Epilepsy Answers
Epilepsy Answers
Epilepsy Answers
• Seizure = neurons in the brain are synchronously firing (or active) when they are not
supposed to be .
SEIZURES IN EPILEPSY
• During a seizure, there is episodic high frequency discharge of impulses by a group of
neurons in the brain
• clusters of neurons in the brain become temporarily impaired and start to send out
many excitatory signals repeatedly (paroxysmal signals).
• These paroxysmal electrical discharges occur because of either:
• Too much excitation
• Not enough inhibition
ELECTRICAL SIGNALS IN THE BRAIN
• Each electrical signal that passes through a neuron is typically ions flowing in and out
through protein channels.
• In epilepsy, the ions of interest are Na+ and Ca2+ ions (influx causes depolarisation
excitability) and Cl 1- ions (influx causes hyperpolarisation inhibition)
Partial Seizure
All these generalised seizures involve both hemispheres of the brain and the patient loses
consciousness either briefly or for long periods of time
TONIC SEIZURE
• The muscles become stiff and flexed suddenly
• This can cause the patient to fall backward
CLONIC SEIZURE
• Involves violent muscle contractions – also known as convulsions
TONIC – CLONIC
• Patients experience a tonic phase where the muscles suddenly tense up followed by a
clonic phase where the muscles rapidly contract and relax.
ATONIC SEIZURE
• Muscle suddenly relax – floppy or jelly muscles
• This can cause the patient to fall forward (not backward like in tonic seizure)
MYOCLONIC SEIZURE
• Short muscle twitches – sometimes just a single twitch and sometimes many in a short
amount of time
ABSENCE SEIZURE
• Patients loses consciousness and then quickly regains consciousness
• Patient may appear “spaced out” – e.g. if they were walking, they might suddenly stand
still
DURATION OF SEIZURES
• Continuous seizure activity for 5 minutes or more without return of consciousness, or
recurrent seizures (2 or more) without an intervening period of neurological recovery is
called STATUS EPILEPTICUS
• usually falls under the tonic-clonic subtype
• Dangerous situation - can be life threatening if not treated immediately
• Patients experiencing status epilepticus are often treated acutely with diazepam
(benzodiazepine) injection – you wont be able to give this medicine orally to
someone with status epilepticus (remember they will have impaired consciousness
and wont be able to swallow) – Diazepam will counteract the excitation and help
resolve the seizure. Also by injecting this drug you get quicker onset of action than if
orally administered (as you by pass first pass metabolism) - you need fast onset of
action in an emergency situation!
AFTER A SEIZURE
• The patient may experience the following symptoms:
• post-ictal confusion (postictal referring to after-seizure)
• Paralysis that affects the arms or the legs – usually will affect only one side of the
body. This is known as Todd’s paralysis (Todd’s paresis) and can last (on average)
for up to 15 hours. Resolves completely after 2 days.
• Mechanism unknown but is thought to occur because of temporary but major
suppression of the area of the brain affected by the seizure
END OF SECTION ONE - MCQ
• Q1: What is a seizure?
• When neurons in the brain are synchronously active when they are not supposed to be
• When neurons in the brain are asynchronous
• When there is too much inhibition of electrical signalling in the brain
• A state of hyperpolarisation
• Q2: Paroxysmal electrical discharges in the brain responsible for causing seizures may occur
because of:
• A) Too much excitation
• B) Not enough excitation
• C) Too much inhibition
• D) Not enough inhibition
• Options a) and d)
END OF SECTION ONE - MCQ
• Q3: In EPILEPSY, the key excitatory neurotransmitter is:
• Glutamate
• Aspartame
• Glycine
• GABA
• Q4: In EPILEPSY, the key inhibitory neurotransmitter is:
• Glutamate
• Aspartame
• Glycine
• GABA
END OF SECTION ONE - MCQ
• Q5: Which of the following receptors are important in EPILEPSY?
• A) NMDA
• B) Dopamine
• C) 5HT1a
• D) AMPA
• E) GABA
• F) options A, D and E
• Q6: In which of these seizures will the patient likely be fully conscious?
• Generalised
• Complex partial
• Simple partial
• Tonic-clonic
• Myoclonic
END OF SECTION ONE - MCQ
• Q7: True or False: Confusion and Todd’s paresis are possible transient post-ictal signs/symptoms?
• Q8: During which of the following seizure types is the patient likely to fall forward?
• Atonic
• Tonic-clonic
• Myoclonic
• Status epilepticus
http://bealbio.wikispaces.com/On+Line+and+Upload+Period+4+Nervous+System?showComments=1
LETS LOOK AT A REPRESENTATION OF A
POSTSYNAPTIC NEURON
In epilepsy the important receptors are:
• NMDA receptor
• AMPA receptor
• GABA receptor
• Na+ channels
• T-Type Ca2+ channels
NOTICE THE SITES ON THE RECEPTORS
Notice how each receptor has
various sites on it – these
sites are the targets for
neurotransmitters and drugs
• The receptor may be affected by an underling genetic cause but may also be
affected by brain tumour, brain injury or infection
LAMOTRIGINE
1. Lamotrigine prevents the
release of glutamate from
glutaminergic neurons
2. This in turn prevents the
spread of the epileiptic action
potential risk of seizure
alleviated
DRUGS THAT BIND TO GLYCINE SITE ON NMDA
• The NMDA receptor’s glycine site
is the target site for some anti-
epileptic medications such as
felbamate.
1. Topiramate binds to the AMPA receptor’s glutamate binding site receptor without
causing the ion channel to open.
2. When glutamate is released from glutaminergic neurons (due to stimulation by
an EF) it travels across the synaptic cleft but won’t be able to bind to the
glutamate site on the AMPA receptor as it is occupied and blocked by
topiramate.
This stops the propagation of the action potential from the EF and a seizure is
avoided.
GLUTAMATE TO GABA??
• GABA is synthesized from glutamate using the enzyme glutamate decarboxylase (GAD)
and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor.
• This process converts glutamate, the principal excitatory neurotransmitter, into the
principal inhibitory neurotransmitter (GABA).
GABA RECEPTOR
Phenobarbital (a barbiturate) acts on the barbiturate site of the GABA receptor whereas
diazepam (a benzodiazepine) acts on the benzodiazepine site of this receptor. Both of
these drugs allow influx of chloride ions into the postsynaptic neuron
hyperpolarisation and inhibition seizure avoided
TIAGABINE
1: Tiagabine primarily acts to prevent the uptake of GABA into GABAergic neurons
2: This means more GABA is available to reach the GABA site on the GABA receptor
bypassing the breakdown of GABA by GABA-T into SSA
3: When more GABA is available to bind to the GABA site on the GABA receptor, the ion
channel opens allowing the flow of chloride ions into the postsynaptic neuron. This in
turn causes greater hyperpolarisation and inhibition.
GABA-T INHIBITORS – VALPROATE AND VIGABATRIN
1.Valproate and Vigabatrin inhibit
GAB-T
1. There are a number of sodium channels present on the postsynaptic neuron. When the
sodium ion channels open, the influx of Na+ into the postsynaptic neuron causes
depolarisation and excitation. This in turn can lead to proliferation of any action potentials
from an EF and propagate the spread of seizure.
2. Phenytoin and carbamazapine act to block these sodium channels
3. By blocking the sodium channels, sodium is prevented from entering reduces
depolarisation and excitation reduces risk of seizure.
DRUGS THAT TARGET CALCIUM CHANNELS
1. The postsynaptic neuron also has a number of open t-type calcium channels.
These allow calcium to enter the post-synaptic neuron. As a result you get
depolarisation and excitation spread of seizure
2. Ethosuxamide acts to blocks these t-type calcium channels
3. This will prevent the influx of calcium into the post-synaptic neuron reduces
chance of seizures
SPECIAL MENTION TO SODIUM VALPROATE
• Has several mechanisms of action
• It targets the voltage gated channels AND stimulates GABA activity
• It is also a GABA-T inhibitor
SUMMARY: DRUGS TO TREAT EPILEPSY
1. Drugs that inhibit voltage gated sodium and calcium ion channels responsible for the propagation of the impulse
• Carbamazepine
• Phenytoin
• Ethosuxamide
• Lamotrigine
2. Drugs that enhance synaptic inhibition – stopping the impulse by increasing GABA activity (GABA is the inhibitory
neurotransmitter in the CNS)
• Benzodiazepines e.g. diazepam – stimulate GABA receptor activity and therefore inhibit depolarisation
(stop the excitement)
• Barbiturates e.g. phenobarbital
• Vigabatrin – inhibits GABA-T (the enzyme that converts GABA to SSA and result in more GABA being
available in the synaptic cleft
• Tiagibine – inhibits the reuptake of GABA resulting in more GABA activity in the synaptic cleft
EXERCISE
For each of the following anti-epileptic drugs (AEDs) indicate what ADEC category (A, B1, B2, B3, C, D, X)
they are in pregnancy
To revisit ADEC categories see: http://esa.act.gov.au/wp-content/uploads/Pregnancy-Categories.pdf
Note: DPMQ gives you an idea of the cost of drug – amount remaining after the patient has
paid the mandatory co-payment is subsidised by the government.
END OF SECTION TWO: MCQ
• Which of these drugs blocks t-type calcium channels:
• Ethosuxamide
• Methotrexate
• Amitryptiline
• Vigabatrin
• True or False: Valproate and Vigabatrin prevent the breakdown of GABA by GABA-T?
Note: phenytoin should not be given IM as absorption is poor and some muscle
necrosis results
PHENYTOIN – PHARMACOKINETICS
• Absorption: Phenytoin has delayed absorption; although it is readily absorbed from the
intestinal tract. Its peak plasma levels are achieved 8 to 12 hours after dosing.
• This mean that beyond a certain dose, a small dosage increase will produce a
disproportionate increase in the blood level. It is therefore recommended that dosage
increases should be made in increments smaller than 100 mg (usually 30 mg).
• Note: Saturation of the enzymes also results in the plasma half-life becoming longer. With
levels above 20 mg/L, the half-life may become 2 - 3 days. Thus the time before steady
state is achieved may be 2 - 3 weeks.
PHENYTOIN – METABOLISM AND TOXICITY
• Metabolism: Phenytoin is metabolised to an inactive metabolite by the liver.
• Therapeutic plasma levels: Therapeutic plasma levels have been listed as being between
10 to 20 mg/L. The response is variable with good control attained in some patients with
levels below 10 mg/L. On the other hand, levels above 20 mg/L are necessary in other
patients for seizure control and are usually well tolerated.
• Toxicity: Symptoms of toxicity usually occur with levels above 30 mg/L however can also
occur with levels in the mid teens. Symptoms of drug include central nervous system effects
such as lethargy, ataxia and visual disturbance. Phenytoin is well tolerated by most patients
in doses of 4 to 8 mg/kg/day. Initiation of therapy can be done by orally loading the patient
with a dose of 10 to 15 mg/kg in three equal doses given over eight hours.
PHENYTOIN Q+A
• Why would you give diazepam and phenytoin intravenously to a fitting person?
Cannulating a vein can be difficult in a fitting patient – why couldn’t you just give the drug
subcutaneously (into the layer of fat beneath the skin) or into muscle?
You would need to ensure that you administer diazepam and phenytoin in a way that would
facilitate quick entry into systematic circulation and therefore into the brain. When you
administer a drug intravenously, you administer it directly into the systemic circulation and
bypass any absorption process that would be required if the drug were to be administered
subcutaneously (or orally). This absorption process will delay the drug’s onset of action and
could be costly in the management of a fitting individual. (Note: Diazepam is administered in
these circumstances to settle or sedate the fitting individual).
PHENYTOIN Q+A
• Why is the phenytoin infused over 30 minutes when diazepam is given rapidly?
Diazepam distributes rapidly and has a large therapeutic index whereas phenytoin has slow
distribution kinetics and a narrow therapeutic index. If administered rapidly, phenytoin may not
get time to distribute, meaning that for a short time, the plasma concentration will be greater
than that predicted by the volume of distribution. This can be a problem because phenytoin
also has a small therapeutic index (little difference between plasma concentration required for
therapeutic effect and plasma concentration which is toxic). Therefore, if infused rapidly,
phenytoin may be present at high enough concentration in plasma to be toxic.
PHENYTOIN Q+A
• Why is phenytoin given as a once daily dose? What determines frequency of drug
dosing?
• persistence of drug in plasma, measured by half-life t½ (time taken for plasma
concentration to fall by 50%)
• normally dose every half-life to reduce variation in plasma level
• for phenytoin t1/2 ~20-24 hours
REFERENCES AND ACKNOWLEDGMENTS
• https://www.youtube.com/watch?v=GMyCWup1Xqo
• https://www.youtube.com/watch?v=c-Cf1xkKofg&spfreload=5
• http://bealbio.wikispaces.com/On+Line+and+Upload+Period+4+Nervous+System?
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