active metabolites: 1) phenobarbital (10-20%) 2) phenylethylmalonamide (50-70%).- Half-life: primidone » 8 hours. phenylethylmalonamide » 16 hoursToxicity- Sedation and drowsiness occur early in treatment- Toxicity is very similar to that of phenobarbitalTherapeutic uses and contraindications- As alternative drug in partial and tonic-clonic seizures.- Contraindications are the same as for phenobarbital.

PHARMACODYNAMICS OF VALPROIC ACID

Chemistry- Valproic acid is the dipropylacetic acid. Salts, ester and amides of this

acid also are active antiepileptic agents.Mechanism of action- Increased GABA content in the brain (inhibition of GABA-

aminotransferase? Facilitation of glutamic acid decarboxylase?).- State-dependent blockade of inactivated Na+ channels.- Increased membrane K+ conductance (at high doses)[likely valproate works by several mechanisms but the precise mode of

action remain uncertain]Effects- Valproate can be considered a broad spectrum antiepileptic drug (see

therapeutic uses)- It is less sedating than other antiseizure drugs.- It inhibits the biotransformation of several drugs including phenytoin,

phenobarbital and carbamazepine.

Chemical structure

PHARMACOKINETICS OF VALPROIC ACID

ABSORPTIONOral bioavailability: 100%- Oral Tmax: » 2 hours.DISTRIBUTION- Bound in plasma: » 95%- - Vd (70 Kg): » 9 L - Concentration in the cerebrospinal fluid is equal to unbound

concentration in plasma BIOTRANSFORMATION- > 95% by the liver (some metabolites are active)EXCRETION - < 5% by the kidneyTotal Clearance: » 7.5 mL/min (70 Kg)Half-life: » 14 hours

TOXICITY OF VALPROIC ACID

Central nervous system- Fine hand tremor (frequent with high doses)- Sedation (when given with other CNS depressants)- Nervousness, excitation, aggressiveness (rare)- Headache, ataxia, nystagmus , diplopia, dysarthria,

dizziness, hallucinations (with high doses).Gastrointestinal system- Anorexia, nausea and vomiting, abdominal cramps heartburn (common, dose-related).- Weight gain, increased appetite (uncommon).- Fulminant hepatitis (rare)- Acute pancreatitis (very rare)

Other systems- Transient hair loss, skin rashes, pruritus,

photosensitivity, erythema multiforme.- Thrombocytopenia, inhibition of platelet

aggregation.- Transient elevation of hepatic enzymes in plasma

(in up to 40 % of patients)- Menstrual disturbances (up to 20% of patients)Pregnancy- Increased incidence of spina bifida (the risk of

neural tube defect may be increased 20 fold)

TOXICITY OF VALPROIC ACID

VALPROATE HEPATITIS

- The occurrence is 1 in 37000 patients if the drug is given alone, but 1 in 6500 patient if other drugs are administered concurrently.

- Children below 2 years of age (or with mental retardation or congenital neurological disease) are especially at risk.

- Hepatitis appears usually after two months of therapy, but it may show after few days or after six months.

- Increase in hepatic enzymes has no prognostic value since it is very common in patients taking valproate.

- Hepatitis is always serious, often lethal.- The pathologic lesion consists in a microvescicular

steatosis without any signs of inflammation.- Pathogenesis is unknown (probably idiosyncratic)

THERAPEUTIC USES Epilepsy- It is the best drug available to control myoclonic seizures (results are good

and sometimes excellent) and atonic seizures (results are sometimes rather good)

- It is considered a drug of choice (together with carbamazepine and phenytoin) for tonic‑clonic seizures.

- It is considered a drug of choice (together with ethosuximide) in absence seizures (for uncomplicated absence seizures ethosuximide is preferred because of valproate hepatotoxicity)

- It is the preferred drug in patients with absence seizures and concomitant grand mal seizures.

- It is considered less effective than (or equally effective as) carbamazepine and phenytoin (but more effective than phenobarbital and primidone) in simple and complex partial seizures.

- It is an alternative drug in infantile spasms. Bipolar affective disorder- As an alternative to lithium for the therapy of acute mania and the prophylactic

treatment of bipolar disorder.Migraine prophylaxis- It has been approved by FDA for the prevention of migraine attack. There is

no evidence that it might be useful in treatment of acute migraine.

CONTRAINDICATIONS AND PRECAUTIONS

- Children below 2 years of age

- Hepatic disfunction, hepatic disease

- Hypoalbuminemia (protein binding may be reduced)

- Thrombocytopenia, blood discrasias

- Pregnancy

ETHOSUXIMIDE PHARMACODYNAMICS

Chemistry- Ethosuximide is the more effective and less toxic among the three

antiepileptic succinimides (ethosuximide, methsuximide and phensuximide).

Mechanism of action- Blockade of voltage-sensitive T type Ca++ channels in thalamic

neurons (the T type Ca++ current is thought to provide a pacemaker current in thalamic neurons responsible for generating the rhythmic cortical discharge of an absence attack)

Effects- Suppression of the excessive discharge of the thalamic seizure focus.- Prevention of the spread of excitation into thalamic-cortico-thalamic

circuits.

Chemical structure

ETHOSUXIMIDE PHARMACOKINETICS

ABSORPTION- Oral bioavailability: > 90 %- Oral Tmax: 3-7 hours.

DISTRIBUTION- Bound in plasma: 0 %- Vd (70 Kg): » 45 L - Concentration in CSF is equal to concentration in plasma

BIOTRANSFORMATION- » 75% by the liver (metabolites are inactive)

EXCRETION- » 25% by the kidney.

Total Clearance: mL/min(70 Kg) » 13

Half-life: adults:» 45 hours; children: » 30 hours

ETHOSUXIMIDE TOXICITY

(the overall incidence of adverse effects is low)Central nervous system- Drowsiness, fatigue, headache, dizziness, euphoria (mild, dose-

related effects)- Vertigo, ataxia, nystagmus (after high doses).- Restlessness ,agitation, anxiety, aggressiveness, inability to

concentrate (in children with a prior history of psychiatric disturbances)

Gastrointestinal system- Anorexia, nausea and vomiting, hiccup, diarrhea, abdominal cramps

(common, dose-related effects)Hematopoietic system- Leukopenia, thrombocytopenia, pancytopenia (rare)- Agranulocytosis, aplastic anemia (very rare)Allergic skin reactions- Skin rashes, urticaria (rare)- Stevens-Johnson syndrome (very rare).

THERAPEUTIC USES

- It is the preferred drug in absence seizures, where it completely prevents the attacks in 60% of patients and diminishes their frequency in 20-30% of patients.

- It is considered a second choice drug in myoclonic and atonic seizures.

CONTRAINDICATIONS AND PRECAUTIONS

- Tonic-clonic seizures (if given alone. Therefore in case of absence seizures associated with grand mal seizures the drug must be given together with carbamazepine or phenytoin).

- Serious hepatic or renal diseases

- Pregnancy

PHARMACOLOGY OF TRIMETHADIONE AND PARAMETHADIONE

Pharmacodynamics- These drugs are oxazolidinediones, that is they contain an heterocyclic oxazolidine ring.- Their mechanism of antiepileptic action is very similar to that of succinimides.Trimethadione pharmacokinetics- Oral bioavailability: > 90%- Bound in plasma: 0%.- Biotransformed to dimethadione, an active metabolite with an extremely long half-life (» 240 hour)Toxicity - Sedation, hemeralopia.- Exfoliative dermatitis, lupoid syndrome, hepatitis, nephrotic syndrome, myasthenic syndrome, fulminating aplastic anemia.- Fetal malformations (the teratogenic risk is high).Therapeutic uses - As alternative drugs in absence seizures.(rarely used today because of their potential for serious toxicity).

BENZODIAZEPINES AS ANTISEIZURE DRUGS

Chemistry- All benzodiazepines have antiseizure properties but some selectivity seems to exist (certain compounds appear more effective than others in specific seizure types). Diazepam and clonazepam are the most used. Mechanism of action- Enhancement of GABA-induced increased frequency of bursts of openings of chloride channels.Effects- Prevention of the spread of excitation from seizure focus - All other effects of benzodiazepine class.Therapeutic uses - Clonazepam is a first choice drug in myoclonic seizures and a second choice drug in absence seizures and infantile spasms- Unfortunately the antiseizure effect of benzodiazepines undergoes tolerance after 1-6 months of therapy.- Diazepam is the drug of choice to treat acute convulsive episodes irrespective to the cause.- Diazepam, rectally administered at the onset of fever, is the drug of choice to prevent recurrent febrile seizures in children.

DIAZEPAM PHARMACOKINETICS

ABSORPTION- Oral bioavailability: 100 %- Intramuscular bioavailability: unreliable.

DISTRIBUTION- Bound in plasma: 99 %- Vd (70 Kg): » 77 L - Initially concentrated in brain but rapidly redistributed in other tissues (redistribution half-time:» 1 hour)

BIOTRANSFORMATION- > 99% by the liver (many metabolites are active)

EXCRETION- < 1% by the kidney.

Total Clearance:mL/min(70 Kg) » 26

Half-life: » 45 hours(half-life of active metabolites: » 100 hours)

ADVERSE EFFECTS OF BENZODIAZEPINES

Central nervous system- Sedation, drowsiness, asthenia (common, dose-related adverse effects)- Lethargy, ataxia, hypotonia, dysarthria, dizziness, vivid or disturbing dreams (after high doses).- Hangover effects (after high doses)- Hyperactivity, irritability, aggressiveness (rare, more frequent in children) - Anterograde amnesia (after high doses)- Psychological and physical dependence.Respiratory system- Respiratory depression (only after high IV doses in risk patients)Other systems- Dry mouth, metallic taste, nausea, diarrhea.- Menstrual irregularities, sexual disturbances.Pregnancy- Small increase in the risk of cleft lip or cleft palate.- "Floppy baby syndrome" (if given to the mother during labor)

PHARMACOLOGY OF GABAergic DRUGS

GABAPENTIN Mechanism of action- It is still poorly understood. Likely the drug enhances GABA release from nerve terminals.Pharmacokinetics- Oral bioavailability: > 60% - No biotransformation. Secretion by the kidney.- Half-life: » 6 hours.Toxicity - Drowsiness (19%), dizziness (17%), fatigue (11%)- Ataxia (12 %), nystagmus (8%), tremor (7%), dysarthria, diplopia, amnesia.- Xerostomia (2%), constipation (1.5%).Therapeutic uses - Second choice drug for simplex or complex partial seizures and grand mal seizures.- Second choice drug for neuropathic pain.

VIGABATRINPharmacodynamics(The drug is still investigational in USA)- The drug is an irreversible inhibitor of GABA-aminotransferase (the enzyme responsible for degradation of GABA)Pharmacokinetics- Oral bioavailability: > 80% - Half-life: » 7 hours.Toxicity- Sedation, drowsiness, dizziness, weight gain.- Agitation, confusion.- Depression, psychosis (rare).Therapeutic uses - Second choice drug for in partial seizures and infantile spasms.

TIAGABINE- An inhibitor of GABA reuptake.- Second choice drug for both partial and genralized tonoc-clonic seizure.

CARBONIC ANHYDRASE INHIBITORS AS ANTISEIZURE DRUGS

Chemistry- Acetazolamide, a sulfonamide diuretic, is the prototype for the carbonic inhibitors.Pharmacodynamics- Inhibition of carbonic anhydrase increases the carbon dioxide content in the brain.- Decrease in tissue pH seems to inhibit Na+ entrance into the cells.- Anticonvulsant effects (which are similar to those of carbon dioxide) rapidly undergo tolerance.Toxicity- Skin rashes, drowsiness, paresthesias.- Bone-marrow suppression, interstitial nephritis, (rare)Therapeutic uses- As an alternative drug in all type of seizures (efficacy is low and tolerance limit the use).- In epileptic women who have exacerbation of seizures at the time of menses.

DRUG THERAPY OF INFANTILE SPASMS

- Infantile spasms are an epileptic syndrome very difficult to treat.- Drugs of choice are ACTH and corticosteroids (prednisone, dexamethasone, etc.). ACTH seems more effective but the subject remains controversial.- The mechanism of action of corticosteroids or ACTH in the treatment of infantile spasms is unknown.- Corticosteroids therapy often must be discontinued because of adverse effects.- Alternative drugs for infantile spasms are benzodiazepines (clonazepam, nitrazepam), vigabatrin and valproic acid.- The therapy of infantile spasms is able to reduce the number of attack in 40-50% of patient but it rarely improves the progression of mental retardation.

THERAPEUTIC INDICATIONS FOR ANTISEIZURE DRUGS

Types of epilepsy Preferred drugs Alternative drugs

Tonic-clonicseizures

CarbamazepineValproic acidPhenytoin

PhenobarbitalPrimidoneGabapentinTiagabine

Simple partialseizures

CarbamazepinePhenytoinValproic acid

PhenobarbitalPrimidoneVigabatrinGabapentinLamotrigineTopiramate

Complex partialseizures

CarbamazepinePhenytoinValproic acid

PrimidoneVigabatrin

Absenceseizures

EthosuximideValproic acid

ClonazepamTrimethadione

Myoclonic andAtonic seizures

Valproic acidClonazepam

Ethosuximide

Status Epilepticus Diazepam (1)Lorazepam (1)Phenytoin (2)

Phenobarbital(2)

Infantile spasms ACTHCorticosteroids

ClonazepamVigabatrinValproic acid

Febrile seizures Diazepam

(*) drugs are listed in order of preference (1) acute management (2) preventive management

GENERAL PRINCIPLES FOR THE THERAPY OF EPILEPSIES (1)

- The initial choice of the drug must be based on diagnosis (mainly founded upon anamnesis and EEG record) and spectrum of adverse effects of the drug.- In most instances medication should be started with a single drug (the one that is considered first choice for the type of seizure to be treated).- Initial dosage should be low in order to avoid unwanted effects (many adverse effects undergo tolerance). Loading dosage should be employed only if the urgency for control of seizures exceeds the risk of adverse effects.- Since most antiseizure drugs have a long half-life the steady-state will be reached only after some days of treatment.- It is very important that maintenance dose should be the minimum effective dose. Therefore the dosage should be increased gradually until seizure are controlled or toxicity makes further increase inadvisable.

GENERAL PRINCIPLES FOR THE THERAPY OF EPILEPSIES (2)

- If the initial drug does not control seizures a trial with another agent from a different chemical class should be attempted before considering a multidrug regimen. The second drug should be introduced before the first drug is discontinued.- A combined drug treatment is required in case of refractory seizures or mixed seizures. Polytherapy however increases the likelihood of toxicity and of complex drug interactions.- Most crucial for successful management is the regularity of medication since faulty compliance isthe most frequent cause for failure of therapy. - If the patient has had no seizures (including EEG seizures) for 2 years, drugs may be withdrawn to see weather the seizure threshold has normalized.- Withdrawal should always be done gradually over a period of weeks or months in order to avoid the risk of increased seizure frequency and severity.

PLASMA LEVEL OF COMMONLY USED ANTIEPILEPTIC DRUGS

Drug Effective level (mcg/ml)

Toxic level (mcg/ml)

CarbamazepinePhenytoinPhenobarbitalPrimidoneValproic acidEthosuximideClonazepamDiazepam

4-12 10-20 10-30 5-10 30-100 40-100 0.05-0.07 0.6-1.0

> 9 > 20 > 40 > 10 > 100 > 150 --- ---

ANTISEIZURE DRUG TOXICITY: GENERAL FEATURES

- The therapeutic index for most antiepileptic drugs is low, and toxicity is not uncommon.- Toxicity is mainly dose-dependent; since antiseizure therapy is often long term, the probability of adverse effect is rather high.- For antiepileptic drugs relationships between blood levels and therapeutic (or toxic) effects have been characterized to a particular high degree. Monitoring of plasma concentrations is therefore the best way to control overdose toxicity.- Many CNS and ANS adverse effects undergo tolerance and therefore they can be minimized by gradually increasing the dose.- Most antiepileptic drugs can cause adverse effects upon the CNS; cerebellar-vestibular disorders are especially frequent.- Abrupt withdrawal of an antiepileptic drug is the most common cause of status epilepticus.- All antiseizure drugs (especially if given in combination) may lead to behavioral and cognitive disturbances mainly in children. The occurrence of such disturbances seems more frequent with phenytoin and phenobarbital.- Several lethal cases of overdose toxicity of anticonvulsants are reported in literature. Most of these cases result from skin, liver or hematopoietic disorders.- Children born to mothers taking antiepileptic drugs have an increased risk (perhaps 2-3 fold) of congenital malformations. The risk increases if two or more drugs are taken concurrently.- The formation of epoxide intermediates during the biotransformation of antiseizure drugs has been implicated in the induction of fetal malformations.