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 GABA-
dependente (acid -amino-butiric) – efecte
pre- si postsinaptice
• Inhibarea canalelor de Ca++ voltaj-
dependente 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
• Cu convulsii tonico-clonice secundare generalizate
– Generalizate – ambele emisfere
• absenta epileptica
• mioclonica
• tonico-clonica
• Medicamentele – in functie de tipul de convulsie

•  sinapse inhibitorii (GABA) /  sinapse excitatorii (NMDA, AMPA,

ac .kainic)
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
post-inactivare a
canalelor de Na+ V-
dependente
 Mecanisme de actiune
ale anticonvulsivantelor
 Mecanismele neuronale ale convulsiilor
generalizate
• Descarcare reciproca talamo-corticala
• Absenta epileptica – spike and wave - ~ 3Hz
 Mecanismele neuronale ale convulsiilor
generalizate
• Conexiuni excitatorii reciproce talamocorticale
• Proprietatea intrinseca a neuronilor talamici –
curenti T de Ca++ (low-threshold) - pacemaker
 Medicamente anticonvulsivante
• Ideal: suprima convulsiile fara efecte nedorite
• Real: nu sunt eficiente la unii pacienti, efecte
secundare majore (anemie aplastica, insuf. Hep)
• 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+ / scade
descarcarea repetitiva la depolarizare
sustinuta
• 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 epileptica – 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 Carbamazepine, phenytoin, valproate Gabapentin, lacosamide, lamotrigine,
the region of cortex activated by the levetiracetam, rufinamide, tiagabine,
seizure (e.g., if motor cortex topiramate, zonisamide
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 Carbamazepine, phenytoin, valproate Gabapentin, lacosamide, lamotrigine,
seconds to 2 minutes, often associated levetiracetam, rufinamide, tiagabine,
with purposeless movements such as topiramate, zonisamide
lip smacking or hand wringing.

Partial with secondarily generalized
tonic-clonic seizure
Simple or complex partial seizure Carbamazepine, phenobarbital, Gabapentin, lacosamide, lamotrigine,
evolves into a tonic-clonic seizure with phenytoin, primidone, valproate levetiracetam, rufinamide, tiagabine,
loss of consciousness and sustained topiramate, zonisamide
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 Ethosuximide, valproate, clonazepam Lamotrigine
consciousness associated with staring
and cessation of ongoing activities
typically lasting less than 30 seconds.
Myoclonic seizure A brief (perhaps a second), shocklike Valproate, clonazepam Levetiracetam
contraction of muscles that may be
restricted to part of one extremity or
may be generalized.
Tonic-clonic seizure As described earlier in table for partial Carbamazepine, phenobarbital, Lamotrigine, levetiracetam, topiramate
with secondarily generalized tonic- phenytoin, primidone, valproate
clonic seizures except that it is not
preceded by a partial seizure.
 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
– Asociere