Anticonvulsants Flashcards
what is a seizure? what may be accompanied by them
- A sudden, intense electrical discharge in the thalamocortex
- Goal-directed behaviours not
possible - May or may not be accompanied by motor movement
what are convulsions? what may they be associated with
- A generalized tonic-clonic motor
seizure - Clonus = alternating, rapid contraction & relaxation (e.g., paddling)
- Tonus = increased muscle tone
- May be associated with epilepsy or other disorders (hypoglycemia, hyperthermia, hypoxia, etc.)
what is status epilepticus? length? what damaging effects can occur?
- A series of seizures in rapid succession
- No intervening periods of consciousness
- Lasts 30+ min.
- Hyperthermia, brain damage, death possible
focal vs generalized seizures
Focal seizure (a.k.a. partial seizure, “petit mal” seizure, etc.)
* Often unilateral involvement of cerebrum
* Mild abnormalities that may be difficult to notice (e.g., sensory abnormality, altered consciousness)
Generalized seizure (formerly “grand-mal”)
* Loss of consciousness (usually)
* Bilateral involvement of cerebrum
* Usually tonic-clonic motor activity
what is epilepsy? what occurs with it?
Recurrent, spontaneous impairment of brain function
- Loss of consciousness (almost always)
- Abnormal motor phenomena (usually)
- Mental or sensory disturbances
what is the most commonly used drug in vet med for long term prevention of seizures?
phenobarbitol
what is the goal of anticonvulsant drugs
Goal is to reduce frequency & severity of seizures, not abolish
what drug can also be used in addition to/instead of phenobarbitol
KBr
Levetiracetam, gabapentin, and a few other drugs are sometimes used in combination with one of the above
can you use diazepam in cats
no, hepatic toxicity is likely
what is the drug used to stop almost all seizures? when does tolerance develop?
One main drug used in almost every
case to stop seizures: diazepam
Tolerance develops to diazepam
within ~1-2 months = cannot be used for long term seizure control
why do we use so few anticonvulsant drugs in animals?
1) Many anticonvulsants are metabolized very differently in dogs & cats (e.g., T1/2 of valproic acid in humans is ~15-20 h, in dogs it is 1-3 h); such drugs would require numerous daily doses = burdensome on the client; rarely used except as adjunctive therapy
2) Different adverse effects preclude use of some drugs in dogs & cats that are commonly used in humans (e.g., diazepam-induced hepatotoxicity in cats)
3) Cost: anticonvulsants are often
required for life and some are very expensive (hundreds of dollars per month)
what are some considerations regarding anticonvulsant therapy in companion animals? (7)
- Responses can vary considerably between patients. Each animal is unique regarding the characteristics of its disease and its response to medication
- Achieving steady-state concentrations takes a long time because of the exceptionally long half-lives (weeks to months) of the drugs
- Periodic rechecks should be scheduled to assess efficacy & safety
- Owners should keep a log
- Monitoring plasma concentrations (when possible) can greatly assist drug regimen design
- Discontinue or change drugs GRADUALLY to avoid rebound seizure activity
- Combination drug therapy may give better results and fewer prominent adverse effects (lower dosages of each drug)
what is the #1 anticonvulsant in dogs and cats
phenobarbitol
MOA of phenobarbitol
Facilitates the action of GABA at its receptor = hyperpolarizes neurons
why does half life of phenobarbitol change in dogs
In dogs, half-life decreases with duration of therapy due to induction of P450 enzymes
half life of phenobarbitol in dogs
~48 h, range 20-140 h
how do you compensate phenobarbitol dose in dogs as time goes on
Because of the induction of hepatic P450 enzymes by PB in dogs (much less so in cats), the dosage must be increased gradually throughout life to compensate
If the dog lives long enough it may eventually require a dosage that is hepatotoxic = before this happens, add an adjunct or switch to KBr
advantages of phenobarbitol (4)
- Effective in controlling seizures in many species
- Inexpensive
- Best outcomes of any monotherapy in canine & feline epilepsy (effective as monotherapy in 60-90% of animals)
- Q12h administration
disadvantages of phenobarbitol (5)
- Sedation (usually lasts ~ 2 weeks, but variable)
- Polydipsia, polyuria, polyphagia, vomiting (mainly dogs; may persist)
- Blood levels may stabilize after ~14 days (dogs) but highly variable; ~9 days (cats)
- PB induces cytochrome P450 in dogs (much less so in cats)
*Potential hepatotoxicity (dogs). Due to drug tolerance= must increase dosage periodically, may eventually require a toxic dosage
when giving phenobarbitol, blood levels should be ____
monitored
- Target plasma concentration 65-180 μmol/L
- Measure after 2 weeks then every 6 to 12 months
why cant you stop anticonvulsant drugs suddenly
can cause seizures
what drug is contraindicated in cats
KBr is contraindicated in cats (30-50% develop an asthma-like condition that can be fatal)
why would you use phenobarbitol in large animals
Phenobarbital ia used short-term
only, for seizures associated with:
* Head trauma
* Lead poisoning
* Polioencephalomalacia
mechanism of action of KBr
Br- hyperpolarizes membranes by
flowing through chloride channels in
neuronal plasma membranes (inhibits AP)
advantages of KBr (4)
- Anti-epileptic effect sometimes as
good as phenobarbital - Br- is not metabolized in the liver
-> excreted in urine
-> no hepatic toxicity, no changes in
dosage required over time once
patient is stable - Inexpensive
- Q24h administration
disadvantages of KBr
Narrow therapeutic index
CNS depression:
- hind limb ataxia, dizziness
lethargy, sedation
- small % of dogs highly sensitive
-> intolerable degree of sedation more common than with PB Tx
how long does it take to titrate dose of KBr to correct level
- Takes months to titrate dose to
correct level
-> T1/2 ~24 days (dogs)
Some clinicians will not use KBr because of the time required to determine the appropriate dosage for each patient (>3 months)
what should you avoid changes in diet wise when giving KBr?
- The body treats Br- same as Cl-
= increased NaCl intake leads to
increased Br- excretion (e.g., diets that prevent bladder calculi)
= changes in dietary Cl- should be
avoided - KBr falsely elevates Cl- on blood profile
what is the mechanism of levetiracetam? when is it used?
- Mechanism unknown
- Often used in combination with
PB in dogs & cats (ineffective alone in humans for the control of epileptic seizures; may or may not be effective alone in other species) - May allow reduction of dose of other anticonvulsants
- Usually requires TID admin
gabapentin; MOA, well tolerated in what species, what does it often require
- Synthetic analogue of the inhibitory neurotransmitter GABA
- Well tolerated in dogs & cats
- Often requires TID therapy
- May allow reduction of dose of
other anticonvulsants
can diazepam be used long term in dogs? why or why not?
Cannot be used long-term in dogs
because of short T½ 3-4 times/day
therapy, and development of tolerance within 1-2 months then not effective in emergencies
what is a second option if diazepam fails? what can you try after that if it doesnt work?
-IV phenobarbital is often the second option after diazepam fails
-If that fails, can try general
anesthetics (propofol, inhalant, etc.)
why are primidone, phenytoin and clonazepam not indicated for use in animals?
Primidone (a phenobarbital precursor) -> Hepatic toxicity worse than with PB
Phenytoin
* Half-life in dogs too short to be useful (3-4 h)
Clonazepam
* Ineffective after 1-2 months (tachyphylaxis)
