Sedative-hypnotics and Anti-seizure Drugs NEW

8/13/2019 Sedative-hypnotics and Anti-seizure Drugs NEW

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Handouts in PharmacologyPrepared by: Abraham Daniel C. Cruz, MD

SEDA!"E # H$P%&!C D'()Serms

* Sedation # reduction o+ aniety* Addiction # the state o+ response to a drug -hereby the drug taer +eels compelled to use the drug and su++ers aniety -hen

separated +rom it* Anesthesia # loss o+ consciousness associated -ith absence o+ response to pain* Aniolytic # a drug that reduces aniety, a sedati/e* Dependence # the state o+ response to a drug -hereby remo/al o+ the drug e/oes unpleasant, possibly li+e*threatening

symptoms, o+ten the opposite o+ the drug0s e++ects* Hypnosis # induction o+ sleep* 'EM sleep # phase o+ sleep associated -ith rapid eye mo/ements1 most dreaming taes place during 'EM sleep* Sedation # reduction o+ aniety* olerance # reduction in drug e++ect re2uiring an increase in dosage to maintain the same response

!ntroduction* Sedati/e hypnotics are chemically heterogeneous drugs, almost all o+ -hich produce dose*dependent C%S depression* Ma3or subgroup: benzodiazepines* &ther groups sti ll in use

o 4arbiturates

o Miscellaneous agents: carbamates, alcohols, cyclic ethers

o Atypical drugs

4uspirone * aniolytic

5olpidem, zaleplon, eszopiclone # hypnotic 'amelteon # +or sleep disorders

* Classeso 4enzodiazepines

Short, !ntermediate. 6ong actiono 4arbiturates

(ltra*short, Short, 6ong actiono Miscellaneous agents

4uspirone, chloral hydrate, eszopiclone, ramelteon, zaleplon, zolpidem

Pharmacoinetics* Absorption and Distribution

o Most are lipid*soluble and are absorbed -ell +rom the )! -ith good distribution to the brain

o Drugs -ith the highest lipid solubility 7eg. hiopental8 enter the C%S rapidly and can be used as induction agents in

anesthesia C%S e++ects are terminated by rapid redistribution +rom the brain to other highly per+used tissues 7including

seletal muscle8o &ther drugs -ith rapid onset o+ action # eszopiclone, zaleplon, zolpidem

* Metabolism and Ecretiono Metabolized be+ore elimination +rom the body, mainly by hepatic enzymes. Metabolic rates and path-ays /ary

o Many benzodiazepines are con/erted initially to acti/e metabolites -ith long hal+*li/es.

A+ter se/eral days o+ therapy -ith some drugs 7diazepam, +lurazepam8, accumulation o+ acti/e metabolitescan lead to ecessi/e sedation

6orazepam and oazepam undergo etrahepatic con3ugation and do not +orm acti/e metabolites


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o Drugs acti/e at the benzodiazepine receptor may be di/ided into +our categories based on their elimination hal+*li/es:

ultra*short*acting benzodiazepines

short*acting agents, -ith hal+*li/es less than 9 hours, including triazolam,the nonbenzodiazepinezolpidem7hal+*li+e approimately hours8, and zopiclone 7hal+*li+e ; to 9 hours8

intermediate*acting agents, -ith hal+*li/es o+ 9 to < hours, including estazolamand temazepam

long*acting agents, -ith hal+*li/es o+ greater than < hours, including +lurazepam, diazepam, and quazepam.

o Classi+ication o+ barbiturates

Ultra Short-Acting

duration o+ action o+ =; to >? minutes1 administered !" to induce anesthesia because o+ their high

lipid solubility

Eamples:

o Methoheital

o hiopental

Short-Acting


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duration o+ action: * < hours1 e++ecti/e -hen taen orally the initial and short*term treatment o+

insomnia1 !M +or preanesthetic sedation1 also +or hort*term daytime sedation in patients -ho su++er+rom aniety

Eamples

o Pentobarbital

o Secobarbital

Intermediate-Acting

duration o+ action: < * 9 hours1 used +or the initial and short*term treatment o+ insomnia

o Eample: Amobarbital

Long-Acting

duration o+ action: 9 * @ hours1 used orally to maintain day*long sedation in aniety*tension states

use+ul in the treatment o+ /arious con/ulsi/e disorders

Eamples

o Phenobarbital

o Mephobarbital

o ith the eception o+ phenobarbital, -hich is ecreted partly unchanged in the urine, the barbiturates are etensi/ely

metabolized

o Chloral hydrate is oidized to trichloroethanol, an acti/e metabolite

o 'apid metabolism by li/er enzymes is responsible +or the short duration o+ action o+ zolpidem

A biphasic release +orm etends its plasma hal+*li+eo 5aleplon undergoes e/en more rapid hepatic metabolism by aldehyde oidase and cytochrome P? hours 7chlordiazepoide, clorazepate, diazepam, phenobarbital8

Mechanisms o+ action* %o single mechanism o+ action has been identi+ied1 di++erent chemical subgroups may ha/e di++erent actions


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* Certain drugs 7benzodiazepines8 +acilitate neuronal membrane inhibition by actions at speci+ic receptors

* 4enzodiazepineso 45 receptors

present in many brain regions 7incl. halamus, limbic structures, and the cerebral corte8

+orm part o+ the )A4AAreceptor chloride ion channel macromolecular comple

pentameric structure assembled +rom ; subunits each -ith < transmembrane domains

a ma3or iso+orm o+ the )A4AAreceptor consists o+ =, , and = Fsubunits

other iso+orms # , >, ;

binding o+ benzodiazepines +acilitates the inhibitory actions o+ )A4A, -hich are eerted through

increased chloride ion conductanceo increase +re2uency o+ )A4A*mediated chloride ion channel opening

o Blumazenil * 45 antagonist 7in/erse agonist81 re/erses the C%S e++ects o+ benzodiazepines

* 4arbiturateso Depress neuronal acti/ity in the midbrain reticular +ormation, +acilitating and prolonging the inhibitory e++ects o+ )A4A

and glycineo 4ind to multiple iso+orms o+ )A4AA receptor but at di++erent sites +rom those -ith -hich benzodiazepines interactal

o Actions are not antagonized by +lumazenil

o !ncrease the duration o+ )A4A*mediated chloride ion channel opening

o May also bloc the ecitatory transmitter glutamic acid, and, at high concentration, sodium channels

* &ther Drugso 5olpidem, zaleplon, eszopiclone appear to eert their C%S e++ects /ia interaction -ith certain benzodiazepine

receptors # 45=or G=subtypeso Compared to 45, these drugs bind more selecti/ely, interacting only -ith )A4AAreceptors that contain =subunits

o C%S depressant e++ects can be antagonized by +lumazenil

Pharmacodynamics* C%S e++ects o+ most sedati/e*hypnotics depend on dose1 range +rom sedation and relie+ o+ aniety 7aniolysis8, through

hypnosis 7+acilitation o+ sleep8, to anesthesia and coma* Depressant e++ects are additi/e -hen or more drugs are gi/en together* steepness o+ the dose*repsonse cur/e /aries among drug groups # those -ith +latter cur/es 7D'() 4 * benzodiazepines and

ne-er hypnotics eg, zolpidemI8, are sa+er +or clinical use


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* Sedationo &ccur -ith all drugs in this class1 usually accompanied by some impairment o+ psychomotor +unctions, and

beha/ioural disinhibition may also occur* Hypnosis

o Promote sleep and increase the duration o+ sleep rate1 'EM sleep is usually decreased at high doses # rebound

increase in 'EM sleep may occur on -ithdra-al +rom chronic useo E++ects on sleep patterns occur in+re2uently -ith ne-er hypnotics 7zaleplon, zolpidem8

* Anesthesiao At high doses o+ most older sedati/e*hypnotics, loss o+ consciousness may occure, -ith amnesia and suppression o+

re+leeso Anterograde amnesia more liely -ith 45 than -ith other sedati/e*hypnotics

o Anesthesia can be produced by most barbiturates 7eg, thiopental8 and certain 45 7eg, alprazolam8

* Anticon/ulsant Actionso occurs -ith high doses o+ most o+ the barbiturates and some o+ the benzodiazepines, but is usually at the cost o+

mared sedationo Selecti/e anticon/ulsant action 7suppression o+ con/ulsion at doses that do not cause se/ere sedation8 occurs -ith

only a +e- o+ these drugs 7eg, Phenobarbital, clonazepam8o High doses o+ !" diazepam, lorazepam, or phenobarbital are used in status epilepticus 7-here hea/y sedation is

desirable8* Muscle 'elaation

o &ccurs only -ith high doses o+ most sedati/e*hypnotics

o diazepam is e++ecti/e at sedati/e dose le/els +or speci+ic spasticity states such as cerebral palsy

o meprobamate also has some selecti/ity as a muscle relaant

* Medullary depressiono &ccurs at high doses, particularly -ith alcohols and barbiturates, leading to respiratory arrest, hypotension, and

cardio/ascular collapse, -hich are the causes o+ death in suicidal o/erdose* olerance

o &ccurs -hen used chronically or in high dosage

o Cross*tolerance may occur -ith di++erent chemical subgroups

* Dependenceo Psychological * occurs +re2uently1 mani+ested by the compulsi/e use o+ these drugs to reduce aniety

o Physiologic # altered state that leads to an abstinence syndrome 7-ithdra-al state8 -hen the drug is discontinued

ithdra-al signs # aniety, tremors, hyperre+leia, seizures # occur more +re2uently -ith shorter actingdrugs

o Dependence liability o+ zolpidem, zaleplon, and eszopiclone may be less than that o+ the benzodiazepines since

-ithdra-al symptoms are minimal a+ter abrupt discontinuance

Clinical (ses

* Aniety Stateso 4enzodiazepines are the +a/oured drug treatment o+ acute aniety states and +or rapid control o+ panic attacs

o Alprazolam and clonazepam ha/e greater e++icacy than other benzodiazepines in the longer term treatment o+ panic

and phobic disorderso %ote: there is increasing use o+ ne-er antidepressants in the treatment o+ chronic aniety states

* Sleep Disorderso 4enzodiazepines, including estazolam, +lurazepam, and triazolam, ha/e been -idel used in primary insomnia and +or

the management o+ certain other sleep disorderso 6o-er doses +or elderly patients 7more sensiti/e to C%S depressant e++ects8

o 5olpidem, zaleplon, and eszopiclone are increasingly being used because o+ their rapid onset -ith minimal e++ects on

sleep patterns and cause less daytime cogniti/e impairment than benzodiazepineso Jsedati/e*hypnotics are not recommended +or breathing*related sleep disorders

* &ther useso hiopental # commonly used +or induction o+ anesthesia

o Certain benzodiazepines 7diazepam, midazolam8 are used as anesthesia protocols including those used day surgeryo Special uses: management o+ seizure disorders 7clonazepam, phenobarbital8 and bipolar disorder 7clonazepam8 and

treatment o+ muscle spasticity 7diazepam8

6onger acting benzodiazepines 7chlordiazepoide, diazepam8 are used in the management o+ -ithdra-alstates in persons psychologoically dependent on ethanol and other sedati/e hypnotics

oicity* Psychomotor dys+unction

o Cogniti/e impairment, decreased psychomotor sills, un-anted daytime sedation

More common -ith benzodiazepines that ha/e acti/e metabolites -ith long hal+*li/es 7diazepam,+lurazepam8, but can also occur a+ter a single dose o+ a short*acting benzodiazepine such as triazolam

Dosage should be reduced in elderly patients -ho are more susceptible

Ecessi/e daytime sedation increases the ris o+ +alls and +ractures


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o Anterograde amnesia may also occur -ith benzodiazepines, especially -hen used at high dosage basis +or

criminal use in cases o+ Kdate rapeLo 5olpidem and the ne-er hypnotics cause modest day*a+ter psychomotor depression -ith +e- amnestic e++ects

o All prescription drugs used as Ksleep aidsL may cause +unctional impairment, including Ksleep dri/ing,L de+ined s

Kdri/ing -hile not +ully a-ae a+ter ingestion o+ sedati/e*hypnotic product, -ith no memory o+ the e/ent.L* Additi/e C%S depression

o &ccurs -hen used -ith other drugs in the class as -ell as -ith alcoholic be/erages, antihistamines, antipsychotic

drugs, opioid analgesics, and tricyclic antidepressantso Most common type o+ drug interaction in/ol/ing sedati/e*hypnotics

* &/erdosage

o Causes se/ere respiratory depression and cardio/ascular depression Potentially lethal1 more liely to occur -ith alcohols, barbiturates, and carbamates than -ith

benzodiazepines or the ne- hypnotics such as zolpidem

Management o+ intoication re2uires maintenance o+ a patent air-ay and /entilatory support.o Blumazenil may re/erse C%S deperessant e++ects o+ benzodiazepines, eszopiclone, zolpidem, and zaleplon, but has

no bene+icial actions in o/erdosage -ith other sedati/e*hypnotics* &ther ad/erse e++ects

o 4arbiturates and carbamates 7but not benzodiazepines, eszopiclone, zolpidem, or zaleplon8 induce the +ormation o+

li/er microsomal enzymes that metabolize drugso 4arbiturates may also precipitate acute intermittent porphyria in susceptible patients

o Chloral hydrate may displace coumarins +rom plasma protein binding sites and increase anticoagulant e++ects

Atypical Sedati/e*Hypnotics* 4uspirone

o Selecti/e aniolytic -ith minimal C%S depressant e++ect 7does not a++ect dri/ing sills8 and has no anticon/ulsant or

muscle relaant propertieso !nteracts -ith the ;*H=A subclass o+ brain serotonin receptors as a partial agonist

o Precise mechanism o+ aniolytic e++ect is unno-n

o Slo- onset o+ action 7 = -ee8, used in generalized aniety disordeinrs, but less e++ecti/e in panic disorders

o Minimal tolerance de/elopment -ith chronic use, little rebound aniety or -ithdra-al symptoms on discontinuance

o Metabolized by C$P>A


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* Pentobarbital* Phenobarbital* Secobarbital* hiopental

benzodiazepines81+acilitate chloridechannel opening

sedation7secobarbital81seizure disorders7phenobarbital8

metabolism o+ manydrugs1 hal+*li/es:


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% Duration and fre&uenc! of the action potential is l imited b! properties intrinsic to the sodium channel' he /oltage*

sensiti/e %aO

channel eists in three di++erent con+ormations during the course o+ an action potential. A+ter opening transientlyin response to membrane depolarization (2 ) , the %a O channel spontaneously inacti/ates (3). his closure o+ the channeldecreases the strength o+ the %a O *mediated depolarization. %a O channels reco/er +rom inacti/ation only -hen the membranepotential is restored to its resting le/el 7" r8. Membrane depolarization also has the e++ect o+ opening /oltage*sensiti/e

O channels, -hich hyperpolarize the cell. (nder hyperpolarizing conditions, the %a O channel adopts its resting 7closed8con+ormation (1). During these re+ractory periods o+ %a O channel inacti/ation and membrane hyperpolarization, the neuron isessentially insensiti/e to depolarizing signals

o neural net(orks * ensure the speci+ icity o+ neuronal signaling by restricting the e++ects o+ a gi/en

action potential to a de+ined area

the +iring neuron acti/ates immediately neighboring neurons in addition to interneurons that

transmit inhibitory )*A+A, signals to surrounding neurons local ampli+ ication and

surrounding cell inhibit ion surround inhibition

Many seizure disorders appear to result +rom disruption o+ this intricate balance

JSurround inhibition pre#ents s!nchroniation of ad.acent neurons' !n this simpli+ ied neuronal circuit, neuronA sends ecitatory pro3ections (blue) to proimal neurons such as B. !n addition to acti/ating nearby neurons, cellA also acti/ates )A4Aergic interneurons (C) that send inhibitory pro3ections (gray) to surrounding neurons (D) .his type o+ circuit creates an Kinhibitory surroundL (dark gray) , so that action potentials generated by neuron A ,e/en i+ rapid and robust, are unable to acti/ate surrounding circuits.


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Pathophysiology

Seizures are sti l l classi+ ied according to their clinical mani+estations rather than their biologic underpinnings

- Seizures that begin +ocally )partial seiures, are clinically distinct +rom seizures that begin generally andin/ol/e both hemispheres )generalied seiures,

- All seizures share the common characteristic o+ abnormal synchronous dischargeo protecti/e mechanisms must be compromised at the cellular and net-or le/els1 direct causes o+

these changes can be:

primary 7e.g., genetic abnormalit ies such as channel de+ects8

secondar! )e'g'/ changes in the neuro nal en#ironment induced b! toins or ac&uired

lesions such as strokes or neoplasms, combination o+ the t-o 7e.g., +ebrile seizures in children8

Pathophysiology o+ Partial Seizures

- occurs in three speci+ ic stepso 7=8 init iation at the cellular le/el by an increase in electrical acti/ity

o 78 synchronization o+ surrounding neurons

o 7>8 spread to ad3acent regions o+ the brain

- !nit iation

o sudden depolarization -ithin a group o+ neurons paro!smal depolariing shift )PDS,

l asts up to ?? ms1 resu lt s in the genera t ion o + an abnormall y rapid t rain o + ac tionpotentials

Changes in the etracellular milieu/ attributable/ for instance/ to a space-occup!inglesion )as in the case,/ can ha#e ma.or effects on neuronal burst acti#it!'

an increase in etracellular 0 $ (ould blunt the effects of 0 $-mediated after

h!perpolariation b! decreasing the magnitude of the 0 $ gradient bet(een theoutside and inside of the cell

an increase in eci tator! neurotransmit ters or modulation of eci tator!

receptors b! other eogenous molecules

properties intr insic to the cell )abnormal channel conductance or al tered

membrane characteristics,

- Synchronizationo Surround inh ibi tion normal l y contain loca l d ischarges - ithin a focus , a nd d o n ot in du ce

symptomatic pathology

6ocal discharges are seen on an electroencephalogram )11*, as sharp interictal spies

!denti+ ication o+ spies locate seizure +ocus in a patient -ho is not acti/ely undergoing aseizure

Se/eral path-ays can o/erride surround inhibit ion

repetit i/e + iring o+ neurons result in:

o increase in et racel lu lar O -eaens O*mediated hyperpolarizat ion

allo-ing the seizure acti/ity to spreado opening o+ depolarizat ion*sensit i/e %MDA channels and accumulate Ca O in

t he ir s yna pt ic t er mi na ls r esul t i n ncreased l iel ihood o + s ignapropagation and local synchronization

o Decreases in )A4A*mediated inhibit ion

Most important compromise of surround inhibition

Due to eogenous +actors, degeneration o+ )A4Aergic neurons, orchanges at the receptor le/el ma3or +actors that aid in thesynchronization o+ a seizure +ocus

- Spread to ad3acent regions in the braino ! + the synchronizing +ocus is su++ icient ly strong, the abnormal, synchronized + i r ing +rom a smal

neural net-or -ill begin to spread to neighboring regions o+ the corteo During this spread to neighboring areas/ the patient ma! eperience an aura/ a conscious

2(arning3 of the spread of the seiure' This ma! be aura manifested as a blank/ fearful stare'Although the aura is usual ly stereotypical +or a gi/en pat ient, a -ide /ariety o+ auras eist . heseinclude a sense o+ +ear and con+usion, disturbances o+ memory 7e.g. , dQ3R /u8 or language, al teredsensations, or an ol+actory hallucination.

o As the seizure continues to spread, it can lead to additional clinical mani+estations

speci+ ic mani+estation depends on the brain regions that become in/ol/ed

clinical s!mptoms ma! initiall! started (ith shaking of the hands and progressed tothe arm and then to the leg' This is a 4acksonian march )named after the 1ngl ishneurologist 5ughlings 4ackson/ (ho first described the s!mptoms,/ (here the clinicas!mptoms result from spread of s!nchronous acti#it! across the motor homunculus'


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J !n a partial seizure, paroysmal acti/ity begins in a seizure +ocus (blue) and spreads to ad3acent areas /ia di++use neuronalconnections. hen acti/ity is con+ined to one region o+ the corte that ser/es a basic +unction, such as motor mo/ement orsensation, and there is no change in the patients mental status, the seizure is re+erred to as a simple partial seizure. Seizures that in/ol/e brain regions ser/ing more comple +unctions such as language, memory, and emotions are re+erred toas comple partial seizures

Pathophysiology o+ Secondary )eneralized Seizures

- Partial seizures may become generalized by spreading along di++use connections to in/ol/e both cerebralhemispheres

- ypically, seizures spread to distant sites by +ollo-ing normal circuitso U fibersconnect /arious regions o+ the corte

o corpus callosumallo-s +or spread bet-een hemispheres

o thalamocortical pro.ections pro/ide a path-ay +or di++use synchronized spread throughout thebrain

- &nce seizure acti/ity spreads to in/ol/e both hemispheres, a patient usually loses consciousness

- tonic"clonic subtype is the most common

- In the clinical case/ 6ob under(ent a period (here he appe ared to be contracting e#er! muscle in hisbod!/ follo(ed b! an episode of uncontrolled shaking of all f our limbs7 the eplanation at the le#el ofion channels is gi#en belo(8

o Initial9tonic phase

sudden loss of *A+A input leads to a long train of firing lasting for se#eralseconds

sustained/ rapid firing manifests clinicall! as contraction of both agonist and

antagonist muscleso Clonic phase

*A+A-mediated inhibition begins to be restored

AMPA-mediated and :MDA-mediated ecitation starts to oscillat e (ith the inhibitor!component

oscillator! pattern )(hen in#ol#ing the motor corte, results in clonic or shakingmo#ements of the bod!

ith time, the )A4A*mediated inhibit ion pre/ails, and the patient becomes +laccid and remains unconsciousduring the postictal period until normal brain +unction returns.

J !n a secondary generalized seizure, paroysmal acti/ity begins in a +ocus but then spreads to subcortical areas. Di++useconnections +rom the thalamus then synchronize the spread o+ acti/ity to both hemispheres.


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JAbnormal channel acti#it! in the tonic"clonic seiure' he tonic phase o+ the tonic#clonic seizure is initiated by a suddenloss o+ )A4A*mediated surround inhibition. 6oss o+ inhibition results in a rapid train o+ action potentials, -hich mani+estsclinically as tonic contraction o+ the muscles. As )A4Aergic inner/ation is restored, it begins to oscil late rhythmically -ith theecitatory component. he oscil lation o+ ecitatory and inhibitory components mani+ests clinically as clonic mo/ements. hepostictal phase is characterized by enhanced )A4A*mediated inhibition.

Pathophysiology o+ Primary )eneralized Seizures

- the primary generalized seizure emanates +rom central brain regions and then spreads rapidly to bothhemispheres

o do not necessarily begin -ith an aura distinguishes primary generalized seizures +rom partial

seizures that secondarily generalize

J Primary generalized seizures, such as the absence seizure, result +rom abnormal synchronization bet-een thalamic andcortical cells

-Absence seiure 7also no-n as the petit mal seiure 8

o best understood o+ the primary generalized seizures

o characterized by sudden interruptions in consciousness that are o+ten accompanied by a blan

stare and occasional motor symptoms 7rapid blining and lip smacing8o result +rom abnormal synchronization o+ thalamocortical and cortical cells

o pathophysiology

patients eperiencing absence seizures ha/e EE) readings some-hat similar to thepatterns generated during slo(-(a#e )stage ;, sleep'

'elay neurons connecting the thalamus to the corte eist in t-o di++erent states dependingon the le/el o+ -ae+ulness

a-ae state * neurons +unction in transmission mode - incoming sensory signals

are +aith+ully transmitted to the corte

slo-*-a/e sleep * transient, bursting acti/ity o+ a uni2ue, dendrit ic T-t!pe calcium

channel alters incoming signals output signals to the corte ha/e an oscil latory

+iring rate 7burst mode81 EE) Kspie and -a/eL sensory in+ormation i s nottransmitted to the corte

associated -ith acti/ation o+ the T-t!pe calcium channel during the a-ae state

channel is acti/e only -hen the cell is hyperpolarized

se/eral +actors can acti/ate the channel during the a-ae state

o increase in intracellular O

o increase in )A4Aergic input +rom the reticular nucleus

o loss o+ ecitatory input

acti/ity in the relay neurons is essential to the >*per*second spie*and*-a/e

acti/ity obser/ed in absence seizures

primary target in the pharmacologic treatment o+ absence seizures


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JMechanism of absence seiure' A' EE) recordings o+ patients eperiencing absence seizures are similar to Ksleep spindleLpatterns generated during slo-*-a/e sleep. he >*per*second oscil latory pattern is generated by the burst acti/ity o+ a

dendritic *type calcium channel in the thalamus.


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o phen!toin/ carbamaepine/ lamotrigine , and #alproic acidenhance inhibit ion at the single*cell

le/el by acting directly on the %a Ochannel

- !n general, a#tiepileptic drugs t!at act o# &a Oc!a##els s!o$ stro#g speci" ici ty "or t!e treatme#t o" partiala#d seco#dary ge#eralized seizures

o act in a use*dependent manner 7l ie the action o+ l idocaine on peripheral ner/es8

o neurons that + ire rapidly are particularly susceptible to inhibit ion by this class

o l i t t le e++ect on absence seizures

the rate o+ cyclical %a Ochannel opening and closing -ithin the thalamocortical cells thatare acti/ated during absence seizures is too slo- to be amenable to inhibit ion through use*

dependent %aO

channel inacti/ation

- Phenytoin

o acts directly on the %a Ochannel to slo- the rate o+ channel reco/ery +rom the inacti/ated state to

the closed stateo the probability o+ a channel eisting in a certain state depends on the membrane potential

o slo-s the rate o+ reco/ery +rom the inacti/ated state to the closed state

o net e++ect:

increases the threshold +or action potentials

pre/ents repetit i/e + iringo stabilizes the seizure +ocus by pre/enting the paroysmal depolarizing shi+t 7PDS8 that init iates the

partial seizureo pre/ents the rapid spread o+ seizure acti/ity to other neurons, accounting +or its e++ icacy in

secondarily generalized seizureso metabolism8 sho(s saturation kinetics

o ad/erse e++ects:

ataia, nystagmus, incoordination, con+usion, gingi/al hyperplasia, megaloblastic anemia,hirsutism, +acial coarsening, and a systemic sin rash

o drug interactions 7primarily due to its inacti/ation by Cyt P in du cti on , pa ti en ts ta ke se #er al do se sdail!

Metabolism is linear )i'e'/ it ehibits first-order kinetics, more attracti#e choicethan phen!toin for patients (ith potential drug interactions

- 6amotrigineo stabilies the neuronal membrane b! slo(ing :a$channel reco#er! from the inacti#ated state

o )$, other/ undetermined/ mechanisms of action has (ider clinical applications than the

other :a$channel blockers

use+ul alternati/e to phenytoin and carbamazepine as a treatment +or partial and tonic#clonic seizures

e++ecti/e in the treatment o+ atypical absence seizures

third drug o+ choice +or treatment o+ absence seizures, a+ter ethosuimide and /alproic acid

Drugs that Inhibit Calcium Channels

- t-o main classeso *type calcium channel inhibitor

o high*/oltage*acti/ated 7H"A8 calcium channel inhibitor


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- *type calcium channelso depolarized and inacti/e during the a-ae state

o paroysmal hyperpolarization is thought to acti/ate the channel during the a-ae state, init iating

the spie and-a/e discharges characteristic o+ absence seizures 7petit mal8o HE'EB&'E, drugs i#!ibiti#g t!e 'type calcium c!a##el are speci"ically used to treat abse#ce

seizures .

- H"A calcium channels

o play an important role in controll ing the entry o+ calcium into the presynaptic terminal help to

regulate neurotransmitter releaseo +ormed by an a= protein that assembles into the channel pore, and it has se/eral auil iary subunits

o H"A calcium channel inhibitors tend to ha/e pleiotropic e++ects used primarily +or partial seizures -ith or -ithout secondary generalization

also used +or generalized seizures other than absence seizures

- 1thosuimideo !n /itro * highly speci+ ic molecular pro+ile1

'odent thalamocortical preparations * reduce lo-*threshold *type currents in a /oltage*dependent manner

occurs -ithout altering the /oltage dependence or reco/ery inetics o+ the %a O

channel

does not ha/e any e++ect on )A4A*mediated inhibit iono o+ten the +irst l ine therapy +or uncomplicated absence seizures

o not e++ecti/e in the treatment o+ partial or secondary generalized seizures

-"alproic Acid

o acts pleiotropicall! in #itro

slo(s the rate of :a$channel reco#er! from the inacti#ated state

At slightl! higher concentrations limit the acti#it! of the lo(-threshold T-t!pecalcium channel

other propo sed mechan ism affect *A+A metabo lism

increases the acti/it y o+ glutamic ac id decarbo ylase 7enzyme responsible +or )A4A

synthesis8

inhibits the acti/ity o+ enzymes that degrade )A4A 7)A4A transaminase8

net e++ect increase a/ailabil ity o+ )A4A in the synapse increase )A4A*

mediated inhibit ion

o many potential sites o+ action /aried applications

one o+ the most e++ecti/e antiepileptic drugs +or the treatment o+ patients -ith generalizedepilepsy syndromes ha/ing mied seizure types

drug o+ choice +or patients -ith idiopathic generalized seizures treatment o+ absence seizures that do not respond to ethosuimide

alternati/e to phenytoin and carbamazepine +or the treatment o+ partial seizures

- *abapentino one o+ the +irst antiseizure drugs de/eloped using the concept o+ Krational drug designL

recognition that )A4A receptors play an important role in the control o+ seizure spreado synthesized as a structural analogue o+ )A4A1 predicted to enhance )A4A*mediated inhibit ion

gabapentin has been sho-n to increase the content o+ )A4A in neurons and in glial cells in/itro * consistent -ith hypothesis

o main anti*seizure e++ect is through H"A calcium channel inhibit ion

results in decreased neurotransmitter release

o main ad/antage: structure is similar to that o+ endogenous amino acids +e- interactions -ith

other drugso disad/antage: does not appear to be a particularly e++ecti/e antiepileptic drug +or most patients

Drugs that nhance !"#"$%ediated Inhibition

- ha/e more /aried e++ects and tend not to be as interchangeable, compared to sodium and calcium channelblocers

o due to di/ersity o+ )A4A A receptors in the brain

; subunits, -ith at least t-o alternati/e splice /ariants o+ se/eral o+ the subunits

at least =? no-n subtypes o+ the )A4A A receptor, -ith /arying distributions o+ thesesubtypes

benzodiazepines act on a speci+ ic subset o+ )A4A A channels

barbiturates appear to act on all )A4A Achannels

di++erence in speci+ icity results in distinct clinical pro+iles


15/22

nonspeci+ ic increase )A4A content 7e.g., through enhancement o+ synthetic

path-ays8 pro+ile is similar to the barbiturates

- +enodiaepines )Diaepam/ Loraepam/ Midaolam/ Clonaepam,

o increase the a++inity o+ )A4A +or the )A4A A receptor enhance )A4AAchannel gating in the

presence o+ )A4A increase Cl * in+lu through the channel1 dual e++ect:

suppress the seizure +ocus 7by raising the threshold o+ the action potential8

strengthening surround inhibit ion

o HE'EB&'E: diaepam, loraepam , and midaolam -ell suited +or the treatmen t o+ partial and

tonic#clonic seizures

prominent ad/erse e++ects: dizziness, ataia, and dro-siness H(S, used only to ablate seizures acutely

o Clonaepam

uni2ue among the benzodiazepines can inhibit *type Ca O channel currents in in /itropreparations o+ thalamocortical circuits

!n /i/o acts speci+ ically at )A4A A receptors in the reticular nucleus

augments inhibit ion in these neurons Kturns o++L the nucleus pre/ents )A4A*

mediated hyperpolarization o+ the thalamus indirectly inacti/ates the *type Ca O channel 7responsible +or generating absence seizures8 7see abo/e8

l ie diazepam, is l imited because o+ its etensi/e side e++ects

+ourth drug o+ choice in the treatment o+ absence seizures, a+ter lamotrigine

- +arbiturates )Phenobarbital,

o binds to an allosteric site on the )A4A Areceptor potentiates the action o+ )A4A by increasing

the duration o+ Cl * channel opening greater in+lu o+ Cl * ions +or each acti/ation o+ the channel

-e a ag on is t act i/ it y at the )A 4A Achannel +urthers the ability o+ this drug to increaseCl * in+lu

eplains the e++ecti/eness o+ phenobarbital in the treatment o+ partial seizures and

tonic#clonic seizures.o may eacerbate absence seizures1 caused by +actors:

act at all )A4AA receptors

45Ds selecti/ely augment )A4A inhibit ion in the reticular nucleus

4arbiturates potentiate )A4AA receptors in both the reticular nucleus and the

thalamic relay cells

o latter e++ect enhances the *type calcium currents responsible +or

absence seizureso act on the )A4AAchannel in the absence o+ the nati/e ligand.

increases nonspeci+ ic acti/ity o+ the barbiturates

o used primarily as an alternati/e drug in the treatment o+ partial seizures and tonic#clonic seizures

o pronounced sedati/e e++ects o+ this drug clinical use has been decreasing as more e++ecti/e

medications ha/e become a/ailable

Drugs That Inhibit !lutamate &eceptors

- ionotropic glutamate receptors mediate the e++ects o+ glutamate, the principal ecitatory neurotransmittero+ the C%S

- ecessi/e acti/ation ey component o+ most +orms o+ seizure acti/ity

- inhibit ion o+ the %MDA and AMPA subtypes o+ glutamate receptors can inhibit the generation o+ seizureacti/ity and protect neurons +rom seizure*induced in3ury

- %&%E o+ the speci+ ic and potent glutamate receptor antagonists 7etamine, phencyclidine8 ha/e beenroutinely used due to unacceptable beha/ioral ad/erse e++ects

-elbamate

o has a /ariety o+ actions, including the inhibit ion o+ %MDA receptors

o 7O8 selecti/ity +or %MDA receptors that include the %'4 subunit not epressed ubi2uitously

throughout the brain

Eplains its lac o+ beha/ioral ad/erse e++ects obser/ed -ith the other agents.o etremely potent antiepileptic drug

o additional bene+it: lacs the sedati/e e++ects common to many other drugs

o limited use because it -as +ound to be asso ciate d -it h a numbe r o+ cases o+ + atal aplas tic anemia and

li/er +ailure use is restricted primarily to patients -ith etremely re+ractory epilepsy

Conclusion and uture Directions


16/22

- impro/ed understanding o+ the physiology and pathophysiology o+ neuronal signaling in the C%S has led toa more thorough understanding o+ the current antiepileptic drugs 7AEDs8, as -ell as the design anddisco/ery o+ no/el agents

o normally, %aOchannel inacti/ation and )A4A*mediated surround inhibit ion pre/ent uncontrolled,

rapid spread o+ electrical acti/ityo potential alterations in the brain that can -eaen these inhibitory +orces:

damage and degeneration o+ )A4Aergic neurons, abnormal ion gradients induced byspace*occupying lesions, and gene mutations that alter channel +unction

- drugs described restore the inherent inhibitory capacity o+ the braino phenytoin * increases %a Ochannel inacti/ation

o

clonazepam* -hich enhances )A4A*mediated inhibit iono %e-er classes * modulation o+ the Ca O channel re2uired +or neurotransmitter release and

modulation o+ ecitatory receptors such as the %MDA receptor

- Ho-e/er, the e++icacy o+ many o+ the anticon/ulsants is only partially eplained by their no-n molecularpro+ile

o decisions about therapy are o+ten dri/en more by empirical eample than by no-n e molecular

mechanismso As no-ledge o+ the mechanisms o+ /arious seizure types and antiseizure drugs increases, the

application o+ a more rational, mechanism*based pharmacology -ill become increasingly possible

Drug Sodium Channels T-T!pe CalciumChannels

5igh-BoltageActi#atedCalcium Channels

* A+ A S! st em * lu ta ma te6eceptors

Main 1ffects on Ion Channels

Phenytoin

Carbamazepine

6amotrigine

5onisamide

Ethosuimide

Main 1ffects on *A+A Mechanisms

4enzodiazepines

iagabine

Mied Actions"alproic Acid

)abapentin

6e/etiracetam

opiramate

BelbamatePhenobarbital


17/22

JA ' he partial seizure (1 ) results +rom rapid, uncontrolled neuronal +ir ing and a loss o+ surround inhibition (2). Antiepilepticdrugs act at +our molecular targets to enhance inhibition and pre/ent spread o+ synchronous acti/ity (3). 4arbiturates andbenzodiazepines pre/ent seizure spread by acting on the )A4A A receptor to potentiate )A4A*mediated inhibition. %a

O channeinhibitors such as phenytoin, carbamazepine, and lamotrigine pre/ent rapid neuronal +ir ing by selecti/ely prolonging %a O channel inacti/ation in rapidly +ir ing neurons 7see Bigs. =?*T, =?*@8. Belbamate suppresses seizure acti/ity by inhibiting the%MDA receptor and thereby decreasing glutamate*mediated ecitation. )abapentin decreases release o+ ecitatoryneurotransmitter by inhibiting the high*/oltage*acti/ated 7H"A8 calcium channel. +' he absence seizure (1 ) is caused by asel+*sustaining cycle o+ acti/ity generated bet-een thalamic and cortical cells (2). Antiepileptic drugs pre/ent thissynchronous thalamocortical cycle (3 ) by acting at t-o molecular targets. Clonazepam, a benzodiazepine, potentiates )A4A A channels in the reticular thalamic nucleus, thus decreasing the acti/ation o+ the inhibitory reticular neurons and decreasingthe hyperpolarization o+ the thalamic relay neurons. *type calcium channel inhibitors such as ethosuimide and /alproic acidpre/ent the burst acti/ity o+ thalamic relay neurons that is re2uired +or synchronous acti/ation o+ cortical cells.

S(MMA'$erms

* Seizures # Binite episodes o+ brain dys+unction resulting +rom abnormal discharge o+ neurons* Partial seizures, simple # consciousness preser/ed1 mani+ested /ariously as con/ulsi/e 3ering, paresthesias, psychic

symptoms 7altered sensory perception, illusions, hallucinations, a++ect changes8, and autonomic dys+unction* Partial seizures, comple # impaired consciousness that preceded, accompanied, or +ollo-ed by psychological symptoms* onic*clonic seizures, generalized # tonic phase 7less than = min8 in/ol/es abrupt loss o+ consciousness, muscle rigidity, and

respiration arrest1 clonic phase 7 # > min8 in/ol/es 3ering o+ body muscles, -ith lip or tongue biting, and +ecal and urinaryincontinence1 +ormerly called grand mal

* Absence seizures, generalized # impaired consciousness 7o+ten abrupt onset and brie+8, sometimes -ith automatisms, loss o+postural tone, or enuresis1 begin in childhood 7+ormerlu petit mal8 and usually cease by age ? yrs

* Myoclonic seizures # single or multiple myoclonic muscle 3ers* Status epilepticus # a series o+ seizures 7usually tonic*clonic8 -ithout reco/ery o+ consciousness bet-een attacs1 it is a li+e*

threatening emergency

!ntroduction* Epilepsy # group o+ chronic syndromes that in/ol/e the recurrence o+ seizures 7limited periods o+ abnormal discharge o+

cerebral neurons8* E++ecti/e antiseizure drugs ha/e, to /arying degrees, selecti/e depressant actions on abnormal neuronal acti/ity

o "ary in M&A and e++ecti/eness in speci+ic seizure disorders

* D'()S +or:o onic*clonic and partial seizures

Carbamazepine

6amotrigine

Phenytoin

"alproic acido Absence seizures

Clonazepam

Ethosuimide 6amotrigine

"alproic acido Mycoclonic seizures

Clonazepam

6amotrigine

"alproic acid

o 4ac*up and ad3uncti/e drugs

Belbamate

)abapentin

6amotrigine

6e/etiracetam Phenobarbital

iagabine

opiramate

"igabatrine

5onisamide

Pharmacoinetics* !mportant to understand because these drugs are usually taen +or a long time # a/oid toicity and drug interactions

o Some drugs re2uire determination o+ plasma le/els and clearance +or optimum therapy 7eg. Phenytoin8

* !n general, are -ell absorbed orally and ha/e good oral bioa/ailability* Most are metabolized by hepatic enzymes 7ecept gabapentin and /igabatrin8

o Borm acti/e metabolites in some cases

* 'esistance to antiseizure drugs may in/ol/e increased epression o+ drug transporters at the le/el o+ the blood brain barrier* P drug interactions are common

o May reach toic le/els i+ combined -ith drugs that inhibit antiseizure drug metabolism or that displace anticon/ulsants

+rom plasma protein binding siteso !nade2uate le/els +or seizure control i+ gi/en -ith drugs that induce hepatic drug*metabolizing enzymes 7ri+ampin8

o May induce hepatic drug metabolism themsel/es # carbamazepine, phenytoin

* Phenytoino &ral bioa/ailability is /ariable due to indi/idual di++erences in +irst*pass metabolism

o 'apid*onset and etended release +orms are a/ailable

o Metabolism is nonlinear1 elimination inetics shi+t +rom +irst*order to zero*order 7saturation inetics8 at moderate to

high dose le/elso 4inds etensi/ely to plasma proteins 7NT*N@U8, and +ree 7unbound8 le/els in plasma are increased transiently by

drugs that compete +or binding 7carbamazepine, sulphonamides, /alproic acid8


18/22

o Metabolism is enhanced in the presence o+ inducers o+ li/er metabolism 7phenobarbital, ri+ampin8 and inhibited by

other drugs 7cimetidine, isoniazid8o !nduces hepatic drug metabolism, decreasing the e++ects o+ other antiepileptic drugs 7carbamazepine, clonazepam,

lamotrigine8o Bosphophenytoin # -ater*soluble prodrug +orm o+ phenytoin used paenterally

* Carbamazepineo !nduces +ormation o+ li/er drug*metabolizing enzymes that increase metabolism o+ the drug itsel+ and may increase

the clearance o+ many other anticon/ulsant drugs including clonazpam, lamotrigine, and /alproic acido Metabolism can be inhibited by other drugs 7propoyphene, /alproic acid8

o

&carbazepine # related drug1 less liely to be in/ol/ed in drug interactions

* "alproic acido Competes +or phenytoin plasma protein binding sites

o !nhibits metabolism o+ carbamazepine, ethosuimide, phenytoin, phenobarbital, and lamotrigine

o Hepatic biotrans+ormation leads to +ormation o+ toic metabolite implicated in hepatotoicity

* &ther Drugso )abapentin, pregabalin, le/etiracetam, and /igabatrin are unusual in that they are eliminated by the idney, largely in

unchanged +orm

"irtually ha/e no drug*drug interactionso opiramate and zonisamide undergo both hepatic metabolism and renal elimination o+ intact drug

o 6amotrigine is eliminated /ia hepatic glucoronidation

Mechanisms o+ Action* )eneral e++ect: suppress repetiti/e action potentials in epileptic +oci in the brain* !n some drugs, many mechanisms may contribute to their antiseizure acti/ity

* Sodium Channel 4locadeo Phenytoin, carbamazepine, lamotrigine, and zonisamide 7at therapeutic concentrations8

o Phenobarbital and /alproic acid 7at high doses8

o Action is rate*dependent 7dependent on +re2uency o+ neuronal discharge81 prolongs the inacti/ated state o+ the %aO

channel and the re+ractory period o+ the neuron

* )A4A*'elated argetso 4enzodiazepines # interact -ith speci+ic receptors on the )A4AAreceptor*chloride ion channel macromolecular

comple1 increased "reque#cyo+ chloride ion channel opening # +acilitate inhibitory e++ects o+ )A4Ao Phenobarbital and other barbiturates # increases duratio#o+ chloride ion channel opening

o "igabatrin # irre/ersibly inacti/ates )A4A aminotransaminase 7)A4A*8, an enzyme that degrades )A4A, and

there+ore terminates its action Can be inhibited by /alproic acid at /ery high concentrations

o iagabine # inhibits a )A4A transporter 7)A # =8 in neurons and glia, prolonging the action o+ )A4A

o )abapentin # structural analog o+ )A4A but does not acti/ate )A4A receptors directly

o &ther drugs that may +acilitate inhibitory actions o+ )A4A

Belbamate, topiramate, /alproic acid

* Calcium Channel 4locadeo Ethosuimude inhibits lo-*threshold 7*type8 CaOcurrents, especially in thalamic neurons that act as pacemaers to

generate rhythmic cortical dischargeo Similar action seen -ith /alproic acid, gabapentin and pregabalin 7may be the primary action o+ the latter drugs8

* &ther Mechanismso "alproic acid # neuronal membrane hyperpolarization by enhancing Ochannel permeability

o Phenobarbital # may also act as antagonist at some glutamate receptorso Belbamate # blocs glutamate %MDA receptors

o opiramate # blocs sodium channels and potentiates the actions o+ )A4A and may also bloc glutamate receptors

Clinical (ses* Diagnosis o+ a speci+ic seizure type is important prior to prescribing drugs* Drug choice is usually based on:

o established e++icacy +or the speci+ic seizure type

o prior responsi/eness o+ patient

o anticipated toicity

* treatment may in/ol/e drug combinations1 add no-n e++ecti/e agents i+ the preceding drugs are not su++icient

* )eneralized onic*Clonic Seizures


19/22

o "alproic acid, or carbamazepine, or phenytoin # drugs o+ choice +or generalize tonic*clonic 7grand mal8 seizures

o Phenobarbital 7or primidone8 # considered as alternati/e agent in adults but continues to be a primary drug in in+ants

o 6amotrigine and topiramate # also appro/ed +or this indication1 others may be used ad3uncti/ely in re+ractory cases

* Partial Seizureso Carbamazepine 7ocarbazepine8 or lamotrigine or phenytoin are the drugs o+ +irst choice

o Alternati/es: +elbamate, phenobarbital, topiramate, /alproic acid

o Ad3uncts: gabapentin and pregabalin, a structural congener

* Absence Seizures

o Ethosuimide or /alproic acid # pre+erred because they cause minimal sedation Ethosuimide # o+ten used in uncomplicated absence seizures i+ patients can tolerate its )! ad/erse e++ects

"alproic acid # particularly use+ul in patients -ith concomitant generalized tonic*clonic or myoclonic seizureso Clonazepam # alternati/e drug but -ith the ad/antage o+ causing sedation and tolerance

o 6amotrigine, zonisamide# also e++ecti/e

* Myoclonic and Atypical Absence Seizureso Myocolonic seizure syndromes

usually treated -ith /alproic acid1 lamotrigine is appro/ed +or ad3uncti/e use 7commonly as monotherapy8

Clonazepam # may be e++ecti/e but the high doses re2uired cause dro-siness

6e/etiracetam, topiramate, and zonisamide # used as bac up drugs

Belbamate # has been used ad3uncti/ely -ith primary drugs but has both hematoic and hepatotoicpotential

* Status Epilepticuso !" diazepam or lorazepam # usually e++ecti/e in terminating attacs and pro/iding short*term control

o !" phenytoin # +or prolonged therapy1 highly e++ecti/e and less sedating than benzodiazepines and barbiturates

May cause cardiotoicity 7probably due to the sol/ent propylene glycol8

Bosphenytoin is a sa+er parenteral agento Phenobarbital # used especially in children

o !+ not responsi/e to the abo/e measures, general anesthesia may be used

* &ther Clinical (seso 4ipolar a++ecti/e disorders

"alproic acid # may be used as +irst line treatment o+ mania

Carbamazepine and lamotrigine # bipolar disprdero rigeminal neuralgia # carbamazepine 7drug o+ choice81 ocarbazepine # may pro/ide similar analgesia -ith +e-er

side e++ects

o Pain o+ neuropathic origin 7including postherpetic neuralgia8 # gabapentin, pregabalino Migraine # gabapentin, phenytoin, topiramate

oicity* See table belo-

* eratogenicityo "alproic acid # neural tube de+ects 7spina bi+ida8

o Carbamazepine # cranio+acial abnormalities and spina bi+ida

o Phenytoin # +etal hydantoin syndrome

* &/erdose oicityo Most cause C%S and respiratory depression

Management is supported # air-ay management, mechanical /entilation

Blumazenil may be used in benzodiazepine o/erdose

* 6i+e threatening oicityo "alproic acid * Batal hepatotoicity1 greatest ris to children younger than years and patients taing multiple

anticon/ulsant drugso 6amotrigine # sin rashes, li+e*threatening Ste/en*Vohnson0s syndrome or toic epidermal necrolysis

Children are at high ris, especially those taing /alproic acido 5onisamide # se/ere sin reactions

o Belbamate # aplastic anemia, acute hepatic +ailure, se/ere and re+ractory seizure states

* ithdra-alo Should be accomplished gradually to a/oid increased seizure +re2uency and se/erity

o ithdra-al o+ anti*absence drugs is more easily accomplished than -ithdra-al +rom drugs used in partial or

generalized tonic*clonic seizure states


20/22

Ad/erse E++ects and Complications o+ Antiepileptic Drugs

Antiepileptic Drug Ad#erse 1ffects4enzodiazepines Sedation, tolerance, dependence

Carbamazepine Diplopia, cogniti/e dys+unction, dro-siness, ataia1 rare occurrences se/ere blood dyscraciasand Ste/ens # Vohnson syndrome1 teratogen potential

Ethosuimide )astrointestinal distress, lethargy, headache, beha/ioural changes

Belbamate Aplastic anemia, hepatic +ailure

)abapentin Dizziness, sedation, ataia, nystagmus1 does not a++ect drug metabolism 7pregabalin issimilar8

6amotrigine Dizziness, ataia, nausea, rash, rare Ste/ens*Vohnson syndrome6e/etiracetam Dizziness, sedation, -eaness, irritability, hallucinations, psychosis

&carbazepine Similar to carbamazepine, but hyponatremia is more common1 unlie carbamazepine, doesnot induce metabolism

Phenobarbital Sedation, cogniti/e dys+unction, tolerance, dependence, induction o+ hepatic drugmetabolism1 primidone is similar

Phenytoin %ystagmus, diplopia, sedation, gingi/al hyperplasia, hirsutism, anemias, peripheralneuropathy, osteoporosis, induction o+ hepatic metabolism

iagabine Abdominal pain, nausea, dizziness, tremor, asthenia, drug metabolism is not induced

opiramate Dro-siness, dizziness, ataia, psychomotor slo-ing and memory impairment, paresthesias,-eight loss, acute myopia

"alproic Acid Dro-siness, nausea, tremor, hair loss, -eight gain, hepatotoicity 7in+ants8, inhibition o+hepatic drug metabolism

"igabatrin Sedation, dizziness, -eight gain, /isual +ield de+ects -ith long term use, -hich may not bere/ersible

5onisamide Dizziness, con+usion, agitation, diarrhea, -eight loss, rash, Ste/ens # Vohnson syndrome

D'() S(MMA'$: Antiseizure Drugs

Subclass Mechanism ofAction

ClinicalApplications

Pharmacokineticsand Interactions

Toicities

Cyclin (reides

* Phenytoin 4locs /oltage*gated %aOchannels

)eneralized tonic*clonic and partialseizures

"ariable absorption,dose*dependentelimination1 proteinbinding1 many druginteractions

Ataia, diplopia,gingi/alhyperplasia,hirsutism,neuropathy

* Phenobarbital Enhances )A4AAreceptorresponses

Same as abo/e 6ong hal+*li+e,inducer o+ P


21/22

myoclonicseizures

metabolism1 manydrug interactions

teratogenic

* 6amotrigine 4locs %aOandCaOchannels,decreasesglutamate

)eneralized tonic*clonic, partial,myoclonic, andabsence seizures

%ot protein*bound,etensi/emetabolism1 manydrug interactions

Dizziness,diplopia,headache, rash

* 6e/etiracetam 4inds synapticprotein S"A *modi+ies synapticrelease o+glutamate and)A4A through anaction on /esicular+unction

)eneralized tonic*clonic and partialseizures

ell absorbed,etensi/emetabolism1 somedrug interactions

Dizziness,ner/ousness,depression,seizures

* iagabine 4locs )A4Areuptae

Partial seizures Etensi/e proteinbinding andmetabolism1 somedrug interactions

Dizziness,ner/ousness,depression,seizures

* opiramate (nno-n )eneralized tonic*clonic, absenceand partialseizures, migraine

4oth hepatic andrenal clearance

Sleepiness,cogniti/e slo-ing,con+usion,paresthesias

* 5onisamide 4locs %aOchannels

)eneralized tonic*clonic, partial, andmyoclonic

seizures

4oth hepatic andrenal clearance

Sleepiness,cogniti/e slo-ing,poor

concentration,paresthesias

Anti-Seiure Drugs and Pregnanc!!t is important to tae specialist ad/ice as to the management o+ epilepsy in -omen o+ childbearing potential.!t is important +or -omen to tae +olic acid prophylais preconceptually and during the +irst trimester. he dose o+ +olic ;mg P&Wday maybe appropriate +or -omen recei/ing established antiepileptic medication 7=8.Drugs +or -hich there is good data include:

carbamaepine * generally percei/ed as the sa+est anti*epileptic agent in pregnancy. !n all cases, patients should be assured

that the chance o+ abnormality is lo-o complications include:

neural tube de+ects * =U ris 78

hypospadias

a higher +re2uency o+ ma3or mal+ormations, particularly heart de+ects, neural tube de+ects and hypospadias,

has been reported in children o+ mothers -ho too carbamazepine during pregnancy than in either childreno+ mothers -ithout epilepsy 7e.g. ;.>U /s. .>U8 or children o+ -omen -hose epilepsy -as treated -ithphenytoin 7=8

sodium #alproate * associated -ith a =.;U ris o+ neural tube de+ects. his may be attributed in part to its e++ect in reducing

serum +olate, itsel+ thought to be protecti/e against neural tube de+ects.o other abnormalities include:

hypospadias

heart de+ects

cranio+acial and seletal anomalies

de/elopmental delay * there is e/idence +rom t-o retrospecti/e studies o+ an association bet-een in*uteroeposure to sodium /alproate and de/elopmental delay 7


22/22

o primidone is largely con/erted to phenobarbital and this is probably responsible +or its antiepileptic action

a ma3or mal+ormation rate o+ ;.T*=U has been reported among pregnancies -ith primidone eposure 7/s.no drug eposure &' up to ;.>, p?.?N8 7=8

counselling about the ris is more di++icult +or the ne-er antiepileptic drugs * lamotrigine, gabapentin, topiramate,

ocarbazepine, tiagabine and le/etiracetam * +or -hich data +or human pregnancies is lacing 78%otes:

stillbirths and neonatal loss are up to t-ice as liely among pregnant -omen -ith epilepsy 7-hether or not they tae

antiepileptic drugs8 compared -ith those -ithout epilepsy 7=8

:IC1 ha#e issued guidance (ith respect to use of #alproate relating to antenatal and postnatal mental health7T8:

o /alproate should not be routinely prescribed to -omen o+ child*bearing potential. !+ there is no e++ecti/e alternati/e,

the riss o+ taing /alproate during pregnancy, and the importance o+ using ade2uate contraception, should beeplained

o /alproate should not be prescribed to -omen younger than =@ years because o+ the ris o+ polycystic o/ary syndrome

and increased ris o+ unplanned pregnancy in this age groupo i+ a -oman -ho is taing /alproate is planning a pregnancy, or is pregnant, she should be ad/ised to stop taing the

drug. here appropriate in the treatment o+ bipolar disorder, an alternati/e drug 7usually an antipsychotic8 should beconsidered

o i+ there is no alternati/e to /alproate, doses should be limited to a maimum o+ = gram per day, administered in

di/ided doses and in the slo- release +orm, -ith ; mgWday +olic acid. Ho-e/er, it is not clear ho- the serum le/el o+/alproate a++ects the ris o+ abnormalities

:IC1 state (ith respect to use of carbamaepine or lamotrigine in antenatal and postnatal mental health7T8:

o i+ a -oman -ho is taing carbamazepine or lamotrigine is planning a pregnancy or has an unplanned pregnancy,

healthcare pro+essionals should ad/ise her to stop taing these drugs because o+ the ris o+ neural tube de+ects andother mal+ormations in the +etus. !+ appropriate an alternati/e drug 7such as an antipsychotic8 should be considered

o carbamazepine or lamotrigine should not be routinely prescribed +or -omen -ho are pregnant because o+ the lac o+

e/idence o+ e++icacy and the ris o+ neural tube de+ects in the +etuso lamotrigine should not be routinely prescribed +or -omen -ho are breast+eeding because o+ the ris o+ dermatologica

problems in the in+ant, such as Ste/ens*Vohnson syndrome'e+erence:

=. Drug and herapeutics 4ulletin ??;1 78:=>*=;.. Prescriber ??=1= 7=@8: >?*>9.>. Prescribers Vournal =NN91 >9: =?.8, N, 9.

;. 4romley '6 et al.Cogniti/e abilities and beha/iour o+ children eposed to antiepileptic drugs in utero.. Curr &pin %eurol. ??NApr178:=9*9

9. 6indhout D et al 7=NN8. Spectrum o+ neural tube de+ects in >< in+ants prenatally eposed to antiepileptic drugs. %eurology1

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