Epilepsies, AEDs and Health Issues: The Love-Hate Relationship

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Epilepsies, AEDs and Health IssuesThe
Love-Hate Relationship

• Janet Mifsud
• Caritas Malta Epilepsy Association
• Epilepsy Society of Malta
• Vice President Europe IBE
• Janet.mifsud_at_um.edu.mt

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• If it were not for the great variability between
  individuals, medicine would be a science not an
  art.
• Sir Walter Osler 1882

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What do we know about epilepsy ?
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• Facts
• Epilepsy, affects as many as 6 million people in
  Europe, is a heterogeneous chronic disorder
  characterized by recurrent seizures
• which differ in nature
• types of seizures
• age at onset
• aetiology

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How is it treated?
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AEDs
Eliscarbazepine
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Pregabalin
Levetiracetam
Oxcarbazepine
Tiagabine
Fosphenytoin
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Topiramate
Gabapentin
Felbamate
Lamotrigine
Zonisamide
10
Vigabatrin
Sodium Valproate
Carbamazepine
Benzodiazepines
Ethosuximide
5
Phenytoin
Primidone
Phenobarbital
Bromide
0
1840
1860
1880
1900
1920
1940
1960
1980
2000
YEAR
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• Yet
• No single AED is appropriate in all types of
  epilepsies since the causes of epilepsy are
  extremely diverse
• genetic and developmental defects
• infections and trauma
• neoplastic
• degenerative disease processes

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Yet.

• Despite the large number of AEDs that suppress or
  prevent seizures are now available, so far, drug
  therapy available will only control the onset of
  seizures
• There are no pharmacological treatments that cure
  epilepsy or modify the detrimental course of the
  disorder.

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Why? What do drugs do?

• IMBALANCES ? DISEASE ? CORRECTION

FROM OUTSIDE Bugs Chemicals FROM INSIDE Too
little Too much
Eliminate threat Prevent /treat with
anti-infectives Agonist Antagonist
P.K. Rangachari, IUPHAR 2010
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How to decide?
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industry
regulators

• users

DRUG
dispensers
prescribers
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• How to decide What is the problem?

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• How to decide which drug?

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Explicit knowledgecodified published
transmissible
How to decide which drug?
Tacit knowledgeprocedures experiences values
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Which drug? Other factors..

• The selection of the appropriate AED
• also depends a variety of specific factors
• age
• underlying physiological conditions. etc
• The prognosis and quality of life of a person
  with epilepsy varies considerably.
• In addition, about 30 of patients, remain
  resistant to drug treatment.
• This has major implications not only for other
  health issues, but also for independent living,
  education and employment, mobility, and personal
  relationships.

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• As there are no major differences in efficacy
  among first-line antiepileptic drugs,
  tolerability and long-term safety must be the
  paramount consideration in patients with epilepsy.

Kwan P, Brodie MJ. Neurology 2003 60 (suppl 4)
S2-S12
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AEDs..when to start?

• Whether to treat first seizure is controversial
• 16-62 will recur within 5 years
• Relapse rate might be reduced by antiepileptic
  drug treatment
• Abnormal imaging, abnormal neurological exam,
  abnormal EEG or family history increase relapse
  risk
• Quality of life issues are important

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AEDs how to?

• Correct therapeutic choice only after diagnosis
• emphasis on monotherapy not polytherapy
• care in special populations e.g. children,
  pregnant women
• folic acid in females
• keep epilepsy diary
• keep same doctor
• many months needed to adjust dose
• Be aware of factors which may precipitate onset
  of seizures e.g. sleep deprivation, substance/
  alcohol abuse, computer/TV games in children (?),
  stress
• other treatment e.g. homeopathy?
• regular discussions with parents/ teachers
  co-operations in - medication taking, correct
  observations

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Choosing an AED

• TonicClonic seizures
• carbamazepine
• phenytoin
• felbamate
• topiramate
• tamotrigine
• valproate
• levetiracetam
• zonisamide
• oxcarbazepine

• Partial seizures
• phenobarbital
• phenytoin
• carbamazepine
• valproate
• gabapentin
• tiagaine
• lamotrigine
• topiramate
• levetiracetam
• oxcarbazepine
• zonisamide
• felbamate
• rufinamide
• eslicarbazepine

• Seizure type
• Epilepsy Syndrome
• Pharmacokinetics
• Interactions
• Other medical conditions
• Efficacy
• Adverse effects
• Cost

• Absence seizures
• ethosuximide
• valproate

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Does the ideal AED exist?

• Effective in refractory patients
• Low toxicity and no significant side effects
• Interacts minimally with other drugs
• Can easily be titrated
• Works via a logical mechanism of action
• Broad spectrum no seizure aggravation
• High efficacy, good tolerability
• No contraindications
• Friendly pharmacokinetics / once daily dosing
• Availability of a friendly pediatric formulation
• Availability of parenteral formulation

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Which AED to choose first?

• Pick a drug with a spectrum of activity and
  side-effects/interaction profile that has the
  potential to produce seizure freedom without
  longterm consequences

• Match the choice to the patients seizures and/or
  epilepsy syndrome, gender, age, weight,
  psychiatric and other comorbidities, risk of
  teratogenesis and concomitant medication etc.
• COST MUST ALSO BE TAKEN INTO CONSIDERATION

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AEDs matching drugs to patients

• Treatment failure is also often related to side
  effects or inability to tolerate the AED.
• Several studies have shown that CNS,
  neuropsychological, systemic, and idiosyncratic
  adverse events lead to treatment failure in up to
  40 of patients.
• For those patients who remain on AED therapy, the
  side effects may contribute to a decreased
  quality of life.

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Traditional AEDs

• For nearly 8 decades just 6 key AEDs.
• Phenobarbital (Luminal) -1912
• Phenytoin (Dilantin) -1938
• Primidone (Mysoline) -1952
• Benzodiazepines -1965
• Ethosuximide (Tegretol) -1958
• Carbamazepine (Tegretol) -1963
• Valproic acid (Depakine)-1967
• Associated with severe problems PK/PD
• Narrow therapeutic indices ? more adverse effects
• Extensive hepatic metabolism ? more drug
  interactions
• Non linear kinetics ? large interindividual
  variation

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New AEDs the boring drugs

• Since 1993, several new AEDS promised improved
  tolerability with different safety and efficacy
  profiles
• Felbamate (Felbatol)
• Fosphenytoin (Cerebix)
• Gabapentin (Neurontin)
• Lamotrigine (Lamictal)
• Levetiracetam (Keppra)
• Oxcarbazepine (Trileptal)
• Pregabalin (Lyrica)
• Tiagabine (Gabitril)
• Topiramate (Topamax)
• Vigabatrin (Sabril)
• Zonisamide (Zonegran)
• Zebinex (Elsicarbezepine)
• new formulations and chemical alterations of
  traditional AEDs

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What did they promise?

• Broad spectrum of activity
• Fewer side effects and better tolerability
• Increased ease of use
• Linear kinetics
• Protein binding
• Lack of drug interactions
• Little liver metabolism and no toxic metabolites
• Rapid titration and less frequent dosing
  schedules
• No TDM needed

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Which AED? Dont forget drug interactions
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Dont forget drug interactions

• It is important for the clinician to recognize
  that treatment with AEDs, particularly the older
  enzyme inducing drugs , may complicate the
  management of other co-morbid disorders. For
  example, cardiovascular disease and perhaps
  affective disorders (i.e. depression) may be
  commonly encountered in the patients with
  epilepsy of all ages, but particularly the
  elderly.
• So dont forget
• drugs used in the treatment of hypertension
• drugs used in the treatment of lipid disorders
• anticoagulants
• drugs used in the treatment of depression
• Check out Virepa course on AEDs

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Generic AEDs..what to do?
http//www.epilepsyfoundation.org/medicationswitch
ing/images/banner650.jpg

• Generic vs originator products
• Excipents

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Are AEDs forever?

• www.epilepsy.com/epilepsy/newsletter/jun09_AEDs

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Why stop AEDs ?

• Side effects ..
• Drug interactions.
• The bother of having to remember to take them, to
  pack them, and to renew them every month.
• Even the idea of needing medicine and the
  associated stigma is philosophically distasteful
  to some people
• EXPENSE

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Discontinuing AEDs - when to consider it

• Seizure freedom for ? 2 years implies overall
  gt60 chance of successful withdrawal in some
  syndromes
• Favorable factors
• Control achieved easily on one drug at low dose
• No previous unsuccessful attempts at withdrawal
• Normal neurologic exam and EEG
• Primary generalized seizures except JME
• Consider relative risks/benefits (e.g., driving,
  pregnancy)

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Yet, if they are stopped

• There is the increased risk of having a seizure.
• SUDEP
• loss of driving license.
• Impaired quality of life?

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Soget the correct info..

• http//www.ema.europa.eu
• Advice from your national medicines authority

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If it were not for the great variability between
individuals, medicine would be a science not an
art.
Yet we can get there