Seizure & Epilepsy Flashcards
How is epilepsy defined?
Any one of:
- at least 2 unprovoked seizures >24h apart
- 1 unprovoked and probability of further seizures after 2 unprovoked seizures, occurring in the next 10 years
- diagnosis of epilepsy syndrome
What are acute symptomatic seizures?
Seizures that result from some immediately recognisable stimulus or cause (eg. about a week after acute brain injury)
What are remote seizures?
Seizures that occur longer than 1 week following a disorder (known to increase risk of developing epilepsy)
What re unprovoked seizures?
Seizures occurring in absence of a potentially responsible clinical condition OR beyond interval estimated (~1 week) for occurence of symptomatic
Metabolic causes of acute symptomatic seizures
Hyponatremia
Hypoglycemia
Hypocalcemia
Hypomagnesemia
Toxic/drug causes of acute symptomatic seizures
Illicit drugs (cocaine, amphetamines)
Drugs (tricyclic antidepressants, carbapenems, baclofen)
ETOH
Benzodiazepine withdrawal
Structural causes of acute symptomatic seizures
Stroke
Traumatic brain injury
Infection/inflammation causing acute symptomatic seizures
CNS infection
Febrile illness
Non-epileptic seizures
Not related to abnormal epileptiform discharges
What is the general pathophysiology for epilepsies?
Neuronal hyperexcitability and hypersynchronisation
What can result in neuronal hyperexcitability?
- Voltage- or ligand-gated channels
- Abnormalities in intra & extracellular substances
- Excessive excitatory neurotransmitters
- Insufficient inhibitory neurotransmitters
Which parts of the brain is associated with neuronal synchronisation?
Hippocampus, neocortex and thalamus
Focal onset
Seizure begins only in one hemisphere
Generalised onset
Seizure begins in both hemispheres
Secondary generalised
Seizure begins in one hemisphere, then spread to other
What do clinical characteristic of a seizure depend on?
- Site of focus
- Degree of irritability of the area surround the focus
- Intensity of impulse
Phases of a seizure (in order)
- Prodromal
- Early ictal (“aura”)
- Ictal
- Postictal
Motor symptoms of focal onset (simple partial)
- Clonic movements (twitching/jerking) of arm, shoulder, face, leg
- Speech arrest
Desired outcomes of epilepsy treatment
- Absence of epileptic seizures
- Absence of ASM-related side effects
- Attainment of quality of life
What are some 1st generation ASMs?
- Carbamazepine
- Phenobarbitone/Phenobarbital
- Phenytoin
- Sodium Valproate
What are some 2nd generation ASMs?
- Lamotrigine
- Levetiracetam
- Topiramate
1st line AEDs for generalised tonic-clonic
- Carbamazepine
- Sodium Valproate
- Lamotrigine
1st line AEDs for tonic/atonic
Sodium Valproate
1st line AEDs for absence
Lamotrigine
Sodium Valproate
1st line AEDs for focal
- Carbamazepine
- Sodium Valproate
- Lamotrigine
- Levetiracetam
What are some problems with 1st generation ASMs?
- Poor water solubility
- Extensive protein binding
- Extensive oxidative metabolism
- Multiple DDIs
What are the potential advantages of newer ASMs?
- Improved water solubility → predictable F
- Negligible protein binding → no need to worry about hypoalbuminemia
- Less reliance on CYP metabolism
Potent enzyme inducers in 1st generation ASMs
Carbamazepine: CYP (1A2, 2C, 3A4), UGTs
Phenytoin: CYP (2C, 3A), UGTs
Phenobarbital: CYP (1A, 2A6,2B,3A), UGTs
Potent enzyme inhibitors in 1st generation ASMs
Valproate: CYP2C9, UGTs
MOA of Carbamazepine
Blockade of voltage gated sodium channels → reduces repetitive firing of sodium dependent action potentials in depolarised neurons
Starting dose of Carbamazepine
Epilepsy: 100-200mg QD or BD
Mania: 100-400mg in 2-4 divided dose
Trigeminal neuralgia: 200-400mg QD
Indications of Carbamazepine
- Epilepsy (NOT for absence!)
- Acute mania
- Trigeminal neuralgia (1st line)
Carbamazepine - renal
No renal adjustment required
DO NOT use for moderate-severe impairment
Carbamazepine - elderly
Beer’s list: Use with caution (likely due to neurological SEs)
Carbamazepine - hepatic
No hepatic adjustment required
Consider dose reduction
Hepatotoxicity is a concern
Carbamazepine - trigeminal
Elderly: 100mg BD
Carbamazepine - common SEs
GI effects - N/V/C/D, loss of appetite, stomach upset
Hyponatremia - muscle cramps, weakness, mental status change
Neurological - drowsy, lightheaded, headache, blurry or double vision
Carbamazepine - rare & serious SEs
SJS/TEN - monitor closely in first 3 months
Liver failure
Blood dycrasias
ASMs & pregnancy principles
Early planning with physicians
- Evaluate concomitant medines + choose ASM with least risk
- Gradually switch to one with lower risk before pregnancy
- Or monitor and adjust accordingly
Carbamazepine - pregnancy
Teratogenic (major congenital malformations)
If used,
- Folic acid supplementation
- Vit K during last period of pregnancy
- TDM
- Switch to levetiracetam, lamotrigine if possible
Carbamazepine - breastfeeding
Encouraged to continue, unless AEs in infants observed.
Carbamazepine - protein binding
75% protein bound; albuminuria increases free drug concentration
Carbamazepine - significant pK
Undergoes autoinduction (induces own metabolism):
Stabilises in around 3 weeks
Increase CL, decrease t1/2
→ start low dose, titrate up, more frequent dosing
Carbamazepine - Initiation
Pharmacogenomic testing (HLA-B*1502)
- To identify risk of SJS/TEN
- Asian patients
- If positive, avoid CBZ & phenytoin
- If negative, continue to monitor patients (at risk of developing SCAR (DRESS))
Carbamazepine - DDI (1)
Macrolides (e.g. clarithromycin)
- CYP3A4 inhibitor
Reduce dose of CBZ
Carbamazepine - DDI (2)
OC (e.g. ethinyl estradiol)
- CBZ induces CYP3A4-mediated metabolism of OC
Consider CBZ alternatives, or use back up contraceptive during co-administration and at least 28 days after discontinuing CBZ
How does Carbamazepine induce hyponatremia
Increases ADH which cause increase expression of aquaporin 2 channels in renal tubules
Carbamazepine & hyponatremia
Serum Na <136mmol/L
Acute onset <48h, associated with neurological complications
Management of hyponatremia when taking Carbamazepine
Symptomatic: stop CBZ and switch to levetiracetam)
Asymptomatic: fluid restriction
Chronic, asymtomatic: fluid restrict + oral salt tablets or loop diuretic
Monitor: serum electrolytes
Carbamazepine - formulation
High oral F → oral formulation
Poor solubility → does not have parenteral
Carbamazepine - monitoring
Baseline:
- FBC, BUN, liver&kidney function, serum Na, ophthalmic test
Follow up:
- Drug concentrations, FBC, liver&kidney function
MOA of Phenytoin
Blockade of voltage-gated sodium channels → reduces repetitive firing of sodium-dependent action potentials in depolarised neurons
Indications of phenytoin
All types of seizures except absence seizure
Phenytoin - bioavailability
Complete but slow absorption
Reduced at higher dose
Reduced by interactions with enteral feeds
- space apart by 2h
Phenytoin - protein binding
Highly protein bound
- Low albumin = more free phenytoin
Phenytoin - pK
Zero-order kinetics (increase in dose =/= increase in concentration)
Phenytoin - pregnancy
Teratogenic
Phenytoin - monitoring
Labs measure total phenytoin level
Corrected equation:
Cobserved/[x(albumin/10)+0.1]
x = 0.275 when CrCl≥10
x = 0.2 when CrCl<10
What drug class is phenobarbital?
Barbiturate
MOA of phenobarbital
Enhance GABA binding (GABA causes Cl- ion channels to open) → greater entry of Cl- → hyperpolarises neurons
At different binding site from benzodiazepines
Which group of patient is phenobarbital mainly used for?
Neonates/paediatric (IV LD followed by PO/IV MD)
Phenobarbital - disadvantages
- Tendency to develop tolerance and dependance
- Severe withdrawal symptoms
Valproate - dosage forms
Oral (tablet, syrup)
Injection (solution, powder)
Valproate - dose
(Starting)
Epilepsy
Absence: 15mg/kg/day (1-4 divided dose)
Complex partial: 10-15mg/kg/day (1-4 divided dose)
GTC: 250mg/day
Valproate - common SEs
Dizziness - get up slowly from sitting/lying
Drowsy
Diarrhoea - drink more water
N/V, stomach cramp
Hirsutism
Weight gain
Slight tremors of hands and fingers when you first start
MOA of valproate
Blockade of voltage-gated sodium and calcium channels
Inhibits GABA transaminase → increase GABA
Valproate - pregnancy
Teratogenic
Major congenital malformations, decreased IQ, neurodevelopmental disorders
Valproate - breastfeeding
Encouraged
Valproate - renal
No dose adjustment necessary but closely monitor clinical response, tolerability, free valproic acid concentration
Valproate - liver
Mild to moderate: not recommended
Severe: Contraindicated
Valproate - elderly
Lower initial and maintenance dose
Monitor closely for AEs
Valproate - paediatric
Weight-based dosing
Valproate - DDIs (1)
CNS depressants
- Strongly bound to plasma proteins, may displace other drugs
Valproate - DDIs (2)
Carbapenems
- May decrease serum concentration of valproate
Valproate - DDIs (3)
Lamotrigine
- May enhance AE & increase serum concentration of lamotrigine
- Lamotrigine dose reduction required; increase monitoring for lamotrigine toxicity (rash, hematologic toxicities)
Valproate - Drug-disease interaction
Hepatotoxicity induced by sodium valproate
Avoid concomitant use of salicylates
