Dr. Tupas - Pharmacotherapy of the Epilepsies
Transcript of 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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Treatment of Seizures
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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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
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Treatment of Seizures
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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Treatment of Seizures
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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Treatment of Seizures
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.