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3-25 Antiepileptics 2
n/a
126
Pharmacology
Graduate
03/31/2010

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Cards

Term
what are the 3 major classes of anticonvulsants?
Definition
1. Na channel inactivators
2. GABAergic agents
3. Ca channel blockers
Term
how do Na channel inactivators work to treat epilepsy?
Definition
prolong Na channel refractory period
Term
indications for Na channel inactivators?
Definition
1. generalized tonic-clonic
2. focal (partial)
Term
Na channel inactivators used to treat epilepsy (6)
Definition
1. carbamazepine
2. phenytoin
3. valproic acid
4. lamotrigine
5. topiramate
6. zonisamide
Term
Na channel inactivators are also used to treat migraine (2)
Definition
1. topiramate
2. zonisamide
Term
*mechanism of action for carbamazepine?
Definition
prolongation of Na channel inactivation
Term
what is the drug of choice for focal onset (partial) seizures?
Definition
carbamazepine
Term
*indications for carbamazepine?
Definition
*drug of choice for focal onset (partial) seizures

generalized tonic-clonic
Term
original use of carbamazepine?
Definition
trigeminal neuralgia (tic doloureaux)
Term
other effects of carbamazepine (5)
Definition
1. anticholinergic, neuromuscular-blocking, muscle relaxant
2. central anti-diuretic
3. anti-arrhythmic
4. antidepressant
5. sedative
Term
adverse effects of carbamazepine (4)
Definition
1. resp depression
2. CNS - nystagmus, diplopia, tiredness, drowsiness, vertigo, headache
3. hepatotoxicity
4. agranulocytosis
Term
mechanism of action of phenytoin?
Definition
*prolongation of Na channel inactivation
Term
indications for phenytoin?
Definition
generalized tonic-clonic and focal (partial) seizures

*NOT absence seizures
Term
pharmacokinetics of phenytoin?
Definition
zero order kinetics

one of the few drugs for which a constant amount of drug is eliminated per unit time
Term
does phenytoin have a sedative effect?
Definition
*NO

unlike phenobarbital
Term
*contraindications for phenytoin
Definition
1. sinus bradycardia, heart block (complete or partial)
2. hypoglycemic seizures
Term
what is fosphenytoin sodium?
Definition
water soluble phosphorylated form of phenytoin

converted to phenytoin by phosphatases
Term
fosphenytoin sodium use?
Definition
status epilepticus
Term
why is fosphenytoin sodium preferred over phenytoin?
Definition
*no phlebitis

can cause arrhythmia
Term
fosphenytoin sodium administration?
Definition
IV/IM
Term
what type of seizures can phenytoin not be used for?
Definition
absence seizures
Term
is phenytoin water soluble?
Definition
NO

precipitates in dextrose and saline
Term
what is phlebitis?
Definition
inflammation at the injection site
Term
what drug can be used in place of phenytoin to reduce the phlebitis?
Definition
fosphenytoin sodium
Term
*phenytoin adverse effects (8)
Definition
1. painful phlebitis
2. gingival hyperplasia
3. excessive hair growth
4. double vision
5. accelerates hepatic degradation of glucocorticoids
6. megaloblastic anemia
7. ataxia and nystagmus
8. osteomalacia
Term
what is an adverse effect of phenytoin when give IV?
Definition
painful phlebitis
Term
how does phenytoin cause gingival hyperplasia?
Definition
altered collagen metabolism leads to thickened, inflamed gums in 20% of patients; can't eat properly
Term
what is hypertrichosis seen with phenytoin use?
Definition
excessive hair growth where hair is normally present
Term
what is hirsutism associated with phenytoin use?
Definition
excessive hair growth in places there is usually no hair
Term
what drug causes alopecia?
Definition
valproic acid
Term
why does phenytoin lead to double vision?
Definition
causes weakness of EOM
Term
a patient taking glucocorticoids is started on phenytoin. the effect of the glucocorticoid is diminished. why?
Definition
*phenytoin accelerated hepatic degradation of glucocorticoids
Term
how does phenytoin lead to osteomalacia?
Definition
1. inhibition of intestinal absorption of Ca
2. catabolism of vitamin K and reduction in vitamin K-dependent proteins for normal Ca metabolism in bone
Term
what is osteomalacia?
Definition
hypocalcemia + elevated alkaline phosphatase activity
Term
why is phenytoin-induced osteomalacia not always ameliorated by the administration of vitamin D?
Definition
due to the catabolism of vitamin K and reduction in vitamin K-dependent proteins for normal Ca metabolism in bone
Term
why would a patient taking phenytoin be more likely to undergo a fracture?
Definition
osteomalacia is an adverse effect
Term
*mechanism of action of valproic acid/valproate sodium?
Definition
1. prolongation of Na channel inactivation
2. increase GABA synthesis; decrease GABA breakdown
3. blocks T type Ca channels
Term
valproic acid/valproate sodium indications?
Definition
*very broad spectrum of action

*focal (partial), generalized tonic-clonic, absence, myoclonic
Term
valproic acid/valproate sodium side effects (4)
Definition
1. thrombocytopenia
*2. alopecia
3. hepatotoxicity
*4. acute pancreatitis
Term
valproic acid/valproate sodium contraindications
Definition
1. bleeding disorders
2. hepatic disease/dysfunction
3. pregnancy - possible teratogen
Term
receptor type of GABAa receptor?
Definition
ligand gated chloride channel
Term
subunits of GABAa receptor?
Definition
alpha, beta, gamma
Term
where does GABA bind the GABAa receptor?
Definition
between the alpha and beta subunits
Term
what happens after GABA binds to the GABAa receptor?
Definition
channel opens --> Cl influx into the neuron --> hyperpolarizes neuron --> inhibits propagation and generation of AP
Term
receptor type of GABAb?
Definition
metabotropic - G protein coupled receptor
Term
what 2 types of drugs also bind to the GABAa receptor?
Definition
benzodiazepines and barbiturates
Term
mechanism of action of benzodiazepines and barbiturates?
Definition
similar to GABA - bind and directly activate GABAa channel --> hyperpolarize neuron
Term
where do benzodiazepines bind on the GABAa receptor?
Definition
alpha and gamma subunits
Term
where do barbiturates bind on the GABAa receptor?
Definition
only alpha subunit
Term
what enzyme produces GABA from glutamic acid?
Definition
glutamic acid decarboxylase
Term
what is the co-enzyme for glutamic acid decarboxylase?
Definition
pyridoxal phosphate
Term
what drug can deplete pyridoxal phosphate?
Definition
isoniazid
Term
GABA is degraded to what?

what is the importance of this degradation product?
Definition
succinic acid

it has a negative feedback on the rate-limiting enzyme in GABA synthesis (glutamic acid decarboxylase)
Term
the date rape drug acts like what NT to cause retrograde amnesia?
Definition
GABA
Term
patient has a head injury and loses consciousness. when they regain consciousness, they don't remember anything about the event.

this is known as ____ and is due to what?
Definition
retrograde amnesia

due to GABA activation
Term
what are the 3 effects of GABA?
Definition
1. anticonvulsive
2. anxiolytic
3. amnestic (retro and anterograde)
Term
how does valproic acid stop GABA synthesis?
Definition
inhibits succinic semialdehyde dehydrogenase

succinic acid can't be produced --> can't negatively feedback on glutamic acid decarboxylase --> more GABA is produced
Term
how does GABA work to cause hyperpolarization?
Definition
at the pre-synaptic axon, Na influx leads to GABA release

GABA binds receptor on post-synaptic neuron --> Cl ions influx --> hyperpolarize the neuron --> an AP can't be generated
Term
where are GABAa receptors located?
Definition
cerebral cortex > limbic system > cerebellum, spinal cord
Term
what drugs work to increase GABA synthesis?
Definition
*valproic acid
vigabatrin
Term
what drug works to increase GABA release?
Definition
gabapentine
Term
what drug works to block GABA reuptake?
Definition
tiagabine
Term
what drug works to decrease GABA breakdown?
Definition
vigabatrin
Term
what drugs are GABA receptor agonists?
Definition
*lorazepam, diazepam
clonazepam
*phenobarbital
topiramate
Term
what are the 2 ways to terminate the action of GABA?
Definition
degrade it or take it back up into the cell that released it
Term
what are the prototype GABA agonists?
Definition
benzodiazepines
Term
mechanism of action of phenobarbital?
Definition
*GABA receptor stimulation; Ca channel inhibition
Term
indications for phenobarbital?
Definition
*generalized tonic-clonic, focal (partial), myoclonic, neonatal, status epilepticus
Term
why is phenobarbital the most widely used anti-epileptic?
Definition
because of efficacy, low toxicity, and low cost
Term
what anti-epileptic can be used in children <2 years of age?
Definition
phenobarbital
Term
adverse effects of phenobarbital?
Definition
*sedation
nystagmus, ataxia
*respiratory depression
megaloblastic anemia
hypoprothrombinemia with hemorrhage in neonates with maternal treatment
Term
how do you treat phenobarbital-induced megaloblastic anemia?
Definition
folate
Term
how do you treat phenobarbital-induced hypoprothrombinemia with hemorrhage in neonates with maternal treatment?
Definition
vitamin K
Term
what 2 side effects of phenobarbital stop its widespread use?
Definition
*sedation
resp depression
Term
what is the only type of seizure that phenobarbital can not be used to treat?
Definition
absence
Term
primidone is metabolized to what?
Definition
phenobarbital
Term
primidone properties?
Definition
anticonvulsant and sedative

like phenobarbital
Term
primidone use?
Definition
*effective in all types of seizures EXCEPT ABSENCE
Term
adverse effects of primidone?
Definition
same as phenobarbital - sedation, resp depression
Term
how do Ca channel blockers work in treatment of seizures?
Definition
reduce pacemaker Ca currents in thalamic neurons
Term
what is the unique drug for absence epilepsy?
Definition
*ethosuximide
Term
patient has epilepsy with no convulsions, very brief loss of consciousness following it. what is the treatment?
Definition
*ethosuximide
Term
what 2 drugs block T type voltage gated Ca channels?
Definition
1. valproate sodium
2. ethosuximide
Term
mechanism of action of ethosuximide?
Definition
*reduction of T-type Ca currents in the thalamus
Term
ethosuximide indications?
Definition
*drug of choice for absence epilepsy
Term
what is the drug of choice for absence epilepsy?
Definition
ethosuximide
Term
ethosuximide adverse effects?
Definition
blood - leukopenia, thrombocytopenia, aplastic anemia due to BM depression

skin - reactions, SLE, urticaria, pruritis
Term
ethosuximide contraindications?
Definition
hepatic or renal disease

safety in pregnancy or children <3 years had not been established
Term
top 3 first line drugs used for all different types of focal onset seizures?
Definition
1. carbamazepine
2. phenytoin
3. valproate
Term
3 antiepileptics also used to treat migraines?
Definition
1. lamotrigine
2. topiramate
3. zonisamide
Term
3 drugs used to treat absence seizure?
Definition
1. ethosuximide
2. valproate
3. lamotrigine - newer
Term
what is a newer drug used in all forms of generalized epilepsy?

what is important about it's administration?
Definition
lamotrigine

not effective alone; has to be administered as an adjunct drug
Term
what is the first line drug for myoclonic seizures?
Definition
valproate
Term
side effects of lamotrigine (5)
Definition
*1. visual disturbance
2. sedation
3. ataxia
4. skin rash
5. dyspepsia
Term
side effects of topiramate?
Definition
*1. diplopia
*2. renal calculi
*3. weight loss
*4. neuropathy

somnolence, dizziness, ataxia, nystagmus, irritability, nausea, dyspepsia, hypohydrosis, hyperthermia
Term
side effects of zonisamide?
Definition
somnolence, confusion, ataxia, anorexia, nausea, vomiting, rash, *renal calculi
Term
how does status epilepticus manifest?
Definition
*multiple grand mals in succession or prolonged grand mal with no recovery of consciousness
Term
how long can status epilepticus last?
Definition
may last up to 30 min
Term
treating status epilepticus is important because?
Definition
it is a medical emergency
Term
what is the first step in treating status epilepticus?
Definition
maintenance of airway
Term
what is the first thing given to a patient with status epilepticus?
Definition
'coma cocktail' with 50% dextrose and 100 mg thiamine
Term
why is dextrose given to a patient with status epilepticus?
Definition
to replenish glucose for neurons and to rule out hypoglycemia as a cause of seizure
Term
why is thiamine given to a patient with status epilepticus?
Definition
to prevent encephalopathies

especially in malnourished patients like alcoholics
Term
if seizures in status epilepticus continue despite IV dextrose, what can be concluded?
Definition
seizure is not due to hypoglycemia
Term
if a patient with status epilepticus continues to seize despite IV dextrose, what is the drug of choice next?
Definition
lorazepam or diazepam (a benzodiaziapine)

used before/over phenytoin to avoid side effects
Term
why would lorazepam be chosen over diazepam to treat status epilepticus?
Definition
because it has a slightly longer duration
Term
if a patient with status epilepticus doesn't respond to the first dose of lorazepam (or diazepam) what should you do next?
Definition
give another dose after 10 min
Term
when do you give fosphenytoin or phenytoin to a patient with status epilepticus?
Definition
REGARDLESS of response of patient to lorazepam (or diazepam)
Term
why would you give fosphenytoin rather than phenytoin in status epilepticus?
Definition
phenytoin precipitates in dextrose-saline and causes phlebitis
Term
if convulsions continue in a patient with status epilepticus despite fosphenytoin what does the patient have?
Definition
refractory status epilepticus
Term
treatment for refractory status epilepticus?
Definition
intubation and artificial ventilation

followed by a general anesthetic (midazolam or propofol) + phenobarbital
Term
what 4 drugs given for refractory status epilepticus require intubation?
Definition
1. phenobarbital
2. midazolam
3. propofol
4. pentobarbital
Term
treating a patient for refractory status epilepticus requires what?
Definition
intubation
Term
what is the definitive antiepileptic drug for status epilepticus?
Definition
fosphenytoin

can't treat immediately due to side effects
Term
what are the goals of pharmacotherapy of epilepsy?
Definition
1. prevent further attacks
2. achieve 3 seizure-free years
3. then gradually withdraw drugs, one by one
Term
what is the risk of drug reaction compared to the risk of a second seizure in a patient with a history of a solitary seizure?
Definition
the same - 15%

don't start treatment right away - if they have another one then it's definitely epilepsy
Term
when do you not initiate anti-seizure therapy for a patient that presents with a history of a solitary seizure?
Definition
1. healthy young adult
2. no family history of epilepsy
3. normal neuro exam
4. normal EEG
5. normal brain MRI scan
Term
when do you consider anti-convulsant therapy for a patient that presents with a history of a solitary seizure?
Definition
1. positive family history of epilepsy
2. abnormal neuro exam
3. abnormal EEG
4. abnormal MRI
Term
if a patient that presents with a history of a solitary seizure has any risk factors or symptoms for epilepsy, what is the risk of seizure recurrence?
Definition
60%
Term
what are the first line drugs for focal or generalized onset tonic-clonic seizure?
Definition
carbamazepine
phenytoin
valproic acid
Term
how are the different drugs used in treating focal or generalized onset tonic-clonic seizures?
Definition
1. use a first line drug
2. if seizures continue despite max tolerated dose - add second drug
3. gradually withdrawal the first
4. use new drugs as adjunctive therapy
Term
what is the drug of choice for absence seizures?
Definition
*ethosuximide
Term
what is the drug of choice for myoclonic seizures?
Definition
*valproic acid
Term
should dosing for antiepileptics be based on serum levels? why or why not?
Definition
NO

many patients require and tolerate 'toxic' levels for therapeutic effect
Term
what must you monitor with anti-epileptic therapy?
Definition
1. CBC at least annually
2. liver function tests - carbamazepine, valproic acid
3. serial blood counts - carbamazepine, ethosuximide
Term
how can drug therapy for epilepsy affect chances of getting status epilepticus?
Definition
poor compliance may precipitate status epilepticus
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