SEIZURES PHARMACOLOGY University of Hawaii Hilo Pre -Nursing Program - PowerPoint PPT Presentation

SEIZURES PHARMACOLOGY University of Hawai‘i Hilo Pre -Nursing Program NURS 203 – General Pharmacology Danita Narciso Pharm D 1

 Understand the pharmacodynamics involved in the medications used to treat seizures  Understand what a seizure is and the general principles behind treatment  Understand the differences between the classes of medications to treat seizures  Know the difference between seizure, convulsions, epilepsy, and status epilepicus LEARNING OBJECTIVES 2

 A seizure is an electrical disturbance in the brain that can affect consciousness, motor activity, and sensation  Epilepsy is a condition associated with periodic unpredictable seizures  Types of seizures  Partial (focal) – abnormal neuronal firing in one brain area in one hemisphere  Generalized – abnormal neuronal firing that progresses to the involvement of many neurons in both hemispheres  Special syndromes WHAT IS A SEIZURE? 3

 A deadly seizure or seizures  1 in 5 is deadly  Greater than 30 minutes in length  Any seizure > than 5 minutes can progress to SE  1 continuous seizure or multiple seizures with no gain of consciousness between seizures  Can cause neuronal damage STATUS EPILEPTICUS (SE) 4

 Infectious illness (meningitis/encephalitis)  Trauma (brain/head)  Metabolic disorders (changes in glucose, sodium, or water that can alter electrical impulses)  Vascular diseases(affecting respiratory gases and changes in perfusion due to hypotension, stroke, shock, or arrhythmias)  Pediatric disorders (fever)  Cancer (Rapidly growing tumors occupying brain space and disrupting blood flow to areas of the brain) WHAT CAUSES SEIZURES? 5

Chloride ion - + + hyperpolarizes the cell Calcium anion GABA Na+ Ca++ polarizes the cell Sodium anion polarizes the cell 6

HOW WE ATTEMPT TO TREAT SEIZURE Chloride ion hyperpolarizes the cell Calcium anion GABA Na+ Ca++ polarizes the cell Sodium anion polarizes the cell 7

 Treatment is based on  Signs/symptoms  Past medical history  Comorbid disease states/pathologies  Drug therapy doses  Start low & go slow  Increase until symptoms resolve or ADRs become intolerable  Additional medications  Taper HOW WE TREAT SEIZURES – DRUG THERAPY 8

 Drugs that stimulate the actions of GABA  Benzodiazepines  Barbiturates  Drugs that inhibit the influx of sodium  Drugs that inhibit the influx of calcium MEDICATIONS WE USE TO TREAT SEIZURES 9

 Kinetics cont.  Distribution - Erythrocytes, kidneys, BBB  Uses  Half life – 2.4-5.8 hours  Glaucoma, edema, centrencephalic epilepsies & symptoms of acute  Excretion – urine (70-100%), extended mountain sickness release capsule 47% as unchanged drug  Kinetics  ADRs  Onset – tables 1-2 hours (IR/ER), IV 2- 10 minutes  Flushing, convulsions, depression, photosensitivity, decreased appetite,  Duration – ER (18-24 hours), IR, (8-12 D/N/V, tinnitus, polyuria, renal failure hours), IV (4-5 hours)  Interactions  Protein bound – 95%  Use carefully with other CNS agents  Absorption – dose dependent, erratic  Pregnancy C  Excreted in breast milk ACETAZOLAMIDE – MOA FOR SEIZURES IS NOT KNOWN 10

SV2A protein • Involved in the • modulation of synaptic vesicle release Levetiracetam • Binds to SV2A • Exact mechanism • and activity not known LEVETIRACETAM 11

 Uses  Myoclonic, partial-onset, generalized  ADRs tonic-clonic seizures  Kinetics  Increase BP (children), behavioral issues, HA, drowsiness, vomiting,  Absorption – rapid/complete (oral), infection, weakness, nasopharyngitis Tmax & Cmax increase when taken  Interactions after a high fat/calorie meal (breakfast)  Minor – CNS depressants  Metabolism – not extensive (liver)  Pregnancy C  Half life – 6-8 hours  Excreted in breast milk  Excretion – urine (66% unchanged) LEVETIRACETAM – ALTERS NT RELEASE VIA SYNAPTIC VESICLE MODULATION 12

G G G G G  Decrease GABA metabolism G G  Enzymes involved G  GABA transaminase G G Cl-  Succinic semialdehyde dehydrogenase G Involved in the breakdown of GABA VALPROIC ACID 13

Sodium Channel  Under normal circumstances Inactivation Gate  Sodium enters the cell  Threshold is met  Action potential takes place + + Na+ Na+ Open Na channel Closed Na channel CARBOXAMIDES VALPROIC ACID  Sodium channel inactivation gate TOPIRAMATE  Blocks the Na channel PHENYTOIN (FOS) 14  Inhibits the influx of sodium LAMOTRIGINE  Delays actions potential LACOSAMIDE  Prolong refractory period

Ca++ Ca++ L-type Ca++ Blockade of Gabapentin the L & T type calcium T-type Ca++ channels Valproic Acid 15

GABA Cl- Cl- Benzodiazepines Barbiturates Chloride DRUGS THAT MIMIC OR STIMULATE GABA 16

 Barbiturates ( phenobarbital )  Benzodiazepines ( diazepam )  Uses – Generalized tonic-clonic, status epilepticus , partial seizures, sedation  Others also used  Dosage forms  Uses – convulsive disorders, adjunct to refractory epilepsy (rectal gel) for patients  Oral already on stable therapy  Injection  Dosage forms  Kinetics  Oral (Solution, tablet)  Protein binding – 20-45%  Injection (IM & IV)  Metabolism – CYP2C19  Rectal  Half life – 2-5 days  Pregnancy D  ADRs  Metabolite in breast milk  Sedation, bradycardia, hypotension, drowsiness, dizziness, HA, N/V, constipation  Interactions  MAJOR!!!! CYP enzyme inducer (3A4, 1A2, 2C9, & more) BENZODIAZEPINES - (INCREASE GABA POTENCY,  Pregnancy B/D GABA A RECEPTOR)  Found in breast milk 17 BARBITURATES - (OPENS GABA A CHLORIDE CHANNELS)

 ADRs  Uses – Partial onset seizures  Dizziness, drowsiness, fatigue, ataxia, infection  Kinetics  Interactions  Absorption – variable  CNS depressants (safe with other  Protein bound - < 3% anticonvulsants )  Half life – 5-7 hours  Pregnancy C  Excretion – urine (unchanged drug)  Excreted in breast milk amount proportional to renal function  Dose adjusted per renal function (renaly dosed) GABAPENTIN – BLOCKS L-TYPE CALCIUM CHANNELS 18

 ADRs  Uses – Epilepsy (monotherapy or  HA, dizziness, insomnia adjunct)  BBW  Kinetics  Stevens-Johnsons syndrome (SJS)  Absorption – immediate & rapid  Toxic epidermal necrosis (TEN)  Metabolized – Liver & kidney  Interactions  Half life – 25-33 hours (longer in the  Substrate for CYP3A4 (3A4 inducers) elderly, with co-administration, & liver  Valproic acid (increase lamotrigine damage ) levels – UGT inhibition)  Excretion – urine (90-94% - only 10% as  Pregnancy C unchanged drug), feces 2%  Excreted in breast milk LAMOTRIGINE – WORKS ON SODIUM CHANNELS 19

 ADRs  Gingival hyperplasia (excessive growth of gum tissue), rash (measles ‐ like), acne,  Phenytoin (fosphenytoin IV) hirsutism (hair growth), GI distress, vitamin D  Uses – Generalized tonic-clonic & complex deficiency, osteomalacia, folic acid partial deficiency, lymph node hyperplasia, teratogenic (similar to fetal alcohol  Kinetics syndrome)  Administration – oral  Nystagmus (oscillations of the eyes), diplopia (double vision), ataxia, drowsiness  Absorption – slow but almost complete (signs of toxicity)  Distribution – very lipophilic  Interactions  Protein bound – 90%  Warfarin, NSAIDS (increase risk of bleed)  Metabolized – Liver ( CYP2C9 & 2C19 )  MAJOR!!! CYP inducer (3A4, 2C9, 2C19, & more)  Half life – 2-22 hours (higher concentrations = higher half lives – enzyme saturation)  Pregnancy D  Excreted in breast milk HYDANTOINS – PHENYTOIN (INCREASED REFRACTORY PERIOD THROUGH PROLONGED CLOSURE OF THE 20 INACTIVATION GATE ON NA CHANNEL)

 Uses  Epilepsy & migraine  ADRs  Kinetics  Drowsiness, fatigue, weight loss  Absorption – Good/rapid  Interactions  Metabolism – liver, renal  CYP inducers, CNS depressants reabsorption (increased by  Mostly minor inducers)  Pregnancy D  Half life – 21-56 hours (depending on product)  Excreted in breast milk  Excretion – urine (70% unchanged drug) TOPIRAMATE – SODIUM CHANNELS 21

Carbamazepine  Uses – Partial seizures & generalized tonic-clonic,  bipolar disorder, alcohol withdrawal Kinetics  Administration – oral  Distribution – very lipophilic  Metabolism – hepatic (CYP3A4) to active Oxcarbazepine   metabolite Prodrug of carbamazepine  Half life – 25-65 hours  Uses – Partial seizures  ADRs  Differences  GI distress, nystagmus, diplopia, ataxia, SJS  No blood dyscrasias  BBW – aplastic anemia & agranulocytosis  Less CYP inducer activity  Interactions  Valproic acid – inhibits one of the metabolic  enzymes of carbamazepine MAJOR!!!!! CYP enzyme inducer (3A4, 2C9, 2C19,  1A2, & more) EVEN INDUCES ITSELF  Pregnancy D  Active metabolites in breast milk  CARBOXAMIDES - INCREASED REFRACTORY PERIOD 22 THROUGH PROLONGED CLOSURE OF THE INACTIVATION GATE ON NA CHANNEL