TDM Antiepileptic Tan.pptx

1. SEIZURES
&
EPILEPSY
INTRODUCTION

2. ILAE (International League Against Epilepsy)
Definition
Epileptic seizures:
• Occurrence of signs and symptoms due to abnormal excessive neuronal activity in brain.
• Excessive electrical discharge in the brain causes uncontrolled muscle spasms, changes in mood, behavior,
thought and altered consciousness.
Epilepsy:
• Neurological disorder characterised by an enduring predisposition to generate epileptic seizures
• Condition of recurrent unprovoked seizures
• Occurrence of at least 2 seizures more than 24 hours apart.
• Occurrence of 1 unprovoked seizure with ≥ 60% risk of further seizures (history of stroke/ brain infection/
brain trauma)
ILAE

4. Focal Onset Seizures
Excessive neuronal firing originates from one brain
hemisphere
• Focal Onset Aware Seizures/
Simple Partial Seizures
Patient is aware of self and environment during seizures
• Focal Onset Impaired Awareness Seizures/
Complex Partial Seizures
Patient is confused or unaware during seizures
Generalised Onset Seizures
Excessive neuronal firing originates from both
brain hemisphere.
Patient most likely to lose consciousness during
seizures.
Unknown Onset Seizures
Seizures of which onset was unobserved.
Cannot be classified into focal or generalized
onset seizures.
Epilepsy

5. Motor Symptoms
Tonic Seizures
Atonic Seizures
Clonic Seizures
Myoclonic Seizures
Tonic Clonic
Seizures
Sudden muscle stiffness
Sudden loss of muscle tone often causing fall
Rhythmic and repetitive muscle jerking
Brief muscle jerking
Sudden muscle stiffness followed by repetitive jerking
Non Motor Symptoms
Absence Seizures/
Petit Mal Seizures
No involvement of muscles. Rapid eye blinking for few
seconds then blank staring into space
Lasts from few seconds to few minutes

6. Diagnosis of Epilepsy
Clinical History
• Diagnosis of epilepsy is primarily based on clinical history
from patient or any eyewitness of the epileptic events.
Electroencephalography (EEG)
• Supportive diagnosis to determine the epileptiform
discharge.
• Normal EEG does not rule out epilepsy.
Neuroimaging
• MRI/ CT is performed to identify underlying brain
abnormalities.
Laboratory Investigations
• To rule out metabolic causes of seizures.
• Hyponatremia, hypoglycemia, hypercalcemia,
alcohol withdrawal.

7. When to Start AEDs?
Single Seizure
• Patients presenting with first single unprovoked seizures present a common clinical dilemma.
• Immediate initiation of AEDs is not necessary unless they are at significant risk of recurrent seizures.
Focal Onset Seizures & Generalised Onset Seizures
• Seizure frequency, severity, patient’s preference.
• Most patients seek treatment after ≥ 2 seizures
Seizures caused by Metabolic Disturbances
• Should not be treated with AEDs.
• Treatment should start by identifying root cause of metabolic disturbances.

8. Recommended AEDs based on Seizure Types
Consensus Guideline on
Management of Epilepsy

9. AEDs:
Mechanism
of Actions
Valproic acid
Carbamazepine
Phenytoin
Medscape: Antiepileptic

10. Na+ Channel Blockers
Sodium Channels
• Na+ Channels in active state: Facilitates influx of Na+
• Net effect: Increase positivity of cells, generates action
potential and cause neurons firing.
CBZ, PYT, VPA
• Na+ Channel Blockers.
• Stabilize Na+ Channels in resting state and inhibit
neurons firing.

11. Ca2+ Channel Blockers
Calcium Channels
• L, N, T-Type: Facilitates influx Ca2+ during resting state
• Net effect: Generates action potential after rapid
depolarization of cells.
• T-Type: Generates rhythmic spike-wave bursts in
generalized absence seizures.
VPA
• T-Type Ca2+ Channel Blockers.
• Inhibit slow depolarization necessary to generate
spike-wave bursts in absence seizures.

12. GABA Enhancers/GAD Modulators
Gamma-aminobutyric Acid (GABA)
• GABA: Inhibitory neurotransmitters
• GABA-A receptors: Facilitates influx of Cl-
• GABA-B receptors: Facilitates efflux of K+
• Net effect: Increase negativity of cells, prevent
production of action potential and inhibit neurons firing.
• GABA is produced by Glutamic Acid Decarboxylase
(GAD).
VPA
• GAD Modulator. Thus, VPA increases production of
GABA and subsequently enhance GABA activity.

13. PK of
AEDs
Sodium Valproate
(VPA)
Carbamazepine
(CBZ)
Phenytoin
(PYT)

14. • VPA follows non-linear pharmacokinetics due to saturable protein-binding.
• Binding of VPA to serum albumin will become saturated within the therapeutic range or when VPA
concentration exceeds 50 mg/L.
• When dose increases, more VPA bind to serum albumin until it becomes saturable and results in more
unbound VPA. These extra unbound VPA are available for hepatic degradation.
• Thus, total VPA concentration will also increase but less than expected when dose slowly increases.

15. Dosing of VPA
Clinical
Pharmacokinetic

16. • CBZ follows non-linear pharmacokinetics due to autoinduction.
• When dosing is initiated, serum concentrations increase according to Cl and t1/2.
• After few doses, there is enough autoinduction that cause increase in Cl, decrease in t1/2 and slow down drug
accumulation.
• With prolonged exposure of liver tissue to CBZ, Cl continues to increase, t1/2 continues to shorten and
serum concentration will slowly increase but less than expected and stabilize with new Cl and t1/2.
• Onset of autoinduction as early as 24hours and maximal induction is achieved 2-3 weeks after initiation dose.

17. Dosing of CBZ
Clinical Pharmacokinetic
Handbook 2020

18. • PYT follows non-linear pharmacokinetics due to saturable hepatic metabolism.
• When dose increases, Css increases, more drugs bind to hepatic enzymes for metabolism until they become
saturated and ultimately reach maximum rate of metabolism (Vmax).
• After Vmax is achieved, dose increases, Css increases even more because rate of metabolism remain constant.
• Small increase in dose results in large increase in Css.

19. Dosing of PYT
Clinical Pharmacokinetic
Handbook 2020

20. VALPROIC ACID
• ENZYME INHIBITOR
PHENYTOIN
• ENZYME INDUCER
CARBAMAZEPINE
• ENZYME INDUCER
Drug-Drug Interaction
Unknown DDI
Drug displacement.
Increases free drug, decrease total drug
concentration
Increases metabolism

21. Monitoring Parameters
Compliance
Fit Frequency
Liver Function Tests (LFT) VPA, CBZ, PYT can cause hepatotoxicity
Full Blood Count (FBC) VPA, CBZ, PYT can cause pancytopenia
Skin Reactions (SJS/TEN) especially CBZ
Serum Ammonia especially VPA due to hyperammoniaemia which can lead to lethargy
and decreased mental function

22. When to Withdraw AEDs?
• Seizure-free period ≥ 2 years
• Risk of seizure relapse
• Patient’s need to work and drive motor vehicle
• Patient’s fear of seizures and attitude to continue
AEDs
Consensus Guideline on
Management of Epilepsy

23. • Consensus Guideline on Management of Epilepsy 2017 suggests for slow discontinuation of AEDs and
duration of tapering should be tailored to individual’s needs and preference.
• Patient should be followed up for ≥ 2 years after discontinuation of AEDs.
How to Withdraw AEDs?
• Cochrane Review 2006 compares slow withdrawal and rapid withdrawal of AEDs.
• Slow withdrawal: more than 3 months
• Rapid withdrawal: within 3 months
• No significant difference between slow and rapid withdrawal of AEDs.

24. When and How to Add-On AEDs?
1. Depending on types of seizures, start single AED as monotherapy.
2. Start at lowest effective dose.
3. Monitor patient’s compliance, side effects and seizure control.
4. Seizures are not controlled despite good compliance. No side effects. Slowly increase dose to achieve good
seizure control.
5. If monotherapy AED is ineffective at maximum tolerated dose, may add-on second AED with different
MOA.
6. May consider to slowly withdraw first AED if patient showed good seizure control after adding second AED.
7. If seizure occurs while tapering down dose of first AED, restart first AED at the dose prior to that stepped
down dose. Continue first and second AED together as polytherapy.
Consensus Guideline on
Management of Epilepsy

25. Convulsive
Non-Convulsive
Non-Convulsive
Status Epilepticus
• Medical emergency caused by failure of AEDs to control seizures from the time when treatment should be
started (t1) which lead to prolonged seizures.
• Medical emergency which may cause long-term consequences after time point (t2).
• Convulsive SE: prolonged tonic-clonic seizures
• Non-Convulsive SE: prolonged absence seizures/ focal seizures with impaired awareness without prominent
motor symptoms

26. First Line: Benzodiazepine
• IV Lorazepam 0.1mg/kg at 2mg/minute.
***If still fit after 3-5 minutes, may give additional dose of IV Lorazepam 4mg (no definite dose of Lorazepam)
• Alternative: IV Diazepam 0.15mg/kg up to 10mg at 5mg/minute
• If no IV access: IM Midazolam 10mg if wt > 40kg/ IM Midazolam 5mg for 13-40kg
Second Line: AEDs
• IV Phenytoin 20mg/kg at 25-50mg/minute.
*still fitting after 10minutes, may give additional dose of 5-10mg/kg up to maximum cumulative dose of 30mg/kg
Pharmacological Management
• Alternative: IV Valproic acid 30mg/kg at 10mg/kg/minute
• Alternative: IV Levetiracetam 60mg/kg up to 4500mg over 15minute

27. Super-refractory SE
• SE that continues or recurs for ≥ 24hours after onset of anasethetic therapy at Refractory SE stage.
• Anaesthetic agents + AEDs.
• Magnesium infusion, Pyridoxine
Refractory SE
• On-going seizures following 1st line and 2nd line drug therapy.
• Administration of anaesthetic agent is recommended.
• If patient is seizure-free for 24hours, can slowly withdraw anaesthetic agent.
• IV Midazolam 0.2mg/kg at 2mg/minute followed by 0.1mg/kg/hour up to 3mg/kg/hour.
• IV Propofol 1-2mg/kg over 5minutes followed by 10-12mg/kg/hour.
• IV Phenobarbital 5mg/kg over 10minutes followed by 1-5mg/kg/hour.
***continue for 24hours even after patient is seizure-free.

28. Thank
you

29. 1. Fisher RS, Cross JH, French JA, Higurashi N, Hirsch E, Jansen FE, Lagae L, Moshé SL, Peltola J, Roulet Perez E,
Scheffer IE. Operational classification of seizure types by the International League Against Epilepsy: Position Paper
of the ILAE Commission for Classification and Terminology. Epilepsia. 2017 Apr;58(4):522-30.
2. Malaysian Society of Neurosciences. Consensus Guidelines on Management of Epilepsy. 2017
3. Types of Seizures [Internet]. Epilepsy Foundation. 2017 [cited 8 October 2020]. Available from:
https://www.epilepsy.com/learn/types-seizures
4. Antiepileptic Drugs: Overview, Mechanism of Action, Sodium Channel Blockers [Internet].
Emedicine.medscape.com. 2020 [cited 10 October 2020]. Available from:
https://emedicine.medscape.com/article/1187334-overview#a2
5. TDM: Valproic Acid [Internet]. Ihuc.edu.iq. [cited 10 October 2020]. Available from:
http://ihuc.edu.iq/uploadiraq/beff2d8f631988TDM%205th%20Stage%20Lec%2013.pdf
6. First order, zero order and non-linear elimination kinetics | Deranged Physiology [Internet].
Derangedphysiology.com. [cited 10 October 2020]. Available from: https://derangedphysiology.com/main/cicm-
primary-exam/required-reading/pharmacokinetics/Chapter%203.3.7/first-order-zero-order-and-non-linear-
elimination-
kinetics#:~:text=Michaelis%2DMenten%20elimination%20kinetics&text=In%20short%2C%20at%20low%20concent
rations,the%20faster%20the%20reaction%20rate.&text=%22drug%22).-
,A%20maximum%20rate%20of%20reaction%20is%20reached%20when%20drug%20concentration,clearance%20
will%20be%20zero%2Dorder.
7. Status Epilepticus [Internet]. Hopkins Medicine. [cited 9 October 2020]. Available from:
https://www.hopkinsmedicine.org/health/conditions-and-diseases/status-
References

30. 8. Ranganathan LN, Ramaratnam S. Rapid versus slow withdrawal of antiepileptic drugs. Cochrane Database of
Systematic Reviews. 2006(2).
9. Uptodate. Convulsive status epilepticus in adults: Treatment and prognosis.
References