Anticonvulsants

Question 1

Partial vs Generalized seizure

Answer 1

Partial - focal/ localised onset, where they [can be] still aware (or not)
Generalised - affecting both hemispheres, with characteristic features of:
- Absence (lapse of awareness)
- Myoclonic (sudden massive jerk - Upper limbs > )
- Atonic
- Tonic - clonic

Question 2

Define Seizure

Answer 2

Clinical manifestation of an abn & excessive paroxysmal discharge of cerebral neurones

Question 3

Define Epilepsy

Answer 3

Chronic condition with recurrent, unprovoked seizures

Question 4

3 goals of anticonvulsant therapy:

Answer 4

1 - seizure free/ significant reduction in seizures
2 - Minimize drug effects
3 - Maintain/ restore QoL

Question 5

Requirements to start AC therapy at first seizure

Answer 5

• Structural brain lesion
• Abnormal neuro exam
• Status epilepticus at presentation
• Strong family Hx
• Epileptiform abnormal on EEG

Question 6

Which Anti-convulsant drug has the best side effects profile and is most effective

Answer 6

HAH! TRICK QUESTION! (sorry liv). NO single ACD is most effective / best tolerated

Question 7

How to select ACD

Answer 7

o Type of seizure
o Potential for drug interaction
o Comorbid disease / SE profile
o Pregnancy risk
o Cost

Question 8

How do you go about initiating ACD in terms of dosage

Answer 8

Start low and increase gradually to build a therapeutic dose

Question 9

How many different agents should be used:

Answer 9

MONOTHERAPY IS THE GOAL

Question 10

If trial of one drug is failing what are you next steps:

Answer 10

check adherence, drug concentration at therapeutic range – if no cause found then gradually withdraw – try another monotherapy

Question 11

Problems with multimodal AC therapy (multiple drugs)

Answer 11

higher toxicity risk
interaction
jeopardises adherence

Question 12

When to stop ACT

Answer 12

Consider if seizure free >2 yrs - Especially if normal EEG, no structural lesion, normal intelligence
Taper off very slowly (3/12)
Patient must understand risk

Question 13

2 main mechanisms of actions of anticonvulsants:

Answer 13

1 - Reduce high frequency neuronal firing by modifying neurotransmitter activity [ie. benzos; valproate]
o Increase GABA activity
o Reduce excitatory glutamate
2- Modify activity of ion channels [ie. carba.; phenytoin etc.]
o Voltage gate Na channels
o Ca channels

Question 14

Why therapeutic drug monitoring is important in epilepsy

Answer 14

High variability in PK/PD (efficacy and toxicity)

Question 15

When to start therapeutic drug monitoring

Answer 15

Poor seizure control
Features of toxicity
Possible interacting drug co-administered
Assess adherence
Guide dose adjustments when interacting drug added to or removed from regimen or during pregnancy
NOT if seizures well controlled & no toxicity

Question 16

How to do therapeutic drug monitoring

Answer 16

Wait until steady state achieved (4-5 half lives) before starting monitoring
Therapeutic range = guide only
Dose determination depends on ind response & adverse effects
Most have narrow therapeutic index

Question 17

What is status epilepticus

Answer 17

A seizure or cluster of seizures lasting 30 minutes > without intervening periods of consciousness. It is a medical emergency because death and permanent brain damage risk increase with length of attack.

Question 18

Management of status epilepticus

Answer 18

1 - abort the seizure - IV benzo [Lora/dia/clonazepam], if no IV access can use buccal or IM [lorazepam/clonazepam only], or PR [diazepam]
2 - Airway maintenance after seizure aborted
3 - Prevent further seizures - IV infusion phenytoin loading dose followed by maintenance doses (phenobarb preferred in children)

Question 19

If you cannot control seizures in S.Epilepticus

Answer 19

Intubate and Thiopental/Propofol

Question 19

If you cannot control seizures in S.Epilepticus

Answer 19

Intubate and Thiopental/Propofol infusion

Question 20

Anticonvulsants in pregnancy

Answer 20

AVOID Sodium valproate, Carbamazepine is lowest risk
* Folate supplementation essential- preferably before conception
* Pregnancy reduces drug levels in 2nd and 3rd trimesters, adjust dose according to levels

Question 21

BONUSSSSS - Drugs possible for … type of seizures:
1 - Tonic-clonic
2- Absence
3- Myoclonic
4- Focal seizures

Answer 21

Tonic-clonic: Carb; Phenytoin; Phenobarbital; Lamotrigine; Valproate
Absence: Ethosuximide; Valproate; (Lamotrigine – off label) +++
Myoclonic: Clonazepam; Valproate
Focal seizures: Carb; Gabapentin; Phenytoin; Phenobarbital; Lamotrigine; Valproate; +++

Question 22

Phenobarbital (barbiturate)
Indications
MOA
PK
CI’s

Answer 22

Indications: Epilepsy except for absence or myoclonic; Status epilepticus
MOA: GABA receptor mediation
PK: Good oral bioavailibility (70%-90%), Metab. in liver, Excreted in urine, steady state in 10-16 days
CI’s: Severe hepatic/renal impairment, Porphyria

Question 23

Phenobarbital (barbiturate)
Cautions
Adverse effects
Drug Interactions

Answer 23

Cautions: DM, Hyperthy., asthma (other resp. diseases), geriatric things (confusion, depression), pregnancy (not safe but risks < seizures)
Adverse effects: drowsiness (decreases over time), CNS (ataxia, nystag., dizzy), derm (hypersens. and photosensitivity), Vitamin D def., withdrawal and dependence
Drug Interactions: Induces!!!!! hepatic microsomal enzymes therefore Hepatic metab. agents [warfarin, COCs, Corticosteroids, tetracyclines, digoxin, beta blockers]; ARVs (reduces levels);

Question 24

Phenytoin Indications MOA PK CI's

Answer 24

Indications: Epilepsy except absence or myoclonic , Status epilepticus MOA: Prolongs inactivation of voltage sensitive Na Channels PK: variable oral bioavail.; protein bound; Metab. in liver but it is saturable [inc. doses small]; renal excretion; steady in 5-10 days CI's: Impaired cardiac func, Porphyria

Question 25

Phenytoin Cautions Adverse effects Drug Interactions

Answer 25

Cautions: liv and hep. compromise; Preg. [not safe have to give folic acid and prophylactic vit. K to mother as well as monitor freq.] Adverse effects: CVS arrythmias; CNS cerebellar Sx, skin rashes NB: gum hypertrophy, hirsuitism, decreased bone density, folic acid depletion problems associated: strong inducer of CYP and UGT, reduces effectiveness of most forms of hormonal contraceptives

Question 26

Phenytoin drug interactions

Answer 26

↑ phenytoin levels: Acute alcohol intake Fluconazole Fluoxetine Isoniazid Diazepam ↓ phenytoin levels Chronic alcohol abuse Folic acid Rifampicin Theophylline Ca supplements & antacids (reduced absorption, take 1-3h apart) Other anti-epileptics: unpredictable, must be monitored Lamotrigine: induced lam met ARVS: avoid concurrent use Lithium: toxicity sx but normal range COCs Warfarin: change to anticoag efficacy

Question 27

Carbamazepine Indications Mechanism PK CI's Adverse effects Drug interactions

Answer 27

Indications: Epilepsy except absence or myoclonic or atonic, Management of pain esp neuralgia Mechanism: Prolongs inactivation of voltage sensitive Na Channels and potentiates postsynaptic actions of GABA PK: Slow and variable absorp.; enhanced with food; metab. by liver exc. renal; AUTOINDUCTION CI's: AV block, porphyria Adverse Effects - Drowsiness, vertigo, ataxia, diplopia and blurred vision Heamatological toxicity – aplastic anaemia, agranulocytosis; Hypersensitivity Extra: before initiation: FBC, renal & LFTS before Monitor serum Na (SIADH) Take with food

Question 28

Valproate Indications Drug interactions Mechanism Adverse effects

Answer 28

AVOID IN WOMAN OF CHILDBEARING AGE

Question 29

what is the metabolism of phenytoin

Answer 29

saturable, zero-order increased dose means plasma conc rises exponentially (not linearly)

Question 30

Why is phenytoin monitoring a bit tricky?

Answer 30

Highly protein-bound narrow therapeutic window nonlinear PK