1. АНТИЕПИЛЕПТИЧНИ
ЛЕКАРСТВА (резюме)
Доц. д-р Иван Ламбев

3. 1. Карбоксамиди (ензимни индуктори на CYP450):
Carbamazepine (+ невропатична болка – на n. trigeminus,
постхерпетична и др.), Oxcarbazepine
2. Хидантоини: Phenytoin (ензимен индуктор; показан и при
дигиталисова интоксикация)
3. Барбитурати (Phenobarbital – ензимен индуктор с > t1/2) и техни
аналози (Primidone – prodrug)
4. Сукцинимиди: Ethosuximide (casp. 250 mg – petit mal)
5. Валпроати (ензимни инхибитори): Sodium valproate (Depakin®)
6. Бензодиазепини: Clonazepam, Clorazepate, Diazepam (СПП 99%,
t1/2 43 h, amp. 10 mg/2 ml i.m./i.v., Lorazepam, Nitrazepam
7. Аналози на ГАМК: Gabapentine, Tiagabine
8. Хетерогенни антиконвулсанти: Lamotrigine (глутаматен
инхибитор), Levetiracetam, Pregabalin (парциални гърчове,
периферна невропатична болка), Topiramate, Vigabatrin

4. МЕХАНИЗЪМ НА ДЕЙСТВИЕ    GABA Na+ Ca2+ Barbiturates Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin
МЕХАНИЗЪМ НА
ДЕЙСТВИЕ 
Na+
Ca2+
Carbamazepine
Lamotrigine
Oxcarbazepine
Phenytoin
Topiramate
Valproate
Ethosuximide
Levetiracetam
Pregabalin
Valproate  

5. 

6. Инхибирането на потенциал-зависимите Na+-канали 
Инхибирането на потенциал-зависимите Na+-канали
в ЦНС намалява глутаматната екзоцитоза.

7. 

8. INDIVIDUAL ANTIEPILEPTICS
▼CARBAMAZEPINE blocks voltage-dependent sodium ion channels,
reducing membrane excitability. The t1/2 of drug falls from 35 to
20 h over the first few weeks of therapy due to the induction of hepatic
enzymes that metabolize it as well as other drugs (including adrenal
corticosteroids, hormonal contraceptives, theophylline and warfarin.
Standard tablets are taken twice a day. Carbamazepine is a drug of
first choice for focal and secondary generalized epilepsy but
aggravates myoclonic and absence seizure. It is useful for treatment
of trigeminal neuralgia, postherepetic pains etc.
Adverse reactions (ARs): reversible blurring of vision, diplopia,
dizziness, ataxia, depression of AV conduction, skin rashes, liver and
kidney dysfunction.

9. ▼VALPROIC ACID (Sodium valproate) acts by inhibiting GABA
transaminase and increases the concentration of inhibitory neuro-
transmitter GABA at its receptors. Valproic acid has t1/2 13 h and
90% bound to plasma albumin. It is a nonspecific inhibitor of meta-
bolism, and inhibits its own metabolism, and that of lamotrigine,
phenobarbital, phenytoin and carbamazepine. Valproic acid is
effective for treatment of generalized and partial epilepsy, febrile
convulsion and post-traumatic epilepsy.
ARs can be troublesome: weight gain, teratogenicity, polycystic
ovary syndrome, and loss of hair which grows back curly.
Nausea can be a problem, rarely, liver failure (risk maximal at
2–12 weeks). Ketone metabolites may cause confusion in urine
testing in diabetes mellitus.

10. ▼PHENYTOIN (t1/2 6–24 h) is a potent inducer of hepatic metabo-
lizing enzymes affecting itself and other drugs (carbamazepine, war-
farin, adrenal and gonadal steroids, thyroxine, tricyclic antidepressant,
doxycycline, vitamin D, folate). Drugs that inhibit phenytoin metabolism
include: valproic acid, cimetidine, co-trimoxazole, isoniazid, chloram-
phenicol, some NSAIDs, disulfiram. Phenytoin is 90% bound to plasma
albumin and small changes in binding will result in a higher concentra-
tion of free active drug. It is used to prevent all types of partial seizure,
generalized seizure and st. epilepticus. It is not used for absence attacks.
ARs: impairment of cognitive function (which has led many physicians to
prefer carbamazepine and valproate), sedation, hirsutism, skin rashes,
gum hyperplasia (due to the inhibition of collagen metabolism), hyper-
glycemia, anaemia, osteomalacia.

11. Saturation kinetics. Phenytoin is extensively hyd-
roxylated in the liver and this process becomes
saturated at about the doses needed for therapeutic
effect. Thus phenytoin at low doses exhibits first-
order kinetics but saturation or zero-order kinetics
develop as the therapeutic plasma concentration
range (10–20 mg/L) is approached, i.e. the dose
increments of equal size produce disproportional rise
in steady-state plasma concentration.

12. Нелинеарна зависимост м/у ДД фенитоин и неговите Css-
плазмени концентрации при 5 пациента: ТПК mcmol/.
Нужно е прецизиране на ДД (евент. мониториране).

13. ▼BENZODIAZEPINES (in status epilepticus)
Diazepam given intravenously or rectally is highly effective for
stopping continuous seizure activity, especially generalized tonic-
clonic status epilepticus. The drug is occasionally given orally on
a long-term basis, although it is not considered very effective in
this application, probably because of the rapid development of
tolerance. A rectal gel is available for refractory patients who need
acute control of bouts of seizure activity.
Lorazepam appears in some studies to be more effective and
longer-acting than diazepam in the treatment of status epilepticus
and is preferred by some experts.
Clonazepam (t1/2 25 h) is a benzodiazepine used as a
second line drug for treatment of primary generalized epilepsy
and status epilepticus.

14. Cl- GABA GABAA- benzo- diazepine receptor complex
Clonazepam, Clorazepate,
Diazepam, Lorazepam,
Nitrazepam
GABA
GABAA-
site
BDZs
site +
GABAA-
benzo-
diazepine
receptor
complex +
Cl- +
Barbitu-
rate sate
Barbiturates
By Bennett and Brown (2003)

15. ▼BARBITURATES (enzyme inducers)
Antiepilepsy members include phenobarbital (phenobarbitone –
( t1/2 100 h), methylphenobarbital and primidone (which is
largely metabolized to phenobarbital, i.e. it is a prodrug). They are
still used for generalized seizures; sedation is usual.
Primidone and its
active metabolites
Basic & Clinical
Pharmacology –
10th Ed. (2007)

16. ▼LAMOTRIGINE (t1/2 6–24 h) inhibits excitory neurotransmitter
glutamate. Lamotrigine is effective for treatment of partial and
secondarily generalized tonic-clonic seizure. It is generally well
tolerated but may cause serious ARs of the skin, including
Stevens–Johnson syndrome and toxic epidermal necrolysis.
▼TOPIRAMATE (t1/2 21 h) is used as adjunctive treatment for
partial seizure, with or without secondary generalization. ARs:
sedation, weight loss, acute myopia, raised intraocular pressure.
▼ETHOSUXIMIDE (t1/2 55 h) blocks T-type calcium ion
channels. It is active in absence seizures (petit mal).
ARs: gastric upset, CNS effects and allergic reactions.

17. Stevens–Johnson syndrome

18. MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS

19. ИЗБОР НА АНТИЕПИЛЕПТИЧНО ЛЕКАРСТВО
Grand mal: I избор – валпроати или Lamotrigine.
Алтернатива – Carbamazepine, Topiramate или Phenytoin
Petit mal: I избор – Ehosuximide или валпроати.
Алтернатива – Clonazepam или Lamotrigine
Парциални гърчове: I избор – Carbamazepine или
валпроати.
Алтернатива – Phenytoin, Lamotrigine, Vigabatrin, Topiramate
Status epilepticus: I избор – Diazepam или Lorazepam (i.v.)
Алтернатива – Phenobarbital (i.m./i/v.)

20. Treatment of status epilepticus in adults
Patient in opisthotonus (grand mal)

21. АЛТЕРНАТИВНИ
МЕТОДИ ЗА
ЛЕЧЕНИЕ НА
ЕПИЛЕПСИЯТА:
Хирургия +
лазертерапия