Antiseizure drugs

Antiseizure drugs

Dr M Mosaddegh

Overview

• Seizures are sudden episodes of neurological dysfunction caused by abnormal electrical activity of the brain

• Seizures are common• 1% of the population will have a seizure

EpilepsyA group of chronic CNS disorders characterized by recurrent

seizures.

• Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction resulting from abnormal discharge of neuronal cells with associated motor, sensory or behavioral changes.

• Brain Trauma• Encephalitis• Drugs• PKU• Photo epilepsy• Birth trauma• Withdrawal from

depressants• Tumor• Hypoxia• Idiopathic

• High fever(Febrile convulsion)• Hypoglycemia• Extreme acidosis• Extreme alkalosis• Hyponatremia• Hypocalcemia• Infection e.g.

meningitis, brain abscess, viral encephalitis

Causes for Acute Seizures

I. Partial (focal) SeizuresA. Simple Partial SeizuresB. Complex Partial Seizures

II. Generalized SeizuresC. Generalized Tonic-Clonic SeizuresD. Absence SeizuresE. Tonic SeizuresF. Atonic SeizuresG. Clonic and Myoclonic Seizures

F. Infantile Spasms

Classification of Epileptic Seizures

9

• Earlier studies suggested that many patients respond to monotherapy but fewer and fewer patients respond to combination therapy.

AED Response – Established AEDs

Monotherapy

70% controlled*

30% poorly managed

30% controlled* on 2 drugs

Combinations of two or more drugs provide little more benefit

* Controlled was defined as adequately managed but not necessarily seizure-free

I. Partial (Focal) Seizures

A. Simple Partial SeizuresB. Complex Partial Seizures

Scheme of Seizure SpreadSimple (Focal) Partial

Seizures

Contralateral spread

A. Simple Partial Seizures (Jacksonian)• Involves one side of the brain at onset.• Focal w/motor, sensory or speech disturbances.• Confined to a single limb or muscle group.• Seizure-symptoms don’t change during seizure.• No alteration of consciousness.EEG: Excessive synchronized discharge by a small group of

neurons. Contralateral discharge.

I. Partial (Focal) Seizures

Scheme of Seizure Spread

Complex Partial Seizures

Complex Secondarily Generalized Partial Seizures

B. Complex Partial Seizures (Temporal Lobe epilepsy or Psychomotor Seizures)

• Produces confusion and inappropriate or dazed behavior.

• Motor activity appears as non-reflex actions. Automatisms (repetitive coordinated movements).

• Wide variety of clinical manifestations.• Consciousness is impaired or lost.

EEG: Bizarre generalized EEG activity with evidence of anterior temporal lobe focal abnormalities. Bilateral.

I. Partial (focal) Seizures

II. Generalized Seizures

In Generalized seizures, both hemispheres are widely involved from the outset.

Manifestations of the seizure are determined by the cortical site at which the seizure arises.

Present in 40% of all epileptic Syndromes.

II. Generalized Seizures (con’t)A. Generalized Tonic-Clonic Seizures

Recruitment of neurons throughout the cerebrum

Major convulsions, usually with two phases:1) Tonic phase2) Clonic phase

Convulsions: motor manifestations, may or may not be present during seizures, excessive neuronal discharge. Convulsions appear in Simple Partial and Complex Partial Seizures if the focal neuronal discharge includes motor centers; they occur in all Generalized Tonic-Clonic Seizures regardless of the site of origin. Atonic, Akinetic, Absence Seizures are non-convulsive

II. Generalized Seizures (con’t)A. Generalized Tonic-Clonic Seizures

Tonic phase:- Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation.

EEG: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials.

II. Generalized Seizures (con’t)A. Generalized Tonic-Clonic Seizures

Clonic phase:- Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical or “running” movements.

EEG: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials.

Scheme of Seizure Spread

Generalized Tonic-Clonic Seizures

Both hemispheres areinvolved from outset

Neuronal Correlates of Paroxysmal Discharges

Generalized Seizures

Neuronal Correlates of Paroxysmal Discharges

B. Absence Seizures (Petite Mal)• Brief and abrupt loss of consciousness.• Sometimes with no motor manifestations.• Usually symmetrical clonic motor activity

varying from occasional eyelid flutter to jerking of the entire body.

• Typical 2.5 – 3.5 Hz spike-and-wave discharge.

• Usually of short duration (5-10 sec), but may occur dozens of times a day.

II. Generalized Seizures

B. Absence Seizures (Petite Mal) (con’t)• Often begin during childhood (daydreaming attitude,

no participation, lack of concentration).• A low threshold Ca2+ current has been found to

govern oscillatory responses in thalamic neurons (pacemaker) and it is probably involve in the generation of these types of seizures.

EEG: Bilaterally synchronous, high voltage 3-per-second spike-and-wave discharge pattern.

spike phase: neurons generate short duration depolarization and a burst of action potentials. No sustained depolarization or repetitive firing.

II. Generalized Seizures

Scheme of Seizure Spread

Primary GeneralizedAbsence Seizures

Thalamocortial relays are believed

to act on a hyperexcitable

cortex

Neuronal Correlates of Paroxysmal Discharges

Generalized Absence Seizures

Scheme of Seizure Spread

II. Generalized Seizures (con’t)

C. Tonic Seizures• Opisthotonus, loss of consciousness.• Marked autonomic manifestations

D. Atonic Seizures (atypical)• Loss of postural tone, with sagging of the

head or falling.• May loose consciousness.

II. Generalized Seizures (con’t)E. Clonic and Myoclonic Seizures• Clonic Seizures: Rhythmic clonic contractions of all

muscles, loss of consciousness, and marked autonomic manifestations.

• Myoclonic Seizures: Isolated clonic jerks associated with brief bursts of multiple spikes in the EEG.

F. Infantile Spasms• An epileptic syndrome.• Attacks, although fragmentary, are often bilateral.• Characterized by brief recurrent myoclonic jerks of

the body with sudden flexion or extension of the body and limbs.

Primary

Types of s

(focal)

Treatment of Seizures

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 Seizures

Strategies:• Modification of ion conductances.

• Increase inhibitory (GABAergic) transmission.

• Decrease excitatory (glutamatergic) activity.

Actions of Phenytoin on Na+ Channels

A. Resting State

B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.

C. Refractory State, Inactivation

Na+

Na+

Na+

Sustain channel in this conformation

GABAergic SYNAPSE

Drugs that Act at the GABAergic Synapse

• GABA agonists• GABA antagonists• Barbiturates• Benzodiazepines• GABA synthesizing

enzymes• GABA uptake inhibitors• GABA metabolizing

enzymes

GAD

GAT

GABA-T

GLUTAMATERGIC SYNAPSE

• Excitatory Synapse.• Permeable to Na+, Ca2+

and K+.• Magnesium ions block

channel in resting state.• Glycine (GLY) binding

enhances the ability of GLU or NMDA to open the channel.

• Agonists: NMDA, AMPA, Kianate.

Mg++

Na+

AGONISTS

GLU

Ca2+

K+

GLY

Chemical Structure of Classical Antiseizure Agents

X may vary as follows:

Barbiturates - C – N -Hydantoins - N –Oxazolidinediones – O –Succinimides – C –Acetylureas - NH2 –* *(N connected to C2)

Small changes can alter clinical activity and site of action.e.g. At R1, a phenyl group (phenytoin) confers activity against partial seizures, but an alkyl group (ethosuximide) confers activity against generalized absence seizures.

“Older” AEDs• Phenobarbital 1912• Phenytoin 1938• Primidone 1952• Ethosuximide 1960• Carbamazepine 1974• Valproate 1978

Newer AEDS

• felbamate 1993• gabapentin 1994• lamotrigine 1995• topiramate 1996• tiagabine 1998• levetiracetam 1999• oxcarbazepine 2000• Zonisamide 2000• pregabalin 2005

Treatment of Seizures1) Hydantoins: phenytoin2) Barbiturates: phenobarbital3) Oxazolidinediones: trimethadione4) Succinimides: ethosuximide5) Acetylureas: phenacemide6) Other: carbamazepine, lamotrigine, vigabatrin,

etc.7) Diet8) Surgery, Vagus Nerve Stimulation (VNS).

• Most classical antiepileptic drugs exhibit similar pharmacokinetic properties.

• Good absorption (although most are sparingly soluble).

• Low plasma protein binding (except for phenytoin, BDZs, valproate, and tiagabine).

• Conversion to active metabolites (carbamazepine, primidone, fosphenytoin).

• Cleared by the liver but with low extraction ratios.• Distributed in total body water.• Plasma clearance is slow.• At high concentrations phenytoin exhibits zero order

kinetics.

Treatment of Seizures

Treatment of SeizuresStructurally dissimilar drugs:

• Carbamazepine• Valproic acid• BDZs.

New compounds:• Felbamate • Gabapentin• Lamotrigine• Tiagabine• Topiramate• Vigabatrin

Pharmacokinetic Parameters

TREATMENT OF SEIZURESDrugs Seizure disorderCarbamazepine or Valproate orPhenytoin orPhenobarbital

Tonic-clonic(Grand mal)Drug of Choice

Topiramte Lamotrigine (as adjunct or alone) Gabapentin (as adjunct)

Alternatives:

Carbamazepine or Topiramte or Phenytoin or Valproate

Partial (simple or complex) Drug of choice

Phenobarbital Lamotringine (as adjunct or alone) Gabapentin (as adjunct )

Alternatives:

Treatament cont,dValproate or Ethosuximide

Absence ( petit mal) Drug of choice

ClonazepamLamotrigine

Alternatives:

Valproate Myoclonic, Atonic Drug of choice

Clonazepam Alternatives:

Diazepam, i.v.or Phenytoin, i.v. or Vaproate

Status EpilepticusDrug of choice

Phenobarbital, i.v Alternatives:Diazepam, rectal*Diazepam ,i.vValproate

Febrile Seizures

* Preferred

• Up to 80% of patients can expect partial or complete control of seizures with appropriate treatment.

• Antiepileptic drugs suppress but do not cure seizures

• Antiepileptics are indicated when there is two or more seizures occurred in short interval (6m -1 y)

• An initial therapeutic aim is to use only one drug (monotherapy)

Treatment:

Treatment ( Cont. )• Advantage of monotherapy: • fewer side effects, decreased drug-drug interactions, better

compliance, lower costs• Addition of a second drug is likely to result in significant

improvement in only approx. 10 % of patients.

Treatment ( Cont. ) • when a total daily dose is increased, sufficient time

(about 5 t 1l2) should be allowed for the serum drug level to reach a new steady-state level.

• The drugs are usually administered orally

• The monitoring of plasma drug levels is very useful

• Precipitating or aggravating factors can affect seizure control by drugs

Treatment ( Cont. )• The sudden withdrawal of drugs should be avoided withdrawal may be considered after seizure- free

period of 2-3 or more years

• Relapse rate when antiepileptics are withdrawn is 20 -40 %

When to Withdraw Antiepileptic Drugs?

Normal neurological examination Normal IQ Normal EEG prior to withdrawal Seizure- free for 2-5 yrs or longer NO juvenile myoclonic epilepsy

Patients not meeting this ideal profile in all points, withdrawal may be encouraged after careful assessement of the individual patient.

The Cytochrome P-450 Enzyme System

Inducers Inhibitors

phenobarbital valproate

primidone topiramate (CYP2C19)

phenytoin oxcarbazepine (CYP2C19)

carbamazepine felbamate (CYP2C19)

felbamate (CYP3A) (increase phenytoin, topiramate (CYP3A) phenobarbital)oxcarbazepine (CYP3A)

Phenytoin

Pharmacokinetics• Well absorbed when given orally, however, it is also

available as iv. (for emergency) • 80-90% protein bound• Induces liver enzymes (Very Important)• Metabolized by the liver to inactive metabolite• Metabolism shows saturation kinetics and hence t ½

increases as the dose increased• Excreted in urine as glucuronide conjugate• Plasma t ½ approx. 20 hours• Therapeutic plasma concentration 10-20 µg/ml (narrow)• Dose 300-400 mg/day

Phenytoin ( Cont. )Mechanism of Action: Membrane stabilization by blocking Na & Ca influx

into the neuronal axon.or inhibits the release of excitatory amino acids via

inhibition of Ca influx

Clinical Uses: Used for partial Seizures & generalized tonic-clonic

seizures. But not effective for absence Seizures .Also can be used for Rx of ventricular fibrillation.

Side effects:Dose Related:• G.I.T upset• Neurological like headache, vertigo,

ataxia, diplopia, nystagmus• Sedation

Side effects of Phenytoin ( Cont. )Non-dose related:• Gingival hyperplasia• Hirsutism• Megaloblastic anaemia• Hypersensitivity reactions (mainly skin rashes and

lesions, mouth ulcer) • Hepatitis –rare• Fetal malformations- esp. cleft plate• Bleeding disorders (infants)• Osteomalacia due to abnormalities in vit D

metabolism

• Side effects of phenytoin ( Cont.)

• Pharmacokinetic Interactions

– Inhibitors of liver enzymes elevate its plasma levels e.g. Chloramphenicol, INH,cimetidine.

– Inducers of liver enzymes reduce its plasma levels e.g. Carbamazipine; Rifampicin, phenobarbital.

Fosphenytoin

• A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body.

• Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes.

• Otherwise similar toxicities to phenytoin.

CARBAMAZEPINE Its mechanism of action and clinical uses are similar to that

of phenytoin. However, it is also commonly used for Rx of mania and trigeminal neuralgia.

Pharmacokineticsavailable as an oral form only Well absorbed 80 % protein bound Strong inducing agent including its own (can lead to failure of

other drugs e.g. oral contraceptives, warfarin, etc.Metabolized by the liver to CBZ 10.11-epioxide(active) and

CBZ -10-11-dihydroxide (inactive)

Pharmacokinetics of CBZ( Cont. )• Excreted in urine as glucuronide conjugate

• Plasma t1/2 approx. 30 hours

• Therapeutic plasma concentration 6-12 µg/ml (narrow).

• Dose 200-800 mg/day (given BID as sustained release form)

• Side Effects of Carbamazepine: • G.I upset• Drowziness, ataxia and headache; diplopia• Hepatotoxicity- rare• Congenital malformation (craniofacial anomalies &

neural tube defects).• Hyponatraemia & water intoxication.• Late hypersensitivity reaction (erythematous skin rashes,

mouth ulceration and lymphadenopathy. • Blood dyscrasias as fetal aplastic anemia (stop

medication); mild leukopenia (decrease the dose)

Pharmacokinetic interactions of CBZ

• Inducers of liver enzymes reduce its plasma level e.g. Phenytoin; Phenobarbital; Rifampicin

• inhibitors of liver enzymes elevate its plasma levels e.g. erythromycin,INH ,verapamil; Cimetidine

Phenobarbital Mechanism of Action:• Increases the inhibitory neurotransmitters

(e.g: GABA ) and decreasing the excitatory transmission.

• Also, it also prolongs the opening of Cl- channels.

• Absorption: rapid• Half-life: 53-118 hours (long)•

Phenobarbital• Partial seizures, effective in neonates• Second-line drug in adults due to more severe CNS

sedation• Adverse effects: CNS sedation but may produce

excitement in some patients. Skin rashes if allergic. Tolerance and physical dependence possible.

• Interactions: severe CNS depression when combined with alcohol or benzodiazapines. Stimulates cytochrome P-450

Primidone• Partial seizures• Mechanims—see phenobarbital• Absorption: Individual variability in rates. Not highly

bound to plasma proteins.• Metabolism: Converted to phenobarbital and phenylethyl

malonamide, 40% excreted unchanged.• Half-life: variable, 5-15 hours. • Adverse effects: CNS sedative• Drug interactions: enhances CNS depressants, drug

metabolism, phenytoin increases conversion to PB

Vigabatrin (restricted) Pharmacological effects:Drug of choice for

infantile spasms, Use for partial seizures and West’s syndrome.

• Not bound to proteins ,Not metabolized and excreted unchanged in urine

• Plasma t1/2 4-7 hrsSide effects: Visual field defects, psychosis and depression

(limits its use).

VIGABATRIN (-vinyl-GABA)

• Contraindicated if preexisting mental illness is present.

• Irreversible inhibitor of GABA-aminotransferase (enzyme responsible for metabolism of GABA) => Increases inhibitory effects of GABA.

Toxicity:• Drowsiness• Dizziness• Weight gain• Agitation• Confusion• Psychosis

Lamotrigine Pharmacological effects Resembles phenytoin in its pharmacological effects Well absorbed from GIT Metabolised primarily by glucuronidation Does not induce or inhibit C. P-450 isozymes ( its metabolism is

inhibitted by valproate ) Plasma t 1/2 approx. 24 hrs.• Mechanism of Action: Inhibits excitatory amino acid release (glutamate & aspartate )

by blockade of Na channels.• Side effects: • Skin rash, somnolence, blurred vision, diplopia, ataxia,

headache, aggression, influenza – like syndrome

LAMOTRIGINE (Lamictal)

• Add-on therapy with valproic acid (w/v.a. conc. have be reduced => reduced clearance).

• Low plasma protein binding• Effective in myoclonic and generalized

seizures in childhood and absence attacks.

• Involves blockade of repetitive firing involving Na channels, like phenytoin.

Toxicity:• Dizziness• Headache• Diplopia• Nausea• Somnolenc

e• Life

threatening rash “Stevens-Johnson”

FELBAMATE

• Effective against partial seizures but has severe side effects.

• Because of its severe side effects, it has been relegated to a third-line drug used only for refractory cases.

Toxicity:• Aplastic anemia• Severe hepatitis

Gabapentin• Structural analogue of GABA .May increase the

activity of GABA or inhibits its re-uptake. Pharmacokinetics: Not bound to proteins Not metabolized and excreted unchanged in urine• Does not induce or inhibit hepatic enzymes (similar

to lamotrigine) • Plasma t ½ 5-7 hours

GABAPENTIN• Used as an adjunct in partial and

generalized tonic-clonic seizures.• drug-drug interactions are negligible.• Low potency.• An a.a.. Analog of GABA that does not

act on GABA receptors, it may however alter its metabolism, non-synaptic release and transport.

Toxicity:• Somnolence.• Dizziness.• Ataxia.• Headache.• Tremor.

Topimerate• Add-on for refractory partial or generalized seizures. Effective as monotherapy for partial or generalized seizures, Lennox-Gastaut syndrome.

• Use-dependent blockade of Na+ channels, increases frequency of GABAA channel openings, may interfere with glutamate binding to AMPA/KA receptor

• Half-life: 20-30 hours (long)• Adverse effects: CNS sedative• Drug interactions: Stimulates CYP3A and inhibits CYP2C19,

can lessen effectiveness of birth control pills

Topiramate ( Cont. )

Clinical Uses:Recently, this drug become one of the safest antiepileptics which can be used alone for partial and generalized tonic-clonic, and absence seizures.

TIAGABINE (Gabatril)• Adjunctive therapy in partial and

generalized tonic-clonic seizures• Bioavailability > 90 %• Highly protein bound ( 96% )• Metabolized in the liver• Plasma t ½ 4 -7 hrs• Mode of action: • inhibits GABA uptake and

increases its level

Toxicity:• Abdominal pain and

nausea (must be taken w/food)

• Dizziness• Nervousness• Tremor• Difficulty concentrating• Depression• Asthenia• Emotional liability• Psychosis• Skin rash

Zonisamide

Pharmacokinetics:• Well absorbed from GIT

(100 %) • Protein binding 40% • Extensively metabolized in

the liver• No effect on liver enzymes• Plasma t ½ 50 -68 hrsClinical Uses:Add-on therapy for partial

seizuresSide Effects:Drowsiness, ataxia ,

headache, loss of appetite,nausea& vomiting, Somnolence .

Levetiracetam• Add-on therapy for partial seizures• Binds to synaptic vesicle protein SV2A, may

regulate neurotransmitter release• Half-life: 6-8 hours (short)• Adverse effects: CNS depresssion• Drug interactions: minimal

Ethosuximide• Absence seizures• Blocks T-type Ca++ currents in thalamus• Half-life: long—40 hours• Adverse effects: gastric distress—pain, nausea,

vomiting. Less CNS effects that other AEDs, transient fatigue, dizziness, headache

• Drug interactions: administration with valproate results in inhibition of its metabolism

VALPROATE (Depakene)• Fully ionized at body pH, thus active

form is valproate ion.• Mechanism of action, similar to

phenytoin. • levels of GABA in brain.• Facilitates Glutamic acid

decarboxylase (GAD).• Inhibits the GABA-transporter in

neurons and glia (GAT).• [aspartate]Brain?• May increase membrane potassium

conductance.

Toxicity:• Elevated liver enzymes

including own.• Nausea and vomiting.• Abdominal pain and

heartburn.• Tremor, hair loss, • Weight gain.• Idiosyncratic hepatotoxicity.• Negative interactions with

other antiepileptics.• Teratogen: spina bifida

• Inhibits metabolism of several drugs such as Carbamazepine; phenytoin, Topiramate and phenobarbital.

• Clinical Use:–Very effective against absence, myoclonic

seizures.–Also, effective in gen. tonic-clonic siezures

(primarly Gen)– Less effective as compared to carbamazepine

for partial seizures– Like Carbamazepine also can be used for Rx of

mania

• Side Effects of Sod. valproate:• Nausea, vomiting and GIT disturbances (Start

with low doses)• Increased appetite & weight gain • Transient hair loss.• Hepatotoxicity • Thrombocytopenia• Neural Tube defect (e.g. Spina bifida) in the

offspring of women. (contraindicated in pregnancy)

Status EpilepticusStatus epilepticus exists when seizures recur within

a short period of time , such that baseline consciousness is not regained between the seizures. They last for at least 30 minutes. Can lead to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse, and renal shutdown.

• The most common, generalized tonic-clonic status epilepticus is life-threatening and must be treated immediately with concomitant cardiovascular, respiratory and metabolic management.

Treatment of Status Epilepticus in Adults

Initial• Diazepam, i.v. 5-10 mg (1-2 mg/min)

repeat dose (5-10 mg) every 20-30 min.• Lorazepam, i.v. 2-6 mg (1 mg/min)

repeat dose (2-6 mg) every 20-30 min.Follow-up• Phenytoin, i.v. 15-20 mg/Kg (30-50 mg/min).

repeat dose (100-150 mg) every 30 min.• Phenobarbital, i.v. 10-20 mg/Kg (25-30mg/min).

repeat dose (120-240 mg) every 20 min.

DIAZEPAM AND LORAZEPAM

• Given I.V.• Lorazepam may be longer acting.• Have muscle relaxant activity.• Allosteric modulators of GABA

receptors.• Potentiate GABA function by

increasing the frequency of channel opening.

Toxicity• Sedation• Children may

manifest a paradoxical hyperactivity.

• Tolerance

Treatment of SeizuresPARTIAL SEIZURES ( Simple and Complex, including

secondarily generalized)Drugs of choice: Carbamazepine

Phenytoin Valproate

Alternatives: Lamotrigine, phenobarbital, primidone, oxcarbamazepine.

Add-on therapy: Gabapentin, topiramate, tiagabine, levetiracetam, zonisamide.

Treatment of Seizures

PRIMARY GENERALIZED TONIC-CLONIC SEIZURES (Grand Mal)Drugs of choice: Carbamazepine

Phenytoin Valproate*

Alternatives: Lamotrigine, phenobarbital, topiramate, oxcartbazepine, primidone, levetiracetam.

*Not approved except if absence seizure is involved

Treatment of SeizuresGENERALIZED ABSENCE SEIZURES

Drugs of choice: Ethosuximide Valproate*

Alternatives: Lamotrigine, clonazepam, zonisamide, topiramate (?).

* First choice if primary generalized tonic-clonic seizure is also present.

Treatment of SeizuresATYPICAL ABSENCE, MYOCLONIC, ATONIC*

SEIZURESDrugs of choice: Valproate

ClonazepamLamotrigine**

Alternatives: Topiramate, clonazepam, zonisamide, felbamate.

* Often refractory to medications.

**Not FDA approved for this indication. May worsen myoclonus.

Treatment of Seizures

INFANTILE SPASMS

Drugs of choice: Corticotropin (IM) or Corticosteroids (Prednisone)

Zonisamide

Alternatives: Clonazepam, nitrazepam, vigabatrin, phenobarbital.

Treatment of Seizures in PregnancyPhenytoin PhenobarbitalCarbamazepine Primidone

They may all cause hemorrhage in the infant due to vitamin K deficiency, requiring treatment of mother and newborn.

They all have risks of congenital anomalies (oral cleft, cardiac and neural tube defects).Teratogens: Valproic acid causes spina bifida. Topiramate causes limb agenesis in rodents and hypospadias in male infants.Zonisamide is teratogenic in animals.

INTERACTIONS BETWEEN ANTISEIZURE DRUGS

With other antiepileptic Drugs:- Carbamazepine with

phenytoin Increased metabolism of carbamazepinephenobarbital Increased metabolism of epoxide.

- Phenytoin withprimidone Increased conversion to phenobarbital.

- Valproic acid withclonazepam May precipitate nonconvulsive status

epilepticusphenobarbital Decrease metabolism, increase toxicity.phenytoin Displacement from binding, increase

toxicity.

ANTISEIZURE DRUG INTERACTIONS

With other drugs:antibiotics phenytoin, phenobarb, carb.anticoagulants phenytoin and phenobarb

met.cimetidine displaces pheny, and BDZsisoniazid toxicity of phenytoinoral contraceptives antiepileptics metabolism.salicylates displaces phenytoin and v.a. theophyline carb and phenytoin may

effect.

Table 2. Proposed Mechanisms of Antiepileptic Drug Action

↓Na+ ↓Ca+ ↓K+ ↑ Inh. ↓Excitatorychannels channels channels transmission transmission

________________________________________________________________________________Established AED’sPHT +++CBZ +++ESM +++PB + +++ +BZD’s +++VPA + + ++ +

New AED’sLTG +++ +OXC +++ + +ZNS ++ ++VGB +++TGB +++GBP + + ++FBM ++ ++ ++ ++TPM ++ ++ ++ ++LEV + + +________________________________________________________________________________+++ primary action, ++ possible action, + probable action.From P. Kwan et al. (2001) Pharmacology and therapeutics 90:21-34. [Data from Upton (1994), Schachter (1995), McDonald and Kelly (1995), Meldrum (1996), Coulter (1997), and White (1999).]

Weight Issues• Risk of weight gain– Valproate – Gabapentin and

pregabalin

• “Risk” of weight loss– Topiramate – Zonisamide – Felbamate

Drugs that decrease efficacy of oral contraceptives

• Phenytoin • Carbamazepine • Phenobarbital• Primidone • Topiramate at

higher doses• Oxcarbazepine

Lifestyle changes to minimize seizures

• Avoid sleep deprivation

• Avoid alcohol• Treat fevers quickly• Occasional patients

should avoid specific factors such as strobe lights, etc

• Pill boxes/reminders

Herbal meds reported to worsen seizures

• Bearberry• Black cohosh• Borage• Damiana• Echinacea• Ephedra*• Ergot• Evening Primrose Oil• Gingko (prob safe)• Ginseng• Goldenseal• Green Tea• Guarana

• Histalet Forte• Kava Kava• Ma Huang*• Metabolife• Monkshood• Phen-Fen*• Sage• St. John’s Wort• Uva-Ursi• Water-hemlock• European water hemlock• Wormwood• Yohimbe

Herbal meds with significant interactions with seizure meds

• Chamomila• Choke cherry• Comfrey• Dillapiol• Echinacea• Eucalyptus Oil• Grapefruit juice• Licorice• Mentat• Nicotinamide• Paeoniae radix

• Piperine• Psyllium• Pyrrolizidine• Sage• St. John’s Wort• Septilin• Shankapushpi• Sho-seiryu-to• Wild cherry