Dr. Tupas - Pharmacotherapy of the Epilepsies

7/29/2019 Dr. Tupas - Pharmacotherapy of the Epilepsies

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Seizure

Non-epileptic: eg. Due to electric shock or

chemical convulsant (Pentyleneterazole, kainic

acid)

Epileptic: Occurs without provocation


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Classification of Seizure

*Partial: simple or complexSimple Partial: w/ preservation of consciousness

Complex Partial: w/o preservation of conciousness

*Generalized: absence, tonic,

clonic, tonic-clonic, myoclonic,

febrile


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Mechanism of Seizure

Partial & Generalized:

Inactivation of Na Channels

Enhanced GABA synaptic inhibition

Increased EAA input

Absence:

Limit activation of Ca channels known as T current


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Strategies in Treatment

Stabilize membrane and preventdepolarization by action on ion channels

Increase GABAergic transmission

Decrease EAA transmission


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Classification of Anticonvulsants

Action on Ion

Channels

Enhance GABA

Transmission

Inhibit EAA

TransmissionNa+:

Phenytoin,

Carbamazepine,

Lamotrigine

Topiramate

Valproic acid

Ca++:

Ethosuximide

Valproic acid

Benzodiazepines

(diazepam, clonazepam)

Barbiturates

(phenobarbital)

Valproic acid

Gabapentin

Vigabatrin

Topiramate

Felbamate

Felbamate

Topiramate

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


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Classification of Anticonvulsants

Classical

Phenytoin

Phenobarbital

Primidone Carbamazepine

Ethosuximide

Valproic Acid

Trimethadione

Newer

Lamotrigine

Felbamate

Topiramate

Gabapentin

Tiagabine

Vigabatrin

Oxycarbazepine

Levetiracetam Fosphenytoin

Others


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Treatment of Seizures

1) Hydantoins: phenytoin2) Barbiturates: phenobarbital

3) Oxazolidinediones: trimethadione

4) Succinimides: ethosuximide5) Acetylureas: phenacemide

6) Other: carbamazepine, lamotrigine, vigabatrin,

etc.7) Diet

8) Surgery, Vagus Nerve Stimulation (VNS).


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Pharmacokinetic Parameters


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PHENYTOIN (Dilantin)

Oldest nonsedative antiepileptic drug.

Fosphenytoin, a more soluble prodrug is used forparenteral use.

Fetal hydantoin syndrome.

Manufacturers and preparations.

It alters Na+, Ca2+ and K+ conductances.

Inhibits high frequency repetitive firing.

Alters membrane potentials.

Alters a.a. concentration.

Alters NTs (NE, ACh, GABA)


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Phenytoin Toxicity and Adverse

Events

Acute Toxicity

High i.v. rate: cardiac arrhythmias

hypotension; CNS depression.

Acute oral overdose: cerebellar and vestibular

symptoms and signs:nystagmus, ataxia, diplopia vertigo.


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Phenytoin Toxicity

Chronic Toxicity

Dose related vestibular/cerebellar effects

Behavioral changes

Gingival Hyperplasia GI Disturbances

Sexual-Endocrine Effects:

Osteomalacia

Hirsutism

Hyperglycemia


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Phenytoin Toxicity and Adverse

EventsChronic Toxicity Folate Deficiency - megaloblastic anemia

Hypoprothrombinemia and hemorrhage in newborns

Hypersenstivity Reactions could be severe. SLE, fatalhepatic necrosis, Stevens-Johnson syndrome.

Pseudolymphoma syndrome

Teratogenic

Drug Interactions: decrease (cimetidine, isoniazid) orincrease (phenobarbital, other AEDs) rate ofmetabolism; competition for protein binding sites.


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CARBAMAZEPINE (Tegretol) IMINOSTILBENE

3-D conformation similar tophenytoin.

Mechanism of action, similar tophenytoin. Inhibits high frequency

repetitive firing. Decreases synaptic activity

presynaptically.

Inh. uptake and release of NE, but

not GABA. Potentiates postsynaptic effects of

GABA.

Metabolite is active.

Other uses: Trigeminal neuralgia

Toxicity:

Autoinduction of

metabolism.

Nausea and visualdisturbances.

Anti-diuretic effect

Aplastic anemia.

Exacerbates absence

seizures.


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OXCARBAZEPINE (Trileptal)

Closely related to carbamazepine.

With improved toxicity profile.

Less potent than carbamazepine.

Active metabolite.

Use in partial and generalizedseizures as adjunct therapy.

May aggravate myoclonic andabsence seizures.

Mechanism of action, similar tocarbamazepine It alters Na+

conductance and inhibits highfrequency repetitive firing.

Toxicity:Hyponatremia

Less

hypersensitivity

and induction of

hepatic

enzymes than

with

carbamazepine


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Phenobarbital

The only barbiturate with selective anticonvulsant effect.

Bind at allosteric site on GABA receptor and duration ofopening of Cl channel.

Ca-dependent release of neurotransmitters at high

doses. Inducer of microsomal enzymes drug interactions.

Toxic effects: sedation (early; tolerance develops);nystagmus & ataxia at higher dose; osteomalacia, folatedeficiency and vit. K deficiency.

In children: paradoxical irritability, hyperactivity andbehavioral changes.

Deoxybarbiturates: primidone: active but also converted tophenobarbital. Some serious additional ADRs: leukopenia, SLE-like.


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Benzodiazepines

Sedative - hypnotic- anxiolytic drugs.

Bind to another site on GABA receptor. Other mechanismsmay contribute. frequency of opening of Cl channel.

Clonazepam and clorazepate for long term treatment of

some epilepsies. Diazepam and lorazepam: for control of status epilepticus.

Disadvantage: short acting.

Toxicities: chronic: lethargy drowsiness.

in status epilepticus: iv administration: respiratoryandcardiovascular depression. Phenytoin and PB also used.


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PRIMIDONE (Mysolin)

Metabolized to phenobarbital

and phenylethylmalonamide(PEMA), both active metabolites.

Effective against partial and

generalized tonic-clonic seizures.

Absorbed completely, low

binding to plasma proteins.

Should be started slowly to avoid

sedation and GI problems. Its mechanism of action may be

closer to phenytoin than the

barbiturates.

Toxicity:

Same as phenobarbital

Sedation occurs early.

Gastrointestinal complaints.


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VALPROATE (Depakene)

Fully ionized at body pH, thus active form

is valproate ion.

One of a series of carboxylic acids withantiepileptic activity. Its amides and

esters are also active.

Mechanism of action, similar to

phenytoin. levels of GABA in brain.

Facilitates Glutamic acid decarboxylase

(GAD).

Inhibits the GABA-transporter in neuronsand 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


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ETHOSUXIMIDE (Zarontin)

Drug of choice for absence seizures.

High efficacy and safety.

Not plasma protein or fat binding

Mechanism of action involvesreducing low-threshold Ca2+ channel

current (T-type channel) in thalamus.At high concentrations:

Inhibits Na+/K+ ATPase.

Depresses cerebral metabolic rate.

Inhibits GABA aminotransferase.

Phensuximide = less effective

Methsuximide = more toxic

Toxicity:

Gastric distress,

including, pain, nausea

and vomiting

Lethargy and fatigue

HeadacheHiccups

Euphoria

Skin rashes

Lupus erythematosus (?)


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CLONAZEPAM (Klonopin)

A benzodiazepine.

Long acting drug with efficacyfor absence seizures.

One of the most potentantiepileptic agents known.

Also effective in some cases ofmyoclonic seizures.

Has been tried in infantilespasms.

Doses should start small.

Increases the frequency of Cl-channel opening.

Toxicity:

Sedation is prominent.

Ataxia.

Behavior disorders.


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VIGABATRIN (-vinyl-GABA)

Absorption is rapid, bioavailabilityis ~ 60%, T 1/2 6-8 hrs, eliminatedby the kidneys.

Use for partial seizures and Wests

syndrome. Contraindicated if preexisting

mental illness is present.

Irreversible inhibitor of GABA-

aminotransferase (enzymeresponsible for metabolism ofGABA) => Increases inhibitoryeffects of GABA.

Toxicity:

Drowsiness

Dizziness

Weight gain

Agitation

Confusion

Psychosis


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LAMOTRIGINE (Lamictal) Add-on therapy with valproic acid (w/v.a.

conc. have be reduced => reduced

clearance).

Almost completely absorbed

T1/2 = 24 hrs

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.

Also effective in myoclonic and generalized

seizures in childhood and absence attacks.

Toxicity:

Dizziness

Headache

Diplopia

Nausea

SomnolenceLife threatening

rash Stevens-

Johnson


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FELBAMATE (Felbatrol)

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 refractorycases.

Toxicity:

Aplastic anemia

Severe hepatitis


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TOPIRAMATE (Topamax)

Toxicity:

Somnolence

Fatigue

Dizziness

Cognitive slowing

Paresthesias

Nervousness

Confusion

Weak carbonicanhydrase inhibitor

Urolithiasis

Rapidly absorbed, bioav. is > 80%,has no active metabolites,

excreted in urine.T1/2 = 20-30 hrs

Blocks repetitive firing of culturedneurons, thus its mechanism mayinvolve blocking of voltage-

dependent sodium channels

Potentiates inhibitory effects ofGABA (acting at a site differentfrom BDZs and BARBs).

Depresses excitatory action ofkainate on AMPA receptors.

Teratogenic in animal models.


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TIAGABINE (Gabatril)

Derivative of nipecotic acid.

100% bioavailable, highly protein

bound.

T1/2 = 5 -8 hrs

Effective against partial seizures

in pts at least 12 years old.

Approved as adjunctive therapy.

GABA uptake inhibitor aminibutyric acid transporter

(GAT) by neurons and glial cells.

Toxicity:

Abdominal pain and

nausea (must be taken

w/food)

Dizziness

Nervousness

Tremor

Difficulty concentrating

DepressionAsthenia

Emotional liability

Psychosis

Skin rash


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ZONISAMIDE (Zonegran) Marketed in Japan. Sulfonamide

derivative. Good bioavailability, low pb.

T1/2 = 1 - 3 days

Effective against partial and generalizedtonic-clonic seizures.

Approved by FDA as adjunctive therapy

in adults. Mechanism of action involves voltage

and use-dependent inactivation ofsodium channels.

Inhibition of Ca2+

T-channels. Binds GABA receptors

Facilitates 5-HT and DAneurotransmission

Toxicity:

DrowsinessCognitive

impairment

Anorexia

Nausea

High incidence ofrenal stones (mild

anhydrase inh.).

Metabolized by

CYP3A4


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GABAPENTIN (Neurontin)

Used as an adjunct in partial and

generalized tonic-clonic seizures. Does not induce liver enzymes.

not bound to plasma proteins.

drug-drug interactions arenegligible.

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.


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Status Epilepticus

Status epilepticus exists when seizures recur withina short period of time , such that baselineconsciousness is not regained between theseizures. They last for at least 30 minutes. Can

lead to systemic hypoxia, acidemia,hyperpyrexia, cardiovascular collapse, and renalshutdown.

The most common, generalized tonic-clonic statusepilepticus is life-threatening and must be treatedimmediately with concomitant cardiovascular,respiratory and metabolic management.


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Treatment ofStatus 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.


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PARTIAL SEIZURES ( Simple and Complex, includingsecondarily generalized)

Drugs of choice: CarbamazepinePhenytoin

Valproate

Alternatives: Lamotrigine, phenobarbital,primidone, oxcarbamazepine.

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


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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


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GENERALIZED ABSENCE SEIZURES

Drugs of choice: Ethosuximide

Valproate*

Alternatives: Lamotrigine, clonazepam,

zonisamide, topiramate (?).

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

present.


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ATYPICAL ABSENCE, MYOCLONIC, ATONIC*

SEIZURESDrugs of choice: Valproate

Clonazepam

Lamotrigine**

Alternatives: Topiramate, clonazepam,

zonisamide, felbamate.

* Often refractory to medications.

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


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INFANTILE SPASMS

Drugs of choice: Corticotropin (IM) or

Corticosteroids (Prednisone)

Zonisamide

Alternatives: Clonazepam, nitrazepam,vigabatrin, phenobarbital.


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Treatment of Seizures in Pregnancy

Phenytoin Phenobarbital

Carbamazepine Primidone

They may all cause hemorrhage in the infant due tovitamin K deficiency, requiring treatment of motherand 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 inrodents and hypospadias in male infants.

Zonisamide is teratogenic in animals.


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INTERACTIONS BETWEEN ANTISEIZURE DRUGS

With other antiepileptic Drugs:- Carbamazepine with

phenytoin Increased metabolism of carbamazepine

phenobarbital Increased metabolism of epoxide.

- Phenytoin withprimidone Increased conversion to phenobarbital.

- Valproic acid with

clonazepam May precipitate nonconvulsive statusepilepticus

phenobarbital Decrease metabolism, increase toxicity.

phenytoin Displacement from binding, increase toxicity.


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ANTISEIZURE DRUG INTERACTIONS

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

met.

cimetidine displaces pheny, v.a. and BDZs

isoniazid toxicity of phenytoinoral contraceptives antiepilepticsmetabolism.salicylates displaces phenytoin and v.a.

theophyline carb and phenytoin mayeffect.

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Dr. Tupas - Pharmacotherapy of the Epilepsies