Epilepsy + Pharmacology of Antiepileptic Drugs Flashcards
what are epileptic seizures
disturbance of neuronal environment lowering the threshold for electrical activity
excessive and/or hypersynchronous electrical activity in the cerebral cortex
what does an epileptic seizure result in
paroxysmal episodes of abnormal consciousness, motor activity, sensory input and/or autonomic function
how do epileptic seizures arise
- inadequate neuronal inhibition
- excessive neuronal excitation
- combination of the above
how does inadequate neuronal inhibition cause epileptic seizures
abnormality of inhibitory neurotransmitters –> GABA = major inhibitory neurotransmitter
primary loss of inhibitory neurons
decreased neuromodulation by serotonin, dopamine, or noradrenaline
how does excessive neuronal excitation cause epileptic seizures
abnormality of excitatory neurotransmitters –> L-glutamate = major excitatory neurotransmitters
increased acetylcholine
what is the normal neuronal cell physiology
- cell membrane is hyperpolarized
- membrane potential is determined by influx/efflux of ions through voltage gated channels (extracellular sodium >>> intracellular, extracellular potassium <<< intracellular)
- action potentials are created by a reduction in the cell membrane potential
- increased permeability of voltage gated channels to sodium results in depolarization (sodium flows into cell)
- at the axon terminal this depolarization results in opening of calcium channels
- calcium enters cell resulting in release of neurotransmitters
how are seizures terminated
- input from subcortical areas
- development of lactic acidosis
what are the purpose of antiepileptic drugs
- prevent excessive or hypersynchronous neuronal activity
- avoid spread of seizure activity within brain
- protects brain from the excitoxic effects of seizures and neuronal damage
- delary or halt the progression of seizures over time
what are the major CNS targets for AED (3)
- GABA
- glutamate
- voltage-gated channels (Na, Ca, Cl)
what do AED’s need to be in order to be effect
highly lipid soluble to penetrate CNS
what is the effects of AED’s
hyperpolarize the inside of the cell
- GABA binding sites: open the Cl channel
- benzodiazepine binding sites: increases the binding of GABA
- barbiturate binding site: increases the duration of GABA-dependent chloride channel opening
what are major classes of veterinary AEDs (11)
- barbiturates: phenobarbital
- benzodiazepines: diazepam, midazolam, clonazepam, clorazepate
- impitoin: pexion
- bromide: potassium bromide
- fatty acids: sodium valproate
- fructose derivatives: topiramate
- GABA analogs: gabapentin, pregabalin
- hydantoins: phenytoin
- pyrimidinediones; primidone
- pyrrolidines: levetiracetam
- sulfonamides: zonisamide
how doe cases with epileptic seizures present
- occasional brief seizures (few mins long)
- emergencies during severe seizures –> clusters of short seizures with minimal to no recovery between seizures (cluster seizure = more than 1 in a 24 hour period) and status epilepticus = prolonged seizure lasting more than 20-30 mins
how are epileptic seizures managed
- addressing any underlying cause
- irrespective of the cause: symptomatic control of the seizures with medications
- symptomatic control with:
- chronic ongoing therapy for dogs with occasional brief seizures
- immediate, short-term emergency therapy for dogs presenting during status epilepticus ro a severe cluster of seizures
what are the aims of treatment for chronic epileptic seizures
treatment unlikely to abolish seizures
- reduce freq, severity and duration
- delay progression of seizures
- minimize side effects
- minimize demands on owner
what medications are most effective in treating chronic seizures
clinical effect is based on maintaining an effective serum concentration
*drugs that are eliminated slowly
what are suitable medications for chronic therapy
- phenobarbital
- imepitoin
- potassium bromide
- diazepam
- levetiracetam
- zonisamide
- gabapentin
what are exception to using standard anti-epileptic drugs
extra-cranial causes
- hepatic encephalopathy
- hypoglycemia
- multiple toxic causes: carbamates, methaldehyde, organophosphates
- ion imbalance: hypocalcemia
what medications do we chose for chronic epilepsy in dogs
initial therapy: phenobarbital or imepitoin
in dogs regractory to Pb add potassium bromide (KBr) in addition to Pb
in dogs refractory to this combination therapy: add or change to levetiracetam, zonisamide or gabapentin
initial therapy in dogs with hepatic impairment: potassium bromide or levetiracetam
how is chronic epilepsy treated in cats
initial therapy: phenobarbital, levetiracetum or diazepam (imepitoin also safe to use in cats)
refractory to a single medication try the other or try a combination of the two
DO NOT USE KBr IN CATS
when do you start maintenance treatment
ideally as soon as animal develops epileptic seizures –> definitely if there is more than 1 seizure per month
or if:
- owner objects to their freq
- very severe seizure or a cluster of seizures (irrespective of freq)
- seizures are increasing in freq or severity
- underyling progressive disorder is identified
- objective post-ictal signs (aggression)
how must clients be educated
daily antiepileptic treatment may reduce seizure severity, freq or both, but absence of seizures is difficult to achieve
medication aims at controlling seizures
side effects are common initially
side effects may be more severe than seizures
owners must keep a diary of seizure events
withdrawal effects: may precipitate seizures
what is the mechanism of action of phenobarbital
variety of actions, not all of which are fully understood, but major mode of action is probably mediated through GABA
- enahances the activity of GABA, the major inhibitory CNS neurotransmitter and thereby increases neuronal inhibition
- reduces neuronal excitability through interaction with glutamate receptors
- inhibits voltage gated Ca channels
- competitive binding of chloride channel picrotoxin site
what are the pharacokinetics of phenobarbital (absorption, distribution, metabolism, elimination half life, serum concentrations)
1. absorption: rapid oral absorption, high bioavailability (86-96%)
2. distribution: widely distributed, lower lipid solubility than other barbiturates and slower penetration of CNS than other barbiturates
3. metabolism: primarily hepatic metabolism (25% excreted unchanged by kidneys)
4. elimination half life: 30h-90h in dogs and 3h-83h in cats
5. serum concentrations: doses should be guided by serum concentration and not oral dose –> concentrations will decrease with chronic therapy and therefore doses will need to increase
what is serum concentration
measured serum concentration is most important not the administered oral dose
therapeutic range = serum concentration providing optimal seizure control while minimizing side effects
what is steady serum state
5 elimination half lives
what is the steady serum state in phenobarbital
7 days to 2 weeks in phenobarbital
what is the steady serum state in bromide
3 months (up to 6)
what occurs as serum concentration increases
sub-therapeutic –> therapeutic –> toxic
what is the loading dose
use to increase serum conc. to steady state faster
what does the loading dose require
administration of the 5x maintenance dose
must take into account possible side effects associated with administration of such a high dose
*because of side effects loading doses are restricted to emergency use
how are phenobarbital serum concentrations monitored
timing of sample collection relative to time of dose admin is not important at starting doses
timing is clinically relevant at high doses in dogs –> collect blood sample at same time relative to time of drug admin
less hepatic induction in cats: timing is less important
serum separation tubes may falsely reduce the serum phenobarbital conc. –> DON’T USE
what are the adverse effects of phenobarbitals
divided into those initially (most dogs develop tolerance after 2-4 weeks) and those assoicated with long term therapy
- initially: polyuria, polydipsia, polyphagia, transient sedation or less commonly hyperexcitability, transient ataxia
- less commonly: blood dyscrasias (including neutropenia, anemia, thrombocytopenia), usually as idiosyncratic or allergic response that resolves with cessation of therapy
what are the adverse effects associated with longer term therapy phenobarbital
1. hepatic toxicity: reduced by maintaining serum concentrations with the therapeutic range, by avoiding combinations of hepatotoxic therapies and by monitoring serum biochemistry every 6 months
induction of hepatic enzymes (ALP and ALT) –> no hepatic enzyme induction in cats
2. mild reduction in serum albumin
3. increased metobolism of thyroid hormones and suppression of TSH
4. induction of hepatic microsomal p450 enzyme systems
how is hepatic function monitored
induction of hepatic enzymes these are a poor guide to hepatic impairement
bile acid assay is the best guide to hepatic function in animals on Pb therapy, particularly a significantly elevated pre- and post-prandial bile acid assay
dramatic elevation of ALP and ALT: greather than would be expected with enzyme induction should raise concern
dramatic or sustained hypoalbuminemia
what is the routine monitoring of patients on treatment for epileptic seizures
- regulary (6 monthly) monitoring of serum phenobarbital levels
- regular (6-12 monthly) monitoring of hepatic and bone marrow function (hematology, biochemistry and bile acid assay)
what are indications of phenobarbital treatment failure
- low serum concentration (dose too low, poor owner compliance, interference with absorption)
- drug interaction
- incorrect diagnosis
- a second disease causing seizures
- refractory epilepsy: 25-40% of dogs with priamry epilepsy
what is refractory epilepsy
seizures refractory to phenobarbital –> add another maintenance drug
what are examples of maintenance drugs in refractory epilepsy
- bromide (potassium or sodium salt)
- imepitoin (pexion)
- levetriracetam
- zonisamide
- gabapentin
- long acting phenytoin
- long acting benzodiazepam: clorazepate dipotassium
what is the mechanism of action of potassium bromide
interaction with chloride channels
- Cl channels regulated by GABA –> hyperpolarize the neuronal membrane making it more stable
- bromide crosses the Cl channels in preference to Cl –> smaller hydrated diameter
- facilitates effect of neurotransmitters acting on GABA channel by hyperpolarizing the cell membrane
- bromide may act synergistically with phenobarbital
what are the pharmacokinetics (absorption, distribution, metabolism, elimination half life, serum concentration)
1. absorption: absorbed from small intestine (peak 1.5 hours), not protein bound
2. distribution: extracellular space, eliminated slowly due to marked renal reabsorption (increased dietary salt will increase elimination)
3. metabolism: no hepatic metabolism (combined with absence of protein binding useful for dogs with hepatic disease)
4. elimination half life: 25 days, requires 3-4 weeks of therapy to achieve therapeutic effect and 3-4 months to achieve steady state
5. serum concentration: drug doses should be guided by serum concentration and not oral dose
what are the adverse effects of potassium bromide
- initially: vomiting and anorexia (often will resolve if a different formula used –> capsules, suspension, powder, tablets, syrup or if medication used with food)
- ataxia and sedation
- asthma in over 50% of cats (can be fatal –> contraindictated)
- pancreatitis
- pruritis
what are the uses of bromide in dogs
sole anticonvulsant if Pb is contraindicated
with Pb in refractory epilepsy (preferably only when Pb is at top end of therapeutic range)
what is the mechanism of action of Pexion
partial agonist at benzodiazepin recognition site of GABA receptor
potentiates GABA receptor mediated inhibitory effects on neurons
also has weak calcium channel blocking effect
what are the pharmacokinetics (absorption, distribution, metabolism, elimination half life)
1. absorption: >92% absorbed, peak absorption around 2 hours, bioavailability varies with food so relation with feeding should be consistent
2. distribution: wide, rapidly crosses BBB, not protein bound, no accumulation once steady state reached
3. metabolism: metabolized prior to elimination (urine and feces)
4. elimination half life: 1.5-2 hours
what are the adverse effects of Pexion
not yet fully known –> polyphagia, hyperactivity, polyuria, polydipsia, somnolence, hypersalivation, vomiting, ataxia, apathy, diarrhea, decreased sight and sound sensitivity reported at beginning of treatment
fewer than phenobarbital fewer adverse events
what are the uses of pexion
reducing frequency of generalized seizures due to idiopathic epilepsy in dogs
efficacy as an add on therapy not demonstrated
after 20wks considered as effective as phenobarbitone
no loss of anticonvulsant acitivty, no increase in liver enzymes
what are the use of levetiracetam (keppra)
add on medication in refractory dogs or as sole anticonvulsant in cats
useful in animal with hepatic impairment
what is the mechanism of levetiracetam (keppra)
unknown
what are the pharmacokinetics of levetiracetam (keppra)
rapidly absorbed, minimally protein bound and around 90% renal excretion
what is the elimination half life of levetiracetam (keppra)
dogs: 2.3-3.6hrs
cats: 5.3hrs
what are the serum concentration of levetiracetam (keppra)
not useful in guiding therapy
what are the adverse effects of levetiracetam (keppra)
sedation
occasionally restlessness, vomiting and ataxia in dogs
what are the use of zonisamide (zonegran)
add on medication in refractory dogs
what is the mechanism of action of zonisamide (zonegran)
unknown
what is the pharmacokinetics of zonisamide (zonegran)
rapidy absorbed and low protein binding
mostly excreted unchanged in urine (around 20% undergoes hepatic metabolism)
no induction of hepatic enzymes
what is the elimination half life of zonisamide (zonegran)
dogs: 15 hours (dramitically reduced if given concurrently with drugs that induce hepatic microsomal enzyme systems)
what is the serum concentration of zonisamide (zonegran)
not useful in guiding therapy
what are the adverse effects of zonisamide (zonegran)
sedation, ataxia, anorexia
contraindicated in dogs with hypersensitivity to sulphonamides and caution if there is concurrent renal or hepatic impairment
what are the uses of gabapentin
add on medication in refractory dogs, esp those with severe clusters of seizures
what are the mechanism of action of gabapentin
unknown
but thought to inhibit CNS voltage-gated sodium channels
may enhance GABA release
what are the pharmacokinetics of gabapentin
rapidly absorbed and not protein bound
metabolized to N-methylhabapentin with around 1/3 renally excreted (in dogs)
what is the elimination half life of gabapentin
3-4 hours in dogs
what are serum concentrations in gabapentin
not useful in guiding therapy
what are the adverse effects of gabapentin
sedation
GIT irritation
what are status epilepticus seizures
1 epileptic seizure lasting more than 5 mins or
2 or more epileptic seizures without a break within a 5 min period
what are cluster seizures
2 or more generalized epileptic seizures in 24 hours
what are the aims of treatment for emergency severe seizures
- abolish the acute seizure episode
- emergency treatment only for the duration of the severe episode
- if ongoing underlying cause then the animal may also demonstrate chronic seizures that may require control with chronic therapy
what medications are the most effective for treatment of severe emergency seizures
short acting medications and don’t achieve a maintained serum concentration
short-acting nature means that higher doses can be used with a lower risk of overdose
drugs are not suitable for maintenance therapy (except diazepam in cats)
what are the medications suitable for emergency therapy
- diazepam
- midazolam
- levetiracetam (particularly cluster seizures)
- phenobarbital loading dose (rapidly increase blood levels)
- pentobarbitone
- propofol infusion
- potassium bromide loading dose
what are the phamacokinetics of diazepam
maintenance medication in cats, emergency medication only in dogs
wide margin of safety
anticonvulsant effect following IV admin 2-3 mins
half life of over 3 hours –> CNS concentrations decline rapidly and anticonvulsant effect only lasts around 20 minutes in dgos (repeated treatment)
what are the pharmacokinetics of midazolam
wide margin of safety and broad therapeutic index
rapid elimination (half life = 53-77 mins)
what are cluster seizures
2 or more generalized epileptic seizures in 24 hours
how are cluster seizures managed
in severe seizures and in addition to maintenance therapy can use additional pulse therapy during the cluster with –> levetiracetam (keppra)
rectal diazepam
gabapentin
what is the aim when treating cluster seizures
reduce number of seizures in a cluster
what is the medication of choice in treating cluster seizures
levetiracetam (keppra)
at end of cluster stop the additional drug, all the time the dog remains on its normal maintenance therapy
most clusters last between 24-72 hours
reduce the dose if the dog appears too sedated
what are the aims of managing status epilepticus
- stop seizures, use short acting anticonvulsat drugs
- supportive care
- follow up maintenance anticonvulsant therapy
- obtain diagnostic samples
what is the specific short acting therapy of diazepam for status epilepticus
2-3 mins to clinical effect
repeat up to three times
how is phenobarbital used in naive animals for status epilepticus
initial loading dose 12mg/kg IV
blood conc of 65-100 umol/l
clinical effect in 20 min
if animal not too sedated: further boluses at 3mg/kg to take total dose to 18-24mg/kg
what is the treatment of phenobarbitol in status epilepticus of animals already on Pb
already have blood levels –> large bolus will result in toxic levels
single bolus of 3mg/kg to slightly increase levels (blood sample for Pb level first)
potassium bromide loading dose
what is the bromide loading regime in status epilepticus
dogs going into status epilepticus in the presnce of therapuetic levels of pb
oral or rectal loading dose
rectal dose may cause severe diarrhea
200mg/kg daily for 5 days, divided into 4-6 doses
single loading dose of 600 to 1000mg/kg, divided into multiple doses
monitor level post load and one month later
what if the seizures continue in status epilepticus
sedate or GA for 12-36 hours
constant diazepam infusion
constant midazolam infusion
levetiracetam infusion
propofol coma
what is the supportive care in status epilepticus if sedated or GA
maintain normal body temp
maintain patient airway
turn patient every 2-4 hours
monitor vital parameters
broad spectrum antibiotic
