Anti-epileptic drugs

Question 1

What is epilepsy

Answer 1

Chronic disorder characterised by recurrent episodes of seizures

Question 2

What is the pathophysiology of epilepsy

Answer 2

Increased excitatory activity
Decreased inhibitory activity
Loss of control of neuronal membrane potential
Neurones heavily Depolarise and increased rate of discharge
Spread of hyperactivity by synaptic transmission

Question 3

What are the types of epilepsy

Answer 3

Partial:
Simple
Complex
Secondarily generalised

Generalised:
Tonic clonic
Absence

Status epilepticus

Question 4

What are the causes of epilepsy

Answer 4

Primary: idiopathic, 70%
Secondary to Brain damage: 
Head injury 
Asphyxia
Infection 
Stroke/haemorrhage 
Malignancy

Question 5

What are precipitants of epilepsy

Answer 5

Sensory: flashing lights
Alcohol
Drugs
Stroke/haemorrhage 
Metabolic: hypo/hyperglycaemia, hypo/hypernatraemia
Infections

Question 6

What are main therapeutic targets of antiepileptic drugs

Answer 6

Inhibition of Voltage gated Na channels

Enhance GABA-mediated inhibition

Question 7

What are the types of VG Na Channel inhibitors

Answer 7

Carbamazepine
Lamotrigine
Phenytoin

Question 8

What is mechanism of action of VG Na channel inhibitors

Answer 8

Inhibit INACTIVE VG Na channels
Prolong inactive state
Preferentially act on neurones with high frequency depolarisation + discharge
Due to higher proportion of inactive Na channels
Reset rate of discharge in neurones with high rate of discharge

Question 9

What are PK properties of carbamazepine

Answer 9

Protein binding 70%
CYP450 inducer 
Induces own metabolism
Starting T1/2 30hr 
Repeated use T1/2 15hr 
Linear PK

Question 10

What are side effects of carbamazepine

Answer 10

Dizziness, drowsiness, ataxia, numbness
Vomiting
Variation in BP 
Rash
Neutropenia

Question 11

What are DDIs of carbamazepine

Answer 11

CYP450 induction - raises levels of:
Warfarin
Phenytoin 
Oral contraceptives 
Corticosteroids 

Reduced activity with Antidepressants

Question 12

What monitoring is required with Carbamazepine

Answer 12

Adjust dose to therapeutic effect

Due to decreasing T1/2 with repeated use

Question 13

What are indications of carbamazepine

Answer 13

All partial seizures
Tonic clonic seizures
Not absence seizures

Question 14

What are PK properties of phenytoin

Answer 14

Protein binding 90%
CYP450 inducer
Non linear PK at therapeutic dose
Variable T1/2

Question 15

What are side effects of phenytoin

Answer 15

Dizziness, headache, ataxia, nystagmus
Gingivial hyperplasia
Rash
Stevens Johnson syndrome

Question 16

What are DDIs of phenytoin

Answer 16

Increased phenytoin levels (PK binding) with:
NSAID
Valproate
Salicylate

Decrease oral contraceptive levels (CYP450)

Increased phenytoin levels w Cimetidine

Question 17

What drug monitoring is required with phenytoin

Answer 17

Free plasma concentration levels

Salivary levels - indicator for plasma levels

Question 18

What are indications for phenytoin

Answer 18

All partial seizures
Tonic clonic seizures
Not absence seizures

Question 19

What are PK properties of lamotrigine

Answer 19

Linear PK

Not CYP450 inducer

Question 20

What are side effects of lamotrigine

Answer 20

Dizziness, ataxia
Nausea
Rash
(Fewer SEs)

Question 21

What are DDIs of lamotrigine

Answer 21

Adjunct to other AEDs
Reduced activity LTG with oral contraceptives
Potentiation of LTG with valproate
(fewer DDIs)

Question 22

What are indications of Lamotrigine

Answer 22

All partial seizures
Tonic clonic seizures
Absence seizures

AED of choice for women of child bearing age
Not first line for children (increased rate of SEs)

Question 23

What is mechanism of action of AEDs enhancing GABA-mediated inhibition

Answer 23

GABA agonists:
Positive allosteric binding at GABA receptors
At benzodiazepine binding site
Enhance GABA activity at receptor

Affect GABA metabolism:
Activate GABA synthesising enzymes
Inhibit GABA re-uptake enzymes
Increase GABA levels

Question 24

How does GABA activity mediate inhibition

Answer 24

GABA is a natural anticonvulsant
40% synapses in brain are GABA-ergic
GABA receptor is Cl channel causing hyperpolarisation

Question 25

What is mechanism of action of valproate

Answer 25

Affects GABA metabolism: Inhibit GABA reuptake Activate GABA synthesis

Question 26

What are PK properties of valproate

Answer 26

90% protein bound | Linear PK

Question 27

What are side effects of valproate

Answer 27

CNS - ataxia, tremor, sedation | Hepatic - raised transaminases, hepatic failure

Question 28

What are DDIs of valproate

Answer 28

Around Adjunct therapy w other AEDs Decreased valproate activity w antidepressants Decreased valproate activity w antipsychotics Potentate valproate activity w aspirin (PK binding)

Question 29

What drug monitoring is required with valproate

Answer 29

Free plasma conc levels | Salivary levels

Question 30

What are indications of valproate

Answer 30

All partial seizures Tonic clonic seizures Absence seizures

Question 31

What is mechanism of action of benzodiazepines

Answer 31

GABA receptor agonist Bind to Benzodiazepine binding site on GABA receptors Enhance GABA activity

Question 32

What are PK properties of benzodiazepines

Answer 32

90% protein bound | Linear PK

Question 33

What are side effects of benzodiazepines

Answer 33

``` Confusion Sedation Tolerance (long term use) Dependence + withdrawal (long term use) Rebound seizure with abrupt withdrawal Resp + CVS depression ```

Question 34

What are DDIs of benzodiazepines

Answer 34

IV flumazenil causing rebound seizure

Question 35

What are indications of benzodiazepines

Answer 35

Status epilepticus: lorazepam, diazepam | Absence seizure: clonazepam - short term

Question 36

What are prescribing rules of antiepileptic drugs

Answer 36

Monotherapy is the aim Drug choice dependent on patient + condition If first line ineffective, Switch to another AED before starting combination therapy Patient must remain under review Start at low dose + titrate to therapeutic effect Significant seizures can be treated by sedation + paralysis + intubation in ITU

Question 37

What are general indications of anti epileptic drugs

Answer 37

First line for generalised: valproate First line for partial: carbamazepine First line for women of CBA: lamotrigine First line for Status epilepticus: lorazepam

Question 38

What are prescribing rules for women of child bearing age

Answer 38

Balance risk of seizure + teratogenic risk of drug | Assess individual: severity/frequency of seizure, history of status epilepticus

Question 39

What are the risks of medication to foetus

Answer 39

Phenytoin + carbamazepine: Increased failure rate of conception Valproate: Neural tube defects Neuro developmental defects - autism, learning disability Any AEDs: Increased risk of birth defects Congenital malformations Facial/digital hypoplasia

Question 40

What are prescribing rules for pregnant women

Answer 40

``` Aim for Monotherapy Lowest dose Lamotrigine is safest Avoid valproate Prescribe Folate supplements (NTDs) Prescribe Vit K supplements in last trimester: AEDs associated with vitamin K deficiency in newborn ```

Question 41

What is management of Status Epilepticus

Answer 41

ABC Exclude hypoglycaemia 1st line: IV lorazepam (preferred to diazepam due to longer T1/2 so better control) 2nd line: IV Phenytoin (cardiac monitoring needed) Sedation + Paralysis + Intubation at ITU if above fails