Pharmacology of Epilepsy Flashcards
What are the 4 most common main drug classes prescribed for epilepsy / convulsions?
- Lamotrigine
- Sodium valproate
- Diazepam
- Levetiracetam
What is the primary mechanism of action for Lamotrigine?
Blocks voltage gated Na+ channels preventing Na+ influx
Prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity
What is the drug target site for Lamotrigine?
Voltage gated Na+ channels
What are the main side effects for Lamotrigine?
Side effects:
Common: Rash, drowsiness
Less common but serious:
Steven-Johnson’s syndrome, suicidal thoughts
What is some extra information about Lamotrigine?
Introducing lamotrigine gradually is one of the keys to reducing the frequency and severity of allergic skin reactions
What is the primary mechanism of action for Sodium valproate?
Inhibition of GABA transaminase prevents the breakdown of GABA
This increases GABA concentrations directly in the synapse presynaptically and also indirectly prolongs GABA in the synapse due to the fact that extraneuronal metanolism of GABA is slowed which also slows GABA removal from the synapse
What is the drug target site for Sodium valproate?
GABA transaminase
What are the main side effects for Sodium valproate?
Side effects (MANY):
Common: Stomach pain and diarrhoea, drowsiness, weight gain, hair loss
Serious:
hepatotoxicity, teratogenicity, pancreatitis
What is some extra information about Sodium valproate?
Broad CYP enzyme inhibitor - increases serum concentration of many co-administered drugs
What is the primary mechanism of action for Diazepam?
Increases choride ion influx in response to GABA binding at the GABA A receptor. Increased chloride ion influx associated with hyperpolarisation of excitatory neurones
What is the drug target site for Diazepam?
Benzodiazepine site on the GABA A receptor
What are the main side effects for Diazepam?
Side effects:
Common: Drowsiness, respiratory depression (if i.v. or at high dose)
Uncommon but serious:
Haemolytic anaemia, jaundice
What is some extra information about Diazepam?
Main reason that diazepam is not used for long term suppression of seizures is due to the development of tolerance
Diazepam is a Schedule 4 controlled drug - addiction prone individuals more likely to become dependent on diazepam
What is the primary mechanism of action for Levetiracetam?
Inhibition of the synaptic vesicle protein SV2A. It inhibits this protein and prevents vesicle exocytosis. A reduction in glutamate secretion is reduces glutamate excitotoxicity
What is the drug target site for Levetiracetam?
Synaptic vesicle protein SV2A
What are the main side effects for Levetiracetam?
Common:
dizziness, somnolence, fatigue and headache
What is some extra information about Levetiracetam?
The metabolism of levetiracetam has no effect on the cytochrome P450 enzyme system so it is favorable in terms of no drug–drug interactions
What are the first three steps for pharmacology?
Identify the patient’s problem
Specify the therapeutic objective
Select a drug
Essie = 21F referred to first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking.
Was sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Stressed lately, not much sleep. Essie’s boyfriend confirms Essie lost consciousness and started convulsing before she ‘came around’ a minute later. Essie makes strange quick jerk of her arms when she wakes up in the morning. 18 months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused.
A full physical examination is performed and Essie is sent for an EEG.
In A&E – Urea, electrolytes , calcium and glucose: All normal
General and neurological examinations were normal
What is the patient’s problem?
Epilepsy
Tonic clonic seizures
Myoclonic seizures
What are the types of seizures?
Absence Focal Generalised tonic-clonic Myoclonic Tonic or atonic
What are the stages of tonic-clonic seizures?
Tonic stage: lose of consciousness, stiffening of the body
Clonic stage: Jerk
What did the EEG show?
Interictal epileptiform discharge - risk of seizure recurrence
What is the therapeutic objective for the patient?
Reduce severity of seizures
Reduce frequency of seizures
Prevent long term effects
Identify triggers (stress, lack of sleep etc.)
Educate patient
Friends and family should be educated on management of seizures
What are the main goals of anti-epileptic drug treatment?
Eliminate seizures or reduce frequency
Evade the adverse effects associated with long term treatment
Aid patients in maintaining or restoring their usual psychical and vocational activities and in maintaining a normal lifestyle
What drugs could be give to treat tonic-clonic seizures in women of child bearing age?
Lamotrigine or Carbemazepine
What is the mechanism of action of Lamotrigine?
Blocks voltage gated Na+ channels preventing Na+ influx
Prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity
Why is sodium valproate not given to women of child bearing age?
Can cross placental barrier and cause physical birth defects or developmental uses
e.g. Neural tube defects
Decreased IQ
Why might the OCP affect Lamotrigine concentration?
OCP may impact lamotrigine absorption so less gets into the blooding the first place
OCP may enhance metabolism so more is cleared from the blood
OCP may enhance excretion of Lamotrigine
She begins taking the OCP, why might she be feeling more drowsy during the fourth week of her cycle?
During the fourth week of contraceptive cycle you stop taking the OCP
Therefore the concentration of the anti-epileptic while be twice as high in the fourth week as there is nothing reducing its concentration.
Increasing the side effects of Lamotrigine one of which is drowsiness
What are the side effects of Lamotrigine?
Dizziness Diarrhoea Loss of balance Abnormal eye movements Trouble speaking Drowsiness
What is the mechanism of action levetiracetam?
Inhibition of the synaptic vesicle protein SV2A
It inhibits this protein and prevents vesicle exocytosis
A reduction in glutamate secretion is reduces glutamate excitotoxicity
What is the mechanism of action of Sodium Valproate?
Inhibition of GABA transaminase prevents the breakdown of GABA
This increases GABA concentrations directly in the synapse presynaptically and also indirectly prolongs GABA in the synapse due to the fact that extraneuronal metanolism of GABA is slowed which also slows GABA removal from the synapse
What adjuvant therapy would you offer the patient?
How would administration differ in community or in hospital?
Benzodiazepines e.g. IV lorazepam
But continue usual therapy
In community take drug orally due to absence of trained staff to administer IV or rectally
Essie - individuaalised treatment:
Oestrogens are generally thought of as seizure promoting and progesterone has been shown to be seizure inhibiting. Many women have an increased frequency of seizures during a particular phase of the ovulatory cycle e.g. day 10-13 (periovulatory estrogen peak)
If lamotrigine is effective and well tolerated by Essie, then the simplest solution will be to change her oral contraceptive to a long-term progesterone implant such as Implanon/Nexplanon
If Essie were to get pregnant later in life there is a chance her seizure frequency could increase. Lamotrigine dose may be reduced due to fears of harming the unborn child. In addition, pregnancy may lead to changes in liver metabolism. As a result, lamotrigine levels may decrease and be associated with increased seizures. Essie would need to have serum lamotrigine checked at the beginning of pregnancy and during the second and third trimester. Dose could then be adjusted as described.
