Epilepsy Flashcards
What is receptor is responsible for excitatory?
Glutamate
What receptor is responsible for inhibitory?
GABA
How is a seizure defined?
The clinical manifestation resulting from an abnormal or excessive discharge of a set of neurons in the brain.
How is epilepsy defined?
A chronic condition characterized by recurrent (>2) epileptic seizures, unprovoked by any immediate identifiable cause
What are alterations of consciousness, motor, sensory, automatic or psychic events?
Clinical manifestations
What can cause a seizure?
Fever Withdrawal from CNS depressants Metabolic abnormalities Uremia Encephalitis/meningitis Head trauma Brain tumor Stroke Lead poisoning Sleep deprivation Medications
What drugs are known to cause seizures?
Antimicrobials Anesthetics and analgesics Immunosuppressants Psychotropics Radiographic contrast agents Theophylline Sedative hypnotic drug withdrawal Drugs of abuse Flumazenil
Epidemiology of epilepsy
Increases in people >70 y/o
Most common neurological disorder in children
70% of patients can be seizure free with appropriate therapy
Pathophysiology of seizures involves what?
Origination from the gray matter of any cortical area (neurons fire abnormally)
Due to excessive excitation or disordered inhibition of neurons (normal membrane function breakdown, excess excitability)
What are the physiologic consequences of a seizure?
Increased consumption of oxygen & glucose
Increased production of lactate and CO2
Increased cerebral blood flow is generally sufficient to compensate for changes
Brief seizures rarely cause long-term seqeulae
Why don’t you want a seizure to occur over a long period of time?
Seizures cost a lot and take a lot out of a person depriving the brain of oxygen and glucose after a long period of time
What are the physiological consequences of a seizure?
Sympathetic discharge results in tachycardia, HTN, and hyperglycemia
Difficulty maintaining the airway
What results when an airway is not maintained during a seizure?
Hypoxia, hypercarbia, and respiratory acidosis
What results from a prolonged seizure?
Lactic acidosis, rhabdomyolosis, hyperkalemia, hyperthermia, and hypoglycemia.
Diagnosis can be made based on:
Patient hx
PE- neurological findings, cranial nerves, motor function, cerebellar function, and sensory function
Lab- metabolic causes- glucose, electrolytes, calcium, and renal function, also drugs/ETOH screen
EEG
MRI
What is an EEG and what is its significance?
An EEG confirms the presence of electrical activity, classifies the seizure type, and indicates the location of focus.
These are performed w/in 48 hrs of a seizure
More than 1/2 of epileptics initially have normal EEGs
What defines a primary seizure?
No specific anatomic cause and involves chronic treatment
How is secondary epilepsy caused?
Tumors, head injury, hypoglycemia, meningitis, or rapid withdrawal from ETOH. Drugs are used for tx until primary cause is corrected
What is the difference between a focal (partial) and generalized seizure?
The location of the cerebrum where the seizure originates
What is the difference between a simple and complex seizure?
Impairment of consciousness (whether the patient looses consciousness or not.
A seizure that begins in one hemisphere of the brain, has symptoms classified as motor, autonomic, or sensory, has ASYMMETRIC MANIFESTATIONS, and accounts for 80% of all adult epilepsies is what type of seizure?
Focal Seizure
A seizure that begins in BOTH hemispheres of the brain and has BILATERAL MANIFESTATIONS is what type of seizure?
Generalized Seizure
A seizure that does not result in loss of consciousness is a?
Simple focal seizure
A seizure that results in a loss or alteration of consciousness is what type of seizure?
Complex focal seizure
A focal onset evolving to generalized tonic-clonic seizures is what type of seizure?
Secondary generalized focal seizure
Tonic seizure is defined as?
A generalized seizure that consists of continuos muscle contraction
Clonic seizure is defined as?
A generalized seizure that consists of rhythmic muscle contractions
Tonic-clonic seizure is defined as?
A generalized seizure that involves an alteration b/w tonic and clonic
Myoclonic seizure is defined as?
A generalized seizure involving sudden, brief muscle spasm
Atonic seizure is defined as?
A generalized seizure consisting of a sudden brief loss of muscle tone
Absence seizure is defined as?
A generalized seizure that involves Impaired awareness or interaction
What is the clinical presentation of a focal seizure?
Asymmetrical manifestation
Symptoms of the motor (any part of the body), autonomic (pallor, flushing, vomiting, sweating, vertigo, or tachycardia), and sensory (visual, auditory, or olfactory)
What is the clinical presentation of a complex seizure?
Prodrome, aura, and automatisms
What is an awareness of an impending seizure such as HA, insomnia, irritability, feeling of impeding doom?
Prodrome
What is a simple focal seizure consisting of autonomic or sensory symptoms?
Aura
What is lip smacking, chewing, swallowing, abnormal tongue movements, thrashing, fumbling or snapping of fingers?
Automatisms
What is the clinical presentation of a generalized seizure?
Bilateral motor manifestations
Tonic-clonic (Grand Mal)- sometimes w/ aura, LOC, sudden tonic contractions followed by rigidity and clonic movements, cries or moans, loss of sphincter control, and unconsciousness followed by a deep sleep.
What type of seizure involves sometimes w/ aura, LOC, sudden tonic contractions followed by rigidity and clonic movements, cries or moans, loss of sphincter control, and unconsciousness followed by a deep sleep.
Tonic-Clonic (Grand Mal)
What is the clinical presentation of a absence (petit mal) seizure?
Sudden onset, interruption of activity
What is the clinical presentation of a complex seizure?
Prodrome, aura, and automatisms
What is an awareness of an impending seizure such as HA, insomnia, irritability, feeling of impeding doom?
Prodrome
What is a simple focal seizure consisting of autonomic or sensory symptoms?
Aura
What is lip smacking, chewing, swallowing, abnormal tongue movements, thrashing, fumbling or snapping of fingers?
Automatisms
What is the clinical presentation of a generalized seizure?
Bilateral motor manifestations
Tonic-clonic (Grand Mal)- sometimes w/ aura, LOC, sudden tonic contractions followed by rigidity and clonic movements, cries or moans, loss of sphincter control, and unconsciousness followed by a deep sleep.
What type of seizure involves sometimes w/ aura, LOC, sudden tonic contractions followed by rigidity and clonic movements, cries or moans, loss of sphincter control, and unconsciousness followed by a deep sleep.
Tonic-Clonic (Grand Mal)
What is the clinical presentation of a ansence (petit mal) seizure?
Sudden onset, interruption of activity
What is the clinical presentation of myoclonic seizure?
Brief shock-like contraction of face, trunk, and upper extremities.
What is the clinical presentation of an atonic seizure?
Head dropping, slumping to the ground
What is the clinical presentation of a febrile seizure?
Generalized seizure
Illness accompanied with a high fever
3 mo. to 5 y/o
Benign; rarely required medication
What are the goals of treatment for seizures?
Accurate diagnosis
Suppress seizure activity
Minimize adverse drug reactions
Optimize QOL
GABA Neurotransmitter
Major inhibitory amino acid
Alters the conductance of ion-selective channels -> K+ efflux or Cl- influx results in membrane hyperpolarization
Drugs- BZDP and barbituates
Glutamate Neurotransmitter
Primary excitatory amino acid
Influx of Na+ ions or reduced outflow of K+ ions depolarize membrane
Drugs- mostly experimental
Drugs that modulate GABA receptors affect what?
Arousal and attention Memory formation Anxiety Sleep Muscle tone
What is GABAs metabolism?
Glutamate synthesis and metabolism intertwined with GABA synthesis and metabolism.
Synthesis: decarboxylation of glutamate -> GABA.
Packaged into vesicles and in response to the action potential exocytosis of the vesicle with the release of GABA into the synaptic cleft occurs.
Termination of GABA action is via uptake by neurons and glia cells (GABA transporters), GABA-transminase converts GABA to succinic semiadehyde which is oxidized to succinic acid and then via the krebs cycle to a-ketoglutarate, GABA-transaminase regenerated glutamate from a-ketoglutarate. Then it is diffused out of the synaptic cleft.
What are the two types of GABA receptors?
Ionotropic and metabotropic
What do ionotropic receptors bind and what is there mechanism?
BInd GABAa and GABAb.
Binds GABA and opens intrinsic chloride ion channels
What do metabotropic receptors bing and what is there mechanism?
BInd GABAb
G-protien-coupled receptors that affect neuronal ion current through 2nd messenger system.
What is the biggest difference between ionotropic and metabotropic receptors?
Ionotropic occur really fast and metabotropic are slower to terminate. Metabotropic uses second messenger systems slowing the mechanism down.
What are the two pathways that metabolism occurs in glutamatergic neurotransmission?
a-ketoglutarate formed in Krebs cycle transaminated to glutamate in CNS nerve terminal.
Glutamine produced and secreted by glial cells transported into nerve and converted into glutamate.
Which anticonvulsants work by prolonged inactivation of the voltage-sensitive sodium channel?
Phenytoin, carbamazepine, and iamotrigine
Which anticonvulsants work by enhancing GABA-mediated inhibition? Directly and indirectly?
Direct-BZDP, barbiturates, topiramate
Indirect-Gabapentin, tiagabine, vigabatrin
Which anticonvulsants work by reduction of glutaminergic excitation?
AMPA- PB, topiramate
What is the general treatment approach to an epileptic patient?
Accurate dx of seizure type
Idenitify patient specific treatment goals
Monotherapy
If seizures not controlled, add on a drug with a different MOA
Patient education (dose titration, compliance, ADRS)
What are the 8 ideal pharmacokinetic characteristics of anticonvulsants?
Good oral bioavailability Penetration through BBB Long half life Low binding to plasma protiens Lack of metabolism Renal elimination Linear pharmacokinetics No drug interactions
What are the first line DOC based on seizure type for partial seizures?
Carbamzepine Phenytoin Lamotrigine Oxcarbazepine Topiramate
What are the second line DOC based on seizure type for partial seizures?
Gabapentin Levetiracetam Phenobarbital Pregabalin Primidone Tiagabine Valproic acid
What are the first line DOC based on seizure type for absence seizures?
Ethosuximide
Lamotrigine
Valproic acid
What are the first line DOC based on seizure type for myoclonic and atonic seizures?
Valproic acid
Lamotrigine
What are the first line DOC based on seizure type for tonic-clonic seizures?
Valproic acid
Carbamazepine
Oxcarbazepine
Lamotrigine
Phenytoin (Dilantin) MOA and Indications
Blocks voltage gated Na+ channels reducin the propogation of abnormal impulses in the brain.
Indications- simple and complex partial sz, generalized tonic-clonic sz, and status epilepticus caused by recurrent tonic-clonic sz.
Phenytoin Pharmakokinetics and administration considerations
Metabolized by P450 system
Potent non-specific inducer of many drug metabolizing enzymes
Highly protein bound
Nonlinear kinetics
Requires dosing therapeutic monitoring
Enteral feeding reduces oral absorption, oral suspension shake vigoriously.
IV formulation can cause pain, phlebitis, and extravasation.
No IM injection
Phenytoin anti arrhythmia and drug interactions
Dont stop abruptly
Inducers- carbamazepine, OCP, doxyclycline, quinidine, cyclosporin, methadone, levodopa
Inhibitors- chloramphenicol, CIMETIDINE sulfonamide, and ISONIAZID
Phenytoin ADRs
Dose related- nystagmus, ataxia, drowsiness, cognitive impairment
Non-dose related- GINGIVAL HYPERPLASIA, hirsutism, acne, rash, hepatotoxicity
Teratogenic- Fetal hydantoin syndrome (cleft lip and palate, congenital heart disease, slowed growth and mental deficiency)
Carbamazepine (Tegretol) MOA and indications
Blocks Na+ channels
Indications- first line tx of simple partial, complex partial, and generalized tonic-clonic
Carbamazepine (Tegretol) Pharmakokinetics
Monitoring through autoinduction (first 20-30 days of tx, autoinduction is dose dependent, after complete, steady state concentrations are achieved after 3 days)
Potent non-specidic inducer of many drugs and transporters
Carbamazepine (Tegretol) ADRs
Dose related- vertigo, ataxia, diplopia, drowsiness, nausea
CNS side effects- HA, paraesthesis, confusion, psychosis
Non-specific- SIADH, leukopenia, thrombocytopenia, stevens johnson syndrome.
Phenobarbital (Luminal) MOA, indications, and side effects
MOA unknown
Indications- generalized tonic clonic, partial sz, neonatal sz, febrile sz,
Side effects- sedation, irritability, slowed thinking, ataxia, hyperactivity, and rash
Phenobarbital (Luminal) pharmacokinetics
Extremely long 1/2 life (96 hours)
Time to steady state is 20-30 days
Metabolized by P450 system
Primidone (mysoline) MOA and indication
Structurally related to phenobarbita l
Efficacy from metabolites (phenobarbital- tonic clonic sz and simple partial sz, and pehnyethylmalonamide- complex partial sz)
Well absorbed orally; poor protein binding, same ADRs as phenobarbital
Indications- alternative choice in partial sz and tonic-clonic sz
Valproic acid (Depakene) & Sodium Valproate (Depakote) MOA and indication
Na+ blockade and enhancement of GABAergic transmission
Indication- Myoclonic, tonic, atonic, absence
Valproic acid (Depakene) Pharmacokinetics
Completely absorbed
Saturable protein binding
Hepatic metabolism but DOESN’T induce P450
Inhibits metabolism of phenobarbital, carbamazepine, ethosuximide
What drugs does Valproic acid (Depakene) inhibit the metabolism?
Phenobarbital, carbamazepine, ethosuximide.
Valproic acid side effects
Dose related- N/V, Abd pain, diarrhea, sedation, tremor, unsteadiness
Non-dose related- acute hepatic failure, acute pancreatitis.
Ethosuximide (Zarontin) MOA and indication
MOA- inhibits calcium channels.
Indication- DOC for absence seizures.
Ethosuximide (Zarontin) pharmacokinetics and side effects
Absorbed orally; not protein bound; metabolized by but not inducer of P450
Side effects dose related- GI, lethargy, HA, dizziness, anxiety
What are the second generations anti-epileptic drugs?
Gabapentin (neurontin) Oxcarbamazepine (Trileptal) Tiagapine (Gabitril) Felbamate (Felbatol) Lamotrigine (Lamictal) Zonisamide (Zonegran) Levetiracetam (Keppra) Pregabalin (Lyrica)
Oxcarbamazepine (trileptal) MOA and indication
Active metabolite blocks Na+ channels
Indication- partial sz with or w/out secondary generalization
Analogue of cabamazepine w/ fewer side effects than cabamazepine and phenytoin
Oxcarbamazepine (trileptal) Side effects
Dizziness, ataxia, fatigue, GI, hyponatremia, rash
30% reactivity for rash with CBZ
No PK monitoring; no autoinduction
Gabapentin (Neurotin) MOA and indication
Analog of GABA; MOA unknown
Indication- adjunct to partial and GTC sz, tx of peripheral neuropathy.
Gabapentin (Neurotin) favorable pharmacokinetic profile
Dose-dependent oral absorption
Not protein bound
Excreted unchanged via kidneys
No serum level monitoring
Gabapentin (Neurotin) Side effects
Somnolence, dizziness, ataxia, nystagmus
Tiagabine (Gabitril) MOA and Indication
Competitive inhibitor of GABA transporter in neurons and glia (inhibitors re-uptake)
Indication- adjunctive tx of partial sz
TAKE WITH FOOD
Tiagabine (Gabitril) pharmacokinetics and side effects
Quickly and completely absorbed
Increased clearance in peds, with enzyme inducers
Serum concentrations unnecessary
Side effects- Dose related: dizziness, fatigue, nervousness, difficulty concentrating
Lamotrigine (lamictal) MOA and indication
Blocks Na+ and Ca++ channels
Adjunctive in children and mono therapy in adults
Indications- GTC, partial seizures, absence
Lamotrigine (lamictal) adverse side effects
Rash (10%), confusion, depression, N/V, diplopia, severe idiosyncratic (skin, blood)
Slow taper essential, initial dose dependent on other meds
Topiramate (Topamax) MOA and indication
Blocks Na+ channels and binds GABA thus opening Cl- channels
Indication- tx for partial and generalized sz in pediatrics and adults.
Topiramate (Topamax) pharmacokinetics and adverse effects
70% renal elimination 1st order kinetics Clearance increased w/ enzyme inhibitors AE- dose related- drowsiness, parasthesias, psychomotor slowing, weight loss, renal calculi NOTE- Maintain adequate fluid levels
Felbamate (felbtol) MOA and indication
Blocks Na+ channels, competes for NMDA receptor, prevents AMPA receptor stimulation, blocks Ca++ channels
Indication- partial sz and lennox-gastaut syndrome
Use restricted to refractory Lennox-Gastaut syndrome (active metabolism covalently binds liver, bone marrow proteins, and DNA resulting in aplastic anemia and liver failure.
Felbamate (felbtol) Side effects
Dose related- anorexia, N/V, insomnia, HA
Non-dose related- aplastic anemia, hepatic failure
Levetiracetam (Keppra) MOA and indication
MOA unknown
Indication- tx of generalized sz
Adjust dose in renal insufficiency
Levetiracetam (Keppra) favorable PK profile and Side effects
Almost completely absorbed
Metabolism NOT dependent on the P450 system
Minimal protein binding
MInimal drug interactions
Side effects- sedation, behavioral abnormalities
Zonisamide (Zonegran) MOA and Indication
Sulfonamide derivative: blocks Na+ and Ca++ channels and enhances GABA-receptor function
Indication- adjunctive therapy for partial sz
Zonisamide (Zonegran) pharmacokinetics and Side effects
Good oral absorption and renally and hepatically eliminated
Side effects: Dose related: sedation, dizziness, cognitive impairment, nausea
Non-dose related- rash, oligohydrosis, kidney stones
Pregabalin (lyrica) Indication and side effects
Indication- adjunctive tx for partial onset sz, peripheral neuropathy, postherpatic neuralgia, fibromyalgia syndome
Side effects- dizziness, somnolence, dry mouth, PERIPHERAL EDEMA, blurred vision, weight gain.
Topiramate (Topamax) MOA and indication
Blocks Na+ channels and binds GABA thus opening Cl- channels
Indication- tx for partial and generalized sz in pediatrics and adults.
Topiramate (Topamax) pharmacokinetics and adverse effects
70% renal elimination 1st order kinetics Clearance increased w/ enzyme inhibitors AE- dose related- drowsiness, parasthesias, psychomotor slowing, weight loss, renal calculi NOTE- Maintain adequate fluid levels
Felbamate (felbtol) MOA and indication
Blocks Na+ channels, competes for NMDA receptor, prevents AMPA receptor stimulation, blocks Ca++ channels
Indication- partial sz and lennox-gastaut syndrome
Use restricted to refractory Lennox-Gastaut syndrome (active metabolism covalently binds liver, bone marrow proteins, and DNA resulting in aplastic anemia and liver failure.
Felbamate (felbtol) Side effects
Dose related- anorexia, N/V, insomnia, HA
Non-dose related- aplastic anemia, hepatic failure
What comprises a generalized convulsive status epilepticus sz?
Repeated primary or secondary generalized
Persistant postictal state
What comprises a nonconvulsive status epilepticus sz?
Persistent state of impaired consciousness Partial sz (motor or sensory) that may not interfere w/ consciousness
Zonisamide (Zonegran) MOA and Indication
Sulfonamide derivative: blocks Na+ and Ca++ channels and enhances GABA-receptor function
Indication- adjunctive therapy for partial sz
What are the most common etiology for status epilepticus?
Low blood concentration of AED (34%) Remore symptomatic causes (24%) Cerebrovascular accidents (22%) Anoxia or hypoxia (10%) ETOH or drug withdrawal (10%)
Pregabalin (lyrica) Indication and side effects
Indication- adjunctive tx for partial onset sz, peripheral neuropathy, postherpatic neuralgia, fibromyalgia syndome
Side effects- dizziness, somnolence, dry mouth, PERIPHERAL EDEMA, blurred vision, weight gain.
What is the most important factors in choosing an anti-epileptic drug?
Tolerability and long term safety
1) If 1st AED poorly tolerated or fails to control sz what should be used?
2) If 1st AED is well tolerated but doesn’t completely control seizures what should be used?
1) alternative should be used
2) combo should be tried
What four factors are used to determine medication discontinuation?
- Sz free for 2-5 year and AED
- Pt should have single type of partial or generalized tonic-clonic sz
- Patient should have a normal neuro-exam and normal IQ test
- Patients EEG should have normalized w/ AED tx
* *Medication should be titrated off over several months if it is discontinued
How is status epilepticus (SE) defined?
Continuous or intermittent seizures lasting more than 5 minutes, without full recovery of consciousness b/w seizures.
Benzodiazepines
Act as positive allosteric modulators by enhancing channel gating in presence of GABA
Not indicated if sz already stopped or for maintenance therapy.
Benzodiazepines ADRs
Infusion rate related to arrhythmias and hypotension
Respiratory depression
Impairment of consciousness
Lorazepam (Ativan)
DOC for patient w/ IV access
Onset of action 3-5 min
Can cause vein irritation (Dilution of dose)
Lorazepam (ativan) vs diazepam (valium)
Lorazepam is preferred over diazepam secondary to duration of action
Diazepam highly lipophilic and quickly redistributes out of brain to other fat stores.
Diazepam DOA- 15 min to 2 hrs
Lorazepam DOA- 12-24 hrs
Diazepam (valium)
Rapid onset, short duration
option if IV route not available (rectally)R
Midazolam (versed)
Reserved for refractory sz
Buccal, intranasal, IM routes
Give by continuos infusion for refractory SE
Hydantoins place in therapy
Second line (loading dose) if sz continue after 2-3 doses of benzos Consider loading dose and maintenance dose if sz recur or if recurrence anticipated Initiate maintenance doses 12-14 hrs after loading dose Less CNS and respiratory depression than benzo and barbituates
Hydantoins Side effects
Arrhythmias, nystagmus, dizziness, ataxia
Phenytoin Onset of action and administration
Onset of Action- longer time to stop sz than benzos, less lipid soluable and requres slower administration
Admin- erractic absorption and pain w/ IM injections
Dilute with NS
Contains propylene glycol (result in arrhythmias, hypotension, metabolic acidosis with repeated doses)
Fosphenytoin (Cerebyx)
H20 soluble prodrug of phenytoin converted by plasma esterases
Available IM and IV
Doesn’t contain propylene glycol
Compatible with most IV solutions w/ less phlebitis
Paresthesias and pruritis are more frequent
Benzodiazepines ADRs
Infustion rate related to arrhythmias and hypotension
Respiratory depression
Impairment of consciousness
Phenobarbital
3rd line agent, if sz persists despite 2-3 doses of benzos and loading dose of hydantoin
2nd line agent if sz persists after 2-3 doses of benzos and hydantoins contraindicated
Used in pediatric patients
Onset of action w/in minutes of loading dose administration
Phenobarbital ADR
More CNS and respiratory depression than hydantoins
Contains propylene glycol
Diazepam (valium)
Rapid onset, short duration
option if IV route not available (rectally)
Midazolam (versed_
Reserved for refractory sz
Buccal, intranasal, IM routes
Give by continuos infusion for refractory SE
Hydantoins place in therapy
Second line (loading dose) if sz continue after 2-3 doses of benzos Consider loading dose and maintenance dose if sz recur or if recurrence anticipated Initiate maintenance doses 12-14 hrs after loading dose Less CNS and respiratory depression than benzo and barbituates
Hydantoins Side effects
Arrhythmias, nystagmus, dizziness, ataxia
Phenytoin Onset of action and administration
Onset of Action- longer time to stop sz than benzos, less lipid soluable and requres slower administration
Admin- erractic absorption and pain w/ IM injections
Dilute with NS
Contains propylene glycol (result in arrhythmias, hypotension, metabolic acidosis with repeated doses)
Fosphenytoin (Cerebyx)
H20 soluble prodrug of phenytoin converted by plasma esterases
Available IM and IV
Doesn’t contain propylene glycol
Compatible with most IV solutions w/ less phlebitis
Paresthesias and pruritis are more frequent
What is more frequent in fosphenytoin than in phenytoin?
Paresthesias and pruritis
Phenobarbital
3rd line agent, if sz persists despite 2-3 doses of benzos and loading dose of hydantoin
2nd line agent if sz persists after 2-3 doses of benzos and hydantoins contraindicated
Used in pediatric patients
Onset of action w/in minutes of loading dose administration
Phenobarbital ADR
More CNS and respiratory depression than hydantoins
Contains propylene glycol
