membrane structure and function.pptx

5/20/2018 Membrane Structure and Function.pptx

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FRMACOSANTICONVULSIVANTE

S


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Principios del tratamiento de laepilepsia

Reducir la neutrotransmisin excitatoria


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Aumentar la neutrotransmisin inhibitoria


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Dao Neuronal

Excitotxico

Crisis

Convulsivas

Glu

GABA

esequilibrio Inhibicin-Excitaci


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E X C I T O T O X I C I D A D

Sobre-activacin deR-Glu

Aumento de la concentracinintracelular de Ca++

Activacin de los ReceptoresGlutamatrgicos (R-Glu)

Produccin de Oxido Ntrico

Liberacin de PoliaminasEndgenas

Liberacin deGlutamato

Generacin deradicales libres

Dao neuronalexcitotxico

DaoOxidativoActivacin de la Sintasadel Oxido Ntrico

GENERACION DE CRISIS

CONVULSIVAS


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13

The ionotropic GABAAreceptor


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14

Subunit composition of GABAAreceptors

Five subunits, each with four transmembranedomains (like nAChR)

Most have two alpha (),two beta (), onegamma () subunit

1

2

2is predominant in mammalian brain butthere are different combinations in specificbrain regions


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SINAPSIS GABAERGICA


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Sntesis de GABA


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DETERMINANTE?


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Pharmacology of the GABAAreceptor


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GABAAreceptor pharmacology

There are two GABA binding sites per receptor.

Benzodiazepines and the newer hypnotic drugs bindto allosteric sites on the receptor to potentiate

GABA mediated channel opening.

Babiturates act at a distinct allosteric site to alsopotentiate GABA inhibition.

These drugs act as CNS depressants

Picrotoxin blocks the GABA-gated chloride channel


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23


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GABAAreceptor involvement in seizuredisorders

Loss of GABA-ergic transmission contributes toexcessive excitability and impulse spread in epilepsy.

Picrotoxin and bicuculline ( GABA receptor blocker)

inhibit GABAAreceptor function and are convulsants.

BDZs and barbiturates increase GABAAreceptorfunction and are anticonvulsants.

Drugs that block GABA reuptake (GAT) andmetabolism ( GABA-T) to increase available GABA areanticonvulsants


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27


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Glycine as an inhibitory CNS neurotransmitter

Major role is in the spinal cord

Glycine receptor is an ionotropic chloride

channel analagous to the GABAAreceptor.

Strychnine, a competitive antagonist ofglycine, removes spinal inhibition to skeletal

muscle and induces a violent motor response.


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29

Glutamate as a CNSneurotransmitter


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Glutamate and Aspartate


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Glutamate

Neurotransmitter at 75-80% of CNSsynapses

Synthesized within the brain from Glucose (via KREBS cycle/-ketoglutarate) Glutamine (from glial cells)

Actions terminated by uptake throughexcitatory amino acid transporters (EAATs)inneurons and astrocytes


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NH2CHCH2CH2- COOHCOOH

Glutamate Synthesis

Glutamate

-ketoglutarate

Glutamine (from glia)

transaminases


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Learning objects

Describe the process of glutamate synthesis,storage, and metabolism as well as the roles ofneurons and glial cells.

Differentiate the types of glutamate receptorsand their physiological function

Define excitatory neurotoxicity

Define the role of glutamate receptors in

learning and memory

E l t f l t t ti i


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Early reports of glutamate action in

the CNS

Effects of sodium glutamate on the centralnervous system

MSG (monosodium glutamate), may causedizziness and numbness

Crayfish neuromuscular junction, crustaceans

and insects Electrophysiological response: application of

glutamatenerve cell depolarized


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Glutamate synthesis


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Glutamine transporter

Gln is released from astrocytes via system N

transporters (SN1) and taken up by neurons

through sodium-coupled amino acid

transporters (SAT).


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Glutaminase

TCA cycle


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Vesicular Glutamate Transporter

glutamateuptake into synaptic vesicles and aredriven by a proton electrochemicalgradientgenerated by the vacuolar H+-ATPase

three structurally related vesicular transporters(VGLUT13 ) are expressed in the brain with partialoverlapping expression patterns.

VGLUT1 predominates in the cortex, whereasVGLUT2 is highly expressed in the diencephalonand brainstem, and VGLUT3 functions as a co-transmitter transporter in a variety of non-glutamatergic neurons


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Glutamate


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Receptor NMDA

44


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NMDA receptor


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Ionotropic Glutamate Receptors

NMDA

AMPA KAINATE

Non-NMDA

AMPA and Kainatereceptors generallyallow the passage of

Na+and K+

NMDA receptors allowsthe passage of both Na+

and Ca++ions. More

permeable to Ca++

Ligand-gated ion channels
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AMPA ReceptorsAMPA Rc subunit

Encoded by four genes:

GluR1-485-90% of the AMPA receptorshave a GluR2 subunit, whichis Ca++-impermeable (afterRNA editing - replacement of

Arg for Gln in the membranesegment 2)

Combination of four subunits form Receptor

subtypes-homo/heterotetramers

N-terminal domain

C-terminal domain(variable region-mediates interactions with proteins)

4 hydrophobic membrane domains

Postsynaptic location - mediation of the

majority of the fast excitatory synaptic

transmission

Int

Ext

C l i (C ++) bilit f AMPA


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Calcium (Ca++) permeability of AMPA vsNMDA receptors

It is the GluR2 subunit that makes mostAMPA receptors Ca++impermeant

The GluR2 subunit contains one amino acidsubstitution : arginine (R) versus glutamine

(Q) in all other GluRs


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RNA editing of GluR subunits

Functional Effects of Multiple Gene Products for iGluRs:Th Gl R2 S b it D t i C 2+ P bilit


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External Solution:

The GluR2 Subunit Determines Ca2+Permeability

Na+ Ca2+ Na+ Ca2+


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Ad apted from Kandel et al, Fig 12.11

GluR2(Q) Arg GluR2(R) Gln

Na+External

Ca2+

External

RNA Editing in GluR2:The Q/R Site Regulates Ca2+Permeability

K i t R t


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Kainate Receptors

Physiological studies have been identified both post-and presynaptic roles forkainate receptors

-presynaptic kainate receptor facilitate or reduce the neurotransmission depending

on where they are in the brain

- postsynaptic kainate receptors can directly mediate excitatory transmission

As well as GluR2, GLU5 and GLU6can undergo RNA editing (Sommer et al (1991))

that changes an amino acid in the channel pore and regulates permeation properties

AMPA and kainate receptor


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AMPA and kainate receptorDesensitization

Desensitization is defined as a long-lasting

ligand-bound, yet closed state.Desensitization of AMPA and kainate

receptors occurs within a few milliseconds; a

value found to be on the time scale of the

postsynaptic response.


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Spermine and Spermidine

an increase in the magnitude of NMDA-induced

whole-cell currents seen in the presence of

saturating concentrations of glycine

an increase in glycine affinity

a decrease in glutamate affinity, and voltage-

dependent inhibition at higher concentrations.


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Mg2


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AMPA receptorsNMDAreceptor

Na+Na+Na+Na+

Ca2+

synapticstrengtheni With low presynaptic activity only some of the AMPA

receptors are activated, giving rise to a weak EPSP.

Under these circumstances the NMDA receptor isinactive despite binding of glutamate because itschannel is blocked by Mg .2+

With high presynaptic activity most of the AMPAreceptors are activated and the EPSP is strong.

The Ca signal ultimately leads to synapticstrengthening.

2+

The strong EPSP (or back-propagated action potential)lifts the Mg block of the NMDA receptor.2+

Physiological/pathological roles


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Physiological/pathological roles

AMPA receptors mediate most fast EPSPs in the CNS

Kainate receptorsRegulation of neuronal excitability

epilepsy, excitotoxicity and pain

NMDA receptorsmediate most fast EPSPs in the CNSAnaesthesia

Learning and memory Developmental plasticity Epilepsy Excitotoxicity (eg stroke) Schizophrenia


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Exogenousexcitotoxicity?No need to try that again!

We know that it kills neurons.But, what about

endogenous excitotoxicity?


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69 Figure 20A.


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GABA neurotransmission will drive membrane potential toward the Cl-

reversal potential


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reversal potential

GABA can depolarize cells depending on the direction of the chloride gradient

(i E b th h ld)


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(i.e. EClmay be suprathreshold)

Summation of postsynaptic membrane potentials allows multiple synaptici t t b i t t d


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inputs to be integrated


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PHARMACOLOGY OF

ANTIEPILEPTICDRUGSMelanie K. Tallent, Ph.D.

[email protected]

Basic Mechanisms Underlying


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Seizures and Epilepsy

Seizure: the clinical manifestation of anabnormal and excessive excitation andsynchronization of a population of corticalneurons

Epilepsy: a disease characterized by

spontaneous recurrent seizures

Epileptogenesis: sequence of events thatconverts a normal neuronal network into anepileptic network

P ti l S i


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Partial Seizures

Simple

Complex

Secondary generalized

localized onset can be determined

Simple Partial Sei re


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Simple Partial Seizure

Focal with minimal spread of abnormaldischarge

normal consciousness and awareness are

maintained

Complex Partial Seizures


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Complex Partial Seizures

Local onset, then spreads

Impaired consciousness

Clinical manifestations vary with site oforigin and degree of spread

Presence and nature of auraAutomatisms

Other motor activity

Temporal lobe epilepsy

most common

Secondarily Generalized


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y

Seizures

Begins focally, with or without focal neurological

symptoms

Variable symmetry, intensity, and duration of tonic

(stiffening) and clonic (jerking) phases

Typical duration up to 1-2 minutes

Postictal confusion and somnolence

G li d S i


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Generalized Seizures

In generalized seizures,both hemispheres arewidely involved fromthe outset.

Manifestations of theseizure aredetermined by thecortical site at whichthe seizure arises.

Present in 40% of allepileptic Syndromes.

Generalized seizures


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Generalized seizures

Absence seizures (Petit mal): sudden onset andabrupt cessation; brief duration, consciousness is

altered; attack may be associated with mild clonic

jerking of the eyelids or extremities, postural tone

changes, autonomic phenomena and automatisms

(difficult diagnosis from partial); characteristic 2.5-3.5Hz spike-and wave pattern

Myoclonic seizures: myoclonic jerking is seen in a

wide variety of seizures but when this is the majorseizure type it is treated differently to some extent from

partial leading to generalized

Generalized Seizures (cont)


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Generalized Seizures (cont)

Atonic seizures: sudden loss of postural tone;most often in children but may be seen in

adults

Tonic-clonic seizures (grand mal): major

convulsions with rigidity (tonic) and jerking

(clonic), this slows over 60-120 sec followed

by stuporous state (post-ictal depression)

Generalized Tonic-Clonic Seizures


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Recruitment of neurons throughout the cortex

Major convulsions, usually with two phases:

1) Tonic phase: muscles will suddenly tense up, causing the

person to fall to the ground if they are standing. 2) Clonic phase: muscles will start to contract

and relax rapidly, causing convulsions

Convulsions:

motor manifestations

may or may not be present during seizures

excessive neuronal discharge

Convulsions appear in Simple Partial and Complex PartialSeizures if the focal neuronal discharge includes motor centers;they occur in all Generalized Tonic-Clonic Seizures regardless ofthe site of origin.

Atonic and absence Seizures are non-convulsive

Status Epilepticus


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Status Epilepticus

More than 30 minutes of continuous seizure

activity

Two or more sequential seizures spanning

this period without full recovery betweenseizures

Medical emergency

ANTIEPILEPTIC DRUG


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ANTIEPILEPTIC DRUG

A drug which decreases the frequency and/orseverity of seizures in people with epilepsy

Treats the symptom of seizures, not the

underlying epileptic condition Goalmaximize quality of life by minimizing

seizures and adverse drug effects

Currently no anti-epileptogenic drugs available

FDA Indications for AEDs:


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Monotherapy and/or Add-On Therapy

Monotherapy

Carbamazepine

Divalproex ER

EthosuximideOxcarbazepine

Phenobarbital

Phenytoin

PrimidoneLamotrigine1

Felbamate1

Topiramate

1

Approved for conversion to monotherapy.

Add-On Therapy

Carbamazepine Levetiracetam

Divalproex ER Gabapentin

Ethosuximide PhenytoinOxcarbazepine Tiagabine

Phenobarbital Zonisamide

Primidone

Physicians Desk Reference, 2004.

Epilepsia inducida por frmacos


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Epilepsia inducida por frmacos

Mecanismo de accin de antepilpticos


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Therapy Has Improved


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Significantly

Give the sick person some blood from a

pregnant donkey to drink; or steep linen in it,

dry it, pour alcohol onto it and administer this.

Formey, Versuch einer medizinischenTopographie von Berlin 1796, p. 193

Choosing Antiepileptic Drugs


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Choosing Antiepileptic Drugs

Seizure type

Epilepsy syndrome

Pharmacokinetic profileInteractions/other medical conditions

Efficacy

Expected adverse effectsCost

General Facts About AEDs


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General Facts About AEDs

Good oral absorption and bioavailability

Most metabolized in liver but some excreted

unchanged in kidneys

Classic AEDs generally have more severeCNS sedation than newer drugs (except

ethosuximide)

Because of overlapping mechanisms of action,best drug can be chosen based on minimizing

side effects in addition to efficacy

Classification of AEDs


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Classification of AEDs

Classical Phenytoin

Phenobarbital

Primidone

Carbamazepine

Ethosuximide

Valproate (valproic acid)

Trimethadione (not currently

in use)

Newer Lamotrigine

Felbamate

Topiramate

Gabapentin/Pregabalin

Tiagabine

Vigabatrin

Oxycarbazepine

Levetiracetam

Fosphenytoin

Side effect issues


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Side effect issues

Sedation - especially with barbiturates

Weight gainvalproic acid, gabapentin

Weight loss - topiramate

Reproductive functionvalproic acid

Cognitive - topiramate

Behavioralfelbamate, leviteracetam

Allergic - many

Cellular Mechanisms of

S i G ti


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emedicine.com

Seizure Generation

Targets for AEDs


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Targets for AEDs

Increase inhibitory neurotransmitter systemGABA

Decrease excitatory neurotransmitter system

glutamate

Block voltage-gated inward positive currentsNa+or

Ca++

Increase outward positive currentK+

Many AEDs pleiotropicact via multiple mechanisms

EpilepsyGlutamate


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Epilepsy Glutamate

The brains major excitatory neurotransmitter

Two groups of glutamate receptors

Ionotropicfast synaptic transmission NMDA, AMPA, kainate

Gated Ca++ and Gated Na+ channels

Metabotropicslow synaptic transmission Regulation of second messengers (cAMP and

Inositol)

Modulation of synaptic activity

Modulation of glutamate receptors

Glycine, polyamine sites, Zinc, redox site

Epilepsy Glutamate


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EpilepsyGlutamate

E X C I T O T O X I C I D A D


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Sobre-activacin deR-Glu

Aumento de la concentracinintracelular de Ca++

Activacin de los ReceptoresGlutamatrgicos (R-Glu)





Dao neuronal

excitotxico


GENERACION DE CRISISCONVULSIVAS

Glutamate Receptors as AED


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Targets

NMDA receptor sites as targets Ketamine, phencyclidine, dizocilpine block

channel and have anticonvulsant properties but

also dissociative and/or hallucinogenic properties;

open channel blockers.

AMPA receptor sites as targets Since it is the workhorse receptor can anticipate

major sedative effects

Felbamate


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Felbamate

Antagonizes the glycine site on the NMDAreceptor and blocks Na+ channels*

Very potent AED lacking sedative effect (unlike

nearly all other AEDs)Associated with rare but fatal aplastic anemia,

hence is restricted for use only in extreme

refractory epilepsy


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Topiramate


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Topiramate

Acts on AMPA receptors, blocking the glutamate bindingsite, butalso blocks kainate receptors and Na+

channels, and enhances GABA currents (highly

pleiotropic*)

Used for partial seizures, as an adjunct for absence andtonic-clonic seizures (add-on or alternative to phenytoin)

Very long half-life (20h)

EpilepsyGABA


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Epilepsy GABA

Major inhibitory neurotransmitter inthe CNS

Two types of receptorsGABAApost-synaptic, specific

recognition sites, CI-channel

GABAB presynaptic autoreceptors,

also postsynaptic, mediated by K+

currents

GABAA Receptor


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GABAAReceptor

Clonazapam


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Clonazapam

-Benzodiazepine used for absence seizures(and sometimes myoclonic): fourth-line AED

-Most specific AED among benzodiazepines,

appearing to be selective for GABAA activationin the reticular formation leading to inactivationof T-type Ca2+ channels, hence its useful forabsence seizures

-Sedating; May lose effectiveness due todevelopment of tolerance (6 months)

Lorazapam and Diazepam


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Lorazapam and Diazepam

Benzodiazepines used as first-line treatmentfor status epilepticus (delivered IVfastacting)

Lorazepam and diazepam binds to an

allosteric site on GABA-A receptors, which arepentameric ionotropic receptors in the CNS.Binding potentiates the effects of the inhibitoryneurotransmitter GABA, which upon binding

opens the chloride channel in the receptor,allowing chloride influx and causinghyperpolerization of the neuron.

Sedating

Phenobarbital


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Phenobarbital

Barbiturate used for partial seizures, especially inneonates.

Very strong sedation; Cognitive impairment;

Behavioral changes

Very long half-life (up to ~5days); #Induces P450 Primidone, another barbiturate metabolized to

Phenobarbital, and Phenobarbital are now seldom

used in initial therapy, owing to side-effects

It promotes binding to inhibitory gamma-aminobutyricacid subtype receptors, and modulates chloride

currents through receptor channels. It also inhibits

glutamate induced depolarizations

AEDs That Act Primarily onGABA


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GABA

Tiagabine Interferes with GABA re-uptake

Vigabatrin (not currently available in US)

elevates GABA levels by irreversiblyinhibiting its main catabolic enzyme, GABA-transaminase


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epilepsia

Aumentar la neutrotransmisin inhibitoria

Na+ Channels as AED Targets


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g

Neurons fire at high frequencies duringseizures

Action potential generation is dependent on

Na+ channels Use-dependent or time-dependent Na+

channel blockers reduce high frequency firing

without affecting physiological firing

Anticonvulsants:


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A = activation gate

I = inactivation gate

McNamara JO. Goodman & Gilmans. 9th ed. 1996:461-486.

Mechanisms of Action

Na+ Na+

Carbamazepine

Phenytoin

Lamotrigine

ValproateNa+ Na+

I I

Voltage-gated sodium channelOpen Inactivated

X

AEDs That Act Primarily on Na+Channels


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Channels

Phenytoin, Carbamazepine Block voltage-dependent sodium channels at high firing

frequenciesuse dependent

Oxcarbazepine Blocks voltage-dependent sodium channels at high firing

frequencies

Also effects K+ channels

Zonisamide

Blocks voltage-dependent sodium channels and T-typecalcium channels

Phenytoin


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First-line for partial seizures; some use fortonic-clonic seizures

Highly bound to plasma proteinsdisplaced

by Valproate; #Induces P450 resulting inincrease in its own metabolism, but its

metabolism is also increased by alcohol,

diazepam

Sedating

Fosphenytoin:Prodrug for Phenytoin, usedfor IM injection

Carbamazapine


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p

A tricyclic antidepressant used for partial

seizures; some use in tonic-clonic seizures

#Induces P450 resulting in increase in its ownmetabolism;

Sedating; Agranulocytosis and Aplastic anemia

(elderly); Leukopenia (10% of patients);

Hyponatremia; Nausea and visual

disturbances

Oxcarbazapine


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p

Newer drug, closely related toCarbamazapine, approved for monotherapy, or

add-on therapy in partial seizures

May also augment K+ channels* Some #induction of P450 but much less than

that seen with Carbamazapine

Sedating but otherwise less toxic than

Carbamazapine

Zonisamide


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Used as add-on therapy for partial and

generalized seizures

-Also blocks T-type Ca2+ channels* -Very long half-life (1-3days)

Lamotrigine


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g

Add-on therapy, or monotherapy for refractory

partial seizures

Also inhibits glutamate release and (perhaps)Ca2+ channels (=pleiotropic*)

Metabolism affected by Valproate,

Carbamazapine, Phenobarbital, Phenytoin

Less sedating than other AEDs; (Severe

dermatitis in 1-2% of pediatric patients)

Ca2+Channels as Targets


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g

General Ca2+ channel blockers have notproven to be effective AEDs.

Absence seizures are caused by oscillations

between thalamus and cortex that aregenerated in thalamus by T-type (transient)

Ca2+currents

Ethosuximide


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Acts specifically on T-type channels in

thalamus, and is very effective against

absence seizures. Long half-life (~40h)

Causes GI disturbances; Less sedating than

other AEDs

Gabapentin and its second generationderivative Pregabalin


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derivativePregabalin

-Act specifically on calcium channel subunits

called a2d1. It is unclear how this action leads

to their antiepileptic effects, but inhibition ofneurotransmitter release may be one

mechanism

-Used in add-on therapy for partial seizures

and tonic-clonic seizures

-Less sedating than classic AEDs

What about K+ channels?


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K+ channels have important inhibitory controlover neuronal firing in CNSrepolarizesmembrane to end action potentials

K+ channel agonists would decrease

hyperexcitability in brain So far, the only AED with known actions on K+

channels is valproate

Retiagabine is a novel AED in clinical trials that

acts on a specific type of voltage-dependent K+channel (M-channel)

Valproate (Valproic Acid)


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First-line for generalized seizures, also used

for partial seizures

Also blocks Na+ channels and enhancesGABAergic transmission (highly pleiotropic*)

Highly bound to plasma proteins; #Inhibits

P450

CNS depressant; GI disturbances; hair loss;

weight gain; teratogenic; (rare: hepatotoxic)

Regulation of Neurotransmitter release


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Several AED have actions that result in theregulation of neurotransmitter release from the

presynaptic terminal, such as lamotrigine, in

addition to their noted action on ion channels

or receptors.

Levetiracetam appears to have as its primary

action the regulation of neurotransmitter

release by binding to the synaptic vesicleprotein SV2A:

Levetiracetam


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-Add-on therapy for partial seizures

-Short half-life (6-8h)

-CNS depression

AED Treatment Options


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MyoclonicTonic

Primary generalized seizuresPartial seizures

Simple

Complex

SecondaryGeneralized

Ethosuximidephenytoin, carbamazepine, phenobarbital,

gabapentin, oxcarbazepine, pregabalin

valproic acid, lamotrigine, topiramate,

(levetiracetam, zonisamide)

Tonic-

ClonicAtonic Absence

Check notes



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Status Epilepticus


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More than 30 minutes of continuous seizure

activity

Two or more sequential seizures spanning

this period without full recovery betweenseizures

Medical emergency

Status Epilepticus


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Treatment

Diazepam, lorazapam IV (fast, short acting)

Followed by phenytoin, fosphenytoin, or

phenobarbital (longer acting) when control is

established

Alternative Uses for AEDs


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Gabapentin/pregabalin, carbamazepineneuropathic

pain

Lamotrogine, carbamazepinebipolar disorder

Leviteracitam, valproate, topirimate, gabapentin

migraine


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Expresin alternat iva de NR1 y c r is is ind uc idas po r

N-Metil -D-Aspartato despus del tratam ien to

neonatal con g lutamato monosdico.

EPILEPSIA


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ALTERACION FUNCIONAL CRISIS

INFARTO CEREBRAL


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TUMORES CEREBRALESTRAUMA CRANEOENCEFALICO

DAO NEURONALINFECCIONES

esequilibrio Inhibicin-Excitaci


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Dao NeuronalExcitotxico

CrisisConvulsivas

Glu

GABA

E X C I T O T O X I C I D A DActivacin de los Receptores


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Sobre-activacin de

R-Glu

Aumento de la concentracin

intracelular de Ca++

pGlutamatrgicos (R-Glu)





Dao neuronal

excitotxico


GENERACION DE CRISISCONVULSIVAS

Receptores a glutamato


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Ca2+/Na+ Na+

NMDA AMPA KAINATO

NR1

NR2A

NR2B

NR2C

NR2D

NR3

RGLU1

RGLU2

RGLU3

RGLU4

RGLU5

RGLU6RGLU7

KA1

KA2

Ca2+

CLASE

I

AMPc AMPc

CLASE

II

CLASE

III

GLURm1

GLURm5

GLURm2

GLURm3

GLURm4

GLURm6GLURm7

GLURm8

IP3 Ca2+

Receptor NMDA


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138

Variantes de la subunidad NR1Cassette C1NH Dominios transmembranales Cassette C2NR1 1a COO


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Cassette C1NH2 Dominios transmembranales Cassette C2NR1-1a

NR1-3a Cassette C1NH2 Dominios transmembranales

NR1-4a NH2 Dominios transmembranales

NR1-2a NH2

Dominios transmembranales Cassette C2

NR1-4b Cassette NNH2 Dominios transmembranales

NR1-1b Cassette NNH2 Dominios transmembranales Cassette C1 Cassette C2

NR1-2bCassette NNH2 Dominios transmembranales Cassette C2

NR1-3b Cassette NNH2 Dominios transmembranales CassetteC1

COO

COO

COO

COO

COO

COO

COO

COOCassette C2

Cassette C2

Cassette C2

Cassette C2

Efecto del tratamiento neonatal con GMS

sobre la densidad de clulas GABA


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GMS

Intacto

CORTEZA CEREBRAL

CAMPOS DE PROFUNDIDAD CORTICAL

1 2 3 4 5 6

5

10

15

*

No.C

ELULAS/CAMPO

* **

*

* HIPOCAMPO

10

20

30

40

50

CA1 CA2-3 GD

No.CELULAS/C

AMPO

*

* *

DIAGRAMA EXPERIMENTALRatas Wistar

Recin Nacidas


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Recin Nacidas

Grupo ExperimentalTratamiento Neonatal Excitotxico(GMS 4 mg/g de peso corporal; va

subcutnea; los das 1,3,5 y 7 de edad)

Grupo TestigoTratamiento Neonatal Hiperosmtico

(NaCl equimolar: 1.38 mg/g de peso corporal;va subcutnea; los das 1,3,5 y 7 de edad)

Grupo Intacto

EVALUACION DE LASUSCEPTIBILIDAD CONVULSIVA

Registro de la actividad EEG epileptiformey conductas convulsivas generadas por

la infusin ICV de NMDA y 4 AP

Estudios de biologa molecularRT-PCR (8, 14, 30 y 60 das de edad posnatal)

Corteza Cerebral

I. Evaluacin de la susceptibilidadconvulsiva


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1.Convulsionantes: NMDA, 4-AP2.Va de administracin:Infusin intracerebroventricular (ICV) por inyeccin en elhemisferio derecho

3.Implante electrodos monopolares bilaterales en la cortezacerebral; y de una gua de infusin en el ventrculo lateralderecho

4.Parmetros a evaluar:

Patrn de descargas electroencefalogrficasepileptiformes, latencia, duracin, intensidad yfrecuencia, de las mismas

Patrn conductual convulsivo


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C O N D U C T A S

Clonos faciales

Extensin tnica de extremidades delanteras

Clonos de las extremidades delanteras (CED)

Extensin de los msculos del cuello

CED, levantamiento del cuerpo y cada

Sacudidas de perro mojado

Carreras alocadas

Convulsiones tnico-clnicas generalizadas

Status epilepticus (SE)

Porcentaje de animales que present SE

1.25 nmol

Int/GMS

+/+

- /+

- / -

- / -

- / -

- / -

- / -

- / -

- / -

0/0

2.5 nmol

Int/GMS

+/+

- /+

+/+

- /+

- / -

- / -

- / -

- / -

- / -

0/0

3 nmol

Int/GMS

+/+

- /+

+/+

+/+

+/+

+/ -

- /+

- / -

- / -

0/0

5 nmol

Int/GMS

+/+

- /+

+/+

+/+

+/+

+/ -

- /+

+/ -

+/ -

33/0

10 nmol

Int/GMS

+/+

- /+

+/+

+/+

+/+

+/ -

- /+

+/ -

+/ -

66/0

TABLA 8

Conductas estimuladas por la infusin ICV de NMDA en ratas adultas


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CONCLUSIONES


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1. El tratamiento neonatal con GMS altera el patrn de crisis

convulsivas producidas por NMDA y 4-AP.

2. La generacin de crisis convulsivas a travs de la infusinde 4AP es favorecida despus del tratamiento con GMS.

3. La generacin de crisis convulsivas por la infusin ICVde NMDA en ratas adultas, tratadas con GMS, requiereuna dosis mayor de dicho convulsivante que las intactas;lo que puede deberse, al menos en parte, a cambios en la

composicin de las subunidades del R-NMDA, y por endede su funcionalidad.


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NEURONAS PIRAMIDALES DE TERCERA CAPA DELA CORTEZA CEREBRAL PREFRONTAL


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Impregnacin Metlica (Tcnica de Golgi Modificada) Prez-Vega y col., 2000

Olvera-Corts y col., 1998

NEURONA PIRAMIDAL DE TERCERA CAPA DE LA CORTEZACEREBRAL PREFRONRAL

Dendrita Apical


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Perz-Vega, y cols. 2000

Dendrita Apical

Dendrita Basal

Dendrita Oblicua

Efecto del tratamiento neonatal con GMS

sobre la densidad de clulas GABA


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Intacto

CORTEZA CEREBRAL

CAMPOS DE PROFUNDIDAD CORTICAL

1 2 3 4 5 6

5

10

15

*

No.CELULAS/CAMPO

* **

*

* HIPOCAMPO

30

40

50

ULAS/CAMPO

*

* *

membrane structure and function.pptx

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