introd anti convulsants

8/13/2019 Introd Anti Convulsants

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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

introd anti convulsants

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