Antiseizure drugs for partial and generalized tonic clonic seizures

Antiseizure drugs: partial and generalized
tonic-clonic seizures
Domina Petric, MD

Phenytoin
I.
30.3.2018.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

• Phenytoin is the oldest nonsedative antiseizure
drug.
• Phenytoin is a diphenyl-substituted hydantoin.
• It has much lower sedative properties than
compounds with alkyl substituents at the 5
position.
• A more suluble prodrug of phenytoin is
fosphenytoin.
• Fosphenytoin is available for parenteral use.
• This phosphate ester compound is rapidly
converted to phenytoin in the plasma.
Phenytoin
30.3.2018.
pharmacology.

Phenytoin alters:
• Na+, K+, and Ca2+ conductance
• membrane potentials
• concentrations of amino acids
• concentrations of the neurotransmitters
norepinephrine, acetylcholine and
γ-aminobutyric acid (GABA)
Mechanism of action
30.3.2018.
pharmacology.

• Phenytoin blocks sustained high-frequency
repetitive firing of action potentials.
• Phenytoin also blocks the persistent Na+
current.
• This drug paradoxically causes excitation in
some cerebral neurons.
• Phenytoin decreases the synaptic release of
glutamate and enhances the release of GABA.
Mechanism of action
30.3.2018.
pharmacology.

• At therapeutic concentrations, the major
action of phenytoin is to block Na+
channels and inhibit the generation of
rapidly repetitive action potentials.
• Presynaptic actions of glutamate and
GABA release probably arise from actions
other than those on voltage-gated Na+
channels.
Mechanism of action
30.3.2018.
pharmacology.

PARTIAL SEIZURES
GENERALIZED TONIC-CLONIC SEIZURES
(both primary and secondary)
Clinical use
30.3.2018.
pharmacology.

Pharmacokinetics
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pharmacology.

• Phenytoin is highly bound to plasma proteins.
• In uremia and hypoalbuminemia the
percentage of the drug that is bound
decreases and total plasma level too.
• Drug concentration in cerebrospinal fluid is
proportionate to the free plasma level.
• Phenytoin accumulates in brain, liver, muscle
and fat.
Pharmacokinetics
30.3.2018.
pharmacology.

• The elimination of phenytoin is dose-
dependent.
• At very low blood levels, phenytoin metabolism
follows first-order kinetics.
• As blood levels rise within the therapeutic
range, the maximum capacity of the liver to
metabolize phenytoin is approached.
• Further increases in dosage may produce very
large changes in the drug concentration.
Pharmacokinetics
30.3.2018.
pharmacology.

Therapeutic levels
30.3.2018.
pharmacology.

• A loading dose can be given either
orally or intravenously
(fosphenytoin).
• Start oral dose is 300 mg/day.
• If seizures continue, higher doses are
usually necessary: dose increment is
by 25-30 mg in adults.
Dosage
30.3.2018.
pharmacology.

• A common clinical error is to
increase the dosage directly from
300 mg/day to 400 mg/day
because of toxicity!
• Start dose for children is
5 mg/kg/day.
Dosage
30.3.2018.
pharmacology.

• Related to protein binding and metabolism.
• Phenytoin is 90% bound to plasma proteins.
• Other highly bound drugs (phenylbutazone,
sulfonamides) can displace phenytoin from
its binding site.
• Such displacement may cause a transient
increase in free drug.
30.3.2018.
pharmacology.
Drug interactions

• A decrease in protein binding
(hypoalbuminemia) results in decrease
in the total plasma concentrations of
drug, but not the free concentration.
• The protein binding of phenytoin is
decreased in the presence of renal
disease.
30.3.2018.
pharmacology.
Drug interactions

• Phenytoin has an affinity for thyroid-
binding globulin.
• The most reliable screening test of
thyroid function in patients taking
phenytoin is measurement of
thyroid-stimulating hormone (TSH).
30.3.2018.
pharmacology.
Interference with laboratory tests

• Nystagmus and loss of smooth extraocular
pursuit movements occur early.
• Diplopia and ataxia are the most common
dose-related adverse effects requiring
dosage adjustment.
• Sedation usually occcurs only at higher
levels.
• Gingival hyperplasia, hirsutism.
30.3.2018.
pharmacology.
Toxicity

Long-term use is associated in some patients with:
• coarsening of facial features
• mild peripheral neuropathy: diminished
deep tendon reflexes in lower extremities
• abnormalities of vitamin D metabolism,
osteomalacia
• low folate levels and megaloblastic anemia
30.3.2018.
pharmacology.
Toxicity

Relatively rare.
Skin rash, fever, severe and exfoliative skin
lesions (rarely).
Lymphadenopathy.
Agranulocytosis rarely.
30.3.2018.
pharmacology.
Idiosyncratic reactions

30.3.2018.
pharmacology.
Carbamazepine
II.

• Carbamazepine is a tricyclic compound
effective in treatment of bipolar
depression.
• Ureide moiety (-N-CO-NH2) in the
heterocyclic ring is present in most
antiseizure drugs, also in carbamazepine.
• Spatial conformation is similar to that of
phenytoin.
30.3.2018.
pharmacology.
Carbamazepine

• Carbamazepine shows activity against maximal
electroshock seizures.
• It blocks Na+ channels at therapeutic
concentrations.
• It also acts presynaptically to decrease synaptic
transmission.
• Potentiation of a voltage-gated K+ current has
been also described.
30.3.2018.
pharmacology.
Mechanism of action

• Carbamazepine is not sedative in its usual
therapeutic range.
Indications:
• partial seizures
• generalized tonic-clonic seizures
• trigeminal neuralgia
• mania in some patients with bipolar disorder
30.3.2018.
pharmacology.
Clinical uses

• Peak levels after almost complete absorption in
most of the patients are usually achieved 6-8
hours after administration.
• Slowing absorption by giving the drug after
meal helps the patient tolerate larger total
daily doses.
• Distribution is slow.
• Volume of distribution is 1 L/kg.
30.3.2018.
pharmacology.
Pharmacokinetics

• The drug is approximately 70% bound to
plasma proteins.
• Carbamazepine has a very low systemic
clearance of approximately 1 L/kg/day at
the start therapy.
• The drug has a notable ability to induce
microsomal enzymes.
30.3.2018.
pharmacology.
Pharmacokinetics

One of the metabolites,
carbamazepine-10,11-
epoxide, has been shown
to have anticonvulsant
activity.
30.3.2018.
pharmacology.
Pharmacokinetics

• Carbamazepine is available only in oral form.
• Dose for children: 15-25 mg/kg/day.
• Dose for adults: 1 g, up to 2 g/day.
• Higher dosage: multiple divided daily doses.
• Extended release preparations: twice-daily
dosing.
• Therapeutic level just before the morning dose
(trough level): 4-8 mcg/mL.
30.3.2018.
pharmacology.
Dosage

• Related to the drug´s enzyme-inducing
properties.
The increased metabolic capacity of the hepatic
enzymes may cause a reduction in steady-state
carbamazepine concentrations and an increased
rate of metabolism for some drugs:
• primidone, phenytoin, ethosuximide,
valproic acid, clonazepam.
30.3.2018.
pharmacology.
Drug interactions

Valproic acid bay inhibit carbamazepine
clearance and increase steady-state
carbamazepine blood levels.
Phenytoin and phenobarbital may decrease
steady-state concentrations of
carbamazepine through enyzme induction.
30.3.2018.
pharmacology.
Drug interactions

• The most common dose-related adverse effects
are diplopia and ataxia.
• Diplopia often occurs first and may last less
than an hour during a particular time of day.
• Rearrangement of the divided daily dose can
remedy diplopia.
• Other dose-related complaints are mild GI
upsets, unsteadiness and drowsiness (higher
doses).
30.3.2018.
pharmacology.
Toxicity

• Hyponatremia and water intoxication have
occasionally occurred and may be dose related.
• Idiosyncratic blood dyscrasias include fatal
cases of aplastic anemia and agranulocytosis,
mostly in elderly patients with trigeminal
neuralgia and within the first 4 months of
treatment.
• The mild and persistent leukopenia is not
necessarily an indication to stop treatment.
30.3.2018.
pharmacology.
Toxicity

The most common
idiosyncratic reaction
is an erythematous
skin rash.
30.3.2018.
pharmacology.
Toxicity

30.3.2018.
pharmacology.
Phenobarbital
III.

Phenobarbital is one of the four
derivatives of barbituric acid
clinically useful as antiseizure
drugs together with
mephobarbital, metharbital and
primidone.
30.3.2018.
pharmacology.
Phenobarbital

• Phenobarbital may selectively suppress
abnormal neurons, inhibiting the spread
and suppressing firing from the foci.
• Phenobarbital suppresses high-
frequency repetitive firing in neurons in
culture through an action on Na+
conductance at high concentrations.
30.3.2018.
pharmacology.
Mechanism of action

• Also at high concentrations, barbiturates block
some Ca2+ currents (L-type and N-type).
• Phenobarbital binds to an allosteric regulatory
site on the GABAA receptor.
• It enhances the GABA receptor-mediated
current by prolonging the openings of the Cl-
channels.
• Phenobarbital can also decrease excitatory
responses.
30.3.2018.
pharmacology.
Mechanism of action

30.3.2018.
pharmacology.
Mechanism of action

30.3.2018.
pharmacology.
Clinical uses

30.3.2018.
pharmacology.
Primidone
IV.

• Primidone is 2-desoxyphenobarbital.
• Primidone is metabolized to
phenobarbital and
phenylethylmalonamide (PEMA): all
three compouns are active
anticonvulsants.
• Indications: partial seizures and
generalized tonic-clonic seizures.
30.3.2018.
pharmacology.
Primidone

• Primidone is completely absorbed, usually
reaching peak concentrations about 3 hours
after oral administration.
• It is generally distributed in total body
water.
• Volume of distribution is 0,6 L/kg.
• It is not highly bound to plasma proteins.
• 70% circulates as unbound drug.
30.3.2018.
pharmacology.
Pharmacokinetics

• It is metabolized by oxidation to phenobarbital.
• Both primidone and phenobarbital undergo
subsequent conjugation and excretion.
• Primidone has a larger clearance than most
other antiseizure drugs: 2 L/kg/day.
• Half-life is 6-8 hours.
• During chronic therapy, phenobarbital levels
derived from primidone are usually two to
three times higher than primidone levels.
30.3.2018.
pharmacology.
Pharmacokinetics

• Primidone is most efficacious with plasma
levels in the range of 8-12 mcg/mL.
• Dosage: 10-20 mg/kg/day.
• Primidone has to be started at low doses
with gradual increment over days to a few
weeks to avoid prominent sedation and GI
complaints.
30.3.2018.
pharmacology.
Dosage

The dose-related adverse effects are similar to
phenobarbital.
Drowsiness occurs early in treatment and may
be prominent if the initial dose is too large.
Gradual increments are indicated when
starting the drug both in children and adults.
30.3.2018.
pharmacology.
Toxicity

30.3.2018.
pharmacology.
Gabapentin, pregabalin
V.

• Gabapentin is an amino acid, an analog of
GABA.
• It is effective against partial seizures.
• Pregabalin is also GABA analog, closely related
to gabapentin.
• Pregabalin has been approved for both
antiseizure activity and for its analgesic
properties.
30.3.2018.
pharmacology.
Gabapentin, pregabalin

• Gabapentin and pregabalin do not act directly
on GABA receptors.
• They may modify the synaptic or nonsynaptic
release of GABA.
• Gabapentin is transported into the brain by the
L-amino acid transporter.
• Gabapentin and pregabalin bind avidly to the
α2δ subunit of voltage-gated Ca2+ channels.
30.3.2018.
pharmacology.
Mechanism of action

• Gabapentin is effective as an adjunct against
partial seizures and generalized tonic-clonic
seizures in dose up to 2400 mg/day.
• Gabapentin is also used for the treatment of
neuropathic pain.
• It is indicated for postherpetic neuralgia in
adults at doses of 1800 mg and above.
• Side effects: somnolence, dizziness, ataxia,
headache and tremor.
30.3.2018.
pharmacology.
Clinical use

• Pregabalin is approved for the adjunctive
treatment of partial seizures, with or without
secondary generalization.
• Dosage ranges from 150 to 600 mg/day, usually in
two or three divided doses.
• Pregabalin is approved for use in neuropathic pain,
including painful diabetic peripheral neuropathy
and postherpetic neuralgia.
• It is also approved for fibromyalgia and generalized
anxiety disorder.
30.3.2018.
pharmacology.
Clinical use

30.3.2018.
pharmacology.
Other
VI.

• mephenytoin
• ethotoin
• phenacemide
• oxcarbazepine
• eslicarbazine
• felbamate
• lacosamide
• lamotrigine
• levetiracetam
• retigabine
• rufinamide
• stiripentol
• tiagabine
• topiramate
• vigabatrin
• zonisamide
30.3.2018.
pharmacology.
Other

• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
Literature
30.3.2018.
pharmacology.

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