Anti-epilepsy Agents

Dr Gareth Noble
Aims
 To describe the pathophysiology of epilepsy
 To determine the pharmacological agents
used
 Mechanism of action
 Contra-indications
 Adverse effects
 Patient management
Introduction
 1 person in 20 will have an epileptic seizure at some
time in their life
 Epilepsy is diagnosed on the basis of two or more
epileptic seizures.
 Around 450,000 people in the UK have epilepsy (40
million people worldwide)
 A seizure is triggered by a sudden interruption in the
brain's highly complex electro-chemical activity

(National Society for Epilepsy UK)

Age/Incidence
Brain

 100 billion neurons

 Control centre:
 temperature
 sensory input
 motor control
 emotion
 thought?
 body functions
Taken from OUP Illustration Resource, 2002
 Gross anatomy

Front part of the brain;

involved in planning, organizing, problem solving,
selective attention, personality
and a variety of "higher cognitive functions"
including behavior and emotions.
Gross anatomy
The parietal lobes contain the primary
sensory cortex which controls
sensation (touch, pressure).
Gross anatomy

Region in the back of the

brain which processes
visual information.
 Gross anatomy

These lobes allow a person to

distinguish smells and are
believed to be responsible
for short-term memory.
Structure
Action Potential
Synapse Activity
 Seizures are a symptom of an underlying CNS
dysfunction
 It is an abnormal, uncontrolled electrical
discharge from neurons
 Cell membrane disruptions (permeability)
 Altered ion distributions (chemical balance)
 Decreased neurotransmitters (Ach and GABA)
 Everyone has seizure threshold
Classification of Seizures
 Partial:
 Simple partial seizures (no loss of consciousness)
 With motor symptoms
Dependant on which
 With sensory symptoms area of the brain
 With autonomic symptoms
 Only involve 1 hemisphere
 Complex partial (loss of consciousness)
 Simple followed by loss of consciousness
 Impaired at the onset
 Unclassified:
 Classification not possible to problems with
diagnosis – suspected

 Generalised (affect whole brain with loss of

consciousness):
 Clonic, tonic (1min) or tonic-clonic (2-4min):
muscle spasm (extensors), respiration stops,
defecation, salivation, violent jerks
 Myoclonic: seizures of a muscle or group of
muscles
 Absence: Abrupt loss of awareness of
surroundings, little motor disturbance, mostly
children
 Atonic: loss of muscle tone/strength
Pathological Basis
 Abnormal electrical discharge in the brain
 Coordinated activity among neurons depends on a
controlled balance between excitation and inhibition
 Any local imbalance will lead to a seizure
 Imbalances occur between glutamate-mediated
excitatory neurotransmission and gamma-
aminobutyric acid (GABA) mediated inhibitory
neurotransmission
 Generalised epilepsy is characterised by disruption
of large scale neuro-networks in the higher centres.
Normal Processes
 Depolarising Na+ and Ca++ ionic current
shifts are activated by glutamate receptors
 Repolarising K+ currents are mediated by
GABA receptors
 Hyperpolarisation is mediated by GABAa
receptors creating an influx of Cl- =>
inhibition of impulse generation.
 Any defect causes the neuron to be closer to
the all or none threshold for an AP =
HYPEREXCITABLE STATE.

 Leading to instability between excitation and

inhibition => Epilepsy
Other possible causes

 Inherited mutations of proteins involved in

the ion channels

 Reduction in the activity of homeostatic

ATPase pumps within neuron cell membranes
Basis of Pharmacological Rx
Most anti-epileptic agents act either by blockade
of depolarisation channels (Na+ and Ca++)

OR

Enhancing the activity of GABA

(neurotransmission inhibition)
5 Categories of Anti-epileptic Drugs
 All classifications are based upon chemistry:
 Hydantoins
 Succinimides
 Benzodiazepines
 Barbiturates
 Miscellaneous
Hydantoins - Phenytoin (Dilantin)
 Use for pts with Tonic-Clonic seizures

 Acts to promote intracellular removal of sodium during the

refractory period
 Antagonism (blocking) of Na+ channels to reduce excitability
 Antagonism of Ca++ channels
 Potentiation (activation) of GABA receptors to promote the
inhibitory role of GABA

 Can be used in the Rx for neuropathic pain and cardiac

arrhythmias
 Pharmacokinetics:
 Slowly absorbed from gut, use a slow IV if rapid
action is required
 Avoid IM – muscle damage
 Eliminated by hepatic biotransformation
 Can measure amount of free agent in the saliva
 Adverse effects:
 Nausea & Vomiting
 Impaired brainstem & cerebellar function (dizziness,
tremor, nervousness, blurred vision)
 Chronic congestive tissue defects (gun hyperplasia, acne)
 Skin rashes
 Folic acid and Vit. D deficiency (increase metabolism)

 Contraindications: increases metabolism of the

contraceptive pill, anti-coagulants, and pethidine
Succinimides – Ethosuximide (Zarontin)
 Use for pts with Absence seizures

 Acts by antagonising Ca++ channels in the

thalamocortical relay neurons => prevention
of synchronised neuronal firing => raising AP
threshold
 Pharmacokinetics:
 Almost complete absorption from the gut
 Extensive metabolism in the liver with a long
half-life (2-3 days)
 Plasma and salivary concentrations correlate well
for monitoring purposes
 Adverse effects:
 Nausea, vomiting and anorexia
 Cerebellar disturbance (drowsiness, dizziness,
photophobia, headache, depression)
 Skin irritation
 Agranulocytosis is rare but could occur
 Not to be used when pregnant (teratogencity)

 Contraindications: may make tonic-clonic seizures

worse
Bensodiazepines – Clorazepam
(Klonopin), Diazepam (Valium)
 Act by potentiating the actions of GABA
causing neurotransmission inhibition
(primarily in the CNS)

 Can be used to induce sleep (high dose),

anticonvulsant therapy and reduction in
muscle tone.
 Pharmacokinetics:
 Well absorbed from the gut
 Lipid soluble to ensure ready prentration of the
blood brain barrier
 Metabolised in the liver to create active agents
(prolonged therapeutic action)
 Slow elimination from body
 Adverse effects:
 Drowsiness, lightheadness, confusion
 Impaired memory
 Muscle weakness
 Tolerance (very common)
 Dependence – withdrawal effects could last up to
3 weeks
Barbiturates – Phenobarbital (Luminal)
 Used for tonic-clonic seziures.

 Act by increasing the duration of Cl- ion channel

opening by activating neuronal GABAa receptors
 Causing hyperpolarisation of the AP, making it less
likely to fire again
 Essentially, acts like GABA and can even potentiate
the effects of GABA when present.
 Pharmacokinetics:
 Almost complete absorption
 Elimination is by heptic and renal (25% excreted
unchanged)
 Biotransformed in the liver into 2 active
metabolites
 Plasma concentrations relate poorly to seizure
control, use only for monitoring of patient
compliance.
 Adverse effects:
 CNS effects (sedation and fatigue)
 Restlessness/Hyperactivity
 Folate deficiency
 Tolerance
 Dependence with physical withdrawal reactions
 Adverse drug-drug reactions (contraception and warfarin).

 Contraindications: Do not use with patients with respiratory

depression, children or elderly.
 NOTE: low therapeutic index means more toxic and
overdose can have serious consequences
Miscellaneous Agents – Carbamazepine
(Tegretol)
 Used in most epilepsy types.
 MoA not fully understood but believed to be
related to:
 Antagonist action of Na+ channels to inhibit
repetitive neuronal firing
 Decreasing the production (or release) of
glutamate (excitatory chemical)
 Can also be used in the Rx of neuropathic
pain
 Pharmacokinetics:
 Slow and incomplete absorption
 Metabolised in the liver – creates an expoxide metabolite
that can have a weak therapeutic effect
 Relatively long half-life (1-2 days)
 Potency decreases overtime therefore need to increase
dose to ensure adequate control of seizures
 Plasma and salivary concentrations correlate well to
clinical effectiveness
 Adverse effects:
 Nausea & vomiting (especially early Rx),
constipation, diarrhoea and anorexia
 Skin irritation
 CNS toxcity – dizzy, drowsy, confusion
 Bone marrow depression (rare)
 Drug-drug reactions (contraception, warfarin)

 Contraindications: see drug-drug reactions.

Sodium Valproate
 Use in all forms of epilepsy, as it suppresses
the initial seizure discharge and its spread.
 Clinical actions are:
 Antagonism of Na+ and Ca++ channels
 Potentiation of GABA
 Attenuation of Glutamate
 Can be fast acting due to Na+ MoA, although
the full Rx effect usually takes weeks.
 Pharmacokinetics:
 Well absorbed from gut (should be taken with
food to counteract gastric irritation)
 Extensively metabolised in the liver
 Rapidly transported across the blood brain barrier
 Monitor plasma concentration for patient
compliance only
 Adverse effects:
 GI upset (Nausea, vomiting, anorexia, abdominal pain and diarrhoea)
 Weight gain (appetite stimulation)
 Transient hair loss
 Tremor
 Coma (rare)
 Thrombocyptopenia (platelets)
 Oedema
 Severe hepatotoxicity (liver damage)

 Contraindications: People with liver damage or a history

hepatic dysfunction
Vigabatrin
 Only used in conjunction with other agents when pt
becomes resistant (due to tolerance) or poorly
tolerates
 Effective in partial epilepsy but with restricted used
due to severe adverse effects (vision)
 MoA: completely different to other agents as it is a
structural analogue of GABA that the enzyme that
normally inactivates GABA will degrade instead of
GABA.
 More GABA available to inhibit neuron transmission
 Pharmacokinetics:
 Rapidly absorbed from the gut
 Unchanged by renal processes
 Intermediate half-life (hrs)
 Blood concentrations are of no value.
 Adverse effects:
 Sedation, fatigue, dizziness, nervousness,
irritability, depression, impaired concentration.
tremor (CNS effects)
 Psychotic reactions (check pt history)
 Visual defects after prolonged use
 Weight gain and oedema
Lamotrigine (Lamictal)
 Used for partial seizures in adults only
 Acts by the inhibition (antagonism) of neuronal
Na+ channels but is highly selective (onlu
neurons that synthesise glutamate and aspartate)
 Additionally, decrease glutamate release
 Pharmacokinetics: well absorbed, extensively
metabolised in the liver and has a long half-life.
 Adverse effects:
 Fever, influenza-like symptoms
 Skin irritation
 GI disturbances (vomiting, diarrhoea)
 CNS effects (drowsiness, headache, dizziness,
double vision)

 Contraindications: Pts with hepatic

impairment
Gabapentin (Neuronitin)
 Used for partial seizures in adults
 Designed to be a structural analogue of
GABA but it does not mimic GABA in the
brain.
 Acts via:
 Increased synthesis and release of GABA
 Decrease degradation of GABA
 Inhibition of Ca++ channels
 Pharmacokinetics:
 Incompletely absorbed in the gut
 Excreted unchanged via kidney processes
 Short half-life
 Adverse effects:
 CNS effects (dizzy, drowsy, fatigue, headache, double
visions)
 Nausea and vomiting
 Contraindication: be careful with sudden withdrawal
in the elderly due to kidney effects and alterations in
acid-base balance.
 That’s All Folks!!!

Thank you.

Any
Questions?
Textbook References
 Karch AM (2006) Focus on Nursing Pharmacology,
3rd Edition. Lippincott Williams & Wilkins
 Rang et al (2003) Pharmacology, 5th Edition.
Churchill Livingstone.
 Lilley et al (2005) Pharmacology and the Nursing
Process, 4th Edition. Mosby
 Page et al (2002) Integrated Pharmacology, 2nd
Edition. Mosby.
 Martini (2005) Principles of Anatomy and
Physiology, Pearson Education Publishers