Pharmacology for Treatment of Seizures

Disorder of the brain characterized by an enduring predisposition to generate epileptic seizures and by the neurobiological, cognitive, psychological and social consequences of the condition.  Requires the occurrence of atleast one epileptic seizure

Sudden imbalance between excitatory and inhibitory forces in the cortical neurons... too much excitation

subjective disturbance of perception that represents the start of certain seizures

the actual seizure

the period after the seizure when the individual is amnesic confused and disoriented

• LOSS of consciousness
• Entire cortex affected at once
• EEG shows general spike and wave pattern

• Consciousness is NOT lost
• Seizures in specific part of the brain
• EEG is focal

last 2-5 minutes

• Loss of consciousness - no warning
• Tonic Stage - patient falls and cries out
• Clonic Stage - generalized bisynchronous rhythmic forceful jerking movements
• Post-Ictal Stage - exhaustion, sleep, disorientation, amnesia

• may occur up to 100 times a day
• can be provoked
• EEG - 3 Hz "spike and wave" pattern
• 2-20 sec

• Abrupt loss of consciousness-no warning or loss of posture
• Clonic Movements-Twitching of the eyes and hands
• Abrupt consciousness
• Resumption of normal activities

• Focal, Cortical
• Aura - Altered sensations, illusions/hallucinations
• can become tonic clonic

• no loss of consciousness
• asymmetrical convulsion, localized sensory disturbances
• no postictal stage

• Psychomotor/temporal lobe
• impairment of consciousness
• differentiate from psychosis and night terrors
• can become tonic clonic

• 4 A's
• Aura -often olfactory or epigastric 
• Alteration of consciousness
• Automatisms/strange behavior
• Amnesia

two or more seizures without recovery of consciousness

single seizure lasting more than 20-30 minutes

life threatening... must stop as soon as possible

AED's try to stop the spread of seizures.

• Prevent post-tetanic potentiation
• Prolong refractory period
• Potentiate inhibitory activity
• Reduce excitatory activity
• Increase excitatory synaptic threshold

Phenytoin, Carbamazepine, Valproate

Stops the action potential and therefore stops the spread

Barbiturates, Benzodiazepines, Valproate

Ethosuximide

• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine

• Ethosuximide
• Clonazepam

• Valproic Acid
• Lamotrigine

partial, tonic clonic, status epileptics

also used for treatment of trigeminal neuralgia

Digoxin-induced AV-block

blocks sodium channels to prevent spread

• eliminated by zero-order kinetics
• narrow therapeutic window
• mostly bound to albumin
• inactivated by P-450 
• no half life

• CNS
• Nystagmus, ataxia, dysarthria, decreased coordination, mental confusion

• GI
• Nausea, vomiting

• Hypersensitivity Reactions
• rash, t cell mediated, type 4- not dangerous but lets you know that the patient could possibly go to Steven's Johnson Syndrome... if SJS occurs then take them off the drug immediately

Hirsutism

• Connective Tissue
• Gingival Hyperplasia
• Coarsening of facial features

• Folic Acid Deficiency (blocks deconjugases)
• macrocytic anemia, teratogenic

Osteomalacia

• Pregnancy
• folic acid deficiency
• fetal hydantoin syndrome
• hemorrhagic disease in the newborn
• reduced efficacy of OC's

Partial, tonic clonic, status epilepticus

Binds to the barbiturate binding site on GABA_A receptors and prolongs the chloride channel opening

induces P-450 enzymes in the liver

• CNS
• sedation, ataxia, nystagmus, impaired cognition, hyperactivity in children

folate deficiency

• Pregnancy (Category D)
• teratogenic
• hemorrhagic disease in the newborn
• reduced efficacy of OC's

• Contraindications
• acute intermittent porphyria

• Partial seizures, tonic clonic 
• trigeminal neuralgia (drug of choice)
• Bipolar disorder (alternative to lithium)
• Neurogenic Diabetes Insipidus (stimulates ADH)

• Mechanism
• blocks sodium channels to prevent spread

• Pharmacokinetics
• 80% bound to plasma proteins
• induces P-450 enzymes

Partial and tonic clonic seizures

metabolized to phenobarbital and PEMA

• main action is through the phenobarbital
• reduces seizure spread by enhancing GABA

• SE, CI, DI
• Intense sedation, dizziness, and nausea - transient
• also any side effects of phenobarbital

• CNS
• dizziness, ataxia, vertigo, nystagmus, blurred vision

• Hemopoietic complications
• thrombocytopenia, agranulocytosis, aplastic anemia

• Liver toxicity
• cholestatic jaundice

SIADH

• Pregnancy (category D)
• teratogenic (craniofacial and limb abnormalities)
• Hemorrhagic Disease of the Newborn
• Reduced efficacy of OC's

Absence seizure (drug of choice)

blocks calcium channels to prevent the spike and wave

• CNS
• drowsiness, lethargy

• GI
• nausea vomiting

• Absence Seizures
• Anxiety Disorders

blocks seizure spread by enhancing GABA_A

• Side Effects
• drowsiness, ataxia, impaired cognition, memory and behavioral changes, 

Tolerance develops

tonic clonic, absence, complex partial seizures

• Other uses
• Bipolar disorder
• Migraine prophylaxis

• Mechanism
• increases the synthesis of GABA
• blocks sodium channels

• Hypersensitivity reactions
• hepatitis, pancreatitis
• (liver function test before treatment)

Alopecia - treat with baby shampoo

Tremor - fine action tremor of hand

• GI
• nausea, vomiting (give sodium salt to combat this)

Pregnancy (Category D)

tonic clonic, absence, complex partial seizures

Bipolar disorder

• Mechanism
• blocks sodium channels
• Suppresses release of glutamate

• Side Effects
• Rash - Stevens-Johnson Syndrome

• Gabapentin
• partial seizures
• Secondarily generalized tonic clonic
• commonly used for neuropathic pain
• enhances GABA
• reduces glutamate levels

• Tiagabine
• Inhibits GABA uptake
• rerefractory partial and secondarily generalized seizures

• Oxcarbazepine
• Analogue of carbamazepine
• Refractory partial and generalized tonic clonic

• Levetiracetam
• Mechanism unknown
• Refractory partial seizures

• Felbamate
• Refractory complex partial epilepsy
• Refractory Lennox-Gastaut syndrome
• blocks NMDA receptors and calcium channels
• blocks sodium channels to prevent spread
• Aplastic anemia
• Hepatic Failure

• Topiramate
• Multiple mechanisms of action
• migraine prophylaxis
• Angle Closure glaucoma and renal stones

• Zonisamide
• blocks sodium and calcium channels
• CI in pts with sulfa allergies

• Vigabatrin
• increases GABA levels

Lorazepam or Diazepam (IV)

if that doesnt work then try phenytoin or Fosphenytoin(iv version)

if that doesnt work then Phenobarbital (IV)

if that doesnt work put them into a coma

seizure freedom for more than 2 years

• Favorable factors
• control achieved easily on one drug at low dose
• no previous attempts and withdrawal
• normal neurologic exam and EEG
• primary generalized seizures

• Teratogenic Effects (first trimester)
• Valproate
• Phenytoin

• Acute Hemorrhagic Disease of the Newborn
• Phenobarbital
• Primidone
• Phenytoin
• Carbamazepine

• Failure of OC's
• Carbamazepine
• Phenobarbital
• Primidone