anticonvulsives-170928221515

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Antiseizure Drugs
Ms. K.D.S.V. Karunanayaka (B.Pharm) Department
of Pharmacy Faculty of Health Sciences The Open
University Sri Lanka
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Out line

• Epilepsy
• Anatomy of Brain
• Diagnosis triggers
• Classification of epilepsy
• Common drugs used to treat epilepsy

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Causes of seizure

• Infection, such as encephalitis or meningitis
• Fever leading to febrile convulsions
• Metabolic disturbances
• Withdrawal from drugs (anticonvulsants,
  antidepressants, and sedatives such as alcohol,
  barbiturates, and benzodiazepines,)
• Space-occupying lesions in the brain (abscesses,
  tumors)
• Seizures during (or shortly after) pregnancy can
  be a sign of eclampsia.
• Haemorrhagic stroke

• Sleep deprivation
• Flickering lights, (sunlight, TV, computers etc)
• Arterio-venous malformation (AVM)
• Head injury may cause non-epileptic
  post-traumatic seizures or post-traumatic
  epilepsy, in which the seizures chronically
  recur.
• Intoxication with drugs, for example
  aminophylline or local anesthetics.
• Normal doses of certain drugs that lower the
  seizure threshold, such as tricyclic
  antidepressants.

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Disorders that mimic epilepsy

Gastro-oesophageal reflux Breath holding spells
Migraine Sleep disorders
Cardiovascular events (cardiac arrhythmias) Movement disorders (shuddering attacks)
Psychological disorders (panic or hyperventilation attacks) Psychological disorders (panic or hyperventilation attacks)
Diagnosis and Investigation of Epilepsy
Clinical features description of seizure Family history
EEG (electroencephalogram) ECG (electrocardiogram)
Neurological examinations Neuroimaging
Blood count and plasma biochemistry
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Types of Epilepsy

• Tonic Stiffening of the body
• Clonic Rhythmic jerking movements or convulsions
  (Clonic phase)

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Types of Epilepsy

• Tonic phase
• The person will quickly lose consciousness, and
  the skeletal muscles will suddenly tense, often
  causing the extremities to be pulled towards the
  body or rigidly pushed away from it, which will
  cause the person to fall if standing.
• The tonic phase is usually the shortest part of
  the seizure, usually lasting only a few seconds.
• The person may also express vocalizations like a
  loud moan during the tonic stage, due to air
  forcefully expelled from the lungs.

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Types of Epilepsy

• Clonic phase
• The person's muscles will start to contract and
  relax rapidly, causing convulsions.
• These may range from exaggerated twitches of the
  limbs to violent shaking or vibrating of the
  stiffened extremities.
• The person may roll and stretch as the seizure
  spreads.
• The eyes typically roll back or close and the
  tongue often suffers bruising sustained by
  strong jaw contractions. Incontinence is seen in
  some cases.

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Classification of Seizures

• Partial seizures
• Here localized onset of the attack can be
  identified by clinical observation or EEG
• Simple partial seizures (no loss of
  consciousness)
• With motor symptoms

• With sensory symptoms
• With autonomic symptoms
• Only involve one hemisphere

Dependant on which area of the brain

• Complex partial seizures (loss of consciousness)
• Simple followed by loss of consciousness
• Involves limbic systems
• los of memory
• Partial seizures secondarily generalized

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• Unclassified
• Classification not possible to problems with
  diagnosis suspected
• Generalised (affect whole brain with loss of
  consciousness)- grand mal seizure (generalized
  tonic-clonic seizure)
• Clonic, tonic (1min) or tonic-clonic (2-4min)
  muscle spasm (extensors), respiration stops,
  defecation, urinary incontinence, salivation,
  violent jerks, tongue or cheek may be bitten
• Two types
• Primary generalized tonic-clonic seizure
• Secondary generalized tonic-clonic seizure

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Classification of Generalized Seizures

• Atonic
• loss of muscle tone/strength (postural tone), the
  patient may fall suddenly to the floor and may
  be injured
• Many patients with this seizure wear helmet to
  prevent the head injury
• Infantile spasm
• It is an epileptic syndrome
• Characterized by brief, recurrent myoclonic jerks
  of the body with sudden flexion or extension of
  the body and limbs

• Myoclonic jerking
• Seizures of a muscle or group of muscles
• This has been seen in wide variety of seizure
• Absence (petit mal seizures)
• Abrupt loss of awareness of surroundings, little
  motor disturbance, mostly children, mild clonic
  jerking of the eyelid or extremities
• It may occur 100 times a day
• Onset is 10 seconds (maximum up to 45 seconds)

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Choices of Treatment
Seizure type 1st line drug choice 2nd line drug choice
Partial Carbamazepine Phenytoin, Valproate Gabapentin, Lamotrigine, Levetiracetam, Phenobarbitone, valproate
Generalised tonic-clonic
Sodium Valproate Carbamazepine
Phenytoin Phenobarbitone Lamotrigine,
Levetiracetam,
Absence Sodium Valproate Clonazepam, Lamotrigine
Myoclonic Sodium Valproate
Clonazepam, Levetiracetam, Phenobarbitone
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Pathological Basis of seizure

• Abnormal electrical discharge in the brain.
• Coordinated activity among neurons depends on a
  controlled balance between excitation and
  inhibition.
• Any local imbalance will lead to a seizure.
• Imbalances occur between glutamate-mediated
  excitatory neurotransmission and
  gamma-aminobutyric acid (GABA) mediated
  inhibitory neurotransmission.
• Generalised epilepsy is characterised by
  disruption of large scale neuro-networks in the
  higher centres.

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Pathological Basis of seizure

• Normal Processes
• Depolarising Na and Ca ionic current shifts
  are activated by glutamate receptors.
• Repolarising K currents are mediated by GABA
  receptors
• Hyperpolarisation is mediated by GABAa
  receptors creating an influx of Cl- gt
  inhibition of impulse generation.
• In epilepsy
• Any defect causes the neuron to be closer to
  the all or none threshold for an AP
  HYPEREXCITABLE STATE.
• Leading to instability between excitation and
  inhibition gt Epilepsy.

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Basis of Pharmacological Mechanism

• Most anti-epileptic agents act either by blockade
  of depolarisation channels (Na and Ca).
• Enhancing the activity of GABA (neurotransmission
  inhibition).
• Reduction of excitatory (glutamatergic)
  transmission.

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Categories of Anti-epileptic Drugs

• Classification is based upon chemistry
• Hydantoins
• Succinimides
• Benzodiazepines
• Barbiturates
• Miscellaneous

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Phenytoin (Dilantin-Diphenylhydantoin)

• Fosphenytoin is a prodrug given intravenously and
  rapidly converted to phenytoin.
• Clinical use
• Use for patients with Tonic-Clonic seizures (both
  partial and generalized seizure).
• Can be used in the Rx for neuropathic pain and
  cardiac arrhythmias.
• Therapeutic level will be between 10 and 20
  mcg/ml.
• Lower dose of 300 mg/d (oral)will give 10 mcg/ml
  which is the usual starting dose.
• When higher dose required only 25-30 mg should be
  increased slowly.

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Phenytoin (Dilantin-Diphenylhydantoin)

• Mechanism of action
• It blocks sustained-high frequency repetitive
  firing of action potential.
• Acts to promote intracellular removal of sodium
  during the refractory period
• Antagonism (blocking) of Na channels to reduce
  excitability
• Antagonism of Ca channels
• This also reduce the calcium dependent release of
  neurotransmitters and hormones.
• Potentiation (activation) of GABA receptors to
  promote the inhibitory role of GABA.
• Inhibit the action of glutamate.

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Phenytoin (Dilantin-Diphenylhydantoin)

• Pharmacokinetic
• Slowly absorbed from gut, use a slow IV if rapid
  action is required
• Depends on formulation (particle size, additives)
  and dosage form
• Avoid IM muscle damage
• Phenytoin might precipitate in muscle tissues
• Fosphenytoin is more soluble and can be
  administered by IM
• Highly bound to the plasma protein (90)
• Distribute well in to the brain, liver, muscle
  and fat
• Metabolized by hepatic biotransformation (to
  inactive metabolite)
• Only small amount excreted unchanged

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Phenytoin (Dilantin-Diphenylhydantoin)

• Pharmacokinetic
• At lower dose elimination follows first order
  process but when dose exceed very high, even
  with small increase in dose can
• causes the accumulation of drug (steady state
  wont be achieved).
• Therefore half-life is dose dependent (lower to
  middle dose 12 to 36 hours higher dose gt2
  days.
• Can measure amount of free agent in the saliva.

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Phenytoin (Dilantin-Diphenylhydantoin)

• Adverse effects
• Nystagmus, Impaired brainstem cerebellar
  function (dizziness, tremor, nervousness,
  blurred vision), ataxia, diplopia, sedation,
• Chronic congestive tissue defects (gingival
  hyperplasia, acne, hirutism)
• Skin rashes, and other hypersensitivity
  reactions, nausea vomiting
• Folic acid and Vit. D deficiency (increase
  metabolism) which may leads to megaloblastic
  anemia and osteomalacia

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Phenytoin (Dilantin-Diphenylhydantoin)

• Contraindications and drug interactions
• Increases metabolism (inducer) of the
  contraceptive pill, anti- coagulants, and
  pethidine.
• INH inhibit the metabolism of phenytoin.
• Carbamazepine and phenobarbital increase the
  metabolism of phenytoin.
• Displacement drugs such as phenybutazone and
  sulfonamides can displace phenytoin from its
  binding site.
• Decrease in concentration of plasma protein
  (hypoalbuminemia) reduce the total plasma
  concentration of phenytoin but not the free drug.

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Mephenytoin, Ethotoin, Phenacemide

• They are congeners of phenytoin.
• They have similar actions to phenytoin and share
  common pharmacological properties.
• Patients who are allergic to phenytoin can be
  given ethotoin.
• Mephenytoin is metabolized to 5, 5 ethylphenyl
  hydantoin which produce anti-seizure activity.

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Succinimides

• Ethosuximide, phensuximide, methsuximide
• Mechanism of Action
• Acts by antagonising Ca channels in the
  thalamocortical relay neurons gt prevention of
  synchronised neuronal firing gt raising AP
  threshold.
• Reduces the low-threshold (T-type) current as a
  result of the calcium channel blockade.
• Clinical uses
• Use for patients with absence seizures.
• Has very narrow spectrum of clinical activity.

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Succinimides

• Pharmacokinetics
• Almost complete absorption from the gut, peak
  level observed at 3-7 hours, not bound to
  proteins.
• Extensive metabolism in the liver with a long
  half-life (2-3 days).
• Plasma and salivary concentrations correlate well
  for monitoring purposes.
• To achieve a therapeutic level of 60-100 mcg/mL,
  a dose of 750-1500 mg/d is necessary. Level up
  to 125 mcg/mL is tolerated.

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Succinimides Ethosuximide

• Adverse effects
• Pain, Nausea, vomiting and anorexia
• Cerebellar disturbance (drowsiness, dizziness,
  photophobia, headache, depression), hiccup,
  euphoria
• Skin irritation
• Agranulocytosis is rare but could occur
• Contraindications
• may make tonic-clonic seizures worse
• Valproic acid inhibit the metabolism of this drug
  and hence increase its half-life
• Not to be used when pregnant (teratogencity)
• Phensuximide and methsuximide are rarely used
  owing to their toxicity profile and less efficacy

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Benzodiazepines

• Act by potentiating the actions of GABA causing
  neurotransmission inhibition (primarily in the
  CNS).
• Can be used to induce sleep (high dose),
  anticonvulsant therapy and reduction in muscle
  tone.
• Pharmacokinetics
• Well absorbed from the gut, Lipid soluble to
  ensure ready penetration of the blood brain
  barrier, Slow elimination from body.
• Metabolised in the liver to create active agents
  (prolonged therapeutic action).
• Adverse effects
• Drowsiness, light-headness, confusion, Impaired
  memory, Muscle weakness.
• Tolerance (very common), Dependence withdrawal
  effects could last up to 3 weeks.

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Barbiturates Phenobarbital

• Used for tonic-clonic seizures (partial and
  generalized).
• Mechanism of action
• Act by increasing the duration of Cl- ion channel
  opening by activating neuronal GABAa receptors.
• Causing hyperpolarisation of the AP, making it
  less likely to fire again
• Essentially, acts like GABA and can even
  potentiate the effects of GABA when present.
• Pharmacokinetics
• Almost complete absorption.
• Elimination is by heptic and renal (25 excreted
  unchanged).
• Biotransformed in the liver into 2 active
  metabolites.
• Plasma concentrations relate poorly to seizure
  control, use only for monitoring of patient
  compliance.

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Barbiturates Phenobarbital

• Therapeutic level range from 10-40 mcg/mL
• Adverse effects
• CNS effects (sedation and fatigue)
• Restlessness/Hyperactivity
• Folate deficiency
• Tolerance
• Dependence with physical withdrawal reactions.
• Adverse drug-drug reactions (contraception and
  warfarin).
• Contraindications
• Do not use with patients with respiratory
  depression, children or elderly.

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Primidone

• Primidone is metabolized (by oxidation) to
  phenobarbital and phenylethylmalonamide
  (PEMA)-All these are active compounds.
• In infants the drug is slowly metabolized.
• Action is much similar to phenytoin.
• It is effective against partial and generalize
  seizures.
• Completely absorbed orally, Vd0.6 L/kg, 70 of
  the drug unbound to plasma proteins.
• Half-life 6-8 hours.
• Therapeutic level is 8-12 mcg/mL (dose f 10-20
  mg/kg/d is necessary to achieve this level).
• Adverse effects are dose related and resemble
  phenobarbitals adverse effects.

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Carbamazepine

• Structurally similar to imipramine (tricyclic
  antidepressant).
• Effective in treatment of bipolar depression.
• Also used in most epilepsy types.
• Mechanism of Action
• Not fully understood
• But believed to be related to antagonist action
  of Na channels to inhibit high frequency
  repetitive neuronal firing.
• Decreasing the production (or release) of
  glutamate (excitatory chemical).
• Clinical uses
• In partial and generalized tonic-clonic seizure.
• Can also be used in the Rx of neuropathic pain.
• Non-sedative action.

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Carbamazepine

• Pharmacokinetics
• Slow and incomplete absorption. Taking after meal
  is recommended for larger doses
• Distribution is slow (Vd1L/Kg), 70 bound to
  plasma protein, no displacement
• occur
• Metabolised in the liver creates an epoxide
  metabolite that can have a weak therapeutic
  effect, carbamazepine is an enzyme inducer
• Relatively long half-life (1-2 days)
• Potency decreases overtime therefore need to
  increase dose to ensure adequate control of
  seizures
• Plasma and salivary concentrations correlate well
  to clinical effectiveness
• Available only in oral form for decades
• IV preparations have been introduced recently
  (Using cyclodextrins)
• Drug is effective in children and dose is
  15-25mg/kg/d, adults 1-2 g/d is tolerated
  usually in multiple doses.
• Extended release preparations are available that
  will reduce the frequency to twice a day

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Carbamazepine

• Adverse effects
• Nausea vomiting (especially early Rx),
  constipation, diarrhoea and anorexia
• Skin irritation
• CNS toxicity dizzy, drowsy, confusion,
  diplopia, ataxia
• Bone marrow depression (very rare include
  aplastic anemia, granulocytopenia), hyponatremia

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Carbamazepine

• Contraindications and drug interactions
• Enzyme inducer (increase metabolism of primidone,
  phenytoin, ethosuximide, valproic acid,
  clonazepam).
• Drugs that inhibit carbamazepine clearance and
  metabolism (propoxyphene, valproic acid).
• Drugs that increases the metabolism of
  Carbamazepine(phenytoin, phenobarbital).

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Oxcarbazepine

• Similar in actions and pharmacological properties
  to carbamazepine but have less toxicity.
• Half life 1-2 hours.
• Hypersensitivity reaction is very rare and no
  cross-reactivity.
• Less enzyme induction effect.
• Hyponatremia is common than carbamazepine.
• Oxcarbazepine and its active metabolite are
  excreted in human breast milk. Because of the
  potential for serious adverse reactions to
  oxcarbazepine in nursing infants, a decision
  should be made about whether to discontinue
  nursing or to discontinue the drug in nursing
  women.

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Valproic acid and Sodium Valproate

• It is fully ionized at body pH and
  pharmacological action is produced by valproate
  ion.
• MoA actions
• Antagonism of Na and Ca channels-reduce the
  frequency of neuronal firing.
• Potentiation of GABA (possibly by stimulating
  glutamic acid decarboxylase enzyme, inhibitory
  effect on GABAssss, blocking GABA transaminase).
• Attenuation of Glutamate.
• Clinical uses
• Use in all forms of epilepsy, as it suppresses
  the initial seizure discharge and its spread.
• Management of bipolar disorders.
• Migraine prophylaxis.

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Valproic acid and Sodium Valproate

• Pharmacokinetics
• Well absorbed from gut (should be taken with food
  to counteract gastric irritation), oral
  bioavailability is 80
• Food delays the absorption
• 90 bound to plasma protein, Vd0.15 L/kg,
  distribution is only confined to the water
• Extensively metabolised in the liver, clearance
  is very quick (9-18 hours of half-life)
• The tablet of sodium valproate is hygroscopic but
  not magnesium salt, sodium salt preparation also
  available as syrup for pediatric use, enteric
  coated preparation also available
• Rapidly transported across the blood brain
  barrier
• Monitor plasma concentration for patient
  compliance only
• Dosage 25-30 mg/kg/d up to or more than
  60/mg/kg/d also required in some cases
• Therapeutic level is around 50-100 mcg/mL

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Valproic acid and Sodium Valproate

• Adverse effects
• GI upset (Nausea, vomiting, anorexia, abdominal
  pain and diarrhoea)
• Weight gain (appetite stimulation)
• Transient hair loss
• Fine tremor at higher dose
• Coma (rare)
• Thrombocytopenia (platelets)
• Oedema
• Severe hepatotoxicity (liver damage)-deaths have
  been reported
• Some clinicians start oral or IV L-carnitine once
  they suspect severe hepatitis.
• Careful monitoring of liver function is
  necessary.
• Rarely spina bifida in the off-spring.

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Valproic acid and Sodium Valproate

• Contraindications
• People with liver damage or a history hepatic
  dysfunction.
• Drug interactions
• Protein binding displacement, enzyme inhibitor
  and inhibit the metabolism of phenobarbital,
  phenytoin, carbamazepine.

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Vigabatrin

• Only used in conjunction with other agents when
  patient becomes resistant (due to tolerance) or
  poorly tolerates
• Effective in partial epilepsy but with restricted
  use due to severe adverse effects (vision)
• Mechanism of Action
• It is an irreversible inhibitor of GABA
  aminotransferase (GABA-T). This enzyme is
  responsible for the degradation of GABA.
• Increases the release of GABA and more GABA
  available to inhibit neuron transmission.

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Vigabatrin

• Pharmacokinetics
• Rapidly absorbed from the gut, usual oral dose
  is 500 mg bd
• Excreted unchanged by renal processes
• Intermediate half-life (6-8 hrs)
• Blood concentrations are of no value.
• Adverse effects
• Sedation, fatigue, dizziness, nervousness,
  irritability, depression, impaired
  concentration, tremor (CNS effects)
• Psychotic reactions (check patient history)
• Visual defects after prolonged use
• Weight gain and oedema

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Lamotrigine

• Used for partial seizures in adults only (focal
  epilepsy).
• Mechanism of Action
• Acts by the inhibition (antagonism) of neuronal
  Na channels but is highly selective (only
  neurons that synthesise glutamate and aspartate)
  and reduce the frequency of voltage firing
• Additionally, decrease glutamate release
• Pharmacokinetics
• well absorbed, well distributed, protein binding
  is only about 55, extensively metabolised in
  the liver and has a long half-life.
• Half-life is 24 hours.

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Lamotrigine

• Adverse effects
• Fever, influenza-like symptoms
• Skin irritation
• GI disturbances (vomiting, diarrhoea)
• CNS effects (drowsiness, headache, dizziness,
  double vision)
• Contraindications
• Patients with hepatic impairment

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Gabapentin and Pregabalin

• Used for partial seizures in adults (Gabapentin
  2400 mg/d, Pregabalin 150 mg/d to 600 mg/d in
  divided dose).
• They are also useful in neuropathic pain (
  Gabapentin 1800 mg/d).
• Mechanism of Action
• Designed to be a structural analogue of GABA but
  it does not mimic GABA in the brain.
• Increases the synthesis and release of GABA.
• Decrease degradation of GABA.
• Inhibition of Ca channels and inhibit the
  release of glutamate.

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Gabapentin and Pregabalin

• Pharmacokinetics
• Incompletely absorbed in the gut, Excreted
  unchanged via kidney processes
• Short half-life, Gabapentin dose of up to 4800
  mg/d is tolerated
• Adverse effects
• CNS effects (dizzy, drowsy, fatigue, headache,
  double visions)
• Nausea and vomiting
• Contraindication
• Be careful with sudden withdrawal in the elderly
  due to kidney effects and alterations in
  acid-base balance.

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Miscellaneous Drugs

• Felbamate
• It blocks NMDA receptor and potentiate GABA
  receptor
• Effective in partial seizure
• But it causes aplastic anemia and severe
  hepatitis
• Levetiracetam
• It modifies the release of glutamate and GABA by
  acting on the synaptic vesicular function
• Used in partial seizure
• Tiagabine
• It is a GABA reuptake inhibitor
• Adjunctive treatment of partial seizure

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Miscellaneous Drugs

• Topiramate
• Block the sodium channel and reduce the frequency
  of neuronal firing
• It also potentiate the GABA action
• It is effective against both partial and
  generalized tonic-clonic seizure
• Zonisamide
• It blocks sodium and calcium channels
• Effective against both partial and generalized
  seizures
• Trimethadione
• Acetazolamide

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FDA Alert
Carbamazepine, Gabapentin, Lamotrigine,
Levetiracetam Now all have FDA Alert Suicidal
Behaviour and Ideation and Antiepileptic
Drugs The association is controversial and the
benefits will often outweigh the risks in
epilepsy the riskbenefit may be less certain in
other conditions. www.fda.gov/ohrms/dockets/ac/08
/briefing/2008-4372b1-01-FDA.
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Other risks

• Fracture risk
• Patients with epilepsy are at increased risk of
  fractures as a result of
• Falls due to seizures.
• Adverse effects of antiepileptics, Ex- reduced
  BMD (particularly with barbiturates,
  carbamazepine, phenytoin and valproate) and CNS
  effects that increase risk of falling.
• Consider fall prevention strategies and BMD
  monitoring during long- term treatment ensure
  adequate vitamin D and calcium intake.

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Special areas for considerations for AEMs

• Status epilepticus
• Epilepsy in women

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Epilepsy in Women

• Women of child-bearing age
• Discuss possibility of pregnancy before selecting
  an AEM.
• Risks of unplanned treatment withdrawal.
• Contraception
• Several AEMs (carbamazepine, phenytoin,
  barbiturates) induce hepatic enzymes and
  increase metabolism of OCP
• Use high dose combined oral contraceptive or
  medroxyprogesterone depot but still risk of
  failure.
• Non-hormonal contraception is preferable.

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Pregnancy and epilepsy

• Literature reviews indicate that anticonvulsants
  are associated with an increase in congenital
  defects. However the benefits in preventing
  maternal seizures with the use of medication are
  thought to outweigh the risk to the infant .
• The use of more than one antiepileptic drug
  carries a higher risk of birth defects.
• Monitoring anticonvulsant therapy throughout the
  course of the pregnancy will be important, and
  dose adjustments should be made based on serum
  concentration, frequency of seizures, and
  adverse effects/tolerability.

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Cleft lip and/or palate
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Neural Tube Defects
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Pregnancy and epilepsy

• Treatment aims,
• Avoid sodium valproate, especially gt1200mg/day.
• Best choice of treatment is the drug that best
  controls the epilepsy, at the lowest effective
  dose, in monotherapy if possible.
• Some AEMs interfere with folic acid metabolism,
  -need to supplement with folic acid starting at
  least 1 month before and for 3 months after
  conception at 5mg daily.

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Role of the Pharmacist

• Counselling on
• Importance of compliance. Emphasise that AEDs
  should not be stopped abruptly - increased
  seizures and status epilepticus may occur
• When withdrawing treatment, reduce the dosage of
  antiepileptic drugs over several weeks to months
• Adverse drug reactions
• Monitor outcomes of drug therapy
• Drug interactions
• Monitoring
• Reduce stigmatisation
• Issues with driving
• Seizure. 1998 Aug7(4)305-8. Driving and
  epilepsy in Sri Lanka. Seneviratne SL,
  Gunatilake SB, Adhikari AA, De Silva HJ.
  Department of Medicine, Faculty of Medicine,
  University of Kelaniya, Ragama, Sri Lanka.

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References

• Bennet p.n., Brown M.J Sharma P., Clinical
  Pharmacology 11th edition Chapter 21 Page
  349-359.
• Katzung B.G., Masters S.B Trevor A.J., Basic
  Clinical Pharmacology 12th edition Chapter 27
  Page 399 - 422.

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