Anti-epileptics & anti- convulsants Flashcards
State the manifestation of epilepsy
- loss/ disturbance of consciousness
- characteristic body movement
State the pathophysiology of epilepsy
excitation: glutamate
inhibition: GABA
-> imbalance => prone to excitation
Differentiate absence and non absence type epilepsy
absence type:
- focus in thalamus
- neurons fire abnormally and mediated by Ca2+ T type channels (slower)
non absence type:
- excessive neuronal discharge from rapid AP firing mediated by Na+ channels
Phenytoin MOA
- prolongs inactivated state of Na+ channel -> longer refractory period
- depress presynaptic glutamate release
- facilitate GABA release (reduce Ca2+ release)
State use of phenytoin
- used for status epilepticus when foephenytoin not available
- used to be for: GTCS and partial seizure
- now only when better drugs cannot be used
State phenytoin relationship with CYP
- potent inducer of CYP2C8/9, CYP3A4/5
- competitively inhibits CYP2C9/19
State phenytoin metabolism due to interaction
- phenobarbitone inhibts
- carbamazepine induce
- valproate decrease
State how phenytoin affects other drugs
- inhibits warfarin metabolism
- induce enzyme
-> degrade steroids
-> failure of oral contraceptive
Carbamazepine MOA
- actions resemble phenytoin:
1. inhibit high frequency neuronal discharge
2. decrease presynaptic transmitter release
- lithium like effect in mania and bipolar
Use of carbamazepine
- simple and complex partial seizure
- GTCS
(same as phenobarbitone)
-> can exacerbate myoclonic and absence seizures
State carbamazepine interaction
- enzyme inducer
-> reduce efficacy of haloperidol/ oral contraceptive/ lamotrigine/ valproate/ topiramate - its own metabolism
-> induced by phenobarbitone, phenytoin
Ethosuximide MOA and use
- selectively suppress T type Ca2+ channels
- selective action on absence seizures
Ethosuximide side effects
- GI intolerance
- headache
- inability to concentrate
Phenobarbitone MOA
enhance GABAa receptor mediated synaptic inhibition
State phenobarbitone interaction
- CYP450 inducer
- valproate raise phenobarbitone level when given concurrently
Adverse effects of phenobarbitone
- sedation
- hepatotoxicity
- resp/ CV depression -> overdose can be fatal
- behavioural abnormalities
State use of phenobarbitone
- effective in GTCS, simple partial, complex partial seizures （same as carbamazepine)
- now infrequently used due to behavioural side effects
- not effective in absence and atonic seizure
Clonazepam MOA
- BZD with prominent anti-convulsant properties
- potentiate GABA induced Cl- influx -> sedation & anticonvulsant
Use of clonazepam
- primarily for absence seizure
- partial seizure
- myoclonic epilepsy
- suppress acute mania
Clonazepam adverse effect
- sedation and dullness
- lack of concentration
- irritability/ temper
Vigabatrin MOA
- increase overall levels of GABA in GABAnergic neurons
- Inhibits GABA transaminase (degradation of GABA into succinic semialdehyde)
- Inhibits glial/ astrocyte uptake of released GABA from synapse
Use of vigabatrin
- refractory epilepsy
- adjuvants for partial and generalized seizure in infantile spasm
- not effective in absence seizure
Adverse effects of vigabatrin
- visual field contraction, alteration of colour vision
- behavourial changes, psychosis
MOA of valproic acid (sodium valproate)
- mutiple mechanism:
1. frequency-dependent prolongation of Na+ channel inactivation (phenytoin like)
2. weak attenuation of T type Ca2+ channel (ethosuximide like)
3. enhanced release of GABA due to inhibition of GABA transaminase (vigabatrin like)
4. blockade of excitatory NMDA receptor
Adverse effects of valproic acid
- avoid in pregnancy: produce spina bifida & neural tube defects in baby
- fluminant hepatitis -> rare but serious adverse effect
- anorexia, heart burn, loose motion (diarrhoea)
Interaction of valproic acid
- concurrent administration with clonazepam contraindicated - may precipitate absence status epilepticus may precipitate
- increase plasma level of phenobarbitone and lamotrigine
- may cause phenytoin toxicity (displace from protein)
- inhibit hydrolysis of active epoxide metabolite of carbamazepine
State MOA of lamotrigine
- multiple action
1. prolongs Na+ channel inactivation + suppress high frequency firing
2. inhibits voltage gated Ca2+ channels
3. directly block voltage Na+ channel
Use of lamotrigine
- refractory cases of partial seizure and GTCS
- absence and myoclonic epilepsy
- neuralgic pain
MOA of gabapentin
- multiple action
1. lipophilic GABA derivative cross brain -> enhance GABA release
(but NOT a agonist at GABAa receptor)
2. modulate voltage Ca2+ channels -> reduce glutamate release -> lower neuronal excitability
*congener: pregabalin
Use of gabapentin
- reduce seizure frequency in refractory partial seizure
- add on in SPS and CPS
- first line drug for neuralgic pain
MOA of topiramate
- prolongation of Na+ channel inactivation
- GABA potentiation
- antagonism of glutamate receptors
- neuronal hyperpolarization through K+ channels
Use of topiramate
- refractory SPS, CPS and GTCS
- myoclonic epilepsy
- add on inabsence seizure
State anticonvulsants that act by enhancing GABA actions
- Phenobarbitone
- Vigabatrin
- Clonazepam
Name anticonvulsants that inhibit Na+ channels
- Phenytoin
- Carbamazepine
Name anticonvulsant that inhibit T type Ca2+ channels
- Ethosuximide
Name anticonvulsants that act by multiple mechanism
- Valproic acid
- Lamotrigine
- Topiramate
- Gabapentin
Which two drugs induce each other’s metabolism
- phenytoin and carbamazepine
Which two drugs primarily used for absence seizure
- ethosuximide
- clonazepam
Summary of use
(G1) - phenytoin: status epilepticus
(G2)
- carbamazepine/ phenobarbitone/ topiramate: GTSC, SPS, CPS
- gabapentin: SPS and CPS
(G3)
- ethosuximide/ clonazepam: absence seizure
- valproic acid/ lamotrigine: myoclonic, absence seizure
(G4)
- vigabatrin: refractory epilepsy
Use of valproic acid
- absence seizure
- myoclonic seizure
Summary of side effects
- phenytoin: (+) warfarin, (-) oral contraceptive
- carbamazepine: (-) efficacy of halo, oral contraceptive, LVT
- ethosuximide: GI intolerance
- phenobarbitone: overdose fatality (resp and CVS depression)
- clonazepam: sedation (BZD) + lack of concentration
- vigabatrin: eyes - visual field contraction & colour vision altering
- Valproic acid: avoid in pregnancy + contraindicated with clonazepam (prepcipitate absence epilepsy) and phenytoin
8-10: not mentioned
Past paper:
- gum hyperplasia
- Steven Johnson/ HLA-B*1502 allele
- oxidation of other drugs in liver
- status epilepticus
- irreversible block on GABA transaminase
- gum hyperplasia: phenytoin
- Steven Johnson/ HLA-B*1502 allele : carbamazepine
- oxidation of other drugs in liver : carbamazepine
- status epilepticus: lorazepam (BZD)
- irreversible block on GABA transaminase: vigabatrin
Which two drug can inhibit GABA transaminase
- vigabatrin
- valproic acid
-> two Vs
