chap 12

• Epilepsy


  • The third most common neurologic disorder after cerebrovascular & Alzheimer's disease
  • A heterogenous symptom complex - a chronic disorder characterized by recurrent seizures

  
• Seizures


  • Finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons
  • Results in loss of consciousness, abnormal movements, atypical or odd behavior, distorted perceptions

  
• Causes of Seizures


  • Infection
  • Neoplasm
  • Head Injury
  • Heredity
  • Single-gene defects
  • Electrolyte Imbalance
  • Drug abuse
  • Abrupt withdrawal from alcohol
• Convulsion


  When a person's body shakes rapidly and uncontrollably, with muscles contracting and relaxing repeatedly
• Classification of Seizures


  • Partial Seizures
  • Generalized Seizures

  
• Partial Seizures


  • Those in which a localized onset of the attack can be ascertained, either by clinical observation or by electroencephalographic recording
  • The attack begins in a specific locus in the brain

  
• Simple Partial Seizure


  The least complicated partial seizure, characterized by minimal spread of the abnormal discharge such that the normal consciousness and awareness are preserved

  
• Simple Partial Seizure


  • Sudden onset of clonic jerking of an extremity lasting 60-90 seconds; residual weakness may last for 15-30 minutes after the attack
• Complex Partial Seizure


  • Also has a localized onset, but the discharge becomes more widespread (usually bilateral) and almost always involves the limbic system
  • Arise from one of the temporal lobes, possibly because of the susceptibility of this area to insults such as hypoxia and infection
  • The patient may have a brief warning followed by an alteration of consciousness during which some patients stare and others stagger or even fall
  • Automatisms - lip smacking, swallowing, fumbling, scratching & walking about
  • Patient recovers after 30-120 seconds but may feel tired or ill for several hours after the attack

  
• Generalized Seizures


  Those in which there is no evidence of localized onset

  
• Generalized Tonic-Clonic Seizures


  • Also called grand mal seizures
  • The most dramatic of all epileptic seizures
  • Characterized by tonic rigidity of all extremities, followed in 15-30 secs by a tremor that is actually an interruption of the tonus by relaxation
  • As the relaxation phases become longer, the attack enters the clonic phase, with massive jerking of the body (60-120 seconds)
  • Tongue or cheek may be bitten, and urinary incontinence is common

  
• Absence Seizure


  • Also called petit mal seizure
  • Characterized by both sudden onset and abrupt cessation
  • Duration is usually less than 10 seconds and rarely more than 45 seconds
  • Consciousness is altered
  • May also be associated with mild clonic jerking of the eyelids or extremities, with postural tone changes, autonomic phenomena and automatisms
  • Begins in childhood or adolescence and may occur up to hundred times a day

  
• Atypical Absence Seizure


  • Seizure with postural changes that are more abrupt, and such patients are often mentally retarded
  • May be more refractory to therapy

  
• Myoclonic Jerking


  • Consist of short episodes of muscle contractions that may recur for several minutes
  • Usually occur after wakening and exhibit as brief jerks of the limbs
• Atonic Seizures


  • Those in which the patient has sudden loss of postural tone
  • If standing, the patient falls suddenly
  • If seated, the head and torso may suddenly drop forward

  
• Infantile Spasms


  • An epileptic syndrome and not a seizure type
  • Characterized by brief, recurrent myoclonic jerks of the body with sudden flexion or extension of the body and limbs
  • Most patients are mentally retarded
• Causes of Infantile Spasms

  • Infection
  • Kernicterus
  • Tuberous sclerosis
  • Hypoglycemia
• Status Epilepticus


  • Two or more seizures occur without recovery of full consciousness in between episodes
  • Life-threatening (requires fast-acting medication such BZD, followed by slower-acting drugs like phenytoin)
• Mechanisms of Action of Antiseizure Drugs

  • Enhancement of GABAergic (inhibitory) transmission
  • Diminution of excitatory (usually glutamatergic) transmission
  • Modification of ionic conductances
• Phenytoin


  • The oldest nonsedative antiseizure drug
  • Alters Na+, K+ and Ca2+ conductance, membrane potentials, and the concentrations of amino acids and the neurotransmitters norepinephrine, acetylcholine, and GABA
  • Blocks sustained high-frequency repetitive firing of action potentials
  • Inhibits calcium influx across the cell membrane, may explain the ability of phenytoin to inhibit a variety of calcium-induced secretory processes, including release of hormones and neurotransmitters (inhibits glutamate release, enhances GABA release)
• Fosphenytoin


  • A more soluble prodrug of phenytoin
  • Administered parenterally
  • Rapidly converted to phenytoin in the plasma
• Therapeutic Level & Dosage of Phenytoin

  The therapeutic plasma level of phenytoin for most patients is between 10 and 20 mcg/mL
• Drug Interactions & Interference with Laboratory Testing of Phenytoin


  • Phenytoin is 90% bound to plasma proteins
  • Phenylbutazone, sulfonamides displace it from protein binding
  • Has affinity on thyroid-binding globulin, the most reliable screening of thyroid function
  • For patients taking phenytoin, measurement of TSH is done
• Toxicities of Phenytoin


  • Nystagmus
  • Diplopia & Ataxia (most common dose-related adverse effects)
  • Sedation
  • Gingival Hyperplasia
  • Hirsutism
  • Coarsening of facial features with mild peripheral neuropathy
  • Osteomalacia
  • Megaloblastic anemia
• Phenytoin Toxicities


  • Nystagmus
  • Diplopia
  • Gingival Hyperplasia
• Congeners of Phenytoin


  • Phenacemide (withdrawn)
  • Ethotoin
  • Mephenytoin - Nirvanol (active metabolite)
• Carbamazepine


  • Closely related to imipramine and other antidepressants
  • A tricyclic compound effective in the treatment of bipolar depression
  • Initially marketed for the treatment of trigeminal neuralgia
  • Blocks high frequency firing of neurons through action on VG Na+ channels
  • Decreases synaptic release of glutamate
• Clinical Uses of Carbamazepine


  • Drug of choice for both partial seizures and generalized tonic-clonic seizures
  • Trigeminal neuralgia
  • Mania (Bipolar disorder)
• Pharmacokinetics of Carbamazepine


  Undergoes autoinduction
• Therapeutic Levels & Dosage of Carbamazepine

  • Dosage: 15-25 mg/kg/d
  • In adults, 1 or 2 g are tolerated
• Drug Interaction of Carbamazepine

  Enzyme induction
• Toxicities of Carbamazepine


  • Diplopia
  • Ataxia
• Oxcarbazepine


  • Closely related to carbamazepine and is useful in the same seizure types
  • Less potent but appears to induce hepatic enzymes to a lesser extent
• Eslicarbazepine


  • The active metabolite of oxcarbazepine
  • Indicated for partial-onset seizures
  • Mechanism of action: blocks voltage-gated sodium channel
• Phenobarbital


  • The oldest antiseizure drug
  • Derivative of barbituric acid
  • Longest acting barbiturates
  • Enhances inhibitory processes and diminishes excitatory transmission
  • Binds to an allosteric site on the GABAA receptor, and enhances the GABA-receptor mediated current by prolonging the openings of the chloride channels
• Clinical Uses of Phenobarbital


  • Useful in the treatment of partial seizures and generalized tonic-clonic seizures
  • Sedative-hypnotic
  • Therapeutic levels: 10-40 mcg/mL
• Primidone


  • 2-deoxyphenobarbital
  • Metabolized to phenobarbital and phenylethylmalonamide (PEMA)
  • Similar mechanism of action to phenytoin but converted to phenobarbital
  • Effective against partial seizures and generalized tonic-clonic seizures (may be more effective than phenobarbital)
  • Toxicity similar to those of phenobarbital, with drowsiness occurring early in the treatment and if the initial dose is too large
• Vigabatrin


  Mechanism of action: irreversibly inhibit GABA aminotransferase (GABA-T), the enzyme responsible for the catabolism of GABA
• Iseizure


  Derivative of barbituric acid, longest acting barbiturates
• Mechanism of Action


  1. Enhancement of inhibitory processes and diminution of excitatory transmission

  2. Binds to an allosteric site on the GABAA receptor, and enhances the GABA-receptor mediated current by prolonging the openings of the chloride channels