Anticonvulsants Flashcards
What is a seizure?
an abnormal, disorderly discharging of the brain’s nerve cells, resulting in a temporary disturbance of motor, sensory, and mental function
(epilepsy)
What are 10 symptoms of seizures in dogs?
- entire body convulsions
- facial tremors
- excessive drooling
- defecating
- unusual barking
- running in circles
- twitching
- biting
- urinary incontinence
- going unconsious
How do anticonvulsant drugs work? What is the goal of therapy?
block seizure initiation and propagation by blocking either abnormal events in a single neuron or the synchronization of related neurons
reduction in the firing frequency of neurons
Why are there not many human anticonvulsants approved for use in dogs and cats?
too rapidly metabolized in dogs to be effecive, even in high dosages
cats metabolize these drugs more slowly and poorly than dogs
What is the mechanism of action of anticonvulsants? In what 3 ways do they do this?
stabilize neuronal membranes evoking hyperpolarization
- activate GABA-gated Cl- channels
- bind to GABA(a) receptor and facilitate its action (agonist)
- inactivating Na+ and Ca+ conductance
What is the main therapeutic use of anticonvulsants? What are 3 common adverse effects?
reduction of incidence, severity, and duration of seizures
- rapid cessation effect of administration (rapidly cleared by liver)
- liver and serum enzyme induction (more enzymes activated at once)
- hepatotoxicity in dogs due to the higher dose needed for possible effects
What are the 4 most common drugs used as anticonvulsants?
- barbiturates
- benzodiazepines
- hydantoins
- valproic acid
What 4 unconventional drugs are used as anticonvulsants?
- Gabapentin
- Levetiracetam
- Felbamate
- Zonisamide
What is GABA? Where is it produced? What is needed for its synthesis?
(gamma aminobutyric acid)
major inhibitory NT in the CNS —> natural “valium-like” NT
mostly in the brain from glutamic acid/glutamate
vitamin B6
What does GABA play an important role in?
inhibiting or reducing the activity of neurons
- behavior
- cognition
- body response to stress
- fear and anxiety
How do GABA(a) receptors work?
GABA-gated chloride channels cause chloride (Cl-) ions to flow into their neuron when activated, causing is hyperpolarization
- inhibition!
How do barbiturates work? What 3 are most commonly used?
activates GABA-gated Cl- channels
- Phenobarbital (oxybarbiturate)
- Pentobarbital (oxybarbiturate)
- Primidone (analog of phenobarbital)
How is phenobarbital a unique barbituate? What is it usually used for?
produces an anticonvulsant effect at lower doses than those necessary to cause pronounced CNS depression (sedation)
long-term control of seizures
- NOT useful for terminating an ongoing seizure because the time span from administration until offset of effect is too long (given PO)
What are 5 adverse effects of Phenobarbital?
- sedation
- polydipsia
- polyuria
- polyphagia
- dogs develop a tolerance to sedative effects after 1-2 weeks
What kind of barbiturate is Primidone? What happens when it reaches the liver?
it is a deoxybarbiturate
rapidly metabolized into phenobarbital (active form)
Why is Primidone not used in cats?
metabolism into phenobarbital is too slow
What happens with prolonged use of Primidone in dogs?
decreased serum albumin, elevated serum concentrations of liver enzymes, liver damage
In what situation is Pentobarbital used?
status epilepticus —> seizure lasting longer than 5 mins, or having more than one seizure within a 5 min period without returning to a normal level of consciousness between episodes
- terminates seizures at a dose that produces anesthesia, rapid onset IV with short duration
What are 3 common adverse effects of Pentobarbital?
- CNS depressant
- excitement during recovery from anesthesia
- irritating when administered perivascularly
How do Benzodiazepines work as anticonvulsants? In what species are they used? What 4 are most commonly used?
facilitate inhibitory action of GABA by binding GABA(a) receptors and evoking hyperpolarization of the neurons
all domestic species
- Diazepam
- Midazepam (Zolam)
- Clonazepam
- Lorazepam
Can benzodiazepines be used to treat status epilepticus? How are they used in dogs and cats?
yes
DOGS: limited use as a maintenance anticonvulsant due to a development of tolerance because of rapid drug metabolism
CATS: can be used as a maintenance anticonvulsant
How does therapeutic uses of Diazepam as an anticonvulsant compare in dogs and cats?
DOGS: administered IV, drug of choic for the control of status epilepticus and cluster seizures
CATS: administered orally for seizure control
What are 2 adverse effects of Diazepam as an anticonvulsant?
- changes in behavior (irritability, depression, aberrant demeanor)
- cats can develop acute fatal hepatic necrosis
How does Midazolam compare to Diazepam? In what 4 situations is it used?
more potent
- status epilepticus
- muscle relaxant
- tranquilizer
- appetite stimulant
What are 4 common adverse effects of Midazolam?
- mild respiratory depression
- vomiting
- restless behavior, agitation
- local irritation
Why does Clonazepam have a limited value as a maintenance anticonvulsant? What are 2 common adverse effects?
rapid development of drug tolerance
- drug resistance
- GI disturbance, including vomiting, hypersalivation, and diarrhea/constipation
When is Lorazepam most commonly used as an anticonvulsant? What is a major benefit to this drug over other benzodiazepines?
short term at-home treatment for dogs having cluster seizures
maintenance anticonvulsant in cats
may be used safely in patients with compromised liver function and geriatric dogs because it does not produce metabolites
What are 2 common adverse effects of Lorazepam?
- increased appetite
- anxiety during early therapy
How do hydantoins work? What one is usually used as an anticonvulsant?
target sodium (Na+) channels, blocking channels from recovering from the inactive state leading to inhibition of neuron firing
Phenytoin —> derivative
What is Phenytoin use commonly impractical in dogs? What is it usually used for?
short half-life
lidocain-like effects —> treatment of digitalis-induced ventricular arrhythmias in dogs
What is valproic acid? How does it work?
derivative of carboxylic acid (structurally unrelated to other anticonvulsants)
stabilizes membranes by blocking Na+ and Ca++ channels and openining GABA-gated Cl- channels
How does usefulness of valproic acid as an anticonvulsant compare in dogs and cats?
DOG - short half-life makes long-term use impractical, but it can still be useful in controlling seizures
CAT - clinical usefulness has not been evaluated
What are 7 possible adverse effects of valproic acid?
- GI toxicity: vomiting, anorexia, diarrhea
- hepatotoxicity: liver failure in dogs
- CNS effects: sedation, ataxia, behavioral changes
- dermatologic effects: alopecia, rash
- hematologic effects: thrombocytopenia, leukopenia, anemia
- pancreatitis
- edema
How does potassium bromide work as an anticonvulsant? What is its half-life like when administered orally?
Br- enters neurons via Cl- channels causing hyperpolarization of the neuronal membrane
LONG - neither metabolized nor bound to plasma proteins (can take up to 6 months to achieve stable plasma concentrations and elimination)
Is potassium bromide used as an anticonvulsant in cats?
no
What are 5 adverse effects of potassium bromide?
- transient sedation at the beginning of therapy
- GI toxicity: nausea, vomiting, anorexia, constipation
- PD, PU, polyphagia, lethargy, irritability, aimless walking
- pancreatitis
- severe asthma in cats
What is Gabapentin? How is it usually given? What unique treatment is it also used for?
synthetic GABA analog that can cross the BBB to exert its anticonvulsant effect (MOA unknown)
PO, used as adjunctive therapy for refractory of complex partial seizures
chronic pain in dogs and cats
What are 3 adverse effects of Gabapentin? What can abrupt discontinuation cause?
- sedation
- ataxia
- mild polyphagia`
seizures
How does Levetiracetam work? What therapeutic use does it have?
inhibition of firing and propagation of seizure activity through binding synaptic protein 2A
administered orally as adjunctive therapy for refractory canine epilepsy (well tolerated in dogs and cats)
What are 2 adverse effects of Levetiracetam? What can abrupt discontinuation cause?
- GI disturbances: vomiting, anorexia
- changes in behavior, drowsiness
seizures
How does Felbamate work? How is it used?
blockade of neural excitation and potentiation of GABA mediated inhibition through inhibition of voltage-dependent Na+ and Ca++ channels
PO, adjunctive therapy for refractory canine epilepsy
When is Felbamate used as a sole anticonvulsant? When is it particularly useful?
for patients with local and generalized seizures
brain tumor or cerebral infarcts, due to no sedation effect
What is the most common adverse effect of Felbamate? What are 2 rare adverse effects?
liver dysfunction in dogs
- reversible bone marrow depression (thrombocytopenia/leukopenia) in dogs
- generalized tremor and/or keratoconjunctivitis sicca in dogs
How does Zonisamide work? When is it used as adjunctive therapy? Sole anticonvulsant?
induction of neural hyperpolarization through inhibition of voltage-dependent Na+ and Ca++ channels
refractory canine epilepsy (less often in cats)
patients with local and generalized seizures
When is Zonisamide particularly useful? What is its major benefit? What are rare adverse effects?
brain tumors or cerebral infarct (no sedation)
high safety margin in dogs and cats
sedation, ataxia, anorexia
What are 2 major drawbacks to using Zonisamide as an anticonvulsant?
- cost
- not enough data for cats
