Anti-seizures Medication

Seizures are based on paroxistical dysfunctions of brain neurons (they appear suddenly,
uncontrollably and are transient), which can be focused or generalized, due to synchronous and
high frequency paroxistical activities. Manifestations of such a dysfunction may be motor, in the
form of tonic, clonic or tonic-clonic contractions, sensory, or other, depending on the physiological
role of the neurons involved in this dysfunction.
The constituted excitation will extends from close to close, in the oil spot, and may comprise more
or less extensive cerebral areas, up to the whole brain and, depending on this, the seizures may be
partial or generalized. The generalized ones are almost always accompanied by loss of
consciousness. Partial crises can evolve without loss of consciousness, a situation called simple
partial seizures, or loss of consciousness, called complex partial seizures.
Some generalized seizures are manifested in the form of tonic contractions followed by generalized
tonic-clonic contractions due to loss of consciousness and fall of the patient and are called great
malignant epilepticus (grand mal) or sometimes major seizures. Other generalized seizures are not
accompanied by convulsions or falls but are manifested in the form of sudden interruption of
normal activity with loss of contact with the outside environment for a short time, after which the
patient resumes his activity as if nothing had happened. These seizures are called absences, small
epileptic seizures (petit mal) or sometimes minor seizures.
Finally, a special condition is the clinical entity called status epilepticus which is practically a long-
lasting epileptic seizure.

Anticonvulsant drugs are substances that prevent the onset of seizures, and sometimes stop a
seizure, and are used in the treatment of epilepsy, which is why they are also called antiepileptic
drugs.
The mechanism of action of these drugs is estimated to be that they stop or prevent the onset of
the epileptogenic outbreak and prevent the spread of arousal from the epileptogenic outbreak to
the rest of the brain. In principle, these drugs interfere with the pathogenic mechanisms of seizures,
but these mechanisms are complex and most likely differ from one type of seizure to another. Most
often these drugs block sodium channels (carbamazepine, phenytoin) or T-type calcium channels
(ethosuximide), thus decreasing the excitation phenomena, or potentiate the activity of the GABA-
ergic system (barbiturates, benzodiazepines), favoring the inhibition phenomena. There are also
antiepileptic drugs that decrease the activity of excitatory amino acids in the brain, especially
glutamic acid (lamotrigine). These mechanisms make virtually all anticonvulsant drugs have a
sedative effect and potentiate the sedative effect of other substances, including alcohol.
Usually, drugs that block sodium channels (carbamazepine, phenytoin) are effective against tonic-
clonic seizures and the great epileptic seizure, without being effective in the small epileptic seizure
that sometimes even worsens, while drugs that block calcium channel (ethosuximide) are effective
against small epileptic seizures, without being effective in tonic-clonic seizures and grand mal.
However, there are also drugs that are effective in both tonic-clonic seizures and grand mal seizures
and petit mal seizures (valproic acid).
Pharmacokinetically, antiepileptic drugs generally behave like many other fat-soluble drugs.
Digestive absorption is generally good or very good. Plasma protein binding varies from drug to
drug. Some anticonvulsants, such as phenytoin, valproic acid and benzodiazepines, are highly
bound to plasma proteins. Elimination from the body is slow mainly by hepatic metabolism (but
there are exceptions to this rule). The half-life is generally long, most often over 12 hours. The
metabolism of these drugs is mainly through cytochrome P450 and many of them are enzyme
inducers.
The main therapeutic indication for anticonvulsant drugs is epilepsy. Their effect in this disease
consists in the progressive decrease of the frequency of convulsions until their disappearance, thus
allowing the control of the disease, the therapeutic efficacy being appreciated approximately 80%
of the treated patients.
The choice of the optimal drug is made according to the type of epilepsy, some being effective in
the great epileptic disease and in the tonic-clonic convulsions (carbamazepine, phenytoin,
phenobarbital), others in the small epileptic disease (ethosuximide), and others in all forms of
epilepsy (acid valproic, lamotrigine).
Side effects of antiepileptic drugs are relatively common. The most common side effect is sedation.
A negative aspect of all sedative drugs is decreased ability to learn and memorize. Also can
produce nystagmus, diplopia, ataxia, etc. Another category of side effects commonly encountered
with antiepileptic drugs derives from their enzyme-inducing properties. Through this mechanism
they can speed up the elimination from the body of other drugs administered concomitantly but
also of physiological substances such as some vitamins, especially vitamins B, D and K. This
makes epileptic patients treated with anticonvulsant drugs to have megaloblastic anemia due to
deficiency of folic acid, osteoporosis due to vitamin D deficiency, or hemorrhagic phenomena due
to vitamin K deficiency. Supplementation of vitamin intake in epileptic patients in chronic
anticonvulsant treatment is probably welcome. Also, by enzymatic induction, antiepileptic drugs
can aggravate porphyria.
Other common side effects include digestive phenomena such as nausea and vomiting and
dermatological side effects such as various rashes. Finally, antiepileptic drugs are teratogenic.
The chemical structure of antiepileptic drugs is very different from one drug to another.
Carbamazepine is an anticonvulsant with a similar chemical structure as tricyclic antidepressants
being effective in tonic-clonic seizures and in the grand mal, without being effective in petit mal,
which it even aggravates. In addition to epilepsy, carbamazepine is also effective in treating
neuralgic pain, especially trigeminal and glossopharyngeal neuralgia, and in tabetic pain, and is a
mood stabilizer.
The mechanism of action consists in blocking voltage-dependent sodium channels, which causes
a decrease in excitation phenomena in the central nervous system.
The main side effects are characteristic of antiepileptic drugs. Sedation is considered weak.
However, carbamazepine decreases the reaction rate, imposing caution in drivers, potentiates the
effect of other sedatives and alcoholic beverages and sometimes, at high doses, sedation is
accompanied by other neurological phenomena such as dizziness, diplopia, ataxia. It also has
enzyme-inducing effects especially in long-term treatment. In addition, carbamazepine can cause
some idiosyncratic side effects such as rash, blood dyscrasias, and toxic liver damage. It is
administered orally.
Phenytoin is an antiepileptic with a barbiturate-like chemical structure that is effective in major
epileptic seizures and tonic-clonic seizures, without being effective in petit mal. The mechanism
of action, as in the case of carbamazepine, is to block voltage-gated sodium channels. Like
carbamazepine, phenytoin may be effective in treating neuralgic pain. Phenytoin also has
antiarrhythmic properties.
Sedation is considered low intensity but other neurological side effects such as ataxia, diplopia,
vertigo, nystagmus, neuritis, choreiform movements are relatively common. In addition to the side
effects of all antiepileptics, phenytoin frequently causes gum hypertrophy, skin side effects such
as rashes, acne or hirsutism. Very rarely it can have serious immunological side effects such as
lupoid syndrome, lymphadenopathy, various blood dyscrasias.
There is also an intravenous injectable form of phenytoin, called phosphenytoin, used to treat status
epilepticus.
Phenobarbital is the main barbiturate used as an antiepileptic, being effective in tonic-clonic
seizures and in grand mal. Phenobarbital does not aggravate petit mal, and is sometimes even
effective in this disease. The mechanism of action consists in the allosteric potentiation of the
GABA action on the GABA-ergic receptors. It is completely absorbed from the digestive tract,
binds moderately to plasma proteins and is eliminated from the body by hepatic metabolism being
a very strong enzyme inducer. The main side effect is sedation. Enzyme-inducing phenomena are
common. It is used in patients with severe epileptic seizures or tonic-clonic seizures. It is also used
to treat non-epileptic seizures such as febrile seizures in young children.
Primidone is an effective antiepileptic in tonic-clonic seizures and grand mal, without being
effective in petit mal. Chemically it is a phenobarbital analogue which, through hepatic
metabolism, is transformed into phenobarbital. The mechanism of action of primidone is to block
voltage-activated sodium channels, as in the case of carbamazepine and phenytoin, to which is
added the potentiation of GABA-ergic effects by resulted phenobarbital. The effectiveness is
similar to the drugs described above and the side effects are characteristic of sodium channel
blockers and phenobarbital.
Etosuximide is an effective drug in minor epileptic seizures, without being effective in tonic-
clonic seizures or in grand mal. The mechanism of action is to block T-type calcium channels. The
drug is very well tolerated. Digestive disorders such as nausea and vomiting can rarely occur (the
risk is decreased if treatment is started with small doses that increase progressively). Very rarely
the drug causes idiosyncratic side effects such as rash or blood dyscrasias.
Valproic acid is a broad-spectrum antiepileptic and is effective in both tonic-clonic seizures and
major epileptic seizures and petit mal. It is also a mood stabilizing drug. The mechanism of action
is not very clearly specified. Under experimental conditions, valproic acid blocks voltage-gated
sodium channels and T-type calcium channels, increases the availability of GABA in GABA-ergic
synapses probably by inhibiting GABA-transaminase, and decreases the synaptic availability of
glutamic acid. The drug is relatively well tolerated but can relatively frequently cause digestive
disorders such as nausea and vomiting, increased serum transaminases and even toxic damage to
the liver, which can lead to toxic hepatitis, blood dyscrasias. The drug is used as an alternative to
phenytoin and carbamazepine in the treatment of tonic-clonic seizures and severe epileptic
seizures. In petit mal, ethosuximide is preferred.
Lamotrigine is another broad-spectrum antiepileptic, effective in both tonic-clonic seizures and
major epileptic seizures and petit mal. The drug works both by blocking voltage-activated sodium
channels and by decreasing the synaptic availability of glutamic acid, probably by decreasing its
release into the synaptic cleft. Side effects are, in principle, characteristic of antiepileptic drugs.
Sedation is considered to be of low intensity. Lamotrigine does not seem to decrease the ability to
learn and memorize. Neurological phenomena such as dizziness and visual disturbances and
dermatological phenomena and digestive side effects, especially nausea and vomiting, have been
reported.
Benzodiazepines, in principle, all have an anticonvulsant effect, but the antiepileptic effect of
these drugs is self-limiting in time and can disappear virtually completely after 2-6 months of
treatment, which limits their long-term use. Diazepam is most commonly used, usually
intravenously administered, for the treatment of seizures or for the treatment of status epilepticus.
In addition to diazepam, clonazepam is used relatively frequently as an antiepileptic, which is a
broad-spectrum antiepileptic and is effective in both tonic-clonic seizures and small epileptic
seizures. Clonazepam is mainly used to treat myoclonic seizures. Another benzodiazepine
considered a broad-spectrum antiepileptic is clobazam. The mechanism of action of
benzodiazepines is the allosteric modification of the GABA-ergic receptor in such a way that it
favors the binding of GABA to this receptor.
In addition to benzodiazepines and barbiturates, there are other drugs that influence the GABA-
ergic system and are used as antiepileptics. Tiagabine is a substance that inhibits GABA reuptake
from the synaptic space. GABA reuptake is done through 3 transporters marked GAT1-3, and
tiagabine preferentially inhibits GAT1 which is mainly found in the hippocampus. It is used to
treat tonic-clonic seizures in combination with other antiepileptics. The most important side effects
are tremor, dizziness and mental disorders. Vigabatrine is an inhibitor of GABA-
aminotransferase, an enzyme that metabolizes GABA, which causes the drug to increase the
availability of GABA in GABA-ergic synapses. It is effective in tonic-clonic seizures. May cause
tremor, dizziness, mental disorders. It can produce a progressive and irreversible narrowing of the
visual field. Gabapentin and pregabalin are GABA derivatives intended to influence endogenous
GABA kinetics. They are effective antiepileptics in tonic-clonic seizures and in the grand mal.
They also have an analgesic effect, especially in neuropathic pain. However, the mechanism of
action probably consists in blocking sodium and calcium channels and decreasing the release of
glutamic acid. They have interesting pharmacokinetics. It is well absorbed from the digestive tract
and crosses the blood-brain barrier well, most likely through the l-amino acid transporter (LAT).
It does not bind to plasma proteins, does not metabolize in the body, does not influence the
metabolism of other drugs and is eliminated from the body by urinary excretion, t1 / 2 being about
7 hours. As side effects may cause nausea, dizziness, tremor. They are used as a backup
antiepileptic, added to other antiepileptic drugs when they have not had a satisfactory effect.
Acetazolamide is a drug that is effective in petit mal without being effective in other types of
seizures, but its effectiveness is self-limiting over time. The mechanism by which acetazolamide
acts as an antiepileptic is unclear. The drug inhibits carbonic anhydrase, an enzyme that promotes
the formation of carbonic acid from carbon dioxide and water, and it is possible that inhibition of
this enzyme in the brain may be responsible for its anticonvulsant effect. It is possible that the
effect is also manifested by changing the brain concentration of carbonate ions that are known to
cross GABA-ergic chlorine channels and thus participate in the control of transmembrane
electrical potential. Acetazolamide is rarely used as an antiepileptic, only in the small epileptic
seizure and only for short periods of time, up to 3 months of treatment. An interesting use is in
epileptic women in whom epileptic seizures increase in frequency during menstruation.
Other antiepileptic drugs: Felbamate is a medicine that blocks glutamatergic receptors NMDA
and decreases the activity of GABA-ergic receptors in a barbiturate-like manner. It can cause
aplastic anemia and severe liver disease, making it a spare medicine. It is effective in tonic-clonic
seizures and in the grand mal. Retigabine seems to act by facilitating the activity of potassium
channels. It is effective in tonic-clonic seizures and in the grand mal. Topiramate is a drug that
acts on kinases that alter the phosphorylation of voltage-dependent and receptor-dependent ion
channels, thus influencing the activity of sodium, calcium and chlorine channels. It appears to be
a broad-spectrum antiepileptic, active in tonic-clonic seizures and major epileptic seizures but also
in minor epilepsy. Levetiracetam is a derivative of piracetam. The mechanism of action is not
known, but in the clinic, the drug has been shown to be effective in complex partial seizures.