Anti-epileptics

Question 1

Seizure causes

Answer 1

Head injury; stroke, brain tumors, hypoglycemia, fever, hypoxia, withdraw from chronic alcohol use and conditions that alter neuronal function
Acute changes in: availability of excitatory neurotransmitters (e.g. Ingestion of toxin domoate- structural analog of glutamate) or antagonism of GABAa receptors- changes in effect of inhibitory neurotransmitters- penicillin causes seizures this way
Altered function of neural ion channels- rapid, synchronous, and uncontrolled spread of electrical activity

Question 2

Epilepsy

Answer 2

Involves a tendency for recurrent seizures; may have genetic abnormalities
Sufferers may:
-Display neurodevelopmental delay, memory problems and/or cognitive impairment
-Have other co-morbidities, e.g., depression, anxiety, or neuroendocrine disturbances

Question 3

3 Basic physiological mechanisms that fine tune neuronal signaling to prevent the repititious and synchronous firing characteristic of seizure at the cellular level

Answer 3

Na+ channel inactivation driven “refractory period”
K+ channel-mediated hyperpolarization
The “surround inhibition” concept- whereby activation of CNS neurons- activation of surrounding cells including GABA releasing neurons that modulate the firing of surrounding neurons and cells

Question 4

Focal seizures

Answer 4

Abnormality from a seizure focus spreads to adjacent areas via diffuse neuronal connections- unchanged mental status (simple partial)

Seizure that involves brain regions serving more complex functions (e.g., language, memory, and emotions)- focal seizures with altered mental status (or complex partial)

Question 5

Partial seizures with 2nd generalization

Answer 5

Seizure activity from focus spreads to subcortical areas and then spread to both hemispheres by thalamic activities

Question 6

1st generalized seizures

Answer 6

Abnormal synchronization between thalamic and cortical cells or neuronal networks; rapidly spread bilaterally to hemispheres
2 subtypes:
-Generalized convulsive (tonic-clinic or grand mal)- initial brief tonic phase, then colonic phase with muscle spasms (3-5min.); concludes with drowsiness/confusion
-Generalized or non-convulsive (absence seizure or petit mal)- abrupt unconsciousness and decreased muscle tone

Question 7

Classification of anti epileptic drugs

Answer 7

Mechanism based

Seizure type-based

Question 8

Mechanism based anti epileptic drugs

Answer 8

Na+ channel modulators: grouped into two subtypes

 - Enhancers of fast inactivation (ex: Phenytoin; Carbamezapine) 
 - Enhancers of slow inactivation (ex: Lacosamide) 

Ca+ channel blockers (2 sub-categories):

 - T-type Ca+channel blockers (ex: Ethosuximide; Valproic acid) 
 - High-voltage activated (HVA) Ca+ channel inhibitors (ex: Gabapentin, Pregabalin) 

Enhancers of GABA- mediated inhibition:

 - Modulators of GABAa receptor activity (ex: Benzodiazepines (e.g. Clonazepam); Phenobarbital)
 - Modulators of GABA levels in brain (ex: Gabapentin (increase GABA levels via HVA Ca+ channel), Tiagabine (specific GABA reuptake inhibitor) 

Inhibitors of Glutamate receptors:

 - Felbamate (NMDA receptor antagonist); Rufinamide 
 - Topiramide (AMPA/kainate receptor antagonism) 

Inhibitors of brain carbonic anhydrase

Question 9

Seizure

Answer 9

Episode of abnormal electrical activity in the brain causing involuntary movements, sensations, or thoughts
Results from excessive excitation, or from disordered inhibition of large populations of cortical neurons as seen in absence seizure

Question 10

Phenytoin MOA

Answer 10

Slows the rate of recovery of voltage activated Na+ channels from inactivation (i.e., prolong Na+ channel inactivation)
Action is voltage dependent (greater when membrane depolarized), use-dependent and time dependent

Poorly soluble in H2O
Used to treat partial & tonic clonic seizures
Abolishes tonic but may exaggerate clonic
Not used for absence seizure
Anti-seizure property is devoid of general CNS depression
New formulation- Fosphenytoin

Question 10

Phenytoin metabolism

Answer 10

Metabolized by liver CYP2C and CYP3A
Exhibits mixed order elimination kinetics at therapeutic concentrations: lower concentration- dose-dependent elimination by 1st order kinetics
higher concentration- saturation; zero order

Factors influencing bioavailability:
Binding to serum proteins (90% bind to Albumin)
Competition for protein binding
Valproate- increase phenytoin via competition for protein site

Question 11

Phenytoin drug interactions

Answer 11

Inducers or inhibitors of CYPs
Valproate- increase Phenytoin via decrease of CYP2C9 mediated metabolism
Phenytoin induces CYP3A4- increase metabolism of antiepileptic drugs Felbamate, Lamotrigine, Topiramide
Half life: 6-24 hrs at conc.

Question 12

Phenytoin adverse effects

Answer 12

Megaloblastic anemia- due to interference with folate metabolism- fetal hydrantoin syndrome (birth defects characterized by cardiac defects, malformation of ears, lips, mouth, nasal bridge, mental retardation, and microcephaly)

Gingival hyperplasia- condition in which gums extend over teeth due to collagen metabolism

Hirsutism- excessive hair growth

Stevens-Johnson’s syndrome and toxic epidermal necrosis (in Asian patients)- condition linked to a polymorphism in HLA (human leukocyte antigen) allele present in some ethnic populations

Metabolic bone disease- phenytoin interferes with vitamin D metabolism- decrease GIT Ca+ absorption

Cerebellar Syndrome and cognitive impairment- occurs at high serum levels