Drugs for Epilepsy I PDF

PCOL 825B Drugs for Epilepsy I Alison K. Veltri, PhD 1 Contents Epilepsy Classification Other Seizure Types Causes and Diagnosis Therapeutic Goals Drug Options Benzodiazepines Phenytoin 2 Epilepsy (General Information) 4th most common neurologic disorder 10% of people will have at least 1 seizure Se...

PCOL 825B Drugs for Epilepsy I Alison K. Veltri, PhD 1 Contents Epilepsy Classification Other Seizure Types Causes and Diagnosis Therapeutic Goals Drug Options Benzodiazepines Phenytoin 2 Epilepsy (General Information) 4th most common neurologic disorder 10% of people will have at least 1 seizure Seizures can be controlled with 1 medication in ~75% of patients Some patients require more than 1 medication for control Some patients will never obtain total seizure control with any combination of medications 3 Epilepsy Classification International League Against Epilepsy 4 Epilepsy Classification: Focal Seizures Involve only a portion of the brain Symptoms vary Can progress to become generalized tonic-clonic seizures Categorized as simple partial and complex partial 5 Epilepsy Classification: Focal Seizures Simple partial Caused by group of hyperactive neurons that exhibit abnormal electrical activity Confined to single locus Patient does not lose consciousness Seizure does not affect awareness Often exhibits abnormal single limb/muscle group activities, sensory distortions Can occur at any age Also sometimes referred to as auras 6 Epilepsy Classification: Focal Seizures Complex partial Altered consciousness and awareness Complex hallucinations Mental distortions Can occur at any age Can cause motor dysfunctions (chewing, uncontrolled urination, diarrhea) Activity can spread to secondarily generalized convulsions 7 Epilepsy Classification: Generalized Seizures 1. 2. 3. 4. 5. 6. Tonic-clonic (grand mal) Absence (petit mal) Myoclonic Clonic Tonic Atonic 8 Tonic-Clonic (grand mal) Seizures Characterized by loss of consciousness followed by tonic (prolonged contraction) and clonic (rapid contraction and relaxation) phases Violent muscle contractions Sometimes involve impaired respiration Patients may bite their tongue, involuntarily yell or cry out, and lose control of bowels Lasts 1-3 minutes (>5 minutes considered medical emergency) Often followed by period of confusion, exhaustion Glucose depletion 9 Absence (petit mal) Seizures Brief, abrupt loss of consciousness Characterized by staring and rapid blinking (lasting 3-5 seconds) Commonly pediatric onset (3-5 yr) lasting until puberty (and beyond) Exhibits very distinct spike/wave discharge on EEG 10 Myoclonic Seizures Consist of short episodes of muscle contractions Occur often after waking up from sleep Involve brief limb jerking Onset is frequently puberty/early adulthood 11 Clonic Seizures Impaired consciousness Short episodes of muscle contractions Can look similar to myoclonic seizures 12 Tonic Seizures Sudden tension/stiffness Increased muscle tone Impacts arms and legs most frequently Rapid onset and end (less than 60 seconds) 13 Atonic/Akinetic Seizures ‘Drop’ seizures Sudden loss of muscle tone/muscle strength No loss of consciousness 14 Other Seizure Types Symptomatic Due to disease state (for example preeclampsia/eclampsia) or situation (drug overdose) Febrile Occurs in infants and young children following rapid rise in fever over 103ºF 2-3% children will develop epilepsy later Status Epilepticus Seizure lasting more than 5 minutes or several seizures occurring in succession without regaining consciousness Can cause permanent brain damage Can be fatal 15 Epilepsy Causes Genetic Structural/metabolic impairments Unknown 16 Diagnosis Complete neurologic exam Detailed family history Electroencephalogram (EEG) Clinical lab results 17 Biology of Seizure Activity Hyperexcitability Abnormal, excessive, hypersynchronous discharge of a population of cortical neurons Increased excitatory synaptic neurotransmission Decreased inhibitory neurotransmission Ion conductance changes 18 Therapeutic Goals 1. Prevent occurrence of seizures 2. Minimize side effects 3. Maintain QOL 19 Therapeutic Strategies 20 Factors to Consider Drug efficacy for seizure type Adherence (monotherapy preferred) Adverse effect profile Cost to patient PK 21 Antiepileptic Drugs Reduce seizure through several mechanisms Block voltage-gated channels Enhance GABAergic impulses Interfere with excitatory glutamate transmission Multiple CNS targets Unknown MOA 22 Benzodiazepines Rescue Meds MOA: Bind inhibitory GABA receptors Reserved for acute treatment, emergencies (tolerance) Diazepine (Valium) (rectal administration) Interrupt prolonged tonic-clonic seizures and febrile seizures Immediate onset, short acting (30 min) Clonazepam (Klonopin) Onset 20-30 min, DOA 6-8 hr Used frequently for absence and myoclonic seizures Lorazepam (Ativan) Onset 20-30 min, DOA 6-8 hr 1st choice for Status Elepticus (more prolonged CNS action) 23 Adverse Effects of Benzodiazepines Tolerance Therapeutic efficacy can decrease over several weeks to months Dose-dependent CNS depression Pediatric agitation, hyperactivity 24 Phenytoin (Dilantin) MOA: inhibition of voltage-gated sodium channels Used primarily for tonic-clonic, simple and complex partial seizures (first line) 25 Phenytoin (Dilantin) Adverse Effects Adverse Effects: Dose-related: accelerated metabolism of oral contraceptives and warfarin, cognitive impairment, ataxia, nystagmus, osteoporosis, diplopia Non-dose related: gingival hyperplasia, hirsutism 26 Phenytoin (Dilantin) PK Saturable enzyme metabolism (nonlinear PK) Induces drugs metabolized by CYP2C/CYP3A and UGT enzyme families 90% plasma protein bound (watch for DDI) 27 Fosphenytoin (Cerebyx) Prodrug Can be administered IV, IM Phenytoin never administered IM Careful with look alike, sound alike drugs (Celexa, Celebrex, etc) 28 Coming Up Drugs for Epilepsy II 29