Chapter 15: Drugs For Seizures

Epilepsy- neurological disorder characterized by recurrent s/s that may include blackouts, fainting spells, sensory disturbances, jerking body movements and temp loss of memory Seizure- disturbance of electrical activity in the brain that may affect consciousness, motor activity, and sensation ; caused by abnormal or uncontrolled neuronal changes Discharges that remain in one area of the brain → Focus ; or can spread Seizure→ single occurrence Epilepsy→ 2 or more recurring seizures . 30 min or more. Pt does not regain consciousness EEG helps to dx seizures Convulsions → involuntary, violent, spasms of large skeletal muscles of the face, neck, arms, and legs Not all seizures involve convulsions * ASM’s- anti seizure medications AED’S- anti epileptic drugs Triggers of seizures include → exposure to strobe/flickering lights, small fluid and electrolyte imbalances, sleep deprivation * 50% seizures are IDIOPATHIC→ no specific cause identified Fever, medications, anesthesia, drug abuse, withdrawal from meds/alcohol can cause seizures . KNOWN CAUSES → fever , infectious diseases (meningitis / encephalitis→ cause imflammation of brain) , metabolic disorders (hypoglycemia, hyponatremia, water intoxication) , neoplastic disease (rapid growing tumors → increase IC pressure) , trauma ( can also increase IC pressure) , vascular diseases → changes in oxygenation (hypoxia/carbon monoxide poisoning) , or changes in perfusion → hypotension, shock, stroke, cardiac dysrhythmias, AEDS- decrease effectiveness of oral contraceptives → women w epilepsy planning to get or not get preggo need OPTIONS AEDS’s→ most are PREG CAT D * AEDS→ some cause folate deficiency , > r/o neural tube defects Eclampsia- severe HTN disorder that continues to worsen as pregnancy progresses. → characterized by seizures, coma and perinatal mortality → 25% women w eclampsia have seizures 72 hrs postpartum; TX FOR ECLAMPSIA → Mg Sulfate Seizures can increase r/o INJURY while driving, → can limit participation in school, work, social life and affect self esteem TYPES OF SEIZURES Differing presentations of seizures is based off their s/s Partial : -Simple Partial -Complex Partial Generalized: -absence petit mal -atonic (drop attack) -tonic-clonic(grand mal) Specialized syndromes: -Febrile seizure -myclonic seizure -status epilepticus Choice of AED is individualized for each pt based on type of seizure, previous medical hx, EEG data, and associated pathologies Initial meds are started on LOW DOSES→ gradual increase until therapeutic effect is achieved (Seizure control), or until drug s/e prevent additional increases in dosage If seizures continues, SECOND AED is added in SMALL DOSE INCREMENTS while the dose of the first drug is SLOWLY reduced (over 6-12 weeks) Abrupt DC= r/o seizures More recent seizure meds have LESS s/e , well tol, LESS of a health risk in pregnancy Some AEDS ^ r/o suicidal behavior and ideation- CG play close attention to changes in mood and not d/c any meds w/out MD orders/consultation. Some AED combinations actually increase the r/o seizures d/t interactions Goal of antiseizure meds is to suppress neuronal activity enough to prevent an abnormal focus from forming or spreading across the cerebrum ASM’s control movement of electrolytes across neuronal membranes or affect neurotransmitter balance 5 ways AEDS act: 1) 2) 3) 4) 5) Increase activity of GABA in brain (increase influx of Chl ions) Inhibit influx of sodium into neurons Inhibit influx of Calcium into neurons Correct neurotransmitter balance Block Glutamate receptors in brain Influx of SODIUM or CALCIUM= ENHANCED neuronal activity= MORE increase r/o seizures Influx of CHLORIDE or POTASSIUM=SUPPRESSES neuronal activity = DECREASE r/o seizures Primary target for many AEDS is SODIUM CHANNEL GABA is MOST affected by AEDS’s→ increasing GABA activity in CNS DECREASES neuronal firing→ SUPPRESSING seizure activity GLUTAMATE- second neurotransmitter affected , by blocking GLUTAMATE receptors (primary excitatory neurotransmitter) → drugs serve as ANTAGONISTS to GLUTAMATE and SUPPRESS neuronal firing So IN THE END→ you want INCREASED GABA action, DECREASED GLUTAMATE action * Several AEDS work by changing the action of GABA → they mimic the effects of GABA by stimulating an influx of Chloride ions through the GABA receptor channel → INCREASEDD CHLORIDE suppresses abnormal firing of neurons which = prevented or terminated seizure activity Drugs can enhance GABA release or block reuptake of GABA into nerve cells and glia, some increase amount of GABA in the nerve terminal by inhibiting GABA degrading enzymes Drugs that enhance GABA are used for other conditions → depression, migraines, management of neuropathy pain r/t diabetic peripheral neuropathy, postherpetic neuralgia , fibromyalgia, and spinal cord injury, anxiety, bipolar. TX seizures with BARBITURATES Barbiturates intensify the effect of GABA in the brain and generally depress the firing of CNS neurons Still used for epilepsy , but newer drugs have replaced the, Have low margin of SAFETY *, HIGH potential for dependence, cause PROFOUND CNS depression PHENOBARBITAL- able to suppress abnormal neuronal discharges WITHOUT causing MAJOR SEDATION*; its INEXPENSIVE, LONG ACTING; and produces low incidence of A/E . PO ADMIN- several weeks needed for max effects Preferred drug for NEONATAL SEIZURES ** Effective against almost all seizures EXCEPT ABSENCE SEIZURES ! Primidone (mysoline) – other babrbiturate used for seizures Barbiturates once MAIN TX for status epilepticus – have been replaced by IV DIAZEPAM OR LORAZEPAM PHENOBARBITAL (Luminal) Antiseizure drug; sedative / barbiturate; GABA(A) receptor agonist Long acting med used for tx of seizures Produces sedation Should not be used for pain relief b/c may increase sensitivity to pain Enhaces action of GABA Parenteral admin is a soft tissue irritant IM injections produce a local inflammatory reaction IV admin rarely used bc of r/o EXTRAVASATION → lead to tissue necrosis Schedule IV controlled drug PREGNANCY CATEGORY : D A/E: may cause dependence Common s/e→ drowsiness, vit deficiency (Vit D, folate, B12) , laryngospasms (spasms of the vocal cord) OVERDOSE: severe RR depression, CNS depression, coma & DEATH. Contraindicated in pts w SEVERE PAIN, preexisitng CNS depression, porphyrias, severe respiratory disease w dyspnea or obstruction, glaucoma or prostatic hypertrophy. Interacts w MANY drugs Don’t take w alcohol or other CNS depressants → increases sedative effects, RR depression, cardiac arrest Increases metabolism of many other drugs, reducing their effectiveness NO SPECIFIC TX FOR OVERDOSE → drug removal may be done with GASTRIC LAVAGE or sue of activated charcoal Hemodialysis → can facilitate removal Endotracheal intubation and mech ventilation Tx of brady and hypotension may be needed TX seizures w BENZOS Intensify the effect of GABA in the brain Bind directly to GABA receptors, suppressing abnormal neuronal foci. Benzos used for epilepsy → clonazepam, clorazepate, lorazepam, diazepam. BENZOS TX ABSENCE & MYOCLONIC SEIZURES IV diazepam and lorazepam- TX status epilepticus Tol can develop in few months—adjust doses periodically Taken w other AEDS for tx of refractory seizures (Seizures that don’t respond to tx w meds) DIAZEPAM (Valium) Antiseizure drug/ benzo; GABA (A) receptor agonist Primary indication → to tx STATUS EPILEPTICUS Can also prevent seizures in ppl that received toxic susbtances or during acute phase of alcohol or benzo withdrawals Binds to gaba receptor- chloride channels throughout the limbic system PO- max effect reached in 1-2 weeks Tol may develop in 4 weeks IV- max effect in mins , anticonvulsant effects LAST 20 MINS ; MONITOR RR Q 5-15 mins, MAKE SURE AIRWAY AND RESUSCITATIVE equipment is avail. PREGNANCY CAT- D A/E: tol and depence – reserved only for SHORT TERM seizure control or for status epilepticus IV- hypotension, muscle weakness, tachy, RR depression Injection admin contraindicated in: shock, coma, depressed VS, OB pts , infants <30 days old PO admin→ should not be given too infants <6months old Don’t give to pts w glaucoma or w/in 14 days of MAOI therapy Don’t take w alcohol or other CNS depressants – increased sedation Cimetidine, PO contraceptives , valproic acid, metoprolol→ increase action Levadopa and barbiturates→ decrease effects Diazepam > PHENYTOIN levels → can cause PHENYTOIN TOXICITY Phenytoin displays its main signs of toxicity on the nervous and cardiovascular systems. Overdose on oral phenytoin causes mainly neurotoxicity and only very rarely causes cardiovascular toxicity. On the other hand, cardiovascular toxicity is the main side effect of parenteral administration. The symptoms of Dilantin toxicity include fast, uncontrollable eye movements or double vision, dizziness, drowsiness, or confusion, lack of coordination of fingers, hands, arms, legs, or body, slurred speech, nausea or vomiting, decreased appetite, decreased activity, abdominal bloating, or irregular heartbeat. OVERDOSE TX→ give Flumazenil (Romazicon) a benzo receptor antagonist to reverse CNS depression ___________________ DRUGS that suppress SODIUM INFLUX Hydantoins and other related drugs work by delaying and influx of sodium ions across neuronal membranes NA+ is major factor that determines whether a neuron will undergo an action potential If sodium channels are temporarily inactivated -neuro activity is suppressed Channels are NOT BLOCKED, just desensitized Drugs can desensitize channel, affect threshold of neuron firing, or interfere w transduction of excitatory neurotransmitter GLUTAMATE Dilantin (Hydantoin) useful in tx all types of seizures EXCEPT ABSENCE seizures; provides effective sedation w/out abuse potential or CNS depression that barbiturates have. Pts vary in ability to metabolize phenytoin→ doses are individualized Have narrow range between therapeutic and toxic dose Phenytoin and fosphenytoin- 1st line drugs for status epilepticus Phenytoin related drugs: carbamezapine, eslicarbazepine, oxcarbazepine, valproic acid- share same MOA Carbamezapine→ Widely used; SAFE MED → tx tonic-clonic seizures , partial seizures w complex s/s and mixed seizure patterns. DOES NOT WORK W ABSENCE SEIZURES; avail in ER forms CARVENIX – IV carbamezapine used for tonic clonic seizures or partial seizures when pt unable to take PO form Valproic acid- preferred tx for absence seizures and myoclonic Carbamezapine and valproic- also used to tx BIPOLAR Lamotrigine (Lamictal) – tx tonic clonic , partial, absence Keppra and zonisamide- adjunct tx for partial seizures in adults Lennox-Gastaut syndrome (LGS)- severe form of epilepsy characterized by tonic, atonic, atypical absence, and myoclonic s/s . (Nobody is born w LGS- develops over time) Tx can include: valproic acid, lamotrigine, felbamate, topiramate, rufinamide CANNABIDIOL (EpidioleX) – med approved to tx LGS ; first FDA approved drug that has marijuana PHENYTOIN (Dilantin, Phenytek) Antiseizure drug; antidysrhythmic/ hydatoin ; sodium influx suppressing drug Acts by desensitizing sodium channels in CNS – prevents spread of abnormal electrical charges in brain that = seizures. Eff against all seizures except ABSENCE Has antidysrhythmic actions similar to Lidocaine Phenytek – ER form , allows for DAILY DOSING IV admin- mix w saline ONLY and infuse max rate of 50mg/min. mixing w other things =precipitate. Prime/flush IV lines w saline before hanging as piggyback bc traces of dextrose solution in existing main IV or piggyback can cause micro precipitate that can become EMBOLI . USE IV line with FILTER Do not give IM or inject into large vein via central venous cath → soft tissue damage Avoid using hand veins to prevent vasoconstrictive response (purple glove syndrome) ; Purple glove syndrome (PGS) is a poorly understood skin disease in which the extremities become swollen, discoloured and painful.[1] PGS is potentially serious, and may require amputation. PGS is most common among elderly patients and those receiving multiple large intravenous doses of the epilepsy drug phenytoin.[2] Compartment syndrome is a complication of PGS. PREGNANCY CAT D A/E: dysrhythmias – brady, vfib, severe hypotension, hyperglycemia SEVERE CNS REACTIONS – HA , nystagmus (dancing eyes/uncontrolled movement ) , ataxia, confusion, slurred speech, paradoxical nervousness, twitching, insomnia Peripheral neuropathy- w LT use Blood dyscrasias – agranulocytosis/ aplastic anemia Severe skin reactions – rashes, exfoliative dermatitis, SJS , lupus erythematosus, hypertrichosis, hirsutism, gingival hypertrophy BLACK BOX WARNING: rate of IV should not exceeed 50MG/MIN in adults and 1-3mg/kg/min in peds → SEVERE HYPOTENSION AND CARDIAC ARRYTHMIAS CAREFUL CARDIAC MONITORING NEEDED DURING IV ADMIN !! Contraindicated in pts w rash, seizures, brady, heart block Interacts w PO anticoagulants/ glucocorticoids, H2 antagonists, antituberculin drugs, food supplements, folic acid, CA, vit D. Impairs efficacy of drugs → digoxin*, doxycycline, Lasix, PO contraceptive, theophylline When taken w TRYCILIC ANTIDEPRESSANTS→ Trigger seizures May increase BS CHECK DILANTIN LEVELS ! → THERAPEUTIC RANGE FOR DILATING LEVELS 10-20 MCG/ML . >30 = CAN SIGNAL TOXICITY NO specific tx for overdose . May use gastric lavage , charcoal, laxative Maintain airway , breathing Monitor dilating levels and tx a/e VALPROIC ACID (Depakene, others) Antiseizure drug/ valproate Preferred drug for tx epilepsy Valproic acid- standard PO form Valproate sodium(Depacon)- sodium salt of valproic acid – given PO/IV Divalproex sodium (Depakote)- ER combo of valproic acid and sodium salt in 1:1 mixture – PO admin All 3 ^^ form VALPROATE after absorption or on entering the brain Admin as single drug or in combination w other AEDS – tx absence seizures and complex partial Depakote ER- also prevent migraine HA and mania r/t bipolar Off label tx- severe behavioral disturbances → agitation d/t dementia Alzheimers, explosive temper r/t ADHD, persistent hiccups, status epilepticus refractory to IV diazepam Is a GI irritant – don’t chew ER tabs, oral soreness will occur Don’t mix valproic acid syrup w carbonated bvg bc will trigger IR of drug , causes severe mouth/throat irritation Open caps and sprinkle on food if pt unable to swallow PREGNANCY CAT D Onset – 2-4 days A/E- sedation, drosiness, GI upset, prolonged bleeding, visual disturbances, muscle weakness, tremor, psychomotor agitation, bone marrow suppression, weight gain, abd cramps, rash, alopecia, pruritus, photosensitivity, eryhtem , fatal hepatotoxicity BLACK BOX WARNING: fatal hepatic failure , especially in kids <2yrs old . Hepatotoxicity – weakness, facial edema, anorexia, vomiting Liver function tests should be done PRIOR to tx Life threatening teratogenic effects (preg cat d) → SPINA BIFIDA Don’t admin to pts w liver failure, bleeding dysfunction, pacreatitis, and congenital met disorders. Interacts w ASA, cimetidine, chlorpromazine, erythromycin, felbamate- can > valproic acid toxicity Warfarin, ASA, alcohol – can cause severe bleeding Use w clonazepam = absence seizures Increases phenobarbital and phenytoin levels Lamotrigine, phenytoin and rifampin- lower valproic acid levels __________________ TX seizures w SUCCINAMIDES Medications that suppress seizures by delaying CA influx into neurons Raise the seizure threshold , keep neuro from firing too quickly , suppressing abnormal foci GENERALLY ONLY EFFECTIVE AGAINST ABSENCE SEIZURES * Ethosuxinamide (Zarontin) most commonly px one ETHOSUXINAMIDE (Zarontin) Antiseizure med / succinimide Preferred drug for absence seizures Depresses activity of neurons in motor cortex by elevating neuron threshold Ineffective against psychomotor or tonic-clonic seizures – but may be given in combo to tx Avail in PO tab and flavored syrup Abrupt DC = tonic-clonic seizure Pregnancy cat-C Onset- 4-7 – LONG A/E: impair mental/physical abilities, psychosis, extreme mood swings, depression, suicidal behavior→ more likely in pts w hx of psych illness CNS effects- dizziness, HA, lethargy, fatigue, ataxia, sleep pattern disturbances, attention difficulty, hiccups Bone marrow suppression and blood dyscrasias + systemic lupus erythematosus Gingival hypertrophy, tounge swelling Abdominal distress and wt LOSS. Don’t give to pts w SEVERE kidney/liver disease Increases phenytoin levels No tx for overdose Emesis- for drug removal (unless pt comatose or convulsing) Gastric lavage, charcoal, cathartics (Substances that make u poop) Hemodialysis – to help remove drug