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Farmacologia sistemului nervos centralAnticonvulsivanteMecanisme generale de actiune ale anticonvulsivantelorLimitarea descarcarilor repetitive, sustinute, ale neuronilor mentinerea starii inactive a canelelor de Na+ voltaj-dependenteStimularea inhibitiei sinaptice GABA-dependente (acid -amino-butiric) efecte pre- si postsinapticeInhibarea canalelor de Ca++ voltaj-dependente de tip TConvulsii epileptice terminologie si clasificareConvulsie alterarea tranzitorie a comportamentului datorata descarcarii anormale, sincrone si ritmice a populatiilor neuronale cerebraleEpilepsie - disfunctie cerebrala caracterizata aparitia periodica si imprevizibila a convulsiilorConvulsii non- epileptice evocate in creierul normal de electrosocuri sau agenti convulsivanti Agentii farmacologici utilizati inhiba convulsiile anticonvulsivantePreventia epileptogenezei - incerta Convulsii epileptice terminologie si clasificareConvulsiile origine corticala Convulsii epileptice:Partiale origine focala intr-un situs corticalSimple ex. motor clonus teritoriu inervat/ pastrarea constienteiComplexe alterarea constientei origine in lob temporalGeneralizate ambele emisfereEx. 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 convulsieMecanism neuronal convulsii partiale

Mecanisme neuronale ale convulsiilor partialeDeclansator: reducere activitate inhibitorie sinaptica sau crestere activitate excitatorieAntagonisti GABAA sau agonisti receptor glutamat (NMDA, AMPA, acid Kainic) trigger convulsiiModele experimentale epileptogeneza: kindling, status epilepticusMecanisme de actiune ale anticonvulsivantelorPA 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 generalizateDescarcare reciproca talamo-corticalaAbsenta epileptica spike and wave - ~ 3Hz

Mecanismele neuronale ale convulsiilor generalizateConexiuni excitatorii reciproce talamocorticaleProprietatea intrinseca a neuronilor talamici curenti T de Ca++ (low-threshold) - pacemaker

Medicamente anticonvulsivanteIdeal: suprima convulsiile fara efecte nedoriteReal: nu sunt eficiente la unii pacienti, efecte secundare majore2009: avertizare risc ganduri suicidare FDARegula generala: control complet convulsii : 50% din pacienti; 25% imbunatatire semnificativaUn singur medicament inlocuire daca efectul nu apareHidantoineleConvulsii 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

FenitoinaPKFormulare eliberare rapida/ extinsa (+/- Na) echivalent fenitoina monitorizare concentratie plasmaticaLegare (90%) albumina nou nascut, hipoalbuminemie, uremic - fractia liberaValproat competitie legare albumina + inhibare metabolizare CYPRata eliminare ~ [concentratie] nonlinear: t1/2 creste cu concentratiaMetabolism : CYP 2C9 X warfarinaInduce CYP3A4 creste metabolizarea contraceptivelorFosfenitoina solubila apa - injectabilToxicitateFosfenitoina iv aritmii cardiaceFenitoina oral atrofie cerebeloasa, hiperplazie gingivala (metabolism colagen), hirsutismEndocrin inhibitie ADH, hiperglicemie, osteomlacie, vitamina KBarbiturice anticonvulsivante activitatea tuturor tesuturilor excitabile - SNC facilitarea inhibitiaCresc legarea GABA de GABAARPotenteaza curentii Cl- indusi de GABA cresc timp deschidere nu frecventa Concentratii sub-anestezice reduc depolarizarea indusa de glutamatConcentratii anestezice inhiba canalele de Na+ voltaj dependenteFenobarbitalToxicitate redusa, index terapeutic mareAbsorbtie orala completaEfect anticonvulsivant la doze < hipnozaEfect anticonvulsivant creste curent Cl- indus de GABAConcentratii crescute inhiba descarcarea repetitiva status epilepticusPK40-60% proteine circulante si tisulareInduce CYP2C si CYP3A (contraceptive 3A4)Toxicitate: sedare (toleranta), nistagmus, ataxie, agitatie, confuzie (varstnici)IminostilbeneCarbamazepinaStructura ~ antidepresive triciclice Prelungeste inactivarea canale Na+ voltaj-depInhiba descarcarea repetitiva PKAbsorbtie limitata si eratica oral 4-24h peak75% - proteine plasmatice Metabolit activ 10,11 epoxid (CYP3A4)Induce CYP3A (auto inductie)ToxicitateComa, hiperiritabilitate, convulsiiTerapie lunga vertij, ataxie, diplopie, retentie hidrica (ADH)InteractiuniFenobarbital, fenitoin cresc metabolism CYP3A4Oxcarbazepina inductor enzimatic mai putin potent

SuccinimideEtosuximidaAbsenta eileptica selectivitate mareExperimental protectie impotriva convulsiilor induse chimic de pentilentetrazol nu inhiba convulsiile induse de electrosoc maxim sau kindledReduce curentii de Ca++ tip T in neuronii talamiciNu are efect asupra raspunsului GABAPKAbsorbtie orala completaNelegata de proteine (t1/2 40 50 h)ToxicitateGI: greata, varsaturi, anorexieCNS: letargie, somnolenta, ameteli, sughitAcizi carboxilici - Acid valproic Descoperit intamplator vehiculLant ramificat (9 C- sedare)Eficienta diversa: electrosoc maxim, kindle (fenitoin, carbamazepina); pentilentetrazol (etosuximida)Eficient in convulsii tonico-clonice (partial si generalizat) si absenta epilepticaInhiba recuperarea canalelor de Na++ din stare inactivaNu are efect GABA-R dar creste sinteza si scade metabolismul GABAInhiba curenti Ca++ TPKAbsorbtie rapida si completa oral, transportor CSF, legare albumina 90%ToxicitateGI: 16% - grata, varsaturi, anorexieSNC: sedare, ataxie, tremorCrestere in greutate tratament lunga durataCreste transaminaze hepatice rar: hepatita fulminantaInteractiuniInhiba metabolismul fenitoinei si fenobarbitalului (CYP2C9)

BenzodiazepineleEfecte generale: sedare, hipnoza, anxioliza, relaxare musculara, amnezie anterograda, anticonvulsivanteMA: legare receptor GABAA situs diferit de GABA modulare alosterica efect GABA ( barbiturice activare directa GABAR)Cresc curent Cl- = creste frecventa deschidere, cresc durata IPSCNu au efect in absenta GABAActioneaza asupra interneuronilor inhibitoriBenzodiazepinele ca anticonvulsivanteClonazepam, clorazepat, midazolam (pacienti refractari), diazepam, lorazepam (status epilepticus)Mecanism de baza GABAConcentratii mari inhiba descarcarea repetitiva ~ fenitoina, carbamazepinaPKAbsorbtie orala bunaIv redistributie rapida ~ liposolubilitate mareLegare proteine 90%T1/2 diazepam 1-2 zileToxicitateSomnolenta, letargie (50% - toleranta)Gabapentina si PregabalinaMolecula GABA legata covalent de un inel ciclohexan lipofil/ izobutanConceput ca agonist GABA lipofilNu actioneaza pe receptori GABALegare cu afinitate mare de proteine identice ca structura cu o subunitate a canalului de Ca++ - mecanism incertPKAbsorbtie dupa administrare orala nu sunt metabolizate , nelegate de proteine; nici o interactiune cunoscutaUtile pentru convulsii partiale, cu sau fara generalizare secundara, in combinatie cu alte anticonvulsivanteToxicitate Somnolenta, ameteala, oboseala dispar dupa 2 saptamani

LamotriginaDerivat feniltriazinaInitial dezvoltat ca agent antifolatActiune ~ fenitoina, carbamazepina inactivare canale Na+Eficienta in convulsiile partiale Posibil: inhibarea eliberarii de glutamatPKAbsorbtie completa GIMetabolizare prin glucuronidare hepatica Interactiune cu fenitoina, carbamazepina, fenobarbital ( lamotrigina), valproat ( lamotrigina glucoronidare)EA ameteala, ataxie, diplopie, greata, varsaturiLevetiracetamDerivat pirolidinicProfil farmacologic specific tonic-clonic partial si generalizat - adjuvantNici un mecanism identificat (SVA2)Fara interactiuniTiagabinaDerivat acid nipecoticInhibat transportor GABA (GAT-1) X uptake neron/glieEficient in convulsii tonic-clonice partial si generalizatMetabolizat CYP3A

TopiramatMonozaharid sulfamatReduce curent Na+ ~ fenitoina curent K+ postsinaptic Creste efect GABA receptor glutamat (AMPA kainat)Spectru larg anticonvulsivant concentratia estradiolFelbamatDicarbamat1993 anemie aplastica, insuficienta hepaticaInhiba efect NMDA, potenteaza efect GABASdr. Lennox-Gastaut (epilepsie juvenila < 4 ani)

Zonisamida derivat sulfonamidaInhiba curenti tip T Ca++Prelungeste inactivarea canale Na+Eficient in tonic-clonic partial si generalizatLacosamidaAminoacid functionalizatInactivare canale Na+ - slowRufinamidaDerivat triazolInactivare canale Na+Sdr. Lennox-Gastaut

VigabatrinAnalog structural GABAInhiba GABA-transaminazaPierdere vedere bilaterala ultima resursaAcetazolamidaAbsenta epilepticaConvulsii legate de menstruatieInhibitor anhidraza carbonicaMA: CO2 cerebral inhibitor, acidoza ?Toleranta rapida

Simple partialDiverse 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.Carbamazepine, phenytoin, valproateGabapentin, lacosamide, lamotrigine, levetiracetam, rufinamide, tiagabine, topiramate, zonisamideComplex partialImpaired consciousness lasting 30 seconds to 2 minutes, often associated with purposeless movements such as lip smacking or hand wringing.Carbamazepine, phenytoin, valproateGabapentin, lacosamide, lamotrigine, levetiracetam, rufinamide, tiagabine, topiramate, zonisamidePartial with secondarily generalized tonic-clonic seizureSimple or complex partial seizure evolves into a tonic-clonic 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 minutesCarbamazepine, phenobarbital, phenytoin, primidone, valproateGabapentin, lacosamide, lamotrigine, levetiracetam, rufinamide, tiagabine, topiramate, zonisamideGeneralized SeizuresAbsence seizureAbrupt onset of impaired consciousness associated with staring and cessation of ongoing activities typically lasting less than 30 seconds.Ethosuximide, valproate, clonazepamLamotrigineMyoclonic seizureA brief (perhaps a second), shocklike contraction of muscles that may be restricted to part of one extremity or may be generalized.Valproate, clonazepamLevetiracetamTonic-clonic seizureAs described earlier in table for partial with secondarily generalized tonic-clonic seizures except that it is not preceded by a partial seizure.Carbamazepine, phenobarbital, phenytoin, primidone, valproateLamotrigine, levetiracetam, topiramatePrincipiile terapieiInitierea terapiei daca si cand?Convulsie tonico-clonica izolata la un adult tanar fara istoric, cu examen neurologic, EEG, RMN normalProbabilitatea de recurenta (15%) = probabilitate efect adversMonoterapie (exc. Status epilepticus) complianta max.+ doza maxima 50% control complet convulsii Substitutie medicament daca persista convulsii alt mecanismAsociere