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AC- CNS lectures > Module 4.1.1 (Pharmacology of Drugs for Epilepsy) > Flashcards

Module 4.1.1 (Pharmacology of Drugs for Epilepsy) Flashcards

1
Q

What is a seizure?

A

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
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2
Q

What is Epilepsy?

A

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

> detected by EEG

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3
Q

What is the neurobiology of seizures?

A

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
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4
Q

What are the three mechanism of action of antiepileptic drugs?

A

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
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5
Q

How does BDZ and barbiturates work?

A

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.
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6
Q

Explain how the following antiepipletic drugs work:

A) Topiramate

B) Gabapentin

C) Tiagabine

D) Vigabatrin

A

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)
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7
Q

What epeileptic drugs inhibit glutamate neurotransmission?

A

Topiramate and valproate inhibit glutamate neurotransmission

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8
Q

Summary of MOA of drugs Pt 1

A
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9
Q

Summary of drugs Pt 2

A
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10
Q

Summary of drugs Pt 3

A
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11
Q

What are the pharmacokinetics for the following drugs:

A) Carbamazepine

B) Oxcarbazepine

A

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

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12
Q

What are the adverse effects of carbamazepine and oxcarbazepine?

A

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)

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13
Q

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

A

Induces CYP3A4 and increases metabolism of many drugs including itsef

  • Aripiprazole
  • Clarithromycin
  • Dexamethasone
  • Diltiazem
  • Ketoconazole
  • Lamotrigine
  • Warfarin
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14
Q

What is the MOA of phenytoin?

A

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

> delays formation of the next action potential

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15
Q

What are the pharmacokinetics for phenytoin?

A
  • 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

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16
Q

What are some common and rare SE for phenytoin?

A

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
17
Q

Phenytoin and pregnancy?

A

Pregnancy = increase risk of congenital malformation

18
Q

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

A

> 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
19
Q

What is the MOA of lacosamide?

A

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
20
Q

What are the indications for lacosamide?

A

Partial seizures with or without secondary generalisation

21
Q

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

A

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.
22
Q

For lamotrigine:

A) MOA

B) Indications

C) Pharmacokinetics

A

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)
23
Q

What are the adverse effects of lamotrigine?

A

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
24
Q

For topiramate;

A) What is the MOA

B) What is the indication

C) PK?

A

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
25
Q

What are the adverse effects of topiramate?

A

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

26
Q

For Ethosuximide

A) What is the MOA?

B) What are the indications?

C) What is the PK

A

A)

  • Reduces low threshold voltage-dependent Ca++ conductance in thalamic neurones.

B)

  • Absence seizures

C)

  • Long half life (30-60 hours) = once/day dosing
  • Has signficant GI SE therefore usually adminstered in 2 doses/day
27
Q

AE of ethoxuximide?

A

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

28
Q

For valproate:

A) What is the MOA?

B) What is the indication

C) What is the PK

A

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

29
Q

What BZD are used? why are they used?

A

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
30
Q

AE of benzodiazepines?

A

Common

  • Drowsiness „
  • Oversedation „
  • Hypersalivation „
  • Ataxia „
  • Light headedness „
  • Memory loss „
  • Slurred speech „
  • Dependence

Rare

  • Blood disorders eg leucopenia, leucocytosis
31
Q

What is the PK for phenobarbital and primidone ( baributrates)?

phenobarbital: epilpesy and status epilepticus
primidone: epilepsy

A

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

32
Q

What are some AE of phenobarbital and primidone?

A

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).

33
Q

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

A

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
34
Q

MOA of gabapentin and pregabalin? Indication?

A

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

35
Q

AE of gabapentin?

> Incompletely absorbed from the gut via a saturable transporter mechanism Excreted unchanged by the kidney

> half life 6 to 9 hours

A

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

36
Q

AE of pregabalin?

> t1/2 = 2-8 hours (about 6 hours)

> Well absorbed from the gut Largely excreted unchanged by the kidney

A

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

37
Q

MOA of vigabatrin?

A

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

38
Q

For vigabatrin:

A) Indications

B) PK

C) AE

A

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)
39
Q

For levetriacetam:

A) MOA

B) Indications

C) PK

D) AE

A

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

AC- CNS lectures (28 decks)

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