HUF 2-72 Epilepsy and anticonvulsants Flashcards
Seizure, epilepsy, convulsion
Seizure: abnormal movements or behaviour due to unusual electrical activity in brain
Epilepsy: disorders of tendency for recurrent seizures
Convulsion: body ms. contract and relax rapidly and repeatedly
=> Uncontrollable shaking of body
Causes:
1°: idiopathic
2°: brain damage, infection, inherited, drug-induced (overdosing of antiepileptic drugs)
Types of seizures
- Partial (focal): start in part of brain (may spread to whole brain sometimes)
- Simple: patient still conscious
- Complex: impairing consciousness - Generalised: start in all parts of brain simultaneously; no identifiable onset area
- Tonic-clonic (grand mal):
(a) tonic phase (<30-40s): strong contraction of whole body
(b) clonic phase: gross uncontrolled body jerking
- Absence (petit mal): sudden unresponsiveness for short duration with little or no motor disturbance
- Myoclonic: brief ms. spasm; ms. jerking
- Atonic: brief lapse in ms. tone; ms. go limp suddenly
Goals of anticonvulsant treatments
- Prevention of seizures with 1 single drug
- Long term control: age, pregnancy, nature of seizure, DDI
Seizure prophylaxis:
- Primary agents: Carbamazepine, Phenytoin, Valproate, Lamotrigine
- Adjunctive agents: Phenobarbitone, Gabapentin, Topiramate
Exceptional cases:
- Prophylaxis specific for absence seizure: Ethosuximide, Valproate
- Emergency treatment for status epilepticus: Diazepam, Phenytoin
Biological basis of seizure prophylaxis
- Facilitate inhibitory transmission (GABA)
- Suppress neurons that have high excitability
- Specific and potent GLU receptor antagonists are not in routine clinical use because of their unacceptable adverse effects
Pharmacology of anticonvulsants
- ↓ VGNC in use-dependent manner => ↓ neural excitability
- ↑ inhibitory actions of GABA by
- Allosteric modulators of GABA-A R
- GABA transaminase inhibitors (inhibit GABA degradation) - Block T-type Ca2+ channels
- Multiple actions
Carbamazepine
- Partial and generalised seizures; NOT for absence seizures
- VGNC inhibitor (binding to inactivated state)
- t1/2 = 18-65 hrs; CYP450 inducer
- Side effects: ataxia, diplopia, sedation, hepatotoxicity, water retention, aplastic anemia
- May cause Stevens-Johnson syndrome in Han Chinese with allele of HLA-B*1502
Use-dependent block of neuronal VGNC by antiepileptic drugs
Carbamazepine, Phenytoin, Valproate, Lamotrigine, Topiramate
- Inhibit VGNC
=> Prevent high-freq. repetitive neuronal activity
- Binds preferentially to inactivated state of VGNC
=> Stabilise VGNC in inactivated state
=> Prevent them from returning to resting state (similar to MOA of local anaesthetics)
High-freq. repetitive depolarisation (more times of use)
=> ↑ proportion of VGNC in inactivated state
=> “Used” channels are susceptible to blockade
=> Na+ current progressively reduced
=> Insufficient to initiate AP
Phenytoin
- Partial and generalised seizures; NOT for absence seizures
- Fosphenytoin: injectable form of prodrug (for status epilepticus)
- VGNC inhibitor (binding to inactivated state)
- t1/2 = 7-42 h
- Drug can be displaced from plasma proteins by sulfonamides (e.g. sulfonamide class antibiotics, antidiabetic drug sulfonylureas, celecoxib)
=> DDI - CYP450 inducer
- Side effects: minimal sedation, ataxia, gingival hyperplasia, hypertrichosis, teratogenicity
- Rare side effects: skin rashes, hypersensitivity, Stevens-Johnson Syndrome
Ethosuximide
- Absence seizures
- Block VGCC-T
=> ↓ release of GLU and GABA - May exacerbate tonic-clonic seizures
- Side effects: nausea, anorexia, GI distress, drowsiness,, hives
- Other agents will also be used for absence seizures
e. g. Valproate, Lamotrigine, Topiramate
Ohenobarbitone
- Partial and generalised seizures; NOT for absence seizures
- Sedative and hypnotic: ↑ Cl- influx through GABA-A R in presence of GABA
- CYP450 inducer
- Side effects: sedation, hepatotoxicity, dependence, CVS and respiratory repression at high doses (fatal)
Clonazepam
- All types of seizures
- Belongs to BZD class
- ↑ Cl- influx through GABA-A R in presence of GABA
- Inhibit VGCC-T
- Side effects: sedative, dependence, withdrawal syndrome
∴ NOT for long term use
Vigabatrin
- Partial and generalised seizures; NOT for absence seizures
- ↑ overall levels of GABA in GABAergic neurons and eventually throughout brain
(a) inhibit irreversibly conversion of GABA to succinic semialdehyde by GABA-transaminase
(b) Inhibit glial/astrocyte uptake of released GABA - Side effects: visual field defects, sedation, mood change
Valproate
- All types of seizures
- Inhibit VGNC
- Inhibit GABA transaminase
- Non-sedative
- Side effects: weight gain, tremor, GI distress, hepatotoxicity, teratogenicity
New anticonvulsants - acting through multiple actions
Gabapentin
- Adjunctive treatment for partial seizures
- GABA-mimetic actions
- Less severe side effects: sedation, headache, fatigue, dizziness, weight gain
Lamotrigine
- All seizures
- Inhibit VGCC-T, VGNC and release of GLU
Topiramate
- Partial and generalised tonic-clonic seizures
- Inhibit VGNC
- Enhance GABA-A receptor (diff MOA from BZD)
Notable adverse effects of common anticonvulsants
- Nausea and vomiting
- Sedation
- Ataxia
- Rash
- Hyponatremia
- Weight gain or loss
- Teratogenicity
- Osteoporosis
- Suicidal behaviours and ideation
- Multi-organ hypersensitivity reactions (rash, fever, systemic organ involvement)
