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1

 Unlike other classes of drugs, anti-epileptic drugs (AEDs) are all structurally and mechanically unique
 Not possible to discuss them as a single group (unlike ACE inhibitors or B-lactam antibiotics)

 Mechanism of action and clinical pharmacology of each AED must be understood separately

 Possible mechanisms of action:
- Inhibition/enhancement of ion channel
- Enhancement of inhibitory neurotransmitters
- Inhibition of excitatory neurotransmitters
- Action at specific receptor

 Unlike other classes of drugs, anti-epileptic drugs (AEDs) are all structurally and mechanically unique
 Not possible to discuss them as a single group (unlike ACE inhibitors or B-lactam antibiotics)

 Mechanism of action and clinical pharmacology of each AED must be understood separately

 Possible mechanisms of action:
- Inhibition/enhancement of ion channel
- Enhancement of inhibitory neurotransmitters
- Inhibition of excitatory neurotransmitters
- Action at specific receptor

2

Drug Treatment - Strategy

Choosing an appropriate AED depends on

 Accurate classification of epilepsy or epileptic syndrome
 Comorbidities (if any)
 Concurrent medications (if any)

 Balance between therapeutic benefits vs therapeutic risks
- Benefits may depend on therapeutic spectrum of activity
- Risks include potential side effects or toxicity

 Patient’s and/or caregiver’s preferences

Often, identification of an appropriate AED may come down to trial and error

3

Drug Treatment - Strategy
Expert opinion:
ranking

 1st choice Monotherapy
 2nd-choice Monotherapy (alternative agent)
 3rd-choice Monotherapy (3rd agent), or Combination therapy
 4th-choice Surgery

4

Advantages of monotherapy:

 May be of equal or superior efficacy compared to combination therapy
 Likely lower incidence of adverse effects
 Absence of drug interactions
 Reduced risk of birth defects
 Lower cost
 Relatively easier to correlate response, adverse effects and abnormal laboratory values to specific drug
 Improved compliance (simpler, less intrusive drug regimen)

5

Initiation of treatment

 Start with low doses of a 1st-line AED appropriate for the particular seizure type
 If seizures continue but no side effects occur --> gradually increase dose of AED

 If seizures continue despite maximum tolerated dose of 1st line AED:
- Diagnosis should be reviewed
- Ensure that patient has received the appropriate drug for seizure type/epileptic syndrome
- Ascertain degree of patient compliance to meds – ? poor communication, problems with understanding/remembering instructions, side effects, inconvenient regimen, financial issues, etc

6

Follow-up steps

 Second 1st-line AED drug may then be introduced to optimise therapy
 New AED should be titrated to its recommended dose range
 At the same time, first AED may be gradually withdrawn over 1-3 weeks (often more rapidly for inpatients)
 Once withdrawal of first AED is complete, increase dose of new AED to improve symptoms or until adverse effects occur
 This process should be continued until monotherapy with two to three primary drugs (usually 1st-generation AEDs) has failed

 Combination therapy (up to 3 or even 4 meds) may then need to be considered
Factors to consider when combining AEDs:
- Patient’s previous clinical response to each drug alone - Drug(s)’ mechanism of action
- Drug(s)’ tolerability profile
- Drug(s)’ pharmacokinetic profile

 Last Resort
Consider surgery for patients who have failed monotherapy and initial attempt with polytherapy

7

Therapeutic Drug Monitoring

 Use of therapeutic drug monitoring should be considered as an aid to patient’s overall management
 Correlation between maintenance dose of AED and serum concentration is often poor
 However, correlation between serum concentration and therapeutic response/toxic effects may be quite good for some AEDs, e.g., phenytoin, phenobarbitone
 A patient’s clinical response to AED treatment (i.e., frequency and severity of seizure, symptoms of toxicity) should be the major focus for assessment of therapy

Therapeutic Drug Monitoring

 Use of therapeutic drug monitoring should be considered as an aid to patient’s overall management
 Correlation between maintenance dose of AED and serum concentration is often poor
 However, correlation between serum concentration and therapeutic response/toxic effects may be quite good for some AEDs, e.g., phenytoin, phenobarbitone
 A patient’s clinical response to AED treatment (i.e., frequency and severity of seizure, symptoms of toxicity) should be the major focus for assessment of therapy

8

Therapeutic Drug Monitoring

 Response to a particular AED serum concentration is dependent on:
- Interpatient variability
Recommended target serum concentrations are meant to merely be a guide
- Seizure type
E.g., partial seizures generally require a higher serum concentration to control (cf. tonic-clonic seizures)


Remember:Treat the seizure(s), not the numbers’!

Therapeutic Drug Monitoring

 Response to a particular AED serum concentration is dependent on:
- Interpatient variability
Recommended target serum concentrations are meant to merely be a guide
- Seizure type
E.g., partial seizures generally require a higher serum concentration to control (cf. tonic-clonic seizures)


Remember:Treat the seizure(s), not the numbers’!

9

Therapeutic Drug Monitoring

 Measurement of serum drug concentration may also be clinically useful in the following situations:

_________________________

 Uncontrolled seizures despite administration of higher-thanaverage doses
- Drug resistance vs subtherapeutic drug concentrations

 Recurrence of seizures in a previously controlled patient
- Usually a result of non-compliance to prescribed regimen

 Documentation of intoxication
- E.g., in cases of AED-related toxicity

10

Therapeutic Drug Monitoring
 Assessment of patient compliance
- Latest readings should be compared with previous readings to determine reliability of data

 Documentation of desired results from a change in dose or other therapeutic manoeuver
- E.g., following a bolus dose of phenytion injection

 When precise dosage changes are required

Therapeutic Drug Monitoring
 Assessment of patient compliance
- Latest readings should be compared with previous readings to determine reliability of data

 Documentation of desired results from a change in dose or other therapeutic manoeuver
- E.g., following a bolus dose of phenytion injection

 When precise dosage changes are required

11

Pregnancy & Lactation

 Women with epilepsy should be referred to specialist care for pre-conception counselling
 Taking anti-epileptic drugs is not an absolute contraindication to breastfeeding
 All breastfeeding women on AED therapy should be encouraged to breastfeed
- They should also be encouraged to receive support from relevant healthcare professionals

Pregnancy & Lactation

 Women with epilepsy should be referred to specialist care for pre-conception counselling
 Taking anti-epileptic drugs is not an absolute contraindication to breastfeeding
 All breastfeeding women on AED therapy should be encouraged to breastfeed
- They should also be encouraged to receive support from relevant healthcare professionals

12

Hepatic enzyme inducers

 Carbamazepine, phenytoin, phenobarbitone (potent)  Topiramate (CYP3A4), oxcarbazepine (CYP3A4/5)

13

Hepatic enzyme inhibitor

 Sodium valproate (potent)
 Topiramate, felbamate, oxcarbazepine (all CYP2C19)

14

Minimal (or no clinically significant) effect on enzyme activity

Ethosuximide, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide

15

Drug-food interaction

Phenytoin & enteral feeds --> potentially significant reduction in oral absorption of phenytoin

16

Discontinuation of anti-epileptic therapy may be considered by the physician and informed patient/caregiver if:

 Patient has been seizure-free for 2-5 years
- Depends on type of seizure (preferably 3-4 years)

 Patient has single type of partial seizure or primarily generalised tonic-clonic seizure
 Neurologic examination is normal
 Normal EEG assessment
 Intelligence examination (e.g., IQ) is within normal limits

17

Recommended seizure-free periods:
 Absence seizure
 Partial seizures
 Tonic-clonic seizures a/w absence seizures

 Absence seizure 2 years
 Partial seizures 4 years
 Tonic-clonic seizures a/w absence seizures 4 years

18

Additional factors possibly favouring successful discontinuation of AEDs in selected situations:

 Complete seizure control within 1 year of onset
 Early age of seizure onset (between 2-35 years)

19

 Risks associated with withdrawal of AEDs:

 Seizure relapse
- Relapse rate may range from 10-70%
- Generally lower for children (<30%), higher for adults and adolescents (40%)
- Also dependent on duration of time elapsed since withdrawal
after 1 year 25%
after 2 years 29%

 Precipitation of status epilepticus
- Usually associated with rapid withdrawal of AEDs

 Development of anxiety and depression

20

Factors associated with poor outcomes following discontinuation of AEDs:

 History of frequent seizures
 History of repeated status epilepticus
 Neonatal or adolescent-onset epilepsy (epileptic syndromes)
 Combination seizure types (e.g., tonic-clonic-tonic seizures)
 Need for continuous treatment lasting >10 years
 Presence of abnormal mental function
 Abnormal EEG immediately following withdrawal
 Presence of epileptiform activity during withdrawal

21

Discontinuation of Treatment - Strategy

 If guidelines criteria are met, discuss with patient about possibility of withdrawal
 Consider consequences of withdrawal
- Children – minimal
- Adolescents – moderate
Withdrawal should be attempted while patient stays at home, does not have children, has no need to drive, has not entered higher education or work

 Adults – potentially severe
- Serious injury (some individuals)
- Loss of driving privileges
- Threat to employment
- Personal distress
- Anxiety/depression
- Loss of perceived self-control
- Social stigma


 Obtain patient consent for AED withdrawal
Never insist on AED withdrawal if patient is uncomfortable with the idea

 Incorporate AED withdrawal into patient’s care plan

 Discontinue the drug less appropriate for the seizure type
May help to minimise side effects and/or improve cognitive function

 Withdraw AED slowly to minimise risk of relapse or status epilepticus
 Monitor patient for at least 5 years post-withdrawal
 Restart AED therapy immediately if relapse occurs

Discontinuation of Treatment - Strategy

 If guidelines criteria are met, discuss with patient about possibility of withdrawal
 Consider consequences of withdrawal
- Children – minimal
- Adolescents – moderate
Withdrawal should be attempted while patient stays at home, does not have children, has no need to drive, has not entered higher education or work

 Adults – potentially severe
- Serious injury (some individuals)
- Loss of driving privileges
- Threat to employment
- Personal distress
- Anxiety/depression
- Loss of perceived self-control
- Social stigma


 Obtain patient consent for AED withdrawal
Never insist on AED withdrawal if patient is uncomfortable with the idea

 Incorporate AED withdrawal into patient’s care plan

 Discontinue the drug less appropriate for the seizure type
May help to minimise side effects and/or improve cognitive function

 Withdraw AED slowly to minimise risk of relapse or status epilepticus
 Monitor patient for at least 5 years post-withdrawal
 Restart AED therapy immediately if relapse occurs

22

Role of the Pharmacist

 Counsel patient on effectiveness of AEDs
 Monitor patient closely for both beneficial and adverse effects
 Advising patient to keep a seizure diary
 Helping to determine when replacement or additional therapy may be needed
 Reviewing and conveying of information to other healthcare practitioners regarding how an AED may benefit the patient
 Identifying what dosage form is best for a given patient
 Working with the patient to stress the importance of good adherence
 Counselling patient on the dangers of sleep deprivation
 Monitoring all changes in drug therapy

23

Status epilepticus: A seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur

 Clinically, >5 minutes of generalised convulsive seizure activity is unlikely to result in spontaneous seizure recovery
 Experimentally, >30 minutes of seizure activity --> irreversible neuronal damage
 Ongoing studies use 5, 10 or 20 minutes to define presence of SE

Status epilepticus: A seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur

 Clinically, >5 minutes of generalised convulsive seizure activity is unlikely to result in spontaneous seizure recovery
 Experimentally, >30 minutes of seizure activity --> irreversible neuronal damage
 Ongoing studies use 5, 10 or 20 minutes to define presence of SE

24

 Refractory status epilepticus: Episode of status epilepticus that persists despite use of seizure-aborting medications
- Incidence: 35-45% of cases following use of 1st-line agents (e.g., benzodiazepines, phenytoin)
- Represents a more difficult clinical problem cf. SE

 Refractory status epilepticus: Episode of status epilepticus that persists despite use of seizure-aborting medications
- Incidence: 35-45% of cases following use of 1st-line agents (e.g., benzodiazepines, phenytoin)
- Represents a more difficult clinical problem cf. SE

25

 Generalised convulsive SE (GCSE)
Usually tonic-clonic, myoclonic, or clonic seizures, or erratic combination
Operationally, patient will requires anticonvulsant treatment after 5 mins

 Generalised convulsive SE (GCSE)
Usually tonic-clonic, myoclonic, or clonic seizures, or erratic combination
Operationally, patient will requires anticonvulsant treatment after 5 mins

26

 Nonconvulsive SE (NCSE)

Duration of seizure activity not currently incorporated into definition
Diagnosis largely based on:
- Changes from baseline of behaviour and/or mental status
- Concomitant continuous epileptiform discharges on EEG

Subtypes:
 Absence SE
 Complex partial SE – represents ~50% of NCSE
 Subtle SE – usually evolves from previously overt but inadequately treated or untreated GCSE

Duration of seizure activity not currently incorporated into definition
Diagnosis largely based on:
- Changes from baseline of behaviour and/or mental status
- Concomitant continuous epileptiform discharges on EEG

Subtypes:
 Absence SE
 Complex partial SE – represents ~50% of NCSE
 Subtle SE – usually evolves from previously overt but inadequately treated or untreated GCSE

27

Status Epilepsy
 Operationally, 5 minutes is now taken as the time limit for which anticonvulsant therapy should be initiated for a continuous episode of epilepsy

 Alternatively, failure of 2 or 3 anticonvulsants has been suggested in combination with a minimal duration of 1 hour, 2 hours, or regardless of the time elapsed since onset
49

Status Epilepsy
 Operationally, 5 minutes is now taken as the time limit for which anticonvulsant therapy should be initiated for a continuous episode of epilepsy

 Alternatively, failure of 2 or 3 anticonvulsants has been suggested in combination with a minimal duration of 1 hour, 2 hours, or regardless of the time elapsed since onset

28

Status Epilepsy

Receptor trafficking’ theory:

 Involves dynamic changes in GAMMA-aminobutyric acid-A (GABAA) (inhibitory) & N-methyl-D-aspartate (NMDA) (excitatory) receptor function

 Ongoing seizure activity…
- Increased internalisation & degradation of GABAA receptors, and increased NMDA receptors
- Decreased synaptic GABA activation & enhanced NMDA activation
- Propagation of ongoing seizure

 GABAA ‘inhibition’ may independently result in pharmacological resistance (e.g., to benzodiazepines, barbiturates & propofol)

Status Epilepsy

Receptor trafficking’ theory:

 Involves dynamic changes in GAMMA-aminobutyric acid-A (GABAA) (inhibitory) & N-methyl-D-aspartate (NMDA) (excitatory) receptor function

 Ongoing seizure activity…
- Increased internalisation & degradation of GABAA receptors, and increased NMDA receptors
- Decreased synaptic GABA activation & enhanced NMDA activation
- Propagation of ongoing seizure

 GABAA ‘inhibition’ may independently result in pharmacological resistance (e.g., to benzodiazepines, barbiturates & propofol)

29

 Clinical diagnosis of status epilepticus relies heavily on:

 Personal observation
 Medical history regarding nature and duration of the seizure
 Physical history
 Laboratory test assessments (e.g., electrolyte balance, toxicology screens)
 EEG and neurologic imaging

 Clinical diagnosis of status epilepticus relies heavily on:

 Personal observation
 Medical history regarding nature and duration of the seizure
 Physical history
 Laboratory test assessments (e.g., electrolyte balance, toxicology screens)
 EEG and neurologic imaging

30

Desired Treatment Outcomes

 Stabilisation of the patient
- Adequate oxygenation
- Preservation of cardiopulmonary function
- Management of systemic complications

 Correct diagnosis of status epilepticus subtype and identification of precipitating factors
- Prevents a delay in initiation of effective therapy and avoids administration of large amounts of unnecessary medication

 Discontinuation of clinical and electrical seizure activity as rapidly as possible
- THE primary goal
- Drugs form the cornerstone of therapy

 Prevention of seizure recurrence

Desired Treatment Outcomes

 Stabilisation of the patient
- Adequate oxygenation
- Preservation of cardiopulmonary function
- Management of systemic complications

 Correct diagnosis of status epilepticus subtype and identification of precipitating factors
- Prevents a delay in initiation of effective therapy and avoids administration of large amounts of unnecessary medication

 Discontinuation of clinical and electrical seizure activity as rapidly as possible
- THE primary goal
- Drugs form the cornerstone of therapy

 Prevention of seizure recurrence