Anticonvulsants

Question 1

what is a seizure? what may be accompanied by them

Answer 1

• A sudden, intense electrical discharge in the thalamocortex
• Goal-directed behaviours not
  possible
• May or may not be accompanied by motor movement

Question 2

what are convulsions? what may they be associated with

Answer 2

• 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.)

Question 2

what is status epilepticus? length? what damaging effects can occur?

Answer 2

• A series of seizures in rapid succession
• No intervening periods of consciousness
• Lasts 30+ min.
• Hyperthermia, brain damage, death possible

Question 3

focal vs generalized seizures

Answer 3

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

Question 3

what is epilepsy? what occurs with it?

Answer 3

Recurrent, spontaneous impairment of brain function
- Loss of consciousness (almost always)
- Abnormal motor phenomena (usually)
- Mental or sensory disturbances

Question 4

what is the most commonly used drug in vet med for long term prevention of seizures?

Answer 4

phenobarbitol

Question 5

what is the goal of anticonvulsant drugs

Answer 5

Goal is to reduce frequency & severity of seizures, not abolish

Question 5

what drug can also be used in addition to/instead of phenobarbitol

Answer 5

KBr

Levetiracetam, gabapentin, and a few other drugs are sometimes used in combination with one of the above

Question 6

can you use diazepam in cats

Answer 6

no, hepatic toxicity is likely

Question 7

what is the drug used to stop almost all seizures? when does tolerance develop?

Answer 7

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

Question 8

why do we use so few anticonvulsant drugs in animals?

Answer 8

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)

Question 9

what are some considerations regarding anticonvulsant therapy in companion animals? (7)

Answer 9

• 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)

Question 10

what is the #1 anticonvulsant in dogs and cats

Answer 10

phenobarbitol

Question 11

MOA of phenobarbitol

Answer 11

Facilitates the action of GABA at its receptor = hyperpolarizes neurons

Question 12

why does half life of phenobarbitol change in dogs

Answer 12

In dogs, half-life decreases with duration of therapy due to induction of P450 enzymes

Question 13

half life of phenobarbitol in dogs

Answer 13

~48 h, range 20-140 h

Question 14

how do you compensate phenobarbitol dose in dogs as time goes on

Answer 14

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

Question 15

advantages of phenobarbitol (4)

Answer 15

• 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

Question 16

disadvantages of phenobarbitol (5)

Answer 16

• 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

Question 17

when giving phenobarbitol, blood levels should be ____

Answer 17

monitored

• Target plasma concentration 65-180 μmol/L
• Measure after 2 weeks then every 6 to 12 months

Question 18

why cant you stop anticonvulsant drugs suddenly

Answer 18

can cause seizures

Question 19

what drug is contraindicated in cats

Answer 19

KBr is contraindicated in cats (30-50% develop an asthma-like condition that can be fatal)

Question 20

why would you use phenobarbitol in large animals

Answer 20

Phenobarbital ia used short-term
only, for seizures associated with:
* Head trauma
* Lead poisoning
* Polioencephalomalacia

Question 21

mechanism of action of KBr

Answer 21

Br- hyperpolarizes membranes by
flowing through chloride channels in
neuronal plasma membranes (inhibits AP)

Question 22

advantages of KBr (4)

Answer 22

* 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

Question 23

disadvantages of KBr

Answer 23

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

Question 24

how long does it take to titrate dose of KBr to correct level

Answer 24

* 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)

Question 25

what should you avoid changes in diet wise when giving KBr?

Answer 25

* 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

Question 26

what is the mechanism of levetiracetam? when is it used?

Answer 26

* 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

Question 27

gabapentin; MOA, well tolerated in what species, what does it often require

Answer 27

* Synthetic analogue of the inhibitory neurotransmitter GABA * Well tolerated in dogs & cats * Often requires TID therapy * May allow reduction of dose of other anticonvulsants

Question 28

can diazepam be used long term in dogs? why or why not?

Answer 28

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

Question 29

what is a second option if diazepam fails? what can you try after that if it doesnt work?

Answer 29

-IV phenobarbital is often the second option after diazepam fails -If that fails, can try general anesthetics (propofol, inhalant, etc.)

Question 30

why are primidone, phenytoin and clonazepam not indicated for use in animals?

Answer 30

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)