1
Q
A seizure is a _____ event due to _____
A
- paroxysmal
- abnormal, hypersynchronous discharge from a mass of CNS neurons
2
Q
Why are seizures considered to have diverse manifestations?
A
Ranges from convulsion (observable) to an experience (subjective)
3
Q
What are the 2 criteria where seizures are NOT considered epilepsy?
A
- Single seizure
- Due to a correctable/avoidable circumstance (provoked)
1. Alcohol
2. Hypoglycemia
3. Pyrexia
4. Sleep deprivation
4
Q
Epilepsy is a _____-term disease characterised by ______. It (can/cannot) be treated
A
- Long
- Repeated seizures
- Is treatable (When properly managed, 70-80% can lead normal lives)
5
Q
What predisposes someone to be at a higher or lower risk of experiencing recurrent seizures? State 3 each
A
Higher risk
1. Previous (undiagnosed) seizure
2. Epileptiform EEG
3. Abnormal brain scan (tumours can cause epilepsy)
Lower risk
1. Single seizure
2. Normal EEG
3. Normal brain scan
6
Q
Describe the pathophysiology of Epilepsy
A
- Neuronal depolarization depends on membrane potential
- An unbalanced function in excitatory and inhibitory receptor or ion channel → dysregulated discharge
- When there is excessive synchronous depolarization, usually starting from defined regions (“foci”) and spreading to other regions → seizure
7
Q
The most common excitatory neurotransmitter is ______ while the most common inhibitory neurotransmitter is ______?
A
Excitatory: Glutamate
Inhibitory: GABA
8
Q
(FYI) What are the main types of Epilepsy? State whether consciousness is impaired for each
A
Generalized
consciousness impaired
Tonic clonic
Absence
Myoclonic
Atonic
Partial
Simple (consciousness not impaired)
Complex (consciousness impaired)
Status Epilepticus
9
Q
How can the diagnosis of different seizure types be performed?
A
via EEG (Electroencephalogram)
10
Q
What are the main MOA of Antiepileptics?
A
- ↓ Membrane excitability by altering Na+ & Ca2+ conductance during action potentials
(Excitability depends on Na+ & to a lesser extent, Ca2+ conductance) - Enhance effects of inhibitory GABA neurotransmitters
(allow Cl- influx so membrane potential stays negative → will not depolarize)
But not all compounds are effective against all types of seizures
11
Q
State the 3 first-line drugs for newly diagnosed partial & generalized tonic clonic seizures
A
Phenytoin
Carbamazepine
Sodium valproate
12
Q
List all AEDs
A
- Phenytoin
- Carbamazepine
- Sodium valproate
- Diazepam
- Phenobarbital
- Levetiracetam
- Lamotrigine
- Topiramate
13
Q
What is Phenytoin’s MOA & indication?
A
MOA
block voltage-dependent Na+ channels to prevent Na+ influx → ↓ability to generate AP → ↓excitability
Indication
🥓 ALL seizure types EXCEPT ABSENCE
(same as Carbamazepine)
14
Q
What are 2 things you should be careful of when initiating a patient on Phenytoin?
A
- Relatively narrow therapeutic range (plasma concentration 40-100 μM) + unpredictable saturation kinetics & consequent non-linear relationship between dose & plasma concentration = need titration & monitoring 🩺
- Teratogenic (caution in females of child-bearing age) 🍼👶🏻
15
Q
What is Carbamazepine’s MOA & indication?
A
MOA
block voltage-dependent Na+ channels to prevent Na+ influx → ↓ability to generate AP → ↓excitability
Indication
🥓 ALL seizure types EXCEPT ABSENCE
(same as Phenytoin)
16
Q
How is Carbamazepine’s half-life affected with repeated doses?
A
- Is a CYP450 inducer
- so T1/2 shortens with repeated doses
- Resultantly, it also accelerates elimination of other drugs
- Hence, need to ↑ doses slightly to account for higher hepatic enzyme activity
17
Q
🥓 What is a significant consideration for Carbamazepine in terms of side effects?
A
- Pharmacogenomics effects in causing Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis
- 10x higher risk in Asians than Caucasians
- So should perform genetic screening prior to Carbamazepine initiation
18
Q
What is Valproate’s MOA?
A
- Blocks voltage-dependent Na+ & Ca2+ channels
- Also inhibits GABA transaminase (enzyme that breaks down GABA) → ↑ GABA → ↑ inhibitory tone of neuron
19
Q
What is Valproate’s indication?
A
ALL types of seizures, including absence seizures
20
Q
How does Valproate affect other Antiepileptics?
A
- Strongly bound to plasma proteins & displaces other Antiepileptics (e.g. if use combination therapy)
- Results in more free Antiepileptics
- Since apparent level of free drug will be higher, need to dose adjust
21
Q
What are the general dose-related side effects of Antiepileptics?
A
- Drowsiness, confusion, nausea
- Nystagmus (repetitive uncontrolled movement of eye)
- Ataxia (movement disorder)
- Slurred speech, unusual behaviour, mental changes, coma
Higher dose = more likely
22
Q
What are the general non-dose related side effects of Antiepileptics?
A
- Hirsutism, acne
- Gingival hyperplasia
- Folate deficiency
- Osteomalacia (soft bones)
- Hypersensitivity reactions (including Stevens-Johnson syndrome)
🥓 Even a small dose can cause this
23
Q
What is the MOA of Benzodiazepines?
A
- Binding of GABA to GABA(A) receptors causes Cl- channel to open → cell hyperpolarizes
- Benzodiazepines binds on a regulatory site of GABA receptors to enhance GABA binding → ↑ their inhibitory effects
- This potentiates Cl- influx, leading to hyperpolarization → neurons do not fire
24
Q
State the DOA of short, intermediate & long-acting Benzodiazepines
A
Short
3 to 8h
Intermediate
10 to 20h
Long
1 to 3 days
25
🥓 Briefly explain the type of indications that short vs long-acting Benzodiazepines have
**Short**
used for a purpose with a short duration of use e.g. Induce general anaesthesia, Anxiety
RARELY used for Epilepsy
**Long**
used for longer treatments like for Epilepsy treatment
26
State 2 examples of Intermediate-acting Benzodiazepines & their indications
**Clonazepam (e.g. Klonipin)**
1. Panic disorder
2. Seizure
To remember that it is used in seizure: "Clon" = clonic tonic
**Lorazepam (e.g. Ativan)**
1. Anxiety
2. Insomnia
3. Status Epilepticus
27
🥓 State an example of Long-acting Benzodiazepines & their indications
**Diazepam (e.g. Valium)**
1. Status Epilepticus 🥓
2. Seizure, refractory seizure
3. Adjunct skeletal muscle spasm
4. Alcohol-withdrawal syndrome
5. Anxiety
6. Sedation
28
What is 2 acute toxicity/overdose effects of Benzodiazepines
1. Severe respiratory depression (especially if used concurrently with alcohol)
2. Brain can also be depressed/inhibited to the extent that it cannot control autonomic responses
29
How can acute toxicity/overdose of Benzodiazepines be treated?
* Flumazenil, a benzodiazepine antagonist
* Blocks potentiating function of benzodiazepine → less Cl- influx → higher activation of neuron in brain & entire system becomes more activated (depolarization occurs)
30
What are the side effects of Benzodiazepines?
* Drowsiness
* Amnesia, confusion
* Impaired muscle co-ordination (impairs manual skills)
31
🥓 Can you stop Benzodiazepines immediately?
No! Because **dependence** can develop from use
* Withdrawal effects include disturbed sleep, rebound anxiety, tremor & convulsions
* Hence important to withdraw gradually
* Note that Benzodiazepines have abuse potential
32
🥓 Would tolerance develops faster for an indication of Epilepsy or to induce sleep?
Epilepsy
* Tolerance depends on frequency of use
33
What is the difference between tolerance & dependence?
**Tolerance**
Body tolerates drug more, so the same dose will no longer give the same effects (need higher dose)
**Dependence**
Addictive property (psychological need to have the next dose)
So these concepts are different but highly co-related
34
What is the MOA of Barbiturates?
Also potentiate GABA(A) mediated Cl- currents, but at a site distinct from benzodiazepines
35
Is Barbiturates or Benzodiazepines preferred as a sedative-hypnotic?
* Benzodiazepines largely replaced Barbiturates as a sedative-hypnotic
* Due to their tendency to develop tolerance & dependence (even worse than Benzodiazepines, severe withdrawal symptoms)
* Barbiturates mainly limited to use as AED for pediatric or neonatal patients (IV loading dose followed by IV or oral maintenance doses)
36
Can Flumazenil be used for treating Barbiturate overdose?
No, it will be ineffective because they **bind to a different site** on the GABA(A) receptor
37
State the DOA of ultra-short, short & long-acting Barbiturates & their examples/uses
**Ultra-short**
20 min
IV induction of anesthesia e.g. Thiopental
**Short**
3 to 8h
Sedative & Hypnotic e.g. pentobarbital, amobarbital
**Long**
1 to 2 days
Anticonvulsant e.g. phenobarbital
38
Why is Levetiracetam considered a novel chemical entity?
Does not look like existing AEDs
39
What is Levetiracetam's indication?
1. Primarily as **adjunctive therapy** for partial onset seizures, myoclonic & primary generalized tonic-clonic seizures
2. Can be used as monotherapy for partial onset seizures in newly diagnosed epilepsy
40
How is Levetiracetam administered?
Oral or IV infusion
41
What is Levetiracetam's PK profile?
* Highly soluble & permeable
* **Linear** PK profile with **low intra- & inter-subject variability** (Unlike phenytoin)
42
State the common side effects of Levetiracetam
* Headache
* Vertigo
* Cough
* Depression
* Insomnia
43
State the rare side effects of Levetiracetam
* **SAD**
* Agranolocytosis (WBC cannot be produced, potentially fatal)
* Suicide
* Delirium
* Dyskinesia (jerking/spasms, look dance-like)
44
State the MOA of Lamotrigine
Blocks **voltage-gated sodium channels** → inhibits glutamate release → impedes sustained repetitive neuronal depolarization
Similar to Valproate
45
What are the indications of Lamotrigine
* Adjunctive or monotherapy treatment of partial seizures & generalised seizures, including tonic-clonic seizures (focus on it being an adjunctive)
* Monotherapy of typical absence seizures
* Adjunctive or initial AED for Lennox-Gastaut syndrome (severe childhood epilepsy) (this point likely not tested)
46
What are the 2 drugs that can be used in treatment of absence seizures
1. Valproate
2. Lamotrigine
47
State the route of administration and linearity of the PK profile of Lamotrigine
How is its half life affected by the age of the patient?
Oral (chewable)
Linear PK
Half-life is generally shorter in children
48
State the respective drugs that significantly reduce & increase half-life of Lamotrigine when co-administered
**Reduced**
As these **induce** hepatic enzymes
Carbamazepine
Phenytoin
**Increased**
As it **inhibits** hepatic enzymes
Valproate
49
State the common side effects of Lamotrigine
* Headache
* Irritability / aggression
* Tiredness
50
State the rare side effects of Lamotrigine
* **She Hates HAM**
* Agranolocytosis
* Hallucination
* Movement disorders (worsens Parkinson's)
* SJS / TEN (rare EXCEPT in Asians with **HLA-B*1502**)
* Hepatic failure
51
What are the indications for Topiramate?
* Monotherapy of partial seizures & generalised seizures tonic-clonic seizures
* Adjunctive therapy for Lennox-Gastaut syndrome (severe childhood epilepsy)
* 🥓 **Prophylaxis of migraine** headaches in adults (NOT intended for acute treatment)
52
State the route of administration and linearity of the PK profile of Topiramate
* Oral
* Linear
53
Is Topiramate's plasma half life long or short?
Long 🦒
54
How is Topiramate predominantly cleared?
Renal
55
How does the concentration of other drugs change when Topiramate is used?
* Unlikely to affect other drugs
* Because it is not a potent inducer of drug-metabolizing enzymes
56
State the common side effects of Topiramate
* Depression
* Somnolence
* Fatigue
* Nausea
* Weight change
57
State the rare side effects of Topiramate
* **Topiramate Has SomeThing Not Many**
* Neutropenia
* Mania
* Tremor
* Transient blindness
* SJS/TEN
* Hepatic failure
58
What should you consider before initiating a patient on AEDs?
**Considerations**
Individualise according to
Seizure type
Epilepsy syndrome
Co-medication
Comorbidity
Individual's lifestyle & preferences (&/or those of their family, carers as appropriate)
59
Preferably, how many AEDs should be initiated?
* Commence on **monotherapy** initially
* If patient develops an adverse reaction or if the initial monotherapy is unsuccessful → try monotherapy of another drug
* As far as possible, use one drug (unless Status Epilepticus which is very serious)
* Because Epilepsy requires lifelong meds so longer you take = higher risks of various side effects
60
🥓 When are antiepileptic drug levels tested?
Antiepileptic drug levels may help clinical management under the following clinical indications:
1. Assess **compliance** to drug treatment for patients with refractory epilepsy
2. Assess symptoms due to **possible antiepileptic drug toxicity** e.g. slurred speech
3. Titration of **phenytoin** dose
61
Is routine checking of antiepileptic drug levels required?
* Not required & not cost-effective if they do not meet any of the 3 clinical indications for testing AED levels
* Also very disruptive to patients
