Anticonvulsants Flashcards
Partial vs Generalized seizure
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
Define Seizure
Clinical manifestation of an abn & excessive paroxysmal discharge of cerebral neurones
Define Epilepsy
Chronic condition with recurrent, unprovoked seizures
3 goals of anticonvulsant therapy:
1 - seizure free/ significant reduction in seizures
2 - Minimize drug effects
3 - Maintain/ restore QoL
Requirements to start AC therapy at first seizure
- Structural brain lesion
- Abnormal neuro exam
- Status epilepticus at presentation
- Strong family Hx
- Epileptiform abnormal on EEG
Which Anti-convulsant drug has the best side effects profile and is most effective
HAH! TRICK QUESTION! (sorry liv). NO single ACD is most effective / best tolerated
How to select ACD
o Type of seizure
o Potential for drug interaction
o Comorbid disease / SE profile
o Pregnancy risk
o Cost
How do you go about initiating ACD in terms of dosage
Start low and increase gradually to build a therapeutic dose
How many different agents should be used:
MONOTHERAPY IS THE GOAL
If trial of one drug is failing what are you next steps:
check adherence, drug concentration at therapeutic range – if no cause found then gradually withdraw – try another monotherapy
Problems with multimodal AC therapy (multiple drugs)
higher toxicity risk
interaction
jeopardises adherence
When to stop ACT
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
2 main mechanisms of actions of anticonvulsants:
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
Why therapeutic drug monitoring is important in epilepsy
High variability in PK/PD (efficacy and toxicity)
When to start therapeutic drug monitoring
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
How to do therapeutic drug monitoring
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
What is status epilepticus
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.
Management of status epilepticus
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)
If you cannot control seizures in S.Epilepticus
Intubate and Thiopental/Propofol
If you cannot control seizures in S.Epilepticus
Intubate and Thiopental/Propofol infusion
Anticonvulsants in pregnancy
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
BONUSSSSS - Drugs possible for … type of seizures:
1 - Tonic-clonic
2- Absence
3- Myoclonic
4- Focal seizures
Tonic-clonic: Carb; Phenytoin; Phenobarbital; Lamotrigine; Valproate
Absence: Ethosuximide; Valproate; (Lamotrigine – off label) +++
Myoclonic: Clonazepam; Valproate
Focal seizures: Carb; Gabapentin; Phenytoin; Phenobarbital; Lamotrigine; Valproate; +++
Phenobarbital (barbiturate)
Indications
MOA
PK
CI’s
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
Phenobarbital (barbiturate)
Cautions
Adverse effects
Drug Interactions
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);
Phenytoin
Indications
MOA
PK
CI’s
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
Phenytoin
Cautions
Adverse effects
Drug Interactions
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
Phenytoin drug interactions
↑ 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
Carbamazepine
Indications
Mechanism
PK
CI’s
Adverse effects
Drug interactions
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
Valproate
Indications
Drug interactions
Mechanism
Adverse effects
AVOID IN WOMAN OF CHILDBEARING AGE
what is the metabolism of phenytoin
saturable, zero-order
increased dose means plasma conc rises exponentially (not linearly)
Why is phenytoin monitoring a bit tricky?
Highly protein-bound
narrow therapeutic window
nonlinear PK
