Module 4.1.1 (Pharmacology of Drugs for Epilepsy)

Question 1

What is a seizure?

Answer 1

Refers to a transient alteration of behaviour due to disordered, synchronous & rhythmic firing of populations of brain neurons

• Thought to arise from the cerebral cortex

Question 2

What is Epilepsy?

Answer 2

Refers to a disorder of brain function characterised by the periodic & unpredictable occurrence of seizures

> detected by EEG

Question 3

What is the neurobiology of seizures?

Answer 3

Evidence for excessive glutamate excitatory neurotransmission

• glutamate released from presynaptic neuron –> stimulates NMDA –> calcium enters nerve cell –> synthesis of NO –> increased release of glutamate

Glutamate acts at NMDA receptors

• Suppresses GABA which is a inhibitory neurotransmitter
• Increase in calcium influx via T-type calcium channels

Question 4

What are the three mechanism of action of antiepileptic drugs?

Answer 4

Effects on ion channels

• Inhibition of the sodium or calcium influx responsible for neuronal depolarisation
• Prolong inactivation of Na+ channel’s inactivation gate, thereby reducing ability of neurons to fire at high frequencies –> delays formation of next action potential

Effects on GABAergic systems

• Augmentation of inhibitory GABA neurotransmission

Effects on glutaminergic systems

• Inhibition of excitatory glutamate transmission

Question 5

How does BDZ and barbiturates work?

Answer 5

BDZ & barbiturates enhance GABA activation of the GABAA receptor-chloride-ion channel.

• Benzodiazepines promote the binding of the major inhibitory neurotransmitter, GABA, to the GABAA subtype of GABA receptors.

Question 6

Explain how the following antiepipletic drugs work:

A) Topiramate

B) Gabapentin

C) Tiagabine

D) Vigabatrin

Answer 6

A)

• Topiramate also activates GABAA receptors

B)

• Gabapentin acts presynaptically to promote GABA release

C)

• Tiagabine inhibits the GABA transporter (GAT-1) & ↓ neuronal uptake of GABA thus increasing the synaptic concn of GABA & prolonging its action

D)

• Vigabatrin inhibits GABA degradation - is an irreversible inhibitor of GABA transaminase (the enzyme that breaks down GABA)

Question 7

What epeileptic drugs inhibit glutamate neurotransmission?

Answer 7

Topiramate and valproate inhibit glutamate neurotransmission

Question 8

Summary of MOA of drugs Pt 1

Answer 8

Question 9

Summary of drugs Pt 2

Answer 9

Question 10

Summary of drugs Pt 3

Answer 10

Question 11

What are the pharmacokinetics for the following drugs:

A) Carbamazepine

B) Oxcarbazepine

Answer 11

A)

t1/2 = 12-18 hours (longer initially)

• Adequately absorbed after oral administration
• Biotransformed to active metabolite – carbamazepine epoxide (has antiepileptic properties)
• Almost all drug is excreted as metabolites in urine & faeces
• Able to induce its own metabolism
• Should ↑ dose slowly to allow for enzyme induction at start of Tx
• Steady state plasma levels may not be achieved for 2-4 weeks because of autoinduction of metabolism

B)

t1/2 = 2 (parent)/ 8-10 (metabolite)

• Is structurally related to carbamazepine
• Is a prodrug
• Completely absorbed & extensively metabolised by hepatic enzymes to its active hydroxy metabolite, which is responsible for clinical effects
• Metabolite is excreted in urine
• Less potent enzyme inducer than carbamazepine

> Oxcarbazepine may be an alternative to carbamazepine because it has less CNS SE & interactions

Question 12

What are the adverse effects of carbamazepine and oxcarbazepine?

Answer 12

Common

• N, V, D, C, drowsiness, diplopia, blurred vision, dizziness
• Hyponatraemia
• Leucopenia
• Thrombocytopenia

Rare

• Severe skin reactions
• Multi-organ hypersensitivity syndrome

Oxcarbazepine can also cause severe skin reactions, hepatitis and arrhythmias (these are rare)

Question 13

What are some of the main drug interactions of carbamezapine and oxcarbazepine? What enzyme does it induce?

Answer 13

Induces CYP3A4 and increases metabolism of many drugs including itsef

• Aripiprazole
• Clarithromycin
• Dexamethasone
• Diltiazem
• Ketoconazole
• Lamotrigine
• Warfarin

Question 14

What is the MOA of phenytoin?

Answer 14

Phenytoin prolongs the inactivated state of the Na+ channel, presumably by preventing reopening of the inactivation gate

> delays formation of the next action potential

Question 15

What are the pharmacokinetics for phenytoin?

Answer 15

• Indicated for epilepsy & status epilepticus
• Exhibits dose-dependent kinetics ie metabolism becomes saturated with ↑ dose (non-linear elimination kinetics)
• t1/2 range is 6 – 24 hrs at plasma concs < 10mcg/mL but increases with higher concs ∴ plasma drug concs ↑ as dose ↑ but disproportionally so that even small changes in dose can greatly ↑ plasma levels

TR = 10-20mg/L

Question 16

What are some common and rare SE for phenytoin?

Answer 16

Common SE

• Insomnia „ Sedation „ N, V „ Agitation „ Blurred vision „ Confusion „ Diplopia „ Ataxia „ Nystagmus „ Impaired learning (dose related) „ Gingival hypertrophy –> Good dental hygiene can help prevent this „ Hirsutism (long term use)

Rare SE

• Hallucinations „ Peripheral neuropathy „ Blood dyscrasias „ Hyperglycaemia „ Osteomalacia & rickets
• Stevens Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)

> Asian ancestry (especially Han Chinese, Thai, Malay)— more likely to have HLAB*1502 allele, which significantly ↑ risk of severe skin reactions

• Multi-organ hypersensitivity syndrome including liver, organs, kidneys, rash, fever

Question 17

Phenytoin and pregnancy?

Answer 17

Pregnancy = increase risk of congenital malformation

Question 18

What are some of the major interactions with phenytoin? What enzyme does it induce?

Answer 18

> Taking phenytoin for several days induces CYP3A4 and increases metabolism of many drugs = decreased therapeutic effect

> Extensive array of drug interactions, affecting both phenytoin & other drug plasma levels. Can ↑ or ↓ drug conc and either ↑ risk of toxicity or ↓ seizure control

• Amiodarone
• Azoles
• Ciprofloxacin
• COC –> ↑ metabolism of ethinyloestradiol & ↓ contraceptive efficacy
• Corticosteroids
• Diltiazem
• Fluoxetine
• Levodopa
• Trimethoprim
• Warfarin –> decreases anticoagulant effect

Question 19

What is the MOA of lacosamide?

Answer 19

Stabilises neuronal membranes by enhancing slow inactivation of voltage-dependent Na+ channels & limits sustained repetitive firing.

• May also affect collapsin response mediator protein-2, a protein involved in neuronal differentiation and axonal growth, which is dysregulated in epilepsy

Question 20

What are the indications for lacosamide?

Answer 20

Partial seizures with or without secondary generalisation

Question 21

What are the adverse effects of lacosamide? comon, infrequent, rare.

Answer 21

Many adverse effects are dose-related and occur mostly when starting treatment or increasing dose

• Common SE – N, V, dizziness, diplopia, drowsiness, nasopharyngitis
• Infrequent: nystagmus. 1st degree AV block
• Rare: second or third degree AV block (lacosamide may prolong the PR interval ∴ CI in 2nd or 3rd degree AV block), SJS, TEN.

Question 22

For lamotrigine:

A) MOA

B) Indications

C) Pharmacokinetics

Answer 22

A)

Stabilises presynaptic neuronal membranes by blocking voltage- dependent & use-dependent Na+ channels & inhibiting glutamate release

B)

• Focal (partial) & generalised seizures
• Bipolar disorder (prevention of depressive episodes)

C)

• Completely absorbed from gut & metabolised
• t1/2 = 24 – 30 hours (t1/2 & plasma conc of lamotrigine is ↓ when given with phenytoin, carbamazepine or phenobarbital and is ↑ when given with valproate)

Question 23

What are the adverse effects of lamotrigine?

Answer 23

Common: dizziness, ataxia, blurred vision, maculopapular rash. „

Infrequent: alopecia. „

Rare: multi-organ hypersensitivity syndrome

Can cause severe skin rash eg SJS

• Risk ↑ with concurrent valproate use & with rapid ↑ in dose
• Should stop Tx immediately if rash occurs

Question 24

For topiramate;

A) What is the MOA

B) What is the indication

C) PK?

Answer 24

A)

• Stabilises presynaptic neuronal membranes by blocking voltage-dependent sodium channels.
• Enhances activity of GABA on postsynaptic chloride channels.

B)

• Partial seizure with or without secondary generalisation, generalised tonic-clonic seizures & seizures associated with Lennox-Gastaut syndrome (adjunctive Tx or monotherapy)
• Prevention of migraine in adults

C)

• Rapidly absorbed orally
• M, R – nearly 70% is excreted unchanged in urine
• t1/2 ∼ 20 - 30 hours

Question 25

What are the adverse effects of topiramate?

Answer 25

**common**: fatigue, depression, reduced serum bicarbonate * reduced serum bicarbonate can lead to metabolic acidosis (MA), if MA is untreated = increased risk of kidney stones, osteomalacia and osteoprosis **rare**: metabolic acidosis

Question 26

For Ethosuximide A) What is the MOA? B) What are the indications? C) What is the PK

Answer 26

A) * Reduces low threshold voltage-dependent Ca++ conductance in thalamic neurones. \> blocks t-type calcium channels B) * Absence seizures C) * Long half life (30-60 hours) = once/day dosing * Has signficant GI SE therefore usually adminstered in 2 doses/day

Question 27

AE of ethoxuximide?

Answer 27

**Common** - N, V, drowsiness, epigastric pain, hiccups, weight loss, euphoria --\> given bd to reuce GI se **Rare** - depression, psychosis, rash, SJS, haematological SE – agranulocytosis, aplastic anaemia, pancytopenia

Question 28

For valproate: A) What is the MOA? B) What is the indication C) What is the PK D) What is the AE?

Answer 28

A) * Prevents repetitive neuronal discharge by blocking voltage- & use-dependent sodium channels * Enhances the actions of GABA * Inhibits glutamate * Blocks T-type calcium channels B) * Primary generalised epilepsy * Bipolar disorder C) * Well absorbed orally * Extensively metabolised in the liver ∴ should avoid in liver impairment * t1/2 ∼ 8 - 17 hours D) * Common: N, V, ↑ appetite, weight gain, thrombocytopenia. * Rare: liver failure, pancreatitis – usually in first 6 months – can be fatal \> reduces bone mineral density --\> make sure have adequate vitamin D and calcium intake

Question 29

What BZD are used? why are they used?

Answer 29

Clobazam „ Clonazepam „ Diazepam „ Midazolam * BDZ not generally suitable for long-term Tx of epilepsy due to sedative effect & development of tolerance * **Indicated as adjunctive Tx for epilepsy refractory to other antiepileptics; also status epilepticus**

Question 30

AE of benzodiazepines?

Answer 30

Common * Drowsiness „ * Oversedation „ * Hypersalivation „ * Ataxia „ * Light headedness „ * Memory loss „ * Slurred speech „ * Dependence Rare * Blood disorders eg leucopenia, leucocytosis

Question 31

What is the PK for phenobarbital and primidone ( baributrates)? phenobarbital: epilpesy and status epilepticus primidone: epilepsy

Answer 31

**Phenobarbital** t1/2 = 53-118 hours (long acting) * Is absorbed & rapidly distributed to all tissues * **Is metabolized by & induces the hepatic CYP450 enzymes to accelerate its own metabolism & that of other drugs --\> takes 2-4 weeks to reach steady state** * ∼ 25-50% is excreted unchanged in the urine, & the metabolites are excreted in urine as glucuronide conjugates. **Primidone** t1/2 = 6-8 hours * Completely absorbed & metabolised in the liver to 2 major metabolites: phenobarbitone & phenylethylmalonamide (PEMA) \> Both have some degree of anticonvulsant activity \> Primodone also has some antiepileptic activity

Question 32

What are some AE of phenobarbital and primidone?

Answer 32

**Common adverse effects**: sedation cognitive impairment, paradoxical insomnia,. **Infrequent:** ↓ BMD, nystagmus. \> decreased BMD as a result of increasing vit D metabolism which can cause vitamin D deficiency. ensure vit D and Ca intake adequate to prevent osteoporosis and oteomalacia --\> monitor BMD. **Rare:** SJS, TEN, osteomalacia, megaloblastic anaemia \> CI – porphyria. Risk of respiratory depression in respiratory disease (a common adverse effect with IV admin is respiratory depression).

Question 33

What are the main interactions for barbiturates? What enzymes does it induce?

Answer 33

Induce hepatic enzymes & ↑ metabolism of many drugs \> Alcohol & other CNS depressants (TCAs, hypnotics, sedating antihistamines, etc) - ↑ CNS depression * COC * Dexamethasone * Folic acid * Griseofulvin * Lamotrigine * Metronidazole * Valporate * Verapamil * Warfarin

Question 34

MOA of gabapentin and pregabalin? Indication?

Answer 34

Gabapentin & pregabalin bind to alpha-2 delta protein subunit of high threshold voltage dependent calcium channels, reducing calcium influx and neurotransmitter release. * Although structurally related to the neurotransmitter GABA, they are not known to significantly affect GABA or its receptors. **indication:** for epilpesy and neuropathic pain

Question 35

AE of gabapentin? \> Incompletely absorbed from the gut via a saturable transporter mechanism Excreted unchanged by the kidney \> half life 6 to 9 hours

Answer 35

Some common SE – dizziness, fatigue, sedation, hypertension, weight gain, peripheral oedema, diplopia, nystagmus, amblyopia , tremor Some infrequent SE – psychoses, confusion, vertigo, hypoaesthaesthia Some rare SE – jaundice, motor disorders

Question 36

AE of pregabalin? \> t1/2 = 2-8 hours (about 6 hours) \> Well absorbed from the gut Largely excreted unchanged by the kidney

Answer 36

**Some common SE** - visual disturbance (including blurred vision & diplopia), drowsiness, dysarthria, weight gain, peripheral oedema. **Some infrequent SE** – depression, tachycardia, hypotension, hypertension, excessive salivation, urinary incontinence, dysuria **Some rare SE** – neutropenia, dysphagia, rhabdomyolysis

Question 37

MOA of vigabatrin?

Answer 37

Irreversible inhibitor of GABA-transaminase, results in ↑ brain concns of GABA.

Question 38

For vigabatrin: A) Indications B) PK C) AE

Answer 38

A) * Epilepsy --\> when other epilepetic drugs are not enough B) * Rapidly absorbed from gut & excreted unchanged from kidney * Has a short t1/2 = 7-8 hrs but enzyme inhibition is long lasting C) * Common: visual field defect, especially visual field constriction (occurs in 20-40%) – may be asymptomatic & is usually irreversible * Rare: allergic reaction (angioedema, urticarial)

Question 39

For levetriacetam: A) MOA B) Indications C) PK D) AE

Answer 39

A) * Exact mechanism unknown. May modulate neurotransmission by binding to synaptic vesicle protein 2A. B) * Partial seizures with or without 2° generalisation (monotherapy or adjunct therapy) C) * Rapidly absorbed after oral administration „ * t1/2 = 6 – 8 hours „ * Largely excreted unchanged by kidneys D) * Common: behavioural effects (depression, hostility, emotional lability, aggression, agitation, nervousness, anxiety), insomnia * Rare: SJS, TEN