ic4, 6, 7 (seizures, epilepsy) Flashcards
What is a seizure?
Sudden (paroxysmal) event due to abnormal, hypersynchronous neuronal activity in brain
Acute seizure
Remote seizure
Unprovoked seizures
Acute: seizures from immediately recognisable stimulus eg. acute brain insult
Remote: seizures that occur longer than 1 week following a disorder which increases risk of epilepsy
Occurring beyond interval estimated for acute symptomatic seizures
Causes of seizures
Alcohol
Illegal drugs
Benzodiazepine withdrawal
Metabolic
Hypoglycemia
Hyponatremia
Hypomagnesemia
Hypocalcemia
Fever (pyrexia), CNS infection
Sleep deprivation
Hyperventilation
Photostimulation (bright lights)
Physical, emotional stress
Sensory stimuli eg. smells
Hormonal changes eg. during menses, puberty, pregnancy
Which ethnic group has highest prevalence of seizures?
Indians > Chinese > Malays
When is SUDEP most common in?
What happens in SUDEP
Highest in 20-40 yo
Convulsion → Apnoea → Asystole
Risk factors of SUDEP
seizures must be v bad, hence:
Frequent GTC
Nocturnal seizures
Lack of seizure freedom
Do drugs induce seizures?
More like lowering seizure threshold, increasing likelihood of seizures
Shift in excitatory / inhibitory balance
Drugs that induce seizures (5 points)
Antimicrobials (Beta lactams) eg. Cabapenems
Analgesics / Opioids eg. Meperidine, Tramadol
Antipsychotics eg. Clozapine
Immunosuppressants eg. Cyclosporine
Antidepressants / Smoking cessation eg. Bupropion
Pathophysiology of seizures (2 points)
Hyperexcitability and Hypersynchronisation
Definition of epilepsy
At least 2 unprovoked seizures occurring >24hrs apart
signs of seizure
Aura
Cyanosis
Loss of consciousness
Motor manifestations
Generalised stiffness of limb and body
Jerking of limbs
Tongue biting
Urinary incontinence
Post-ictal confusion
Muscle soreness
Examples of non-epileptic events
Psychogenic non-epileptic seizures (PNES)
Physiological non-epileptic events
Eg. migraine aura, TIA, panic attacks
What are some investigations to conduct for pts w epilepsy
Scalp encephalography
MRI with gadolinium
biochemical tests (electrolytes)
When is MRI with gadolinium indicated?
For pts with first seizure, focal neurologic deficits (problems with brain, nerve, spinal cord)
Risk factors for seizure recurrence
Epileptiform abnormalities in EEG
Brain trauma, stroke
Structural abnormality in brain imaging
Nocturnal seizure
Seizure first aid
Ease person to the floor
Turn person gently to one side
Clear area of anything hard or sharp
Put something soft eg. folded jacket under head
Remove spectacles
Loosen ties or anything around neck which constricts breathing
Time seizure, call 995 if more than 10 mins
DO NOT
Hold person down to stop movements
Put anything in their mouth
Give mouth to mouth breaths
Offer person water or food until fully alert
When should non pharm treatment be done in epilepsy?
Reserved for medical refractory epilepsy (when meds dont work)
4 types of non pharm for epilepsy
Ketogenic diet
Vagus nerve stimulation
RNS: Responsive neurostimulator system
Epileptic surgery
What is RNS?
When is responsive neurostimulator system indicated? (3 points)
Stimulator implanted in skull under the scalp, Leads implanted in brain
Continuously monitor electrical activity, detect specific patterns and deliver brief pulses of stimulation
Undergone diagnostic testing that localised 2 or less epileptogenic foci
Refractory to ≥ 2 antiepileptic medications
Frequent, disabling symptoms
What are the 1st gen ASM?
what do kind of metabolism?
Carbamazepine
Phenobarbital
Phenytoin
Sodium Valproate
Hepatic metabolism, hence can cause hepatotoxicity
Problems with 1st gen ASM
Poor water solubility
Extensive protein binding
Extensive CYP metabolism
Multiple DDI
2nd gen ASM
Lamotrigine
Levetiracetam
Topiramate
which asm are CYP inducers?
2C9, 2C19, 3A
(1st gen)
Carbamazepine
Phenobarbital
Phenytoin
(2nd gen)
Lamotrigine (UGT)
Topiramate (3A4)
which ASM are CYP inhibitors?
(1st gen)
Valproate (2C9)
(2nd gen)
Topiramate (2C19)
Which drugs classes will interact with CYP inducers?
Antidepressants, Antipsychotics
Immunosuppressive therapy
Antiretroviral
Chemo
What should be used for new onset Focal onset epilepsy?
Carbamazepine
Levetiracetam
Lamotrigine (elderly)
Valproate (B, 2nd line)
What should be used for new onset GTC?
Carbamazepine
Valproate
Lamotrigine
(same as focal onset but minus Leve)
What is the indication of Phenytoin?
Which drug has same indication
all types of seizure except absence seizure
same as Carbamazepine
Bioavailability of Phenytoin?
What affects bioavailability of Phenytoin?
100%
Enteral feeds, space 2hrs apart
Protein binding of Phenytoin
Highly albumin bound, affected by hypoalbuminemia (increase free Phenytoin)
Displaced by urea, Sodium Valproate
Which drug displays zero order kinetics
What is capacity limited clearance
Phenytoin
as concentration increases, clearance decreases
side effects of Phenytoin
Gingival hyperplasia
Hirsutism
Peripheral neuropathy
May not improve with lower dose
May respond to folate supplementation
MOA of Carbamazepine
Block voltage dependent Na+ channel
Which alleles associated with SJS / TEN in Carbamazepine?
HLA-B 1502, A 3101
1502 should do routine testing, 3101 dont need
quirk about Carbamazepine
Undergoes autoinduction
Higher CL, shorter half life
Maximum autoinduction occurs 2-3 weeks after autoinduction
Do not start with desired maintenance dose, gradually increase dose over initial few weeks
MOA of Sodium Valproate (two points)
1) Block voltage dependent Na+ and Ca2+ channels
2) Inhibit GABA transaminase (which breaks down GABA)
More GABA → more inhibitory CL- influx→ hyperpolarisation
Indication of Sodium Valproate
All types of seizures, including absence seizures
Prophylaxis of migraine
Which drug is a dual inducer and inhibitor?
Topiramate
adverse effects of Sodium Valproate
Alopecia
Weight gain
Reverses when treatment discontinued
Nystagmus (involuntary eye movement)
Ataxia (no balance, coordination)
Slurred speech
why do patient experience more AE with greater valproate dose?
as conc of valproate increases, protein binding is saturated, more free valproate in the body
Which drugs are highly protein bound?
Phenytoin, Valproate
MOA of Diazepam
Binds to regulatory site of GABA receptors
Improve influx of Cl- ions into cell → causing hyperpolarisation
+ Enhance binding of GABA to receptor
serious adverse effect with Diazepam
How to treat?
Severe respiratory depression due to acute toxicity / overdose
Too much inhibition of brain activity → autonomic actions eg. breathing inhibited
Treatment: Flumazenil (benzodiazepine antagonist)
Binds to regulatory site of GABA receptor, displacing benzodiazepine
Lesser Cl- enters cell, cell is more depolarised and neuron is more excitable
Why should Diazepam not be taken for long durations?
Can cause tolerance and dependence
Dependence: addiction, withdrawal effects eg. disturbed sleep, rebound anxiety, tremor, convulsions
Need to withdraw drug gradually
MOA of Phenobarbital
Potentiates Cl- entry through GABA receptor into cell, but at different regulatory site than Benzodiazepines
Higher tendency to develop tolerance and dependence than Diazepam
Which drug has the highest dependency risk?
Barbituate / Phenobarbital
What is the indication of Phenobarbital?
in pediatric or neonatal patients (IV loading dose, IV / oral maintenance dose)
Side effects of Levetiracetam
Agranulocytosis (immune deficiency)
Suicide, delirium
Dyskinesia (uncontrolled facial movements)
MOA of Lamotrigine
1) block voltage gated Na+ channels
2) Inhibit release of Glutamate
(how to rmb: q similar to Valproate)
Which medications block voltage gated sodium channels? (4 points)
Phenytoin, Sodium Valproate, Carbamazepine, Lamotrigine
Indication of Lamotrigine
1) Partial and generalised seizures
2) Absence seizures
Which drugs can treat absence seizures?
Valproate, Lamotrigine (how to rmb: absence, take LeaVe)
Which drugs can cause agranulocytosis
Lamotrigine, Levetiracetam
Topiramate (as neutropenia)
Which drugs can be used for Lennox Gastaut syndrome
Lamotrigine, Topiramate
Indication of Topiramate
GTC, Lennox Gastaut
Migraine prophylaxis
Which antiepileptics are indicated for migraine prophylaxis?
Topiramate, Vaproate
How to rmb: both are CYP inhibitors
Which drug is affected by CYP metabolism?
Which drug is not affected by CYP inhibition?
Lamotrigine
Topiramate (as predominantly renal clearance)
How to mitigate dose limited AE for ASM? (7 points)
Initiate at low dose, lowly increase dose if pt can tolerate
Avoid large dose changes
Restrict therapy to 1 drug only
Administer largest dose at bedtime
Divide daily dose into smaller doses
Use sustained release formulation
Reduce total daily dose if possible
Which drugs cause hepatotoxicity?
1st gen ASM eg. Phenytoin, Valproate, Carbamazepine
What genetic tests should be conducted for Carbamazepine?
Which other ASM should be avoided if found to be positive?
HLA-b*1502
Aromatic ASM
Phenytoin
Phenobarbital
Carbamazepine
Lamotrigine
When should ASM be discontinued?
2 years without seizure
When is seizure considered resolved (2 points)
1) Age dependent epilepsy syndrome but now is past applicable age
2) remain seizure free for last 10 years, with no seizure medications for last 5 years
Which ASM make oral contraceptives ineffective?
Which contraceptives should be considered?
Potent inducers eg. Phenytoin, Carbamazepine
Use copper IUD, Depot injection, Higher dose of estrogen progestin pill + barrier method
Which contraceptive affects the medication?
Lamotrigine, may have breakthrough seizures
What ASM should be used for pregnancy?
Levetiracetam, Lamotrigine
Gabapentin (2nd line)
What should men taking valproate do
Use contraception 3 months after stopping treatment
How to treat status epilepticus? Treatment duration and drug
During 5-20 min phase
Benzodiazepine
IV Lorazepam 0.1mg/kg/dose, Max: 4mg/dose
IV Diazepam 0.2mg/kg/dose, Max 10mg/dose
During 20 min phase
IV Valproic acid 40mg/kg single dose, Max: 3g/dose
IV Levetiracetam 60mg/kg single dose, Max 4.5g/dose
When should Phenytoin conc be calculated?
What is the formula?
When albumin < 40g/L
(check formula)
