Clinical Use

Carbamazepine is considered the drug of choice for

partial seizures, and many physicians also use it first
for generalized tonic-clonic seizures. It can be used
with phenytoin in many patients who are difficult to
control. Carbamazepine is not sedative in its usual
therapeutic range. The drug is also very effective in
some patients with trigeminal neuralgia, although
older patients may tolerate higher doses poorly, with
ataxia and unsteadiness. Carbamazepine is also
useful in some patients with mania (bipolar
disorder).
Pharmacokinetics
The rate of absorption of carbamazepine varies
widely among patients, although almost complete
absorption apparently occurs in all. Peak levels are
usually achieved 68 hours after administration.
Slowing absorption by giving the drug after meals
helps the patient tolerate larger total daily doses.

Distribution is slow, and the volume of distribution

is roughly 1 L/kg. The drug is only 70% bound to
plasma proteins; no displacement of other drugs
from protein binding sites has been observed.
Carbamazepine has a very low systemic clearance of
approximately 1 L/kg/d at the start of therapy.
The drug has a notable ability to induce microsomal
enzymes. Typically, the half-life of 36 hours
observed in subjects following an initial single dose
decreases to much less than 20 hours in subjects
receiving continuous therapy. Considerable dosage
adjustments are thus to be expected during the first
weeks of therapy. Carbamazepine also alters the
clearance of other drugs (see below).
Carbamazepine is completely metabolized in
humans to several derivatives. One of these,
carbamazepine-10,11-epoxide, has been shown to
have anticonvulsant activity. The contribution of this
and other metabolites to the clinical activity of
carbamazepine is unknown.
Therapeutic Levels & Dosage
Carbamazepine is considered the drug of choice in
partial seizures. It is available only in oral form.

Utilizarea clinic
Carbamazepina este considerata medicamentul
potrivit pentru convulsii pariale, i muli medici il
utilizeaza n primul rnd pentru convulsii tonicoclonice generalizate. Aceasta poate fi utilizata cu
fenitoin la muli pacieni care sunt dificil de
controlat . Carbamazepina nu este in mod normal un
sedativ n gama sa terapeutica. Medicamentul este,
de asemenea, foarte eficient la unii pacienti cu
nevralgie de trigemen , dei pacienii mai n vrst
nu tolereaza bine dozele mai mari , prezentand
ataxie i instabilitate . Carbamazepina este de
asemenea util la unii pacieni cu manie ( tulburare
bipolar ) .
Farmacocinetica
Rata de absorbie a carbamazepinei variaza foarte
mult in randul pacientilor , dei absorbia aproape
complet pare c are loc la toti . Nivelurile maxime
sunt atinse , de obicei, la 6-8 ore de la administrare.
Absorbia lenta prin administrarea medicamentului
dupa mese ajuta pacientul sa tolereze doze zilnice
totale mai mari .
Distribuia este lent , iar volumul de distribuie este
de aproximativ 1 L/kg . Medicamentul este
influentat in proportie de doar 70 % de proteinele
plasmatice. Nu s-a observat nici un alt medicament
care sa nu prezinte aceasta dependenta de proteine.
Carbamazepina are un clearance sistemic foarte
sczut de aproximativ 1 l / kg / zi la nceputul
tratamentului .
Medicamentul are o capacitate remarcabil de a
induce enzimele microzomale . De obicei , timpul de
njumtire de 36 de ore observat la subieci dup o
doz unic iniial scade la mai puin de 20 de ore la
subiecii care primesc tratament continuu . Ajustarea
considerabila a dozelor este prin urmare, de ateptat
n primele sptmni de tratament . Carbamazepina
modific, de asemenea, clearance-ul altor
medicamente ( vezi mai jos ) .
Carbamazepina este complet metabolizata la om in
mai multi derivati. Unul dintre acestia,
carbamazepina - 10 ,11 - epoxid , s-a dovedit a avea
o activitate anticonvulsivant . Contribuia acestora
si a altor metabolii la activitatea clinic a
carbamazepinei este necunoscuta .

The drug is effective in children, in whom a dosage

of 1525 mg/kg/d is appropriate. In adults, daily
doses of 1 g or even 2 g are tolerated. Higher dosage
is achieved by giving multiple divided doses daily.
An extended-release preparation permits twice-daily
dosing for most patients. In patients in whom the
blood is drawn just before the morning dose (trough
level), the therapeutic level is usually 48 g/mL;
although many patients complain of diplopia at drug
levels above 7 g/mL, others can tolerate levels above
10 g/mL, especially with monotherapy.

Drug Interactions
Drug interactions involving carbamazepine are
almost exclusively related to the drug's
enzymeinducing properties. As noted previously, the
increased metabolic capacity of the hepatic enzymes
may cause a reduction in steady-state carbamazepine
concentrations and an increased rate of metabolism
of other drugs, eg, primidone, phenytoin,
ethosuximide, valproic acid, and clonazepam.
Other drugs such as propoxyphene, troleandomycin,
and valproic acid may inhibit carbamazepine
clearance and increase steady-state carbamazepine
blood levels. Other anticonvulsants, however, such
as phenytoin and phenobarbital, may decrease
steady-state concentrations of carbamazepine
through enzyme induction. No clinically significant
protein-binding interactions have been reported.

Toxicity
The most common dose-related adverse effects of
carbamazepine are diplopia and ataxia. The
diplopia often occurs first and may last less than an
hour during a particular time of day.
Rearrangement of the divided daily dose can often

Niveluri terapeutice si de dozare

Carbamazepina este considerata medicamentul de
preferat n cazul convulsiilor partiale . Acesta este
disponibil numai sub form oral .
Medicamentul este eficient la copii , la care este
adecvata o doz de 15-25 mg / kg / zi . La adulti
sunt adecvate doze zilnice de 1 g sau chiar 2 . Un
dozaj mai mare se realizeaz prin administrarea de
doze divizate de mai multe ori pe zi . Un preparat cu
eliberare prelungita permite administrarea de dou
ori pe zi la majoritatea pacientilor . La pacienii la
care sangele este recoltat chiar nainte de doza de
diminea (valoare minim ) , nivelul terapeutic este,
de obicei 4-8 g / ml ; dei muli pacieni acuza
simptome de diplopie in cantitati mai mari de 7 g/ml
, altii pot tolera niveluri de peste 10 g / ml , mai ales
cu monoterapie .

Interaciuni cu alte medicamente

Interactiunile cu alte medicamente care implic
carbamazepina sunt legate aproape exclusiv de
proprietile medicamentului de a induce enzime.
Dup cum s-a menionat anterior, capacitatea
crescuta de metabolizare a enzimelor hepatice ar
putea determina o reducere a concentraiilor de
carbamazepin la starea de echilibru i o rat
crescut de metabolizare a altor medicamente , de
exemplu , primidona , fenitoina , etosuximida ,
acidul valproic , i clonazepam .
Alte medicamente, cum ar fi propoxifenul ,
troleandomicina , i acidul valproic pot inhiba
clearance-ul carbamazepinei i sa creasca starea de
echilibru a carbamazepinei in sange . Cu toate
acestea, alte anticonvulsivante cum ar fi fenitoina i
fenobarbitalul , pot scdea concentraiile la starea de
echilibru a carbamazepinei prin inducie enzimatic .
Nu au fost raportate interaciuni semnificative din
punct de vedere clinic cu proteine
Toxicitate
Cele mai frecvente reacii adverse ale unei doze de
carbamazepina sunt diplopia i ataxia .
Diplopia se instaleaza de obicei prima i poate dura
pana la o or, ntr-un anumit moment al zilei.
Ajustarea diviziunilor dozelor zilnice poate de multe
ori remedia acest efect advers . Alte efecte adverse

remedy this complaint. Other dose-related

complaints include mild gastrointestinal upsets,
unsteadiness, and, at much higher doses,
drowsiness. Hyponatremia and water intoxication
have occasionally occurred and may be doserelated.
Considerable concern exists regarding the
occurrence of idiosyncratic blood dyscrasias with
carbamazepine, including fatal cases of aplastic
anemia and agranulocytosis. Most of these have been
in elderly patients with trigeminal neuralgia, and
most have occurred within the first 4 months of
treatment. The mild and persistent leukopenia seen
in some patients is not necessarily an indication to
stop treatment but requires careful monitoring. The
most common idiosyncratic reaction is an
erythematous skin rash; other responses such as
hepatic dysfunction are unusual.

sunt: disconfort gastro-intestinal uoare ,

instabilitate, i, la doze mult mai mari,
somnolen . Hiponatremia i intoxicaia cu ap au
aprut ocazional i ar putea fi cauzate de dozaj.
Exist o preocupare major n ceea ce privete
apariia de discrazii sanguine idiosincratice cu
carbamazepina , inclusiv cazuri letale de anemie
aplastic i agranulocitoz . Cele mai multe dintre
acestea au fost semnalate la pacientii varstnici cu
nevralgie de trigemen , iar cele mai multe s-au
instalat n primele 4 luni de tratament . Leucopenia
usoara si persistenta observata la unii pacienti nu
este neaprat o indicaie de a opri tratamentul , dar
necesit o monitorizare atent . Cea mai frecvent
reacie idiosincratic este o erupie eritematoas pe
piele; alte reacii, cum ar fi disfunciile hepatice sunt
rare .

Oxcarbazepine
Oxcarbazepine is closely related to carbamazepine
and useful in the same seizure types, but it may have
an improved toxicity profile. Oxcarbazepine has a
half-life of only 12 hours. Its activity, therefore,
resides almost exclusively in the 10-hydroxy
metabolite, to which it is rapidly converted and
which has a half-life similar to that of
carbamazepine, ie, 812 hours. The drug is mostly
excreted as the glucuronide of the 10-hydroxy
metabolite.

Oxcarbazepin
Oxcarbazepina este strns legat de carbamazepin
i utila n aceleai tipuri de crize , dar poate avea un
profil de toxicitate mai bun . Oxcarbazepina are un
timp de njumtire de doar 1-2 ore . Activitatea sa ,
prin urmare , consta aproape exclusiv n metabolitul
10 - hidroxi , in care este transformata rapid i care
are un timp de njumtire similar cu cel al
carbamazepinei , adic , 8-12 ore . Medicamentul
este in cea mai mare parte excretat ca glucuronid al
metabolitului 10 - hidroxi .
.

Oxcarbazepine is less potent than carbamazepine,

both in animal models of epilepsy and in epileptic
patients; clinical doses of oxcarbazepine may need to
be 50% higher than those of carbamazepine to obtain
equivalent seizure control. Some studies report fewer
hypersensitivity reactions to oxcarbazepine, and
cross-reactivity with carbamazepine does not always

Oxcarbazepina este mai slaba dect

carbamazepina , att n modelele animale de
epilepsie cat i la pacienii cu epilepsie ;
poate fi necesar ca dozele clinice de
oxcarbazepin s fie cu 50 % mai mari dect
cele de carbamazepina pentru a obine
acelasi rezultat in cazul convulsiilor . Unele
studii raporteaz mai puine reacii de

occur. Furthermore, the drug appears to induce

hepatic enzymes to a lesser extent than
carbamazepine, minimizing drug interactions. Those
adverse effectssuch as hyponatremiathat do
occur with oxcarbazepine are similar in character to
reactions reported with carbamazepine.
ESLICARBAZINE (scris de pe foaie)
Eslicarbazepine acetate (ESL) is a prodrug that has
been approved by Europe as adjunctive therapy in
adults with partial-onset seisures, with or without
secondary generalization. ESL is more rapidly
converted to S(+)-licarbazine (eslicarbazine) than is
oxcarbazepine; clearly both prodrugs have the same
metabolite as active product. The mechanism of
action of carbamazepine, oxcarbazepine, and ESL
appears to be the same, ie, blocking of voltagerelated Na+ channels. The R(-) enantiomer has some
activity, but much less than its counterpart
Like phenytoin, phenobarbital suppresses highfrequency repetitive firing in neurons in culture
through an action on Na+ conductance, but only at
high concentrations.
Also at high concentrations, barbiturates block some
Ca2+ currents (L-type and N-type).
Phenobarbital binds to an allosteric regulatory site
on the GABA-benzodiazepine receptor, and it
enhances the GABA receptor-mediated current by
prolonging the openings of the Cl- channels.
Phenobarbital also blocks excitatory responses
induced by glutamate, principally those mediated by
activation of the AMPA receptor (see Chapter 21).
Both the enhancement of GABA-mediated inhibition
and the reduction of glutamate-mediated excitation
are seen with therapeutically relevant concentrations
of phenobarbital.

hipersensibilitate la oxcarbazepin , i
reactivitatea ncruciat cu carbamazepina nu
se produce ntotdeauna. Mai mult
,medicamentul pare a induce enzime
hepatice n mai mic msur dect
carbamazepina , minimiznd interaciunile
medicamentoase . Aceste efecte adverse ,
cum ar fi - hiponatremia , care apar cu
oxcarbazepina sunt similare cu cele raportate
la carbamazepin .
ESLICARBAZINA ( Scris de pe foaie )
Acetatul de eslicarbazepin ( ESL ) este un
pro-medicament care a fost aprobat in
Europa, ca terapie complementara la adulii
cu convulsii pariale incipiente , cu sau fr
generalizare secundar . ESL este
transformat mai repede in S ( + ) licarbazina (eslicarbazina ) dect este
oxcarbazepina ; c este evident ca ambele
promedicamente au acelasi metabolit ca
produs activ . Mecanismul de aciune al
carbamazepinei, oxcarbazepinei si al ESL pare
s fie acelai , adic blocarea canalelor legate
de tensiune ale Na +. R ( - ) enantiomerul
are o oarecare activitate , dar mult mai mica
dect omologul su.
Ca i fenitoina, fenobarbitalul inhiba
descrcrile repetitive de nalt frecven n
neuroni n cultur printr-o aciune asupra
conductanei Na +, dar numai la concentraii
mari.
De asemenea, la concentraii mari,
barbituricele blocheaza unii curenti de Ca2 +
(cureni de tip L i N).
Fenobarbital se leag la un situs alosteric
reglementare asupra receptorului GABAbenzodiazepin, i mbuntete GABA
mediat de receptor curentul prin prelungirea
deschiderile Cl-canale.
Fenobarbital asemenea blocuri rspunsuri
excitatorii induse de glutamat, n principal
cele mediate prin activarea receptorilor AMPA
(a se vedea capitolul 21). Att creterea
inhibarea mediat de GABA i reducerea
mediate de glutamat excitaie sunt observate
cu concentraii terapeutice relevante ale
fenobarbital.