4.1 Anti Epileptic Drugs Flashcards
Define epilepsy
Recurrent tendency to spontaneous intermittent abnormal electrical activity in brain leading to seizure
Seizures may be with or without loss of __________, and with or without __________
A Seizure in the motor cortex area will cause __________
consciousnes, convulsions, convulsions
What 2 things must we be aware of when prescribing Anti Epileptic Drugs (AEDs)
1) ADRs - Common, some serious
2) DDIs - Some positive combined with other AEDs but often negative PK interactions
Give a medico-social consequence of misdiagnosis of Epilepsy
ban on driving a car (+ other social ,financial, medical implications)
What causes Epilepsy? (4)
(NEIL)
Increase in Cerebral Neurone Excitability by :
- Spread of Neuronal Hyperactivity
- Increased Excitation
- Decreased Inhibition
- Loss of Homeostatic Control
What are the TWO main types of Epilepsy?
FOCAL seizures (partial) – affect one (unilateral) hemisphere
GENERALISED seizures – affect both (bilateral) hemispheres
What is Status Epilepticus and how does it differ from other seizures?
Most seizures are short lived (up to 5 mins) BUT Status Epilepticus is prolonged or repeated frequently WITHOUT recovery interval
Medical Emergency!
What are the major risks if Status Epilepticus is not treated?
1) varying degrees of brain dysfunction/damage ➞ by hypoxic encephalopathy
2) death ➞ sudden unexpected death in epilepsy (SUDEP)
Give 4 dangers of severe Epilepsy (not incl brain damage or SUDEP)
- Physical injury relating to fall /crash
- Hypoxia – respiratory muscles in spasm
- Cognitive impairment
- Serious psychiatric disease
- Significant adverse reactions to medication
- Stigma / Loss of livelihood / life changing event
What are the 2 main therapeutic targets for AEDs
1) Voltage Gated Sodium Channel Blockers
2) Enhancing GABA Mediated Inhibition
Explain the mechanism of VGSC hyperactivity in epilepsy
1) local loss of membrane potential homeostasis starts at focal point
2) small number of neurones form a generator site and heavily depolarise
3) hyperactivity spreads via synaptic transmission to other neurones
What is the purpose of VGSC blockers?
VGSC Blockers reduce probability of high abnormal spiking activity so neurons can only fire at a constant rate.
Explain the MoA of VGSC blockers
1) the VGSC blockers enters the chanel and gains access to binding site during depolarisation (when they are open).
2) the blocker stablises this channel as it enters its refractory peroid which prolongs its inactivation state.
3) by increasing the relative refractory period of the chanels it brings the firing rate back to normal.
4) once neurone membrane potential returns back to normal the VGSC Blocker detaches from binding site.
Give 2 common examples of a VGSC blocker
Carbamazepine and Phenytoin
(both prolong VGSC inactivation state)
Carbamazepine is well absorbed (75% protein bound) and exhibits _______ PK.
Its Initial t1/2 is _____ hrs BUT reduces to a t1/2 of _____hrs.
Linear, 30, 15,
Why does t1/2 of Carbamazapine reduce after repeated use?
Carbamazipine is a strong inducer of CYP450 (3A4).This particular isoform of CYPs is actually the one which metabolises carbamazipine itself, hence this drug activates its own phase 1 metabolism. The effect of this is a reduction in its t1/2 to 15hrs after repeated use.
How does the change in t/12 of carabamazipine over time affect the dosage we prescribe to our patients?
Initially start on lower dosage (100-200mg 1-2 per day)
With continued use dose must be increased in steps of around 100-200mg in 2 weeks (800mg-1.2g divided doses throughout day)
Give 2 epilepsy types treated with Carbamazepine
1) Generalised Tonic-Clonic
2) Partial - All
(Not Absence Seizures)
What are some common symptoms of ADRs experienced with carbamazipine?
Wide ranging Type As: affects on the CNS such as –
dizziness, drowsy, ataxia, motor disturbance, numbness & tingling
Give 4 other systemic ADRs that may be experienced with carbamazipine
- GI - upset vomiting
- CV – can cause variation in BP
- Hypersensitivity (Rashes)
- Hyponatraemia
Rarely: Severe bone marrow depression – neutropenia
What is a major contraindication for carbamazipine?
AV conduction problems
As carbamazipine is a CYP450 inducer, it can also increase metabolism of other drugs which decreases their effectivness
Give 4 examples
1) Phenytoin (AED) ➞ also effects its PK/binding due to ↑ conc of CBZ in plasma
2) Warfarin
3) Systemic Corticosteroids
4) Oral contraceptives
What is Stevens-Johnson syndrome (SJS)?
A rare but serious disorder of hypersensitivity caused by an ADR (unpredictable) or sometimes by an infection
It begins with flu-like symptoms, followed by a red or purple rash that spreads and forms blisters. It affects the skin, mucous membrane, genitals and eyes.
Medical emergency! requires treatment in ITU or burns unit
Give a drug class which interferes with the action of Carbamazepine (+ examples)
Antidepressants - SSRIs MAOIs TCAs and TCA
Give 2 things we must always do for drug monitoring of carbamazipine
1) Monitor dosing to effect and adjust dosing as t1/2 decreases
2) Always check BNF with any other drugs given
Phenytoin is well absorbed but 90% is bound in plasma, what is the implication of this on DDIs?
Give 2 examples
Competitive protein binding can increase levels of free phenytoin in plasma which exacerbates Non-Linear PKs
Valproate (AED) and NSAIDs displace bound phenytoin, increasing plasma levels of the free drug
Because Phenytoin shows non-linear kinetics and large intrasubject variability (for dose required to remain within theraputic window), small increases in plasma conc of free drug will have serious effects
Phenytoin is a CYP450 inducers, specifcally isoform ____
3A4
What is the effect of Phenytoin on CYPP450 and how does this differ from carbamazipine
Both induce the CYP3A4 but, phenytoin is metabolised by CYP2C9 and CYP2C19 and so does NOT increases its own metabolism
Why does Carbamazipine increase metabolism of Phenytoin?
because in additon to increasing its own metabolism by inducing CYP3A4 it also induces CYP2C9 which is a metaboliser of Phenytoin
Why can we not calculate t1/2 for phenytoin?
What does this mean for dosing?
Because at theraputic concs it shows NON-LINEAR kinetics and variable t1/2 = 6-24 hrs
There is also big differences with intra-subject variability and hence there is large variability in dose required to get to therapeutic levels
What are some common symptoms of ADRs experienced with phenytoin?
Very wide ranging Type A’s: effects on the CNS such as –
dizziness, ataxia, headache, nystagmus, nervousness
Phenytoin is well absorbed but 90% is bound in plasma, what is the implication of this on DDIs?
Incl 2 drug examples
If phenytoin is given while patient is on valporate or NSAIDs, competitive protein binding by phenytoin will displace these drugs from their binding sites and increase levels of free drug in plasma
However, it is hard to determine what % of phenytoin actually displaces the already bound drug. ie if patient is given 2mg will the entire 2mg bind, 1mg or 0.25 mg? We dont know.
Due to Phenytoins non-linear kinetics and large intrasubject variability this signifcantly excerbates its non-linear pk
Give 3 systemic ADRs that may be experienced with Phenytoin
1) Gingival Hyperplasia (20%)
2) Rashes - Hypersensitivity
3) + Stevens Johnson (2-5%)
In additon to valporate and NSAIDs give another DDi with Phenytoin
Increases metabolism of the OCP (reducing its effectivness) due to induction of CYP3A4 enzyme
What is Cimetidine and what is its effect on Phenytoin
Cimetidine is a histamine antagonist (anti-histamine)
Inhibits the metabolism of Phenytoin
Give 2 things we must always do for drug monitoring of Phenytoin
1) check BNF for any other drugs given in combination
2) close monitoring of free concentration in plasma (can use salivary levels as indicator of free plasma)
Give 2 types of Epilepsy that can be treated with Phenytoin
1) Generalised Tonic-Clonic
2) Partial - All
(Not Absence Seizures)
What is the action of Lamotrigine?
VGSC blocker ➞ prolongs VGSC inactivation state AND has a seconday role in Ca2+ channel blocking + decreasing glutamate release
Lamotrigine is well absorbed and shows a ________ PK
Its t1/2 is ____ hrs and only undergoes _______ metabolism meaning it does not have CYP450 _______.
Linear, 24, Phase II, induction
What is the benefit of no CYP450 induction by Lamotrigine?
fewer DDIs
Give 3 ADRs of Lamotrigine
1) CNS Dizziness, ataxia, somnolence (less marked thank others)
2) Nausea (some mild (10%) and serious (0.5%))
3) Skin rashes
Give 3 DDIs of Lamotrigine and their effects
1) Adjunct therapy with other AEDs.
2) OCP reduce LTG plasma level
3) Valproate ↑ LTG in plasma (competitive binding)
Give 3 types of Epilepsy treated with Lamotrigine
1) Partial Seizures
2) Generalised -Tonic-clonic
3) Absence Seizures
+ other subtypes
What is the first line AED?
When is it not used as first line and why?
Lamotrigine
Not first line paediatric use as increased ADRs
Which AED is most commonly prescribed during pregnancy?
Lamotrigine
Give a common example of drug which enhances GABA mediated inhibition
γ-Aminobutyric acid
What is the purpose of enhancing GABA mediated Inhibition for epilepsy?
It has a major role in post synaptic inhibition, 40% synapses in brain are GABA-ergic
Increasing GABA is natural anticonvulsant or excitatory ‘brake’
Give the name of the 3 distinct pharmacological targets located on the GABA channel
1) binding with GABAA receptor by direct GABA agonists
2) binding to Benzodiazepine Site on GABA receptor to Enhance GABA action
3) binding to Barbiturate site on GABA receptor to enhance GABA action
Give the general mechanism of GABA mediated inhibition enhancement
Increased Chloride current into neurone - increases threshold for action potential generation
Reduces likelihood of epileptic neuronal hyperactivity
Makes membrane potential more negative
What is the role of Benzodiazepines?
Act at distinct receptor site on GABA Chloride channel. Increases Chloride current into neurone which increases threshold for action potential generation
How do we enhance GABA mediated inhibition furthur
Binding of GABA or BZD enhance each others binding ➞ act as positive allosteric effectors
More bound to each site = more inhibition by GABA
Benzodiazapines are well absorbed (90-100%) and are highly plasma bound 85-100%
They have a _______ PK and a t/2 which varies between ____ and ____ hrs
Linear, 15-45 hrs
Give 4 ADRs of Benzodiazepines
- Sedation
- Tolerance with chronic use
- Confusion impaired co-ordination
- Aggression
- Dependence/Withdrawal with chronic use
- Abrupt withdrawal seizure trigger
- Respiratory and CNS Depression
Give 2 DDIs with Benzodiazepines
1) Some adjunctive use
2) Overdose reversed by IV flumazenil but use may precipitate seizure/arrhythmia.
Give 2 types of epilepsy we can use Benzodiazepines to treat
Incl specific drug examples
1) Lorazepam / Diazepam - for Status Epilepticus
2) Clonazepam - for Absence seizures - short term use
Why are benzodiazapines not first line AEDs?
Side effects limit first line use
Give 3 pharmacological targets against GABA metabolism
1) Inhibition of GABA inactivation
2) Inhibition of GABA re-uptake
3) Increase rate of GABA synthesis
Targeting these sites enhance action of GABA (GABA ↑)
What is the role of Valproate in enhancing GABA mediated Inhibition
There is evidence in vitro for mixed sites of action (pleiotropic)
Thought to be:
- weak inhibition of GABA inactivation enzymes- GABA ↑
- weak stimulus of GABA synthesising enzymes-GABA ↑
- VGSC blocker + weak Ca2+ channel blocker - discharge ↓ (makes excitable neurones less likley to fire)
Valporate is 100% absorbed then 90% plasma bound
It exhibits ______ PK and has a t1/2 of ___ hrs
Linear, 15
Give 3 ADRs of Valproate
Generally less severe than with other AEDs but incl
1) teratogenic causing increased no. of birth defects
2) CNS sedation ataxia tremor - weight gain
3) Hepatic function - ↑ transaminases in 40% patients (can lead to hepatic failure- rare)
Give 4 DDIs of Valproate and how
1) Adjunct therapy with other AEDs (both Valproate and adjunct PKs affected - check BNF)
2) antidepressants - SSRIs MAOIs TCAs & TCA inhibit action of Valproate
3) antipsychotics - antagonise Valproate by lowering convulsive threshold.
4) Aspirin - competitive binding in plasma
What must we do when drug monitoring patients on Valporate?
Why may this be less/more impt for Valporate?
Close monitoring of free concentration in plasma (can use salivary levels as indicator)
Plasma Valproate is not closely associated with the efficacy of the drug however, must monitor for blood, metabolic and hepatic disorder
Give 3 types of Epilepsy treated with Valporate?
1) Partial Seizures
2) Generalised Tonic-Clonic
3) Absence Seizures
What is the use of Cannabis oil in epilepsy?
Used as adjuvant therapy
Contains cannabinoids, notably THC (psychoactive effects) and CBD (therapeutic effects)
- The CBD is an agonists of cannabinoid receptors CB1 and CB2
- CBD is cross-reactive with many GPCRs as agonist and antagonist
- CBD increases plasma conc of Clobazam (benzodiazapine), by inhibition of CYP2C19
What is meant by the ‘balance of risk’ for epilepsy during pregnancy?
potential for seizures damaging to mother and foetus VS potential risk of drug teratogenicity
How does management of epilepsy during pregancy differ in mild vs severe disease?
Mild disease - consider stopping treatment
Severe disease or Status Epilepticus - in most cases preferable to continue treatment
What is the effect of carbamazepine/phenytoin on contraception
Failure rate x 4
Give 3 Dangers to the foetus during pregnancy if mother continues of AESs
1) Congenital malformations
2) Valproate a/w neural tube defects: spina bifida, craniofacial and digital abnormalities
3) Learning difficulties / mild neurological dysfunction
Which AED is specifcally associated with neural tube defects?
Valproate
If mother is required to stay on her AED during pregnancy, how would we manage this?
Multiple AEDs increase teratogenic risk, so use a single AED agent if possible at lowest dose ➞ Lamotrigine
Give 2 dietary supplements a pregnant women on AED’s should take, and why
Folate supplement - to reduce risk of neural tube defects
Vit K supplements (10 mg/day) in last trimester - because AEDs are associated with Vit K deficiency in new born
Give 2 consequences of Vit K deficiency in a newborn
coagulopathy and cerebral haemorrhage
Status Epilepticus is a Medical Emergency. Risk increases with _______ of seizure.
Priorities are _______, _______, _______
_______ may result from high AED doses, which may require intubation and ventilation in ITU.
Do NOT forget to exclude ________.
Duration, Airway, Breathing, Circulation, Hypoventilation, Hypoglycaemia
Give 3 ways benzodiazapines can be administered for status epilepticus
1) IV Lorazepam (0.1 mg/kg) - preferred due to longer half life
2) IV Diazepam (0.2 mg/kg) or Rectal Diazepam 10mg suppository
3) Buccal Midazolam 5-10 mg (Epistatus)
Administration depends on situation, use clinical judgement
If Benzodiazapines do not work, we can use phenytoin.
Give the dosage, one benefit and what we MUST monitor when using this drug
Zero order kinetics, use 15-20 mg/kg
Benefit: rapidly reaches therapeutic levels IV
Cardiac monitoring! For arrhythmias + hypotension
Give 3 other drugs that can be used in treatment of Status Epilepticus
Midazolam, Thiopentone, Propofol
SUMMARY: give the most appropriate drug for the following
- Generalised and Absence seizures
- Pregnancy
- Focal seizures e.g Temporal Lobe
- Status Epilepticus
1) Valproate for Generalised and Absence seizures
2) Lamotrigine in pregnancy
3) Carbamazepine for Focal seizures e.g Temporal Lobe
4) Lorazepam for Status Epilepticus + start Phenytoin
