Antiseizure Drugs Flashcards
Phenobarbitone MOA, ACVIM LoE
Pharmacokinetics
Adverse effects
Potentiates GABA receptors –> increased Cl channel opening –> neuronal hyperpolarisation and reduced excitability
High bioavailability
50% protein bound in blood
Half-life 37-73h - reach steady state faster with bolus
CytP450 induction –> progressive decrease in elimination half life with chronic dosing.
Can affect levels of many other medications (omeprazole, TMS, enro, fluconazole)
Monotherpay efficacy in IE demonstrated in several studies ranging from 60-90% and 30% seizure free
Failure rate 15%
Superior efficacy to KBr in one prospective controlled study
ACVIM LoE 1 - excellent
Strong recommendation for use as first line
AEs: CNS depression, idiosyncratic hepatotoxicity, PUPD, PP, reversible pancytopenia from myelosuppression, rare superficial necrolytic dermatitis
Greater frequency of AEs compared to zonisamide or leve.
What is primidone
Prodrug for phenobarbitone
Not recommended, less effecttive and caused worse hepatopathy
KBr
MOA, ACVIM LoE
Pharmacokinetics
Adverse effects
Depresses neuronal excitability, thought ot replace Cl and hyperpolarise neurons.
ACVIM LoE 1 as monotherapy and II as adjunct. Level B recommendation (not as strong as pheno)
–> only signle study looking at use as a monotherapy
long half life, bolus dosing recommended to reach steady state rapidly.
Wide interpatient bioavailability variability.
Not metabolised or proein bound so minimal pharmacological interactions
Need to monitor once in steady state (1mo if loading 3 mo if not)
AEs: ataxia, sedation, PUPD, PP, vomiting, other GI upset, paraparesis
Idiosyncratic pancreatitis
Renal excretion means should be avoided in patients with renal dysfunction as may cause hyperK
AEs: sedation, PUPD, PP
NOT FOR CATS - fatal bronchitis/bronchospasm
Impeitoin
MOA, ACVIM LoE
Pharmacokinetics
Adverse effects
Low affinity agonist at benzo site potentiates the GABAa receptor mediated CNS inhibition by acting as a low affinity partial agonist for the benzodiazepine R.
Not recommended for clusters or as an add on.
LoE 1 for monotherapy use, strong recommendation
Limited evidence as an add on
Rapid absorption, with half-life of 2-6h
Metabolised by liver and excreted in feces
Unlikely affected by liver/kidney function
High therapeutic index so drug monitoring not indicated
AEs: sedation, transient PP, PUPD, hyperactivity
Do not see changes in liver values in most cases
Does not affect thyroid testing.
Levetiracetam
MOA, ACVIM LoE
Pharmacokinetics
Adverse effects
unknown MOA. It is believed to impede impulse conduction across synapses by binding to a synaptic vesicle protein (SVA2) → modulation of neurotransmitter release
Not recommended as sole therapy, low LoE
As adjunct 1b LoE and good recommendation
Wide therapeutic index
Good bioavailability, rapid onset
Reduces seuizure frequency when used as adjunct
Drug monitoring not indicated
AEs: sedation, ataxia, salivation and vomiting reported. generally well tolerated
Zonisamide
MOA, ACVIM LoE
Pharmacokinetics
Adverse effects
unknown precise MOA. But, believed that the drug blocks sodium and T-type calcium channels, which leads to the suppression of neuronal hypersynchronization
Unknown effect on thyroid function - other sulfonamide drugs can supress thyroid
LoE 3 for use as monotherapy, not recommended
May be useful as adjunctive treatment still only LoE 3
Rapid absorption. long elimination half life
Monitor serum levels
AEs: sedation, ataxia, vomiting, inappetance
Rare acute idiosyncratic hepatotoxicity. Also reported to cause polyarthritis
May affect thyroid function
Potential Diet recommendations in seizuring patients
Medium chain TGs
-month prospective, randomised, double-blinded, placebo-controlled crossover dietary trial. Seizure frequency and monthly seizure days were significantly lower in the 21 dogs finishing the trial when on the test diet for 12 weeks as compared to those on the placebo diet
- 9% ME MCT randomised controlled trial
–> dogs on test diet had lower seizure frequency and and seizure day frequency
–> dogs on test diet had higher BHB levels which have neuroprotective effects through gene expression modulation
–> only 6month torttal duration. Will need longer studies. But similar results reported inhumans - A recent, randomized, single-blinded, controlled crossover trial evaluated the effects of omega-3 fatty acid supplementation in 15 dogs with idiopathic epilepsy and did not identify any difference in seizure frequency or severity
Recent studies on use of CBD in canine IE
JVIm 2022
AE: decreased appetite and vomiting (mild generally)
Underpowered to detect % change from baseline in total seizures but not # of seizure days whcih was lower in CBD group (24% decrease).
- did not establish a therapeutic plasma concentration of CBD, further investigation would be beneficial
JAVMA2019 -
- random, controlled, blinded study. proportion of responders (>50% reduction) similar to placebo.
- greater reduction in seizure frequency in Tx group cf placebo
MOA - altered NT release
Goal of AED treatment
> 50% reduction in seizure frequency with lowest possible drug dose
primary goal is seizure freedom = extending the interseizure interval to 3x longer than pretreatment after a minimum of 3 months therapy
Complete seizure freedom only in 15-24%, should only consider tapering after 2-3y of no seizures.
Causes of refractory Epilepsy
Underlying intracranial disease
Insufficient drug dose
or altered metabolism in individual (or functional tolerance)
–> pharmacodynamic issue (need different drug)
–> pharmacokinetic issue (need higher dose)
each therapeutic trial should have been used at optimal doses to exclude pseudoresistance defined as the lack of a response due to an inadequate dosing or treat- ment regime
Felbamate MOA
Blocks glycine enahnced NMDA induced Na and Ca influx
Can cause aplastic anaemia and fatal hepatotoxicity in humans
Need to monitor liver function and CBC
Options for adjunctive Tx in IE
Pheno + KBr has most evidence
Imepitoin has limited published evidence on efficacy
Levetiracetam has reasonable LoE as use for adjunct
Tx recommendations for status epilepticus
IV benzodiazepam first line
Can give rectal midazolam to same effect or intranasal may be best
Start Pheno loading unless already on pheno in which case give an additional dose
Add on Levetiracetam can also beused IV for clusters
Propofol CRi if truly refractory
Tx of status epilepticus in cats
Ensure no metabolic cause in history - insulin use, thiamine deficient diet
R/o hypoCa and low BG on bloods
Diazepam as first line bolus
Levetiracetam bolus
–> if no improvement then propofol CRI
and commence loading dose PB (takes 30 minutes to start having effect)
Supportive:
Maintain oxygenation
Administer mannitol or hypertonic saline if evidence of increased ICP
Address systemic hypertension if identified if not concerned for Cushing’s reflex)
Give once off treatment of thiamine as precaution as the increased seizure activity could result in increased requirement.
Mannitol MOA and indications and AEs
Non-metabolisable 6 carbon polyalcohol that acts as osmole when given intravenously.
Causes an osmotic diuresis as it is freely filtered by the glomerulus and draws water into the tubules
–> to be effective there must be sufficient renal blood flow.
Also enhances excretion of other electrolytes
These diuretic effects –> immediate reduction in cerebral oedema and thus intracranial pressure
–> improved blood flow and oxygenation of cerebral tissues.
Also has free radical scavenging effects
AEs: may cause fluid imbalance (overload in oliguric patients) or electrolyte derangements (hyperNa, HypoK, pseudohypoNa) and metabolic acidosis
Possible effects on blood coagulation
May be associated with AKI, pulmonary oedema, and BBB barrier disruption with repeated high doses
