introd anti convulsants
TRANSCRIPT
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Introduction to anticonvulsants.Classification of epileptic seizures
Classification of anticonvulsants
agents; Hydantoins, lamotrigine
Dr Keli F
Kenyatta University MedicalSchool 2/5/2013
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What are Seizures ?
A seizure is a transient alteration of
behavior due to abnormal
synchronous electrical activity in the
brain
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What is Epilepsy ?
Epilepsy is a condition where there arerecurring, unprovoked seizures
Diagnosis of epilepsy is based on clinical
findings and EEG features
Abnormal EEG is recognized by rythmicityor amplitude of waves and patterns
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What is a convulsion ?
A medical condition where body musclescontract and relax rapidly and repeatedly,resulting in an uncontrolled shaking of the body
Because a convulsion is often a symptom of anepileptic seizure, the term convulsionis sometimesused as a synonym for seizure
Not all epileptic seizures lead to convulsions,and not all convulsions are caused by epilepticseizures
http://en.wikipedia.org/wiki/Seizurehttp://en.wikipedia.org/wiki/Seizure -
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EEG during a seizure
Focal onset with secondary generalization
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Classification of Seizures
Partial Seizures (Focal Onset)
Simple Partial
Complex Partial
Partial with secondary generalization
Generalized (Bilateral Onset)
Absence seizure
Myoclonic Tonic-clonic
other types
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Parial Seizures
Simple Partial : Diverse manifestationsdetermined by region affected eg motor cortexrepresenting the thumb clonic jerking of the
thumb, if the somato sensory area is affectedthen paraesthezias of thumb
Complex Partial: impaired consciousness lasting
30 sec to 2 min of purposeless movements eghand writing
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Partial Seizures
Partial with Secondarily generalised TonicClonic seizure; its a simple or complex seizurewhich develops into a tonic clonic seizure with
loss of consciousness and sustained contractionwith periods of relaxation lasting 1 to 2 min
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Complex seizures
Absence Seizure: Abrupt onset of impairedconsciousness associated with staring andcessation of ongoing activities < 30 secs
Myoclonic seizure: brief shock like contractionof muscles may be restricted or generalized
Tonic Clonic Seizure: its a generalized seizurecontraction and relaxation of muscles
Atonic seizures: Sudden loss of postural toneConsciousness may be lost
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Target Mechanisms for
anticonvulsants
Inhibit repetitive activity of neurons
blockade of voltage-gated sodium
channels Increase inhibitory inputs
GABA enhancers
Reduce excitatory input
glutamate antagonists
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Enhanced Gaba Synaptic
Transmission
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Sodium channel and Seizure
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Anticonvulsants
Selective CNS drugs (Depressants), used to treatepilepsy. These syndromes affect about 1% ofthe population.
One would hope to have anticonvulsants thataffect pathologically altered neurons of seizurefoci, which would then prevent or reduce theirexcessive discharge.
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Anticonvulsants
The way that anticonvulsants work is:
to reduce the spread of excitation from seizure foci
and prevent detonation and disruption of functionof the normal neurons. The underlying pathology isnot affected.
Idiopathic epilepsy: No visible pathology of
initiation and yet abnormal neuronal firing takesplace and spreads throughout the brain.
The pattern the extent of propagation
determines the type and severity of the seizure.
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Anticonvulsants
A Plethora Of Drugs Hydantoins
Barbiturates Iminostilbenes
Succinimides
Benzodiazepines
Valproic Acids
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Partial seizure drugs
Hydantoins
Barbiturates
Iminostilbenes
Vigabatrin new Lamotrigine a phenyltriazines
Felbamate
Gabapentin analogue of GABA many other uses
Topiramate
Tiagabine nipecotic acid derivative
Zonisamide sulphonamide derivative
Levetiracetam a piracetam
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Drugs for partial and secondarily
generalized seizures
Phenytoin / fosphenytoin
(Hydantoins)
Carbamazepine
Barbiturates
Valproic acidNew and investigational agents
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Generalized Seizure Drugs
Succinimides
Valproic Acids
Oxaline diones
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The Hydantoins
Phenytoin (Dilantin)
Fospenytoin
Mephenytoin (Mesantoin)
Ethotoin (Peganon) Phenacemide (Phenurone)
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Phenytoin
Phenytoin (Dilantin) - Prototypic Drug
Made in 1908
Used for seizure control in 1938 In therapeutic doses, no loss of
consciousness
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Phenytoin
useful for the treatment of
partial seizures
generalized tonicclonic seizures
It does not treat primary generalized seizuressuch as absence seizures or myoclonic seizures
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Phenytoin Mechanism of Action
Stabilizes neural membranes
At therapeutic concentration the main action
is : Blocks voltage-dependent Na+channels
sodium ion movement across the cell
Sodium channels are alteredmaking drugbinding favorable
May prolong the refractory period of excitablecells by delaying the influx of potassium ions
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Sodium channel and Seizure
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Other Mechanisms of Phenytoin
At high concetrations it
inhibits the release of serotonin and norepinephrine
Promotes uptake of dopamine
Inhibits mono amine oxidase
It induces Ca permeability and influx explainingphenytoins ability to inhibit Ca induced
secretory process eg release of hormones andneurotransmitters
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Pharmacokinetics Phenytoin
Absorp form the GI is nearly complete in mostpatients peak at 3 -12 hrs
Half life averagely 24 hrs
After IM use is unpredicatble this route not
recomended hepatic metabolism with saturation kineticsie at large
serum levels maximum capacity of met is saturatedfurther increase in dosage = toxicity druds half lifeincraeses
induces metabolism of other drugs
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Pharmacokinetics Phenytoin
Its highly protein bound levels decrease inuremia and hypoalbuminemia
Plasma level conc = CSF conc
At low blood levels steady states are reached in5-7 days at high levels 4-6 weeks
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Dosage phenytoin
Therapeutic plasma levels 10-20 ug/ml Initiating dose; 300mg/day no regard to wt
It should be increased at 25-30 mg ad give time
to achieve a steady state NEVER 300mg TO400mg
Children dose 5mg/kg/day adjust to achieve
steady therapeutic levelsTwo formulations are available rapidly absorbed
and slow release tabs
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Phenytoin drug interactions
Are related to binding or metabolism
May be displaced by drugs that are highly protienbound since phenytoin is 90% bound eg
phenylbutazone, sulphonamides This results to an apparent plasma increase
A decrease in proteins (hypo albuminemia) may cause a
decrease in total concentration but not the freeconcentration
Attempts to increase drug concentration to therapeuticrange results toxicity
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Phenytoin Toxicity
Similar to other antiseizure meds Occular;Nystagmus early ,Loss of smooth etraoccullar pursuit
gaze paralysis (early)
CNS; Diplopia ataxia are dose related require dose adjustment,
Sedation at high dose Teratogenic:; consists of craniofacial anomalies (broad nasal
bridge, cleft lip and palate, microcephaly) and a mild form ofmental retardation (Fetal hydratoin syndrome)
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Toxicity
Oral; Gingivitis
Dermatological Hirsutim, Coarsening of facialfeatures (hypertrichosis), JSJ, TEN
Peripheral neuropathy manifested by diminisheddeep reflexes
Hematologic; Folate deficiency inhibits folic acidabsorption
Hormonal Long term use may result tointerference with vit D met osteomalacia
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Gingivitis and corrected gingivitis
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Gaze paralysis
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Hirsutism
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SJS steven johnson syndrome
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TEN Toxic Epidermolysis
Necrosis
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Phenytoin
Idiosyncratic reactions
Skin rash indicating hypersensitivity
Lymphadenopathy which resembles that ofmalignancy studies shows there is a causalrelationship with Hogkin s lymphoma
Hematological: agranulocytosis with fever andrash
Not water soluble -for IV must be dissolved inpropylene glycol
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Mephenytoin Mephenytoin:
effective against partial seizures and generalized tonic clonicseiz
Pharmacokinetics: saturable met
Met to 5,5 ethyl-phenylhydantoin by demerthylation activemet therapeutic levels 5-16 ug/ml
Therapeutic level for nivarnol (metabolite of mephenytoin) is20ug/ml
Further met of mephenytoin and nivarnol ocuurs byhydroxylation and conjugation
Toxicity :dermatitis, agranulocytosis, hepatitis is higher thanthat of phenytoin
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Ethotoin
Ethotoin:
Recommended for patients with phenytoinhypersensitivity
Large doses required less effective than phenytoinToxicity less severe
Low efficacy
pharmacokinetics: saturation met
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Medical uses of anticonvulsants
Tegretol
Trigeminal neuralgiaGlossopharyngeal neuralgia
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N d i ti ti l
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New and investigational
anticonvulsants
Topiramate (Topamax)- Mechanism is stillunclear. Affects GABA Cl- flux similar toBDZs, but is not inhibited by Fumazenil. Not
like barbiturates either. Antagonizes non-NMDA glutamate receptors.
Tiagabine (Gabitril) - GABA reuptake
inhibitor. Interesting SAR -vinyl GABA (vigabatrin), (Sabril).Inhibits
GABA transaminase
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Lamotrigine (lamictal) Developed while studying antifolate effects of drugs
phenytoin MOA; like phenytoin suppresses sustained rapid firing
of neuronsvia Na+channels. Similar to phenytoin andcarbamazepine
May have action on Ca2+ channels
Clinical use ; add on therapy for partial seizures somestudies indicate use as monotherapy
May be active against absence and myoclonic seizuresin children
Toxicity ;Dizziness, headache, diplopia, nausea
somnolence, skin rashlife threatening dermatitis
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Gabapentin
Analogue of GABA
Originally planned as a spasmolytic
MOA; similar structure to GABA but no effect on
GABA receptors may alter GABA met, nonsynapticrelease , re uptake by GABA transporters. Also bindsonto Ca2+ channels
Clinical use; adjunct in partial seizures and generalizedtonic clonic seizures, post herpetic neuralgia
Side effects ataxia, somnolence, dizziness,headache,tremor
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Zonisamide (Zonegran)
A SULPHONAMIDE (HIV dermatitis andsulphonamides)
MOA; At Na+ channels or Ca+2 channels.
Clinical use; partial seiz, generalised tonic clonic seiz,INFANTILE SPASMS, some myoclonic seiz
Dose 4-12 mg/d child Adults 100-600mg
AE drowsiness cognitive impairment, PONTETIALLYserious skin rash
No drug interactions
P i i l f th t f
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Principles for the management of
epilepsy
Have a good seizure plan in the clinic
Train personnel to appropriately respond to the seizure
event
Classify, localize and define etiology
Not every seizure needs to be treated
Monotherapy preferred
Treat the patient, not the numbers
80% of patients can achieve control with 1 agent, 90%with multiple agents
Consider surgical approaches
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Clinical Considerations
Is the patient taking their medications
regularly ????
Are there any external triggers whichcould set off the seizure ??? (light,
sound, fatigue, odors)
Are the patients changing medicationsor changing the dose ???
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Clinical Considerations
Are the patients under unusual stress
- divorce, family deaths, etc. Know the side effects of the
medications
P d
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Pregnancy and
anticonvulsants
All presently available anticonvulsants may have
teratogenic effects
Uncontrolled seizures also have an adverse effect
on the fetus First 12 weeks is critical
Fewest drugs and lowest doses are best
Avoid valproic acid if possible (neural tube defects) Abrupt discontinuation of any anticonvulsant is
not a good idea
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Mx Status Epilepticus Goal is control of seizures with 60 minutes
ABCs: Airway, Breathing, Circulation IV access, initial labs, history and exam
Thiamin (100mg IV), glucose (50g IV)
Lorazepam, 1-2 mg IV Q3-5 min to 10 mg totalOR
Fosphenytoin, 15-20 mg/kg IV or IM
OR
Phenobarbital, initial dose 5-10 mg/kg IV
OR
For refractory status; ICU care and use General