Anticonvulsants Flashcards
what is a seizure?
- A sudden, intense electrical discharge in the thalamocortex
- Goal-directed behaviours not possible
- May or may not be accompanied by motor movements
what is a convulsion?
- 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
what is status epilepticus?
- A series of seizures in rapid succession
- No intervening periods of consciousness
- Lasts 30+ min.
- Hyperthermia, brain damage, death possible
what is epilepsy?
Recurrent, spontaneous impairment of brain function
- Loss of consciousness (almost always)
- Abnormal motor phenomena (usually)
- Mental or sensory disturbances
what is a focal vs generalized seizure?
Focal seizure:
* Often unilateral involvement of cerebrum
* Mild abnormalities that may be difficult to notice
(e.g., sensory abnormality, altered consciousness)
Generalized seizure:
* Loss of consciousness (usually)
* Bilateral involvement of cerebrum
* Usually tonic-clonic motor activity
most commonly used drug in vet. med. for long-term prevention of seizures
Phenobarbital
what drug is sometimes used for long term prevention of seizures in combination with or instead of phenobarbital?
KBr
goal of phenobarbital or KBr for seizures
reduce frequency & severity of seizures, not abolish
One main drug used in almost every case to stop seizures:
diazepam
is diazepam useful for long-term seizure control? why?
Tolerance develops to diazepam within ~1-2 months
> cannot be used for long term seizure control
There are 16 classes of anticonvulsants used in humans; why do we use so few drugs in animals?
1) Many anticonvulsants are metabolized very differently in dogs & cats
>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
3) Cost: anticonvulsants are often required for life and some are very expensive
Some considerations regarding anticonvulsant therapy in companion animals:
- 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 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)
are all animals who need anticonvulsant therapy the same and will they respond similarly to medications?
Each animal is unique regarding the characteristics of its disease and its response to medication
will we achieve steady-state concentration of a anticonvulsant medication quickly?
Achieving steady-state concentrations takes a long time because of the exceptionally long half-lives of the drugs
what should we monitor to assist anticonvulsant drug regimen design?
plasma concentrations
if we need to change anticonvulsant drugs, should we do so quickly or slowly?
Discontinue or change drugs GRADUALLY to avoid rebound seizure activity
The #1 anticonvulsant in dogs & cats
phenobarbital
what type of drug is phenobarbital? what are its effects?
A barbiturate with unique anticonvulsant properties at low concentration
mechanism of action for pehnobarbital
Facilitates the action of GABA at its receptor
>hyperpolarizes neurons
half life of phenobarbital
Half-life is long & variable:
* Dogs: ~48 h, range 20-140 h
* Cats: A little less than 48 h (wide range)
* Horses: ~18 h
how does the half life of phenobarbital change over the course of therapy, and why? what does this mean?
In dogs, half-life decreases with duration of therapy due to induction of P450 enzymes
E.g., half life may fall from 120 h (initially) to 60 h after 2 months of therapy, and to 20 h after six months of therapy
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
phenobarbital advantages
- Inexpensive
- Best outcomes of any monotherapy in canine & feline epilepsy
phenobarbital disadvantages
- Sedation (usually lasts ~ 2 weeks, but variable)
- Polydipsia, polyuria, polyphagia, vomiting
Potential hepatotoxicity (dogs)
Due to drug tolerance
> must increase dosage periodically
> may eventually require a toxic dosage
Blood levels should be monitored
Some animals do not respond:
* Monitor every 2 weeks & adjust dose
* Use KBr instead, or use with KBr or other drug(s)
Never stop anticonvulsant therapy suddenly
>seizures
how can we avoid hepatotoxicity of pehnobarbital?
Avoid toxicity by combining lower PB dosage with another drug
what is a rare possible outcome of PB, KBr, combined KBr + PB therapy, and other anticonvulsants
pancreatitis
what should we do if an animal is not responding to phenobarbital?
- Monitor every 2 weeks & adjust dose
- Use KBr instead, or use with KBr or other drug(s)
is it better to use phenobarbital or KBr for seizures in cats? why?
Phenobarbital used most often (less P450 induction)
KBr is contraindicated in cats (30-50% develop an asthma-like condition that can be fatal)
use of phenobarbital in large animals
Phenobarbital used short-term only, for seizures associated with:
* Head trauma
* Lead poisoning
* Polioencephalomalacia
mechanism of action of KBr for seizures
Br- hyperpolarizes membranes by flowing through chloride channels in neuronal plasma membranes
KBr advantages as an anticonvulsant
- 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
KBr disadvantages as an anticonvulsant
- 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
- 30-50% of cats develop life- threatening pulmonary inflammation (contraindicated)
- Takes months to titrate dose to
correct level
> T1/2 ~24 days (dogs)
KBr disadvantages as an anticonvulsant
- 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
- 30-50% of cats develop life- threatening pulmonary inflammation (contraindicated)
- Takes months to titrate dose to
correct level
> T1/2 ~24 days (dogs)
how long does it take to titrate KBr to correct levels and why?
- Takes months to titrate dose to correct level
> T1/2 ~24 days (dogs)
Peak plasma drug concentrations stabilize after ~5 half-lives i.e., 120 days > may use loading dose
body treats Br- the same as what other ion? what is a consideration for this regarding KBr treatment?
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
main uses of diazepam
- Used to stop seizures (highly lipophilic, rapidly crosses BBB)
- Used to abort impending seizures (prodromal signs)
can we use diazepam long term in dogs? why?
Cannot be used long-term in dogs because of short T1⁄2
>3-4 times/day therapy, and development of tolerance within 1-2 months > then not effective in emergencies
can we use use diazepam for long term seizure control in cats? pros and cons?
Reports of long-term control in ~75% of cats
some specialists recommend it in refractory cases, but hepatic toxicity worse than with phenobarbital (potentially fatal ADR when diazepam administered orally to cats: idiosyncratic hepatic necrosis)
route of admin for diazepam
In clinic: Administer IV
For home emergencies, owner can administer injectable diazepam per rectum
route of admin for diazepam
In clinic: Administer IV
For home emergencies, owner can administer injectable diazepam per rectum
What if diazepam fails to stop a seizure?
IV phenobarbital is often the second option after diazepam fails
If that fails, can try general anesthetics
what is primidone? how does it compare to phenobarbital?
- A phenobarbital precursor
- Hepatic toxicity worse than w/ PB
what is phenytoin? why dont we use it as an anticonvulsant?
- Half-life in dogs too short to be useful (3-4 h)
what is the disadvantage of clonazepam?
- Ineffective after 1-2 months (tachyphylaxis)
use of levetracetam in anticonvulsant therapy?
Adjunct
- Mechanism unknown
- Used in combination with PB in dogs & cats
- May allow reduction of dose of other anticonvulsants
- Usually requires TID admin
