5. Anticonvulsants Flashcards
I. Classification (Simplified) of Seizures
A. Generalized Seizures
____
____ (absence) or loss (tonic-clonic) of consciousness
1. \_\_\_\_ Carbamazepine (TEGRETOL) Phenobarbital* Phenytoin (DILANTIN) Primidone (MYSOLINE) Topiramate (TOPAMAX) Valproic Acid (DEPAKENE; DEPAKOTE)
- ____
Acetazolamide (DIAMOX)
Clonazepam (KLONOPIN) Ethosuximide (ZARONTIN) Trimethadione (TRIDIONE)
Valproic Acid (DEPAKENE; DEPAKOTE)
bilateral
reduced
tonic-clonic (grand mal)
absence (petit mal)
B. Partial Seizures (Focal)
____.
Occurs in one ____ or group of muscles.
- Simple Partial
No loss of ____. Drugs: same as for ____.
Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Tiagabine Topiramate Vigabatrin Zonisamide
(FELBATOL) (NEURONTIN) (LAMICTAL) (KEPPRA) (TRILEPTAL) (GABITRIL) (TOPAMAX) (SABRIL) (ZONEGRAN) - Complex Partial
Starts as simple: spreads to ____ area. Associated with ____.
Drugs: same as for ____.
unilateral
one
consciousness
tonic-clonic
wider
confusion
tonic-clonic
II. Seizure Production
A. Etiology
Primary: most ____
Secondary: various causes incl. head ____ & brain tumors
B. Seizure Focus
Always ____
Abnormal ____ even in seizure-free periods; diagnostic value
C. Triggering Factors
Changes in plasma ____, pH and pCO2
Emotional stress
____ changes (e.g., strobe lights, flickering TV screen)
D. Protective Effect of Anticonvulsants
Prevent spread of abnormal ____ stimuli
Stabilize neurons surrounding the seizure focus
cases
trauma
present
EEG
electrolytes
visual
electrical
Facilitate GABA Activity
- Increase ____ of Opening of GABA-A-Activated Cl- Channel
____ (e.g., phenobarbital) / ____
2.Increase ____ of Opening of GABA-A-Activated Cl- Channel ____ (e.g., clonazepam)
- Increase Synaptic ____ of GABA
____
duration
barbiturate
primidone
frequency
benzodiazepines
concentration
valproic acid
IV. Enzyme Inducers \_\_\_\_ Felbamate Phenobarbital Phenytoin Primidone Topiramate
V. Therapeutic Levels
Best correlation with efficacy: ____ plasma levels
Currently used: ____ (free + bound)
Take a look at the table!
carbamazepine
free [unbound]
total
FREE fraction > normal in:
- ____ disease (esp. renal failure)
- ____ disease
- critically ill ____ pts
- or any other condition associated with ____
renal
liver
trauma
hypoalbuminemia
Warnings for Antiepileptic Medications
Increase in ____ on some of these drugs too
suicide
PK (Pharmacokinetic) Data
These are inducers. These other drugs are mainly renaly excreted which means that the doctor needs to know if they’re on kidney disease. If low GFR and if the drug is not highly biotransformed then the ____ is responsible for metabolism. If highly biotransformed then the ____ is responsible for metabolism. Impacts on prescriber to check all medical issues.
High protein binding. 80%+ bound to protein is at risk of interaction because that means that 20% is free. ____ are important to know- bound about 98% to plasma protein meaning only 2% is producing therapeutic affect. If knocked off by another drug and then at 4% because other drug is interacting at protein, then you’re effectively ____ the effect of the drug.
kidney
liver
oral anticoagulants
doubling
BARBITURATES
____
Metharbital(GEMONIL) [N-methylbarbital -> barbital] Mephobarbital (MEBARAL) [N-methyl phenobarbital -> phenobarbital]
ADRs
Sedation
Confusion
Dizziness
Ataxia (muscle incoordination) Blurred vision
Anxiety
Insomnia
Agitation
Hyperkinesia (increased activity)
Rash
____ deficiency
- -Osteomalacia
- -Rickets
____ Deficiency
–Anemia
\_\_\_\_ Deficiency (in neonate born to mother taking these drugs) --Increased bleeding
phenobarbital
vitamin D
folic acid
vitamin K
Barbiturate-Related \_\_\_\_ (MYSOLINE) Parent compound (primidone) is active; also two active metabolites: - \_\_\_\_ - \_\_\_\_
Uses
Similar to barbiturates
ADRs
Similar to barbiturates
primidone
phenylethylmalonamide
phenobarbital
HYDANTOINS \_\_\_\_ (DILANTIN) Mephenytoin (MESANTOIN) \_\_\_\_ (PEGANONE) Less \_\_\_\_ effects than barbiturates Also used as anti-arrhythmic agent
ADRs
____ vision
Weakness / Dizziness / ____ / Drowsiness
phenytoin ethotoin sedative blurred confusion
HYDANTOINS
Nystagmus: > ____ ug/mL plasma*
Ataxia: > ____ ug/mL plasma*
Lethargy: > ____ ug/mL plasma*
* at these levels, biotransformation becomes ____ order: - a small increase in dose will produce a much ____
elevation of plasma level (very disproportionate)
20 30 40 zero larger
HYDANTOINS
ADRs
Hallucinations / Hyperactivity Peripheral neuropathy
____ (drug withdrawal does not cause reversal)
Hirsutism
N & V / Epigastric pain / Anorexia
Decreased insulin secretion = hyperglycemia & glycosuria
____: hypocalcemia due to induced Vitamin D deficiency
Hypersensitivity reaction: ____ Syndrome
- severe–can be ____–form of erythema multiforme - if this rash occurs, must D/C immediately
____ Reactions Leukopenia
Thrombocytopenia
Anemia
Hypoprothrombinemia due to induced Vitamin K deficiency
Liver damage
gingival hyperplasia osteomalacia stevens-johnson fatal hematological
HYDANTOINS
Enzyme Induction
Chronic administration usually produces enzyme induction:
- plasma levels ____
- pt experiences increased frequency of ____
- small increase in dose may re-establish ____ level
Monitoring
Plasma levels of ____ phenytoin provide best parameter for management of pts.
Levels in ____ correlate more reliably to concentations of free phenytoin in plasma than to total phenytoin in plasma.
Use of only the total phenytoin level may cause intoxication.
decrease
seizures
therapeutic
free
brain
HYDANTOINS
Pediatric monitoring
Can use saliva levels:
- very ____ protein
- no ____
Excellent correlation with free phenytoin levels Saliva phenytoin ---------------- Plasma phenytoin = (1.39/1.00)
- higher levels in ____ due possibly to active transport of phenytoin from blood —> saliva
Advantages for pediatric monitoring include:
- can be performed at ____
- daily measurement
- no ____
- improvement in compliance
- enhanced ____ relationship
low
albumin
saliva
home
trauma
SUCCINIMIDES
Ethosuximide (ZARONTIN)
Phensuximide (MILONTIN)
ADRs \_\_\_\_ depression similar to barbiturates Parkinson-like reactions \_\_\_\_ (increased sensitivity to light) Anemia
CNS
photophobia
BENZODIAZEPINES
____ (KLONOPIN)
Clorazepate (TRAXENE)
____ (VALIUM)
Development of ____ limits use
ADRs
CNS depression similar to–but less intense than–barbiturates Wider margin of ____
Generally less ____ depression than barbiturates
clonazepam diazepam tolerance safety respiratory
Carbamazepine (TEGRETOL)
Regarded by many neurologists as DOC in ____
Also used in:
- pain (tic doulourex)
- ____ disorders (e.g., schizophrenia, bipolar)
ADRs CNS depression: similar to barbiturates Ataxia \_\_\_\_ vision Agranulocytosis Rash \_\_\_\_ (possibly due to water retention)
partial seizures
psychiatric
double
hypertension
Felbamate (FELBATOL)
Effective in ____: monotherapy + polytherapy (phenytoin or carbamazepine)
- induces enzymes
- lowers ____ & phenytoin levels
Also efficacious in pts with ____ syndrome
- occurs in childhood
- multiple seizure types + mental retardation
- refractory to standard ____ drugs
ADRs
____ / blurred vision
N & V / anorexia
____
partial seizures
carbamazepine
lennox-gastaut syndrome
anticonvulsant
double
insomnia
Keppra® (levetiracetam)
Ethyl-2-oxo-1-pyrrolidine acetamide.
____ unrelated to existing antiepileptic drugs (AEDs).
Mechanism of Action
Precise mechanism(s) by which levetiracetam exerts its
antiepileptic effect is \_\_\_\_.
In vitro and in vivo recordings of epileptiform activity from hippocampus show it inhibits burst firing without affecting normal neuronal excitability – may selectively prevent both:
● hypersynchronization of ____ burst firing
● propagation of ____ activity.
chemically
unknown
epileptiform
seizure
Keppra (levetiracetam)
Did not demonstrate binding affinity for variety of known
receptors:
● \_\_\_\_
● \_\_\_\_
● \_\_\_\_
No effect on neuronal voltage-gated ____ or T-type calcium
currents
Shown to block negative modulators of \_\_\_\_- and glycine-gated currents. Partially inhibits \_\_\_\_-type calcium currents in neuronal cells. -> reduced \_\_\_\_ release Effective as adjunctive therapy in adult patients with refractory partial onset seizures with or without secondary generalization.
GABA glycine NMDA (N-methyl-D-aspartate) sodium GABA N NT
Keppra (levetiracetam)
This chart shows whats taking effect. Reduction in dosage when there is a decrease in kidney function. Not as much biotransformation. If the organ isn’t functioning well theres an issue. Low biotransformation means its processed in ____. (said this a few times) High biotransformation takes place in the ____.
kidney
liver
Valproic Acid (DEPAKENE) DEPAKOTE: enteric-coated product Mechanisms: 1. Blockade of \_\_\_\_+ channel 2. Inhibition of \_\_\_\_ (catabolic GABA enzyme)
ADRs
Sedation / Ataxia
Tremor
N & V / Anorexia
____:
- can be fatal!
- > 60 deaths have already occurred
- generally occurs within ____ months of initiation of therapy
- may be ____ if therapy terminated in time
Plasma Protein Binding
Valproic acid is highly ____ bound.
Free levels increase:
- as dose ____ (disproportionate)
- when competing drugs are added to therapy (e.g., ____)
Na
GABA transaminase
hepatotoxicity
six
reversible
protein
increase
ASA
WITHDRAWAL of ANTICONVULSANT THERAPY
Can be considered for some pts
if seizure-free for at least ____ years. Must be withdrawn ____ (i.e., over a ____-month period).
% of ____ remaining seizure-free (70-90%) > % of adults(60-65%)
Best chance of success includes pt with:
- no mental ____
- ____
2
slowly
6
children
retardation
monotherapy
EPIDOLEX Contains \_\_\_\_ (CBD). Oral solution: 100 mg/mL
Approved for two potentially fatal forms of severe childhood epilepsy:
- ____ syndrome
- ____ syndrome in pts 2 years of age and older.
DOSAGE AND ADMINISTRATION
Due to risk of hepatocellular injury, obtain serum ____ (ALT
and AST) and total bilirubin levels in all patients prior to starting treatment with Epidiolex
Obtain serum transaminases(ALT and AST) and total bilirubin levels in all patients prior to starting treatment.
Recommended starting dosage: ____mg/kg BID (5mg/kg/day).
After one week, dosage can be increased to maintenance dosage of 5
mg/kg BID
cannabidiol
lennox-gastaut
dravet
transaminases
2.5
EPIDOLEX
CLINICAL PHARMACOLOGY
Precise mechanisms by which EPIDIOLEX exerts its anticonvulsant effect
in humans are unknown.
Cannabidiol does not appear to exert its anticonvulsant effects through interaction with receptors.
Elimination T1/2 – approx. ____ hours.
BIOTRANSFORMATION
Highly biotransformed by ____ and CYP3A4 enzymes
Moderate or strong inhibitors & inducers of ____ or CYP2C19 may require dosage adjustments.
ADRs
Most common (10% or more): ____; decreased appetite; diarrhea;
transaminase elevations; fatigue, malaise, and asthenia; rash;
insomnia, sleep disorder, poor quality sleep; and infections..
cannabinoid 60 CYP2C19 CYP3A4 somnolence
TERATOGENICITY
Anticonvulsant-____ epilepsy > non-____ epilepsy > normal
Teratogens include:
- ____ (possible “Fetal Benzodiazepine Syndrome”)
- ____ (“Fetal Hydantoin Syndrome”)
- ____ (“Fetal Valproate Syndrome”)
____ > benzodiazepines
____ (2 or more anticonvulsant drugs) > monotherapy
- benzodazepines may ____ valproate teratogenicity
treated
treated
benzodiazepines
phenytoin
valproic acid
valproic acid
polytherapy
enhance
Valproic Acid Cases
1. At 12 weeks gestation:
- serum alpha-fetoprotein [AFP] level = ____ mmol/L [N = < 20]
AFP is plasma protein produced by fetal tisues (e.g., liver, GI)
also by neoplastic tissue in adults (can be employed to monitor efficacy of chemotherapy)
during pregnancy, some AFP normally crosses placental barrier
____ levels are elevated in amniotic fluid and maternal blood when fetus has neural tube defect
some states in USA mandate that a pregnant woman is to be notified of possible neural tube defect
90
AFP
Valproic Acid Cases
At 33 weeks gestation:
- myelomeningocele & ____ verified by ultrasound
- parents rejected option of abortion
At 38 weeks gestation:
- ____ delivery
- open lumbosacral myelomeningocele
- sensorimotor deficits from L-3 down
- hydrocephalus required ventriculo-peritoneal shunt (day 7)
- dysmorphic features (chromosomal investigation was ____)
At two years of age:
- severe psychomotor retardation with autistic traits
- no speech ____
hydrocephalus
C-section
normal
development
STATUS EPILEPTICUS
According to the Epilepsy Foundation of America, status epilepticus is more than ____ minutes of:
1. “continuous ____ activity”
or
2. “two or more ____ seizures without full recovery of consciousness between seizures.”
Causes Include--but NOT limited to--the following: - medication change - fever/infection (children > adult) - \_\_\_\_ infection (children > adults) - \_\_\_\_ (includes alcohol) related (adults > children) - head trauma - brain tumors (adults > children)
30 seizure sequential CNS drug
STATUS EPILEPTICUS
Treatment
1. ____
- Muscle paralysis
- only ____ use of short-acting neuromuscular blocker
- NOT effective in terminating seizure activity in brain:
- abnormally increased CNS activity continues
- can result in ____ brain damage if not stopped - ____
- usually ____ occurs first
- induces secretion of insulin
- secondary ____ (usually > 2 hrs after attack begins) - need determination of blood glucose level
- if hypoglycemia is present–or glucose level can not be
determined–glucose should be administered - Blood Pressure
- usually ____ occurs first (first 30-45 min) - hypotension may occur later
- may lead to reduced cerebral perfusion
- potentiation of excitotoxic brain damage
- support BP (if necessary with vasopressors)
oxygenation
acute
permanent
glucose
hyperglycemia
hypoglycemia
hypertension
STATUS EPILEPTICUS (continued)
- Anticonvulsants
____
DOC if pt is currently convulsing (acute management)
Diazepam*
High ____ solubility (oral!) —-> rapid entrance into brain
Rapid ____: brain & plasma levels fall
quickly
____ can recur within 10-20 minutes
May cause respiratory depression & hypotension
Can be given by ____ solution (not suppository) when seizures begin at home.
benzodiazepines lipid redistribution seizures rectal
STATUS EPILEPTICUS (continued)
5. Anticonvulsants Benzodiazepines
DOC if pt is currently convulsing (acute management)
Lorazepam* Less \_\_\_\_ soluble Longer \_\_\_\_ of action Clinical study indicated that efficacy = \_\_\_\_ Same ADRs
Midazolam
High frequency of respiratory ____
Rapid & complete absorption after IM administration
lipid
duration
diazepam
depression
STATUS EPILEPTICUS (continued)
5. Anticonvulsants Benzodiazepines
DOC if pt is currently convulsing (acute management)
Phenytoin*
DOC if pt has stopped ____
Can be added to benzodiazepines
Longer ____ of action than benzodiazepines ADRs include:
- ____
- cardiac disturbances
- less respiratory depression & sedation than benzodiazepines and phenobarbital
Phenobarbital Older drug used for many years Efficacy = combination of \_\_\_\_ ADRs include: - significant \_\_\_\_ - " respiratory depression - " hypotension
- ____ routes of administration for certain benzodiazepines and phenytoin are unreliable; therefore, NOT recommended.
convulsing onset hypotension diazepam + phenytoin sedation IM
A relatively good prognosis of SE is found when the underlying cause is associated with low ____ drug levels or ____ abuse
antiepileptic
alcohol
