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Chalkwalk 9 Managing Seizures in a Dog

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Welcome to char quacks in this case we’re talking about a two and a half year old male castrated cavalier king charles spaniel and he has history of six weeks of seizures and more recently in that he had three seizures within the last week and they each lasted about two minutes on physical exam the only abnormality observe was right vestibular positional pneus

Strabismus is cbc in biochemistry when were without abnormalities and the current thinking was on differential diagnosis of congenital call occipital malformation which can be seen in these this breed of dogs and also idiopathic epilepsy the initial therapy was with phenobarbital phenobarbital we might remember is going to be stimulating the gaba receptor agonist

And it increases chloride channel activity and therefore is a leads to a reduction of the tendency for electrically excitable membranes to fire that is it basically hyper polarizes the nerve membrane and of course gaba is the most common inhibitory neurotransmitter within the central nervous system so the plan would be to start him on this relatively low but

Starting dose fina barb and then monitor in about two weeks so why two weeks we would always like to try to reach a steady state before a monitoring situation is that up so what’s the that’s that steady state is determined by the half-life of the drug and in this case the half-life of phenobarbital is around 48 hours so we consider that steady stages around five

Times the half-life about ten days anytime over ten days we find so two weeks has certainly passed the period study saying 16 is when actually the sample was taken of course during that period of time the owners need to note the efficacy of the of the drug basically this is how you monitor seizures is their reduction and also signs of overdose such as signs of

Lethargy weakness or any exacerbation of the other neuroscience they were certainly concerned about the position on the step strabismus as possibly being associated with a broader neurological condition so continuing on the animal was reexamined in that at that 16 day period and the blood sample was drawn at that period of time and found to be 20 micrograms per dl

So what i’ve shown here is a model on the right of the phenobarbital concentrations against time where the entire plot is four weeks and a highlight here the one-week period of time and and 16 days would be around here so at 16 days you can see we’re well past what looks like steady state there’s small fluctuations between peak and trough and the animal has achieved

Around 20 now it’s certainly above the lowest range for what we consider to be the therapeutic target between 15 and 35 micrograms per mil and the good news was that the dog was not seizuring in fact not shown a seizure in the last week so we said okay great we’re going to monitor this animal in six months and at that time check is cbc biochem and also measure fina

Barb now why do you need to monitor you should monitor phenobarbital because over time you can anticipate that phenobarbital will be inducing its own drug metabolizing enzymes and by doing so as you would find these half-life becoming shorter and you’re given maintenance those would end up being associated with a lower proportionately lower concentration of pinot

Of atholl and so this is known to be auto induction of the cytochrome p450 commonly caused by inna barberton so moving quite a bit farther ahead actually within the first year things seem to be do doing pretty well but and the fina barb concentrations were in the therapeutic range so now the issue is you can see they were just fine and but now and the seizures

Were somewhere between 12 to a month that’s good now the seizures were increasing and we’re two years later after that previous evaluation and just as i just indicated we did see the phenyl arbitrations fall to 15 and 15 at that 2.8 milligram per kilogram dosage was the animal had been fine on for a long time what’s longer than you’d expect and so at this point

In time a new therapy started was to increase by fifty five percent the dosage so the target if you can if you can think of it this way would have been to increase the concentration by 1.55 because at steady state if you were to increase it by 15 that’s going to give us somewhere in the order of around 23 micrograms per mil and so that was a target so that would

Have us back well over the lower area to be right about here so that was a target with that increased dosage and the goal with some ramana tur the phenobarbital at two weeks because each time you start a new therapy it’s going to take another set of five half-lives to get to the new steady state and that’s what was about why this monitoring period was suggested so

Where does that bring us every reexamination after two weeks you can see in the bottom actually led the animal to be right at the point of toxicity where you’d expect toxicity and particularly liver toxicity to be much more prominent animals that have fina barb concentrations above 35 so this was unacceptable this was too high and so it was again suggested that the

Phenobarbital be reduced and it was reduced back to reduced back to reduce pb back to 2.8 and they added additional therapy of zonisamide at 7.1 milligrams per kilogram first every 12 hours and then was increased about a month before the next follow-up to 10.7 milligrams per kilogram with seizures had continued so what’s on this amides iment sonus amide is a newer

Generation anticonvulsant drug that seems to reduce or block the voltage sense of voltage sensitive sodium and calcium channels and also accelerates the release of gaba which would also be consistent with basically hyperpolarizing membranes it’s it also has weak carbonic anhydrase activity and this obviously doesn’t have a lot of clinical significance with regards

To its anti epileptic property at least not that we know so monitoring a month later it was noted by the owner that seizures were not well controlled and the fina barb concentrations were 20 so within the therapeutic target range so the decision was made at that time too let’s start with the fina barb to increase the fianna bar back up to 24 milligrams per kilogram

And we can we can think about how that might target a higher concentration even than 20 and this is considered to be reasonable because of the lack of conceit control and then add a new drug levetiracetam at 44 milligrams per kilogram every 12 hours and this drug is a drug that has a mechanism that is to bind to synaptic vesicle protein in the in the presynaptic

And presynaptic neurons and and by doing so tends to lead to less amount of neurotransmitter release and also in that way leads to a hyperpolarization of the postsynaptic membrane it is a drug debt is got a half-life it’s a short half-life of around two to six hours and that debt makes it more difficult to to dose sometimes it’s recommended q8 our dosing as well

It also has the tendency to reduce the reduced unit barbital half lives so you might expect that the dosing for that would would go up as well so because of the short half-life we target target trough concentrations from monitoring of levetiracetam and so in this case in addition to adding a new drug and redoute and increasing the fina barb it’s important not to

Just take an animal off the other drugs on this amide and so that drug was more carefully tapered and you can see the way that was done was over a month it was the original dosage was reduced so from 150 to 150 it was first reduced to 100 to 150 this is am and pm dosing milligrams for that dog to 100 and 100 and 150 and 15 and 50 and 50 and and it was discontinued

So the basic message of this particular case was that we should we often start with phenobarbital when we have issued want to monitored carefully stay within the therapeutic range add other drugs you can see both zonisamide was tried in this case and levetiracetam sort of newer generation anti epileptics you may also see bromide being used in some cases and the

Another important principle is not to willy nilly take animals off of a particular drug because each has a slightly different mechanism and there have been cellular adjustments that would make basically cold turkey removal from that drug more problematic so see what was done with sona some id as an example to taper drew a drug that you feel as not being effective in a particular case

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Chalkwalk 9 Managing Seizures in a Dog By VetMedAcademy