Farmacologia sistemului

nervos central
Anticonvulsivante

Mecanisme generale de actiune ale

anticonvulsivantelor
Limitarea descarcarilor repetitive,
sustinute, ale neuronilor
mentinerea starii inactive a canelelor
de Na+ voltaj-dependente
Stimularea inhibitiei sinaptice GABAdependente (acid -amino-butiric)
efecte pre- si postsinaptice
Inhibarea canalelor de Ca++ voltajdependente de tip T

Convulsii epileptice terminologie si

clasificare
Convulsie alterarea tranzitorie a
comportamentului datorata descarcarii
anormale, sincrone si ritmice a populatiilor
neuronale cerebrale
Epilepsie - disfunctie cerebrala caracterizata
aparitia periodica si imprevizibila a convulsiilor
Convulsii non- epileptice evocate in creierul
normal de electrosocuri sau agenti convulsivanti
Agentii farmacologici utilizati inhiba convulsiile
anticonvulsivante
Preventia epileptogenezei - incerta

Convulsii epileptice terminologie si

clasificare
Convulsiile origine corticala
Convulsii epileptice:
Partiale origine focala intr-un situs cortical
Simple ex. motor clonus teritoriu inervat/ pastrarea
constientei
Complexe alterarea constientei origine in lob temporal

Generalizate ambele emisfere

Ex. absenta epileptica (
https://www.youtube.com/watch?v=H3iLQi6wt94 ) ,
mioclonica (https://www.youtube.com/watch?v=zPNVYFRhthg ) ,
tonico-clonica (
https://www.youtube.com/watch?v=Nds2U4CzvC4 )

Medicamentele in functie de tipul de convulsie

Mecanism neuronal convulsii partiale

Mecanisme neuronale ale

convulsiilor partiale
Declansator: reducere activitate
inhibitorie sinaptica sau crestere
activitate excitatorie
Antagonisti GABAA sau agonisti
receptor glutamat (NMDA, AMPA,
acid Kainic) trigger convulsii
Modele experimentale
epileptogeneza: kindling, status
epilepticus

Mecanisme de actiune ale

anticonvulsivantelor
PA de frecventa
mare paroxysmal
depolarization
shift (PDS)
Inhibarea
recuperarii postinactivare a
canalelor de Na+
V- dependente

Mecanisme de actiune
ale anticonvulsivantelor

Mecanismele neuronale ale

convulsiilor generalizate
Descarcare reciproca talamocorticala
Absenta epileptica spike and wave ~ 3Hz

Mecanismele neuronale ale

convulsiilor generalizate
Conexiuni excitatorii reciproce
talamocorticale
Proprietatea intrinseca a neuronilor
talamici curenti T de Ca++ (lowthreshold) - pacemaker

Medicamente
anticonvulsivante
Ideal: suprima convulsiile fara efecte nedorite
Real: nu sunt eficiente la unii pacienti, efecte
secundare majore
2009: avertizare risc ganduri suicidare FDA
Regula generala: control complet convulsii :
50% din pacienti; 25% imbunatatire
semnificativa
Un singur medicament inlocuire daca
efectul nu apare

Hidantoinele
Convulsii partiale si tonic-clonice (NU
absenta epileptica)
5-fenil anticonvulsivant (alkil
sedativ)
MA: prelungire inactivare VOC Na+
Aboleste faza tonica dar prelungeste
faza reziduala clonica

Fenitoina
PK
Formulare eliberare rapida/ extinsa (+/- Na) echivalent
fenitoina monitorizare concentratie plasmatica
Legare (90%) albumina nou nascut, hipoalbuminemie,
uremic - fractia libera
Valproat competitie legare albumina + inhibare
metabolizare CYP
Rata eliminare ~ [concentratie] nonlinear: t1/2 creste cu
concentratia
Metabolism : CYP 2C9 X warfarina
Induce CYP3A4 creste metabolizarea contraceptivelor
Fosfenitoina solubila apa - injectabil

Toxicitate
Fosfenitoina iv aritmii cardiace
Fenitoina oral atrofie cerebeloasa,
hiperplazie gingivala (metabolism
colagen), hirsutism
Endocrin inhibitie ADH, hiperglicemie,
osteomlacie, vitamina K

Barbiturice
anticonvulsivante
activitatea tuturor tesuturilor excitabile SNC
facilitarea inhibitia
Cresc legarea GABA de GABAAR
Potenteaza curentii Cl- indusi de GABA
cresc timp deschidere nu frecventa
Concentratii sub-anestezice reduc
depolarizarea indusa de glutamat
Concentratii anestezice inhiba canalele de
Na+ voltaj dependente

Fenobarbital

Toxicitate redusa, index terapeutic mare

Absorbtie orala completa
Efect anticonvulsivant la doze < hipnoza
Efect anticonvulsivant creste curent Cl- indus
de GABA
Concentratii crescute inhiba descarcarea
repetitiva status epilepticus
PK
40-60% proteine circulante si tisulare
Induce CYP2C si CYP3A (contraceptive 3A4)

Toxicitate: sedare (toleranta), nistagmus,

ataxie, agitatie, confuzie (varstnici)

Iminostilbene
Carbamazepina
Structura ~ antidepresive triciclice
Prelungeste inactivarea canale Na+ voltaj-dep
Inhiba descarcarea repetitiva

PK
Absorbtie limitata si eratica oral 4-24h peak
75% - proteine plasmatice
Metabolit activ 10,11 epoxid (CYP3A4)
Induce CYP3A (auto inductie)

Toxicitate
Coma, hiperiritabilitate, convulsii
Terapie lunga vertij, ataxie, diplopie, retentie hidrica (ADH)

Interactiuni
Fenobarbital, fenitoin cresc metabolism CYP3A4
Oxcarbazepina inductor enzimatic mai putin potent

Succinimide
Etosuximida
Absenta eileptica selectivitate mare
Experimental protectie impotriva convulsiilor induse
chimic de pentilentetrazol nu inhiba convulsiile
induse de electrosoc maxim sau kindled
Reduce curentii de Ca++ tip T in neuronii talamici
Nu are efect asupra raspunsului GABA

PK
Absorbtie orala completa
Nelegata de proteine (t1/2 40 50 h)

Toxicitate
GI: greata, varsaturi, anorexie
CNS: letargie, somnolenta, ameteli, sughit

Acizi carboxilici - Acid

valproic
Descoperit intamplator vehicul
Lant ramificat (9 C- sedare)
Eficienta diversa: electrosoc maxim, kindle (fenitoin, carbamazepina);
pentilentetrazol (etosuximida)
Eficient in convulsii tonico-clonice (partial si generalizat) si absenta
epileptica
Inhiba recuperarea canalelor de Na++ din stare inactiva
Nu are efect GABA-R dar creste sinteza si scade metabolismul GABA
Inhiba curenti Ca++ T
PK
Absorbtie rapida si completa oral, transportor CSF, legare albumina 90%

Toxicitate
GI: 16% - grata, varsaturi, anorexie
SNC: sedare, ataxie, tremor
Crestere in greutate tratament lunga durata
Creste transaminaze hepatice rar: hepatita fulminanta

Interactiuni
Inhiba metabolismul fenitoinei si fenobarbitalului (CYP2C9)

Benzodiazepinele
Efecte generale: sedare, hipnoza, anxioliza,
relaxare musculara, amnezie anterograda,
anticonvulsivante
MA: legare receptor GABAA situs diferit de
GABA modulare alosterica efect GABA (
barbiturice activare directa GABAR)
Cresc curent Cl- = creste frecventa deschidere,
cresc durata IPSC

Nu au efect in absenta GABA

Actioneaza asupra interneuronilor inhibitori

Benzodiazepinele ca
anticonvulsivante
Clonazepam, clorazepat, midazolam (pacienti
refractari), diazepam, lorazepam (status epilepticus)
Mecanism de baza GABA
Concentratii mari inhiba descarcarea repetitiva ~
fenitoina, carbamazepina
PK
Absorbtie orala buna
Iv redistributie rapida ~ liposolubilitate mare
Legare proteine 90%
T1/2 diazepam 1-2 zile

Toxicitate
Somnolenta, letargie (50% - toleranta)

Gabapentina si Pregabalina
Molecula GABA legata covalent de un inel ciclohexan
lipofil/ izobutan
Conceput ca agonist GABA lipofil
Nu actioneaza pe receptori GABA
Legare cu afinitate mare de proteine identice ca structura
cu o subunitate a canalului de Ca++ - mecanism incert
PK
Absorbtie dupa administrare orala nu sunt metabolizate ,
nelegate de proteine; nici o interactiune cunoscuta

Utile pentru convulsii partiale, cu sau fara generalizare

secundara, in combinatie cu alte anticonvulsivante
Toxicitate
Somnolenta, ameteala, oboseala dispar dupa 2 saptamani

Lamotrigina
Derivat feniltriazina
Initial dezvoltat ca agent antifolat
Actiune ~ fenitoina, carbamazepina inactivare canale
Na+
Eficienta in convulsiile partiale
Posibil: inhibarea eliberarii de glutamat
PK
Absorbtie completa GI
Metabolizare prin glucuronidare hepatica
Interactiune cu fenitoina, carbamazepina, fenobarbital (
lamotrigina), valproat ( lamotrigina glucoronidare)

EA
ameteala, ataxie, diplopie, greata, varsaturi

 Levetiracetam
Derivat pirolidinic
Profil farmacologic specific tonic-clonic partial
si generalizat - adjuvant
Nici un mecanism identificat (SVA2)
Fara interactiuni

Tiagabina
Derivat acid nipecotic
Inhibat transportor GABA (GAT-1) X uptake
neron/glie
Eficient in convulsii tonic-clonice partial si
generalizat
Metabolizat CYP3A

 Topiramat
Monozaharid sulfamat
Reduce curent Na+ ~ fenitoina
curent K+ postsinaptic
Creste efect GABA
receptor glutamat (AMPA kainat)
Spectru larg anticonvulsivant
concentratia estradiol

Felbamat
Dicarbamat
1993 anemie aplastica, insuficienta hepatica
Inhiba efect NMDA, potenteaza efect GABA
Sdr. Lennox-Gastaut (epilepsie juvenila < 4 ani)

 Zonisamida
derivat sulfonamida
Inhiba curenti tip T Ca++
Prelungeste inactivarea canale Na+
Eficient in tonic-clonic partial si generalizat

Lacosamida
Aminoacid functionalizat
Inactivare canale Na+ - slow

Rufinamida
Derivat triazol
Inactivare canale Na+
Sdr. Lennox-Gastaut

 Vigabatrin
Analog structural GABA
Inhiba GABA-transaminaza
Pierdere vedere bilaterala ultima
resursa

Acetazolamida
Absenta epileptica
Convulsii legate de menstruatie
Inhibitor anhidraza carbonica
MA: CO2 cerebral inhibitor, acidoza ?
Toleranta rapida

Simple partial

Diverse manifestations
determined by the region of
cortex activated by the seizure
(e.g., if motor cortex
representing left thumb, clonic
jerking of left thumb results; if
somatosensory cortex
representing left thumb,
paresthesia of left thumb
results), lasting approximating
20-60 seconds. Key feature is
preservation of consciousness.
Complex partial
Impaired consciousness lasting
30 seconds to 2 minutes, often
associated with purposeless
movements such as lip
smacking or hand wringing.
Partial with secondarily
Simple or complex partial
generalized tonic-clonic seizure seizure evolves into a tonicclonic seizure with loss of
consciousness and sustained
contractions (tonic) of muscles
throughout the body followed
by periods of muscle
contraction alternating with
periods of relaxation (clonic),
typically lasting 1-2 minutes
Generalized Seizures
Absence seizure
Abrupt onset of impaired
consciousness associated with
staring and cessation of
ongoing activities typically
lasting less than 30 seconds.
Myoclonic seizure
A brief (perhaps a second),
shocklike contraction of

Carbamazepine, phenytoin,
valproate

Gabapentin, lacosamide,
lamotrigine, levetiracetam,
rufinamide, tiagabine,
topiramate, zonisamide

Carbamazepine, phenytoin,
valproate

Gabapentin, lacosamide,
lamotrigine, levetiracetam,
rufinamide, tiagabine,
topiramate, zonisamide

Carbamazepine, phenobarbital, Gabapentin, lacosamide,

phenytoin, primidone,
lamotrigine, levetiracetam,
valproate
rufinamide, tiagabine,
topiramate, zonisamide

Ethosuximide, valproate,
clonazepam

Lamotrigine

Valproate, clonazepam

Levetiracetam

Principiile terapiei
Initierea terapiei daca si cand?
Convulsie tonico-clonica izolata la un adult tanar
fara istoric, cu examen neurologic, EEG, RMN
normal
Probabilitatea de recurenta (15%) = probabilitate efect
advers

Monoterapie (exc. Status epilepticus) complianta

max.+ doza maxima 50% control complet
convulsii
Substitutie medicament daca persista convulsii
alt mecanism
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