Epilepsy treatments (DONE) Flashcards
What is epilepsy?
An epileptic seizure is a transient paroxysm of uncontrolled discharges, beginning at the epileptic focus, causing an event which is discernible by the person experiencing the seizure and/or an observer
May be localised, spread to adjacent areas or spread to whole brain
In absence seizures the discharge is regular and oscillatory
Affecting 65 million people worldwide
Epilepsy
5% people in the UK lifetime risk of seizure
7-80% respond to medication
50% can withdraw off medication and remain seizure free
Treatment for at least 3 years- up to life
Treatment aims are to minimise polypharmacy and use one drug to limit side effects
Three main mechanisms of anti-epileptics
Antiepileptic drugs inhibit the abnormal discharge in epilepsy between excess excitation and lack of inhibition but do not resolve the underlying cause
Increase inhibitory brain mechanisms- enhancement of GABA action
Decrease excitatory mechanisms- inhibition of sodium channel function or inhibition of calcium channel function
Enhancement of GABA action
GABA is the main inhibitory neurotransmitter in the brain
Several drugs (benzodiazepines, barbiturates) enhance activation of GABAa receptor
This facilitates GABA-mediated opening of chloride channels
Increasing Cl permeability hyperpolarises the cell as Cl ions enter, reducing its excitability
Examples of drugs that work by enhancing GABA
Tiagabine inhibits GABA uptake into neurons/glia
Vigabatrin irreversibly inhibits GABA transaminase (enzyme responsible for inactivating GABA)
Reducing excitability: inhibition of sodium channels
Many anti-epileptic drugs block voltage dependent sodium channels to reduce cell membrane excitability
Their blocking action is use-dependent
This allows the drugs to preferentially block the excitation of cells that are firing repetitively, so can block the high frequency discharge that occurs in an epileptic fit, without interfering with the low-frequency firing when neurons are in the normal state
Use dependent blocking action
Depolarisation of a neuron increases the proportion of sodium channels in inactivated state
The drugs bind preferentially to the inactivated state of sodium channels, preventing them from returning to the resting state
This reduces the number of sodium channels available to generate action potentials
Anti-epileptic drugs which inhibit sodium channels
Include phenytoin, carbamazepine, lamotrigine and sodium valproate
Inhibition of calcium channel function
Drugs effective in absence seizures (ethosuximide, sodium valproate, clonazepam) block T-type calcium channel activity
T-type channel activity is important for the rhythmic discharge of thalamic neurons in the absence seizures
Gabapentin acts on L and P/Q type channels and reduces calcium entry into nerve terminals and hence release of neurotransmitters
AMPA receptor inhibition
Perampanel (Fycompa)- inhibits AMPA-induced increases in intracellular Ca and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation
SV2A inhibition
Unique class of AED Levetiracetam (multiple possible sites of action), biviracetam (more selective SV2A binding) Synaptic vesicle protein, binding reduces release of glutamate
Topiramate
Multiple proposed mechanisms of action: Voltage gated sodium channels High-voltage activated calcium channels GABA-A receptors AMPA/kainite receptors Carbonic anhydrase isoenzymes
Advice on switching brand
Phenytoin, carbamazepine, phenobarbital, primidone- ensure maintenance on specific brand
Valproate, lamotrigine, perampanel, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine acetate, zonisamine, topiramate- switch brand based on clinical judgement, consultation with patient, avoid if possible
Levetiracetam, lacosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin- fine to switch brand
Combination therapy
Must exhaust one drug at a time first
Enhances toxicity
May not enhance anti-epileptic effect
Interactions complex, variable and often unpredictable
Dose frequency
Determined by half life
Usually twice daily at average doses, needs to be three times daily if large doses
Usually once daily for phenobarbital, lamotrigine and phenytoin
Dose (mg/kg) increased in children as more likely to have seizures
The search for new anti-epileptic drugs
Current therapy fails 50% of those with complex partial seizures
Inadequate control for potentially fatal status epilepticus
No therapy to prevent epileptogenesis
Few drugs for absence seizures
Limited range of drugs for paediatric use
Serious complications with some highly effective drugs e.g. tolerance, foetal malformations
Side effects induce patient non-compliance
Drugs in development
Ganaxolone- positive allosteric modulator of GABAa receptors containing sigma subunits (treatment for rare form of severe epilepsy- synthetic neurosteroid) in trials
Extended release topiramate in trials- tonabersat is a neuronal gap junction inhibitor
Diazepam
Status epilepticus, continuous, severe seizures, potentially fatal IV
Rapid action, elimination half life 60 hours, metabolised by liver microsomal enzymes, excreted as glucuronide metabolites
Sedation, prolonged sleep, confusion, impaired motor performance, enhance depressant effect of alcohol, withdrawal may precipitate seizures
Carbamazepine
Partial and generalised seizures
Well absorbed, 75% bound to albumin, elimination half life 30 hours, metabolised by liver microsomal enzymes, excreted as glucuronide conjugates, strongly induces CYP450s- half life reduces to 15 hours
Drowsiness, dizziness, ataxia, water retention, GI and CV effects, many interactions e.g. warfarin, alcohol
Sodium valproate
All forms of epilepsy
Well absorbed, 10-20% bound to albumin, elimination half life 9-16 hours, metabloised by liver microsomal enzymes, excreted as glucuronide conjugates
Nausea, gastric irritation, ataxia, tremor, hepatotoxicity (fatal), congenital metabolic disorder, foetal abnormalities
Low incidence of side effects
Hydantoin and hydantoin related
Phenytoin- ataxia, incoordination
Mephenytoin- idiopathic toxicities
Ethotoin- fewer side effects, less potent
Phenacemide- toxic, last resort for partial seizures
Phenytoin
Partial and generalised seizures, may exacerbate absence seizures
Well absorbed, 90% albumin bound, elimination half life 20 hours, narrow therapeutic index, metabolised by liver microsomal enzymes, excreted as glucuronide
Vertigo, ataxia, headache, nystagmus, confusion, cognitive dysfunction, acne, foetal malformations, blood/skin disorders
Ethosuximide
Used for absence seizures
Main effect is inhibition of T-type calcium channels
Well absorbed, metabolism and excretion similar to phenobarbital, 60 hour half life
Main side effects are nausea and anorexia
Lamotrigine
Partial seizures and primary and secondary generalised tonic-clonic seizure
Titration needs to take into account any other AEDs
Side effects commonly rashes (may indicate hypersensitivity), blood disorders
Topiramate
Adjunctive treatment of partial seizures and primary tonic-clonic seizures
Side effects: abdominal pain, nausea, anorexia
Can cause acute myopia with secondary closed angle glaucoma
Gabapentin and pregabalin
Gabapentin effective against partial seizures
Shows saturability so relatively safe/free of side effects in overdose
No interactions with other drugs
Pregabalin- analogue of gabapentin but more potent
Use with care in patients with impaired renal function
Tiagabine
Add on for partial seizures
Analogue for GABA, crosses BBB
Inhibits GABA transporter so inhibits removal of GABA from synapse
Side effects- drowsiness and confusion
Levetiracetam
Partial and generalised tonic-clonic seizures
Interferes with neurotransmitter release by binding to SV2A
Zonisamide
Adjunct treatment for partial and generalised seizures
Blocks Na channels and -type calcium channels
May also enhance GABA action
Free of major unwanted side effects and serious drug interactions
Causes drowsiness
Barbiturates and barbiturate-like compounds
Phenobarbital- clonic/tonic, sedation, not absence
Primidone- metabolised to phenobarbital, rarely used
Mephobarbitone- metabolised to phenobarbitone
Methabarbitone- metabolised to barbital, increase sedation
Phenobarbital
All forms of epilepsy except absence
Well absorbed, 50% albumin bound, elimination half life 50-150 hours, oxidised/conjugated by liver microsomal enzymes, induces metabolic enzymes
Sedation, behavioural disturbances, long term motor/cognitive decrements, megalobalstic anaemia, hypersensitivity reactions, can induce porphyria
Overdose- coma, cardiac and respiratory failure
Other drugs
Acetazolamide Eslicarbazepine acetate Rufinamide Stiripentol Lacosamide Piracetam Primidone Vigabatrin Retigabine
Types of epileptic seizure
Generalised: main forms are tonic-clonic and absence seizures
Partial
Generalised seizures
Affect whole brain
Tonic-clonic: patient stiffens, falls and convulses, laboured breathing, hyper-salivation, cyanosis, tongue biting and incontinence
Lasts a few minutes, followed by a headache and drowsiness
Absence seizure
Rarer, almost exclusively in childhood and adolescence
Goes blank, stares, eyelids flutter, head flops
Lasts a few seconds
Child may not be aware of it
Partial seizures
Affect localised brain regions
Attack may involve mainly motor, sensory or behavioural symptoms
Loss of consciousness may occur
Can become secondarily generalised
