Epilepsy

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Epilepsy
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Epilepsy

• Definition
• Epilepsy is a chronic disorder characterized
• by recurrent seizures (or convulsions). Seizures
• are episodes of brain dysfunction resulting from
  abnormal discharge of cerebral neurons

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• Other causes of convulsions (seizures)
• Meningitis, childhood fevers
• Brain tumors
• Degenerative diseases of the cerebral
  circulation
• Toxic manifestation of central nervous system
  (CNS) stimulants and certain other drugs.
• Eclampsia
• Uremia
• Hypoglycemia
• Pyridoxine deficiency
• Abstinence syndrome of individuals physically
  dependent on CNS
• depressants.

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Classification of seizures

• I. Partial (focal) Seizures
• Simple Partial Seizures
• Complex Partial Seizures
• Partial seizures secondarily generalized
• II. Generalized Seizures
• Generalized Tonic-Clonic Seizures
• Absence Seizures
• Tonic Seizures
• Atonic Seizures
• Clonic Seizures
• Myoclonic Seizures
• Infantile Spasms

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Types of seizures
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Antiseizure drugs

• Definition
• Antiseizure drugs are drugs used to treat
  seizures.

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Drugs used in partial seizures and generalized
tonic-clonic seizures

• Phenytoin (and congeners),
• Carbamazepine
• Valproate
• Barbiturates.
• Newer drugs
• Lamotrigine
• Gabapentin
• Oxcarbazepine
• Topiramate
• Vigabatrin
• Levetiracetam

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Antiseizure drugsI- Sodium channel blocking
agents

• Phenytoin
• Carbamazepine
• Oxcarbazepine
• Lamotrigine.
• Valproic acid
• Topiramate
• Zonisamide

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Mechanism of action of anticonvulsant drugs that
act on sodium channels.

• Normally, the sodium channel can exist in one of
  3 states
• closed (A) gate is closed and sodium ions cannot
  pass through the channel
• open (B) the channel gate opens rapidly
  following depolarization and sodium enters
  freely.
• or inactivated (C) soon after opening, an
  inactivation gate (C) closes, preventing further
  entry of sodium ions into the cell.
• Phenytoin and drugs with a similar mechanism of
  action prolong the inactivated state

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Phenytoin (1)

• Mechanism of Action
• 1- At therapeutic concentrations
• Phenytoin binds toand prolongs the inactivated
  state of the sodium channels
• At high concentrations
• 1- phenytoin reduces calcium influx across the
  cell membrane and inhibits the synaptic release
  of hormones and neurotransmitters (decreases the
  release of glutamate)
• 2- phenytoin increase the release of GABA
• 2- phenytoin promotes the uptake of dopamine
• 3- phenytoin inhibits monoamine oxidase activity

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Phenytoin (3)

• Clinical use
• partial seizures
• generalized tonic-clonic seizures (primary or
  secondary to another seizure type).

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Phenytoin (4)

• Pharmacokinetics
• Absorption
• absorption of phenytoin sodium from the
  gastrointestinal tract is nearly complete
• Distribution
• Phenytoin is highly bound (90 bound) to albumin.
  Other substances can also bind to albumin, and
  displace (and be displaced by) phenytoin such
  agents valproic acid and salicylic acid.
• Elimination
• phenytoin is eliminated by metabolism in the
  liver by cytochrome P450 to inactive metabolites
  that are excreted in the urine. Only a very small
  portion of phenytoin is excreted unchanged.
• The elimination of phenytoin is dose-dependent.
  At very low blood levels, phenytoin metabolism
  follows first-order kinetics. As blood levels
  rise within the therapeutic range, the maximum
  capacity of the liver to metabolize phenytoin is
  approached.
• Further increases in dose, even though relatively
  small, may produce very large changes in
  phenytoin concentrations and patients quickly
  develop symptoms of toxicity

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Phenytoin (5)

• Dose
• Intravenous thrapy
• In status epilepticus (diazepam is the drug of
  choice)i.v. loading dose of phenytoin (13-18
  mg/kg body weight dissolved in saline together
  with cardiac monitoring-cardiac toxicity may be
  due to polyethylene glycol which is used to
  dissolve phenytoin). Fosphenytoin is more safe on
  the heart because it is not dissolved in
  polyethylene glycol.
• Oral therapy
• In adults dose is 300 mg/day. If seizures
  continue, the dose is increased by 25 mg and time
  should be allowed for the new dose.
• Different preparations may differ in dissolution
  and bioavailability. Therefore, changing brands
  may decrease effect or produce toxicity.
• In children dose is 5 mg/kg/day

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Phenytoin (6)

• Adverse effects
• Acute dose-related.
• Nystagmus occurs early is not an indication for
  decreasing the dose
• Diplopia and ataxia require dosage adjustment
• Sedation usually occurs only at considerably
  higher levels.
• Chronic
• Gingival hyperplasia and hirsutism
• Coarsening of facial features
• Mild peripheral neuropathy, usually manifested by
  diminished deep tendon reflexes in the lower
  extremities.
• Osteomalacia (from increased vitamin D
  metabolism)
• Megaloblastic anemia (from increased folate
  metabolism)
• Idiosyncratic reactions (rare).
• Skin rash
• Exfoliative dermatitis
• Teratogenicity
• fetal hydantoin syndrome with cleft lip, cleft
  palate growth and mental retardation

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Phenytoin (7)
Drug interactions
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Phenytoin congeners

• Mephenytoin and Ethotoin
• Similar to phenytoin

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Carbamazepine (1)

• Mechanism of action
• Similar to that of phenytoin
• acts presynaptically to decrease synaptic
  transmission.
• Therapeutic uses
• drug of choice for partial seizures.
• generalized tonic-clonic seizures.
• trigeminal neuralgia.
• mania.

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Carbamazepine (2)

• Pharmacokinetics
• Absorption after oral administration is complete
• Distribution
• The drug is only 70 bound to plasma proteins no
  displacement of other drugs from protein binding
  sites has been observed.
• Clearance
• Carbamazepine is completely cleared by
  metabolism in the liver. Metabolism is slow at
  the start of therapy. The drug has a notable
  ability to induce microsomal enzymes.

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Carbamazepine (3)

• Adverse effects
• Dose related
• Diplopia and ataxia (treated by rearrangement of
  the divided doses).
• Mild gastrointestinal disturbances
• drowsiness (at much higher doses),
• Hyponatremia and water intoxication
• Idiosyncratic
• Skin rash (the most common)
• blood dyscrasias in the form of
• aplastic anemia and agranulocytosis.
• leukopenia (not necessarily an indication to stop
  treatment but requires careful monitoring).

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Carbamazepine (4)

• Drug Interactions
• Carbamazepine induces its own metabolism and
  decreases its efficacy. Therefore, dose
  adjustment is required a month after the onset of
  therapy
• Drugs which induce cytochrome P450 as phenytoin
  will increase the metabolism of carbamazepine and
  decrease its activity
• Drugs which inhibit cytochrome p450 will decrease
  the metabolism of carbamazepine and increase its
  plasma concentration and toxicity as
  erythromycin, isoniazid, cimetidine, warfarin,
  sulfonamides and valproic acid.
• Carbamazepine induces cytochrome p450 that
  metabolizes
• phenytoin, primidone, phenobarbital, valproic
  acid,
• clonazepam, ethosuximide oral contraceptives,
  steroids and phenytoin and decrease their
  efficacy.

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Oxcarbazepine

• Oxcarbazepine is chemically and pharmacologically
• closely related to carbamazepine, but it has much
  less
• capacity to induce drug-metabolizing enzymes.
  This
• property decreases the problems associated with
  drug
• interactions when oxcarbazepine is used in
  combination
• with other drugs. The clinical uses and adverse
  effect
• profile of oxcarbazepine appear to be similar to
  those of
• carbamazepine.

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Lamotrigine (1)

• Mechanism of Action
• blockage of voltage dependent sodium channels
  (similar to phenytoin).
• actions on voltage-activated Ca?²channels
  (accounting for its efficacy in absence
  seizures).
• Clinical use
• Monotherapy in partial seizures.
• Add on therapy
• Absence seizures in children.

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Lamotrigine (2)

• Pharmacokinetics
• Lamotrigine is completely absorbed after oral
  administration
• Protein binding is only about 55.
• metabolized primarily by glucuronidation and the
  metabolite is excreted in urine.

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Lamotrigine (3)

• Adverse effects
• Dizziness headache and somnolence
• Diplopia
• Nausea
• Skin rash (hypersensitivity).
• Life-threatening dermatitis

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Valproic acid (1)

• Mechanism of action
• Block voltage-dependent sodium channels
• Increase in brain GABA
• increase membrane potassium conductance leading
  to hyperpolarization of the neuronal membrane)

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Valproic acid (2)

• Uses
• generalized tonic-clonic seizures
• partial seizures
• Absence seizures
• myoclonic seizures
• management of bipolar disorders
• migraine prophylaxis

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Valproic acid (2)

• Pharmacokinetics
• well absorbed following an oral dose
• Valproic acid is 90 bound to plasma proteins

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Valproic acid (3)

• Toxicity
• Dose related
• GIT troubles in the form of nausea, abdominal
  pain and heartburn
• weight gain, increased appetite, and hair loss.
• Idiosyncratic toxicity
• hepatotoxicity,
• thrombocytopenia
• Teratogenicity

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Valproic acid (4)

• Drug interactions
• Valproic acid inhibits the metabolism of several
  drugs, including phenobarbital, primidone,
  carbamazepine, and phenytoin, leading to an
  increased blood level of these compounds.
• At high doses, valproic acid can inhibit its own
  metabolism.
• It can displace phenytoin from binding sites on
  plasma proteins, with a resultant increase in
  unbound phenytoin and increased phenytoin
  toxicity.