Antiseizure drugs

Question 1

Phenytoin, fosphenytoin

Answer 1

• Cyclic ureide
• MOA
• block high-frequency firing of neurons through action on VG Na⁺ channels
• decrease synaptic release of glutamate
• Kinetics
• zero-order
• highly bound to plasma proteins
• no active metabolites
• dose-dependent elimination, t_1/2 12-36h
• fosphenytoin is for IV, IM routes
• Clinical
• generalized tonic-clonic seizures, partial seizures
• Tox, int.
• tox: diplopia, ataxia, gingival hyperplasia, hirsutism, neuropathy
• int: any drug that binds to plasma proteins

Question 2

Phenobarbital (cyclic ureide)

Answer 2

• MOA
• enhances phasic GABA_A receptor responses, reduces excitatory synaptic responses
• Kinetics
• nearly complete absorption, not significantly bound to plasma proteins
• peak conc in 0.5-4h, no active metabolites, t_1/2 varies from 75-125h
• Clinical
• generalized tonic-clonic seizures, partial seizures, myoclonic seizures, generalized seizures, neonatal seizures, status epilepticus
• Tox, int.
• tox: sedation, cognitive issues, ataxia, hyperactivity
• int: so many drugs

Question 3

Ethosuximide

Answer 3

• Cyclic ureide
• MOA
• reduces low-threshold Ca²⁺ currents (T-type)
• Kinetics
• well absorbed orally, peak levels in 3-7h, not protein-bound, completely metabolized to inactive compounds, t_1/2 typically 40h
• Clinical
• absence seizures
• Tox, int.
• tox: nausea, headache, dizziness, lethargy
• int: valproate, phenobarbital, phenytoin, carbamazepine, rifampacin

Question 4

Carbamazepine

Answer 4

• Tricyclic
• MOA
• blocks high-frequency firing of neurons through action on VG Na⁺ channels
• decreases synaptic release of glutamate
• Kinetics
• well absorbed orally, peak levels in 6-8h, no significant protein binding, metabolized in part to active 10-11-epoxide
• t_1/2 8-36h
• Clinical
• generalized tonic-clonic seizures, partial seizures
• Tox, int.
• tox: nausea, diplopia, atazia, hyponatremia, headache
• int: many

Question 5

Diazepam

Answer 5

• MOA
• potentiates GABA_A responses
• Kinetics
• well absorbed orally, rectal administration gives peak conc in approx 1h with 90% bioavailability
• IV for status epilepticus
• highly protein bound, extensively metabolized to several active metabolites, t_1/2 2d
• Clinical
• status epilepticus, seizure clusters
• Tox, int.
• tox: sedation
• int: additive with sedative-hypnotics

Question 6

Clonazepam

Answer 6

• MOA
• potentiates GABA_A responses
• Kinetics
• >80% bioavailability, extensively metabolized but no active metabolites, t_1/2 20-50h
• Clinical
• absence seizures, myoclonic seizures, infantile spasms
• Tox, int.
• tox: sedation
• int: additive with sedative-hypnotics

Question 7

Vigabatrin

Answer 7

• GABA derivate
• MOA
• irreversibly inhibits GABA-transaminase
• Kinetics
• 70% bioavailable, not bound to plasma proteins, not metabolized
• Clinical
• partial seizures, infantile spasms
• Tox, int.
• tox: drowsiness, dizziness, psychosis, visual field loss
• int: minimal

Question 8

Valproate

Answer 8

• MOA
• blocks high-frequency firing of neurons, modifies amino acid metabolism
• Kinetics
• well absorbed from several formulations, highly bound to plasma proteins, extensively metabolized, t_1/2 9-16h
• Clinical
• generalized tonic-clonic seizures, partial seizures, generalized seizures, absence seizures, myoclonic seizures
• Tox, int.
• tox: nausea tremor, weight gain, hair loss, teratogenic, hepatotoxic
• int: many

Question 9

Lamotrigine

Answer 9

• MOA
• prolongs inactivation of VG Na⁺ channels
• acts presynaptically on VG Ca²⁺ channels, decreasing glutamate release
• Kinetics
• well absorbed orally, no significant protein binding, extensively metabolized but no active metabolites, t_1/2 25-35h
• Clinical
• generalized tonic-clonic seizures, generalized seizures, partial seizures, absence seizures
• Tox, int.
• tox: dizziness, headache, diplopia, rash
• int: many

Question 10

Levetiracetam

Answer 10

• MOA
• action on synaptic protein SV₂A
• Kinetics
• well absorbed orally, not bound to plasma proteins, metabolized to 3 inactive metabolites, t_1/2 6-11h
• Clinical
• generalized tonic-clonic seizures, partial seizures, generalized seizures
• Tox, int.
• tox: nervousness, dizziness, depression, seizures
• int: rare