Epilepsy 2 Flashcards
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
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
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
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)
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
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
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
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’!
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
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
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
Hepatic enzyme inducers
Carbamazepine, phenytoin, phenobarbitone (potent) Topiramate (CYP3A4), oxcarbazepine (CYP3A4/5)
Hepatic enzyme inhibitor
Sodium valproate (potent)
Topiramate, felbamate, oxcarbazepine (all CYP2C19)
Minimal (or no clinically significant) effect on enzyme activity
Ethosuximide, lamotrigine, gabapentin, tiagabine, levetiracetam, zonisamide
Drug-food interaction
Phenytoin & enteral feeds –> potentially significant reduction in oral absorption of phenytoin
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
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
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)
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
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
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
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
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
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
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
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
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
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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
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)
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
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
Use of an in-house protocol for general management and specific pharmacological treatment of SE is highly recommended
Use of an in-house protocol for general management and specific pharmacological treatment of SE is highly recommended
