Epilepsy treatments (DONE)

Question 1

What is epilepsy?

Answer 1

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

Question 2

Epilepsy

Answer 2

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

Question 3

Three main mechanisms of anti-epileptics

Answer 3

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

Question 4

Enhancement of GABA action

Answer 4

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

Question 5

Examples of drugs that work by enhancing GABA

Answer 5

Tiagabine inhibits GABA uptake into neurons/glia

Vigabatrin irreversibly inhibits GABA transaminase (enzyme responsible for inactivating GABA)

Question 6

Reducing excitability: inhibition of sodium channels

Answer 6

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

Question 7

Use dependent blocking action

Answer 7

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

Question 8

Anti-epileptic drugs which inhibit sodium channels

Answer 8

Include phenytoin, carbamazepine, lamotrigine and sodium valproate

Question 9

Inhibition of calcium channel function

Answer 9

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

Question 10

AMPA receptor inhibition

Answer 10

Perampanel (Fycompa)- inhibits AMPA-induced increases in intracellular Ca and selectively blocks AMPA receptor-mediated synaptic transmission, thus reducing neuronal excitation

Question 11

SV2A inhibition

Answer 11

Unique class of AED
Levetiracetam (multiple possible sites of action), biviracetam (more selective SV2A binding)
Synaptic vesicle protein, binding reduces release of glutamate

Question 12

Topiramate

Answer 12

Multiple proposed mechanisms of action:
Voltage gated sodium channels
High-voltage activated calcium channels
GABA-A receptors
AMPA/kainite receptors
Carbonic anhydrase isoenzymes

Question 13

Advice on switching brand

Answer 13

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

Question 14

Combination therapy

Answer 14

Must exhaust one drug at a time first
Enhances toxicity
May not enhance anti-epileptic effect
Interactions complex, variable and often unpredictable

Question 15

Dose frequency

Answer 15

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

Question 16

The search for new anti-epileptic drugs

Answer 16

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

Question 17

Drugs in development

Answer 17

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

Question 18

Diazepam

Answer 18

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

Question 19

Carbamazepine

Answer 19

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

Question 20

Sodium valproate

Answer 20

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

Question 21

Hydantoin and hydantoin related

Answer 21

Phenytoin- ataxia, incoordination
Mephenytoin- idiopathic toxicities
Ethotoin- fewer side effects, less potent
Phenacemide- toxic, last resort for partial seizures

Question 22

Phenytoin

Answer 22

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

Question 23

Ethosuximide

Answer 23

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

Question 24

Lamotrigine

Answer 24

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

Question 25

Topiramate

Answer 25

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

Question 26

Gabapentin and pregabalin

Answer 26

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

Question 27

Tiagabine

Answer 27

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

Question 28

Levetiracetam

Answer 28

Partial and generalised tonic-clonic seizures

Interferes with neurotransmitter release by binding to SV2A

Question 29

Zonisamide

Answer 29

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

Question 30

Barbiturates and barbiturate-like compounds

Answer 30

Phenobarbital- clonic/tonic, sedation, not absence
Primidone- metabolised to phenobarbital, rarely used
Mephobarbitone- metabolised to phenobarbitone
Methabarbitone- metabolised to barbital, increase sedation

Question 31

Phenobarbital

Answer 31

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

Question 32

Other drugs

Answer 32

Acetazolamide
Eslicarbazepine acetate
Rufinamide
Stiripentol
Lacosamide
Piracetam
Primidone
Vigabatrin
Retigabine

Question 33

Types of epileptic seizure

Answer 33

Generalised: main forms are tonic-clonic and absence seizures
Partial

Question 34

Generalised seizures

Answer 34

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

Question 35

Absence seizure

Answer 35

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

Question 36

Partial seizures

Answer 36

Affect localised brain regions
Attack may involve mainly motor, sensory or behavioural symptoms
Loss of consciousness may occur
Can become secondarily generalised