Anti-epileptic drugs Flashcards
What are epileptic seizures?
Disturbance of neuronal environment lowering the threshold for electrical activity- can be caused by tumour, inflammation, etc
Excessive and/or hypersynchronous electrical activity in the cerebral cortex
results in paroxysmal episodes of abnormal consciousness, motor activity, sensory input and/or autonomic function
Epilepsy occurs in between 0.5-5.7% of dogs and 0.5-1% of cats.
Epileptic seizures are seen secondary to a variety of underlying causes including forebrain problems, metabolic problems and toxic causes
Causes of epileptic seizures
Intracranial: 1) functional/idiopathic (no abnormalities can be detected on investiation) 2) structural (abnormality within the brain i.e. tumor, encephalitis etc)
extracranial: 1) metabolic (e.g. hypoglycemia, hepatic disease, electrolyte distrubance) 2) toxic (e.g. organophosphate, carbamates, lead, ivermectin, strychnine)
How do seizures arise?
1) inadequate neuronal inhibition: abnormality of inhibitory neurotransmitters. GABA=major inhibitory NT
primary loss of inhibitory neurons
decreased neuromodulation by serotonin, dopamine, or noradrenaline
2) excessive neuronal excitation: abnormality of excitatory NTs–L-glutamate is major excitatory NT
increased ACh
3) combination of above
Normal neuronal cell physiology
Cell membrane is hyperpolarized. membrane potential is determined by influx/efflux of ions through voltage-gated channels.
APs created by reduction in cell membrane potential. Increased permeability of voltage gated chennaleso to sodium results in depolarization (Na+ into cell). At axon terminal, depolarization results in oepning of Ca2+ channels. Calcium enters cell–>release of NTs
Termination of seizures
mechanism is unclear but may involve:
input from subcortical areas
development of lactic acidosis- lactic acidosis is thought to inhibit neuronal excitability
in some patients, there might be a failure to terminate seizure activity resulting in 1) cluster seizure activity
2) status epilepticus- continuous seizure
Purpose of antiepileptic drugs
prevents excessive or hypersynchronous neuronal activity– dampens focus to avoid spread
avoid spread of seizure activity within the brain
protects brain from excitotoxic effects of seizures and neuronal damage
delay or halt progression of seizures over time
Major CNS targets for AEDs
GABA
glutamate
voltage-gated channels: sodium, calcium, chloride
AEDS need to be highly lipid soluble to penetrate CNS
Major effect of AEDs is to hyperpolarize the INSIDE of the cell, as demonstarted by the interaction of major anticonvulsant medications and GABA. Lots of drugs potentiate GABA effects.
Major classes of veterinary AEDS
Barbiturates: phenobarbital
Benzodiazepines: dizepam, midazolam, clonazepam, clorazepate
Imepitoin: pexion
bromide: potassium bromide
fatty acidsL sodium valproate
fructose derivatives: topiramate
GABA analogues: gabapentin, pregablin
Hydantoins: phenytoin
Pyrimidinediones: primidone
Pyrrolidines: Levetiracetam
Sulfonamides: zonisamide
How do cases with seizures present?
two main groups
1) most present with ocassional brief seizures- by the time they present, usually normal
2) present as emergencies during severe seizures
Clusters of short seizures with minimal to no recovery between seizures (cluster seizures=more than one seizure in 24 hour period)
Status epilepticus: prolonged seizure lasting more than 20-30 minutes
As clusters get closer together, more likely to go into status epilepticus.
Management of epileptic seizures
Addressing any underlying cause
Irresepctive of cause, symptomatic control of epileptic seizures with medications
Symptomatic control comprises either 1) chronic ongoing therapy for dogs with occasional brief seizures or 2) immediate, short-term emergency therapy for dogs presenting during status epilepticus or a severe cluster of seizures.
Chronic therapy for seizure
TX unlikely to abolish all seizures
Aims of tx: reduce frequency, severity and duration of seizures
delay progression of seizures
minimise side effects i.e. pacing
minimize demands on owner
what medications are most effective: clinical effect is based on maintaining an effective serum concentration, therefore usually use drugs that are eliminated slowly (except imepitoin)
Suitable meds for chronic therapy
Phenobarbitol (Pb): Dogs- starting dose at 2-3 mg/kg PO q 12 hours, but dose based on serum concentration
cats: 1.5-2.5mg/kg PO q12 hours
Imepitoin: dogs 10-30mg/kg PO q. 12 hours
KBr: Dogs 20-40 mg/kg PO q. 24 hours but dose based on serum concentration. Contraindicated in cats
Diazepam: in dogs only emergency med; in cats: 0.25-0.5 mg/kg PO q. 12 hours
Levetiracetam, Zonisamide, Gabapentin reserved for refractory cases- from human medicine–add on as adjunctive therapy.
Exception to using standard AEDs are some extra-cranial causes
Hepatic encephalopathy
Hypoglycemia
Multiple toxic causes: carbamates, metahldehyde (slug bait), organophosphates, etc
Ion imbalance: hypocalcemia,etc
Chronic therapy in dogs
Initial therapy: Pb or pexion
If dogs refractory to Pb, add KBr in addition to Pb
If dogs refractory to this combo therapy, add or change to levetiracetam, zonisamide or gabapentin
Initial therapy in dogs with hepatic impairment: KBr or levetiracetam
Chronic therapy in cats
Initial therapy: Pb or diazepam
If cats refractory to a single medication, try the other or try a combo of the two.
If cats refractory to those (or adverse side effects) try adding or changing to levetiracetam
DO NOT USE KBr in CATS- can be fatal
When to start maintenance treatment?
ideally as soon as animal develops seizures but definitely if there is more than one seizure per month
or:
if owner objects to their frequency
very severe seizure or cluster seizure (irrespective of frequency)
seizures are increasing in frequency or severity
underlying progressive order ID’ed
objectionable post-ictal signs (i.e. aggression)
Daily AED tx
may reduce seizure severity, frequency, or both, but absence of seizure is difficult to achieve.
medication aims at controlling seizures
side effects are common initially- wobbly, etc, eat drink more
side effects may be more severe than seizures i.e. animal is SO sedate
owners must keep a diary of seizure events
withdrawal effects may precipitate seizures–> gradual withdrawal necessary
Phenobarbital mechanism of action
Variety of actions, not all of which are fully understood bu major mode of action probably mediated through GABA
in contrast to other barbiturtates, Pb exerts its anticonvulsant effect at subhypnotic doses
enhances activity of GABA, and thereby increases neuronal inhibition
reduces neuronal exciability through interaction with glutamate receptors
inhibits voltage-gated calcium channels
competitive binding of chloride channel picrotoxin site
Pharmacokinetics of Pb
Absorption: rapid oral absorption (reduced by 10%if given with food); High bioavailability (86-96%); peak plasma levels at 4-6 hours; plasma binding ~45%
Distribution: widely distributed, but lower lipid solubility than other barbiturates and therefore slower penetration of CNS than other barbiturates. Following IV injection: therapeutic CNS concentrations in 15-20 minutes- this delay has implications for emergency treatment
Metabolism: primarily hepatice. 25% excreted unchanged by kidneys; alkalinization of urine will increase renal excretion of Pb and its metabolites
Elimination half life: ranges from 30-90 hours in dogs and 3-83 hours in cats. In dogs, elimination half life decreases with chronic administration: reduction from 89hours in single dose to 47 hours following 90 days of continuous therapy
Serum concentrations: drug doses should be guided by serum concentration and not oral dose. serum concentrations will decrease with chronic therapy and therefore doses will need to increase. Therapeutic range: 15-45 micrograms/ml or 65 to 170 micromols/liter
Concept of serum concentrations
measured serum concentration is most important, not the administered oral dose
TR= serum concentration providing optimal seizure control while minimizing side effects
Steady serum state= 5 elimination half lives
-7 days to 2 weeks in Pb
3 months (up to 6 months) in KBr
Loading doses
use to increase serum concentration to steady state faster
requires admin of 5x maintenance dose
must take into account possible side effects associated with admin of such a high dose
because of these side effects, loading doses are restricted to emergency use.
How do we monitor serum Pb concentrations?
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 the same time relative to time of drug admin
less hepatic induction in cats: timing probably less important
serum separation tubes may falsely reduce the serum Pb concentration.
nb: 60% of dogs started at manufacturer’s recommended dose will be sub-therapeutic at time of first monitoring
Adverse effects of Pb: initial
Polyuria, polydipsia, polyphagia
transient sedation or less commonly, hyperexcitability
transient ataxia
less commonly: blood dyscrasias (including neutropenia, anemia and thrombocytopenia), usually as an idiosyncratic or allergic response that resolves with cessation of therapy.
Adverse effect of Pb associated with chronic therapy
hepatic toxicity: reduced by maintaing serum concentrations within TR, by avoiding combinations of hepatotoxic therapies and by monitoring serum biochemistry every 6 months
Induction of hepatic enzymes, in particular ALP and ALT (no hepatic enzyme induction in cats)
Mild reduction in serum albumin
Increased metabolism of thyroid hormones and suppression of TSH
Induction of hepatic microsomal P450 enzyme systems (helps eliminate drugs).
Pb half life and chronic therapy
In dogs, Pb half life declines with time
Hepatic enzymes induction–> decreased half life
Monitoring hepatic function with Pb
because of induction of hepatic enzymes, theres are a poor guide to hepatic impairment
Bile acid assay is 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 particularly ALT: greater than would be expected with enzyme induction should raise concern
dramatic or sustained hypoalbuminemia.
Pb treatment failure
“control” epileptic seizures
Minimize side effects- dogs will still seizure despite therapy
Low serum concentration: dose too low (TR), poor owner compliance, interference with absorption
Drug interaction
incorrect diagnosis
a second disease causing seizures
refractory epilepsy: 25-40% of dogs with primary epilepsy. –if refractory to Pb, add KBr or pexion
Potassium bromide mechanism of action
not fully understood but involves bromide interaction with chloride channels
Chloride channels are modulated by GABA and function to hyperpolarize the neuronal cell membrane, making it more stable
Bromide crosses the chloride channels in preference of chloride as it has a smaller hydrated diameter. Bromide therefore faciliates the effect of NTs acting on GABA channel by hyperpolarizing cell membrane.
bromide may act synergisticaly with Pb.
Pharmacokinetics of KBr
Absorption: from SI, peak absorption after 1.5 hours, not protein-bound
Distribution: distributed to the extracellular space. eliminated slowly due to marked renal absorption- however, increased dietary salt will increase elimination.
Metabolism: NO hepatic metabolism: this combined with the absence of protein binding makes it useful in dogs with hepatic disease
Elimination half life: 25 days. therefore requires 3-4 weeks of therapy to achieve therapeutic effect and 3-4 months to achieve steady state.
Serum concentrations: drug doses should be guided by serum concentration and not oral dose
TR: 0.8-2.4mg/ml or 0.8-3.0mg/ml if used as sole anticonvulsant.
Adverse effects of KBr
initially: vomiting and anorexia: these will often resolve if a different formulation is used or if medication is mixed with food
Adverse effects depend on therapy duration and dose:
ataxia and sedation
asthma in over 50% of cats: may be fatal, therefore use is contraindicated
Pancreatitis
Pruritis
Use of KBr in dogs
sole anticonvulsant if Pb is contraindicated (i.e. pre-existing severe hepatic insufficiency)
with Pb in refractory epilepsy: 50% of cases controlled; preferably only when Pb is at top end of TR.
Pexion (Imepitoin)- mechanism of action
Partial agonist at benzodiazepine recognition site of GABA receptor
Potentiates GABA receptor-mediated inhibitory effects on neurons
Also has a weak calcium channel blocking effect.
Pharmacokinetics of Pexion
Absorption: >92% absorbed. Peak absorption around 2 hours. Bioavailability varies with food, so relation with feeding should be consistent
Distribution: wide, rapidly crosses BBB; not protein-bound; no accumulation once steady state reached
Metabolism: metabolised prior to elimination. Metabolites in urine and feces
Elimination half life of 1.5-2 hours
Serum concentrations aren’t measured
Recommended initial dose is 10mg/kg BID
Dose can be increased by 50-100% increments to a max of 30mg/kg BID
Pexion adverse effects
not fully known yet but polyphagia, hyperactivity, polyuria, polydipsia, somnolence, hypersalivation, vomiting, ataxia, apathy, diarrhea, decreased sight and sound sensitivity have all been reported at the beginning of treatment
when compared when Pb, fewer adverse events were noted.
Use of pexion
reducing frequency of generalized seizures due to idiopathic epilepsy in dogs (licensed)
Efficacy as an add-on therapy hasn’t been demonstrated
After 20 weeks, tx considered as effective as Pb
No loss of anticonvulsant activity
No increase in liver enzymes- don’t have to up the dose–> no tolerance seen.
Emergency management of seizures
Status epilepticus: 1 epileptic seizure lasting more than 30 minutes or 2 or more seizures without a break lasting more than 30 minutes in total
Cluster seizures: 2 or more generalized epileptic seizures in 24 hours.
Aims of emergency tx
totally abolish acute seizure episode
emergency tx only for the duration of the episode
if there’s an ongoing underlying cause, then the animal may also demonstrate chronic seizures that may require control with chronic therapy.
Use short-acting medication and therefore don’t achieve maintained serum concentration
short-acting nature means higher doses can be used with a lower risk of OD
These drugs are NOT suitable for maintenance (except diazepam in cats)
Pharmacokinetics of Diazepam and Midazolam
specific to seizure control
Diazepam: effective as maintenance in cats (longer duration of effect). only used as emergency med in dogs.
wide margin of safety
anticonvulsant effect of diazepam following IV admin is 2-3 minutes but despite half life of over 3 hours, CNS concentrations decline rapidly and anticonvulsant effect only lasts around 20 minutes in dog. tx will need to be repeated
Midazolam: wide margin of safety and broad therapeutic index; rapid elimination (half life= 53-77 minutes)
Cluster seizures
2 or more generalized seizures in 24 hours
in severe clusters: in addition to maintenance therapy, can use pulse therapy with:
levetiracetam (Keppra)***
long acting BZP
rectal diazepam
gabapentin
slow release phenytoin formulations
Aim is to reduce number of seizures in a cluster. Keppra at 20-30mg/kg TID to QID for the duration of the cluster only. At the end of the cluster, stop the additional drug. All the time, the dog remains on it’s normal maintenance therapy. Most clusters typically last between 24-72 hours.
Management of Status Epilepticus
Aims: stop seizures using short-acting convulsant drugs; supportive care; follow-up maintenance anticonvulsant therapy; obtain diagnostic samples
Short acting anticonvulsant therapy:
Diazepam: 0.5-1.0mg/kg IV: 2-3 minutes to clinical effect, repeat up to 3 times
Can give rectally at 0.5-2.0mg/kg
Remember: half life of diazepam is longer in cat; dose carefully.
Status epilepticus in Pb-naive animals
initial loading dose of 12mg/kg IV
blood concentration of 65-100 micromol/liter
Clinical effect in 20 minutes
if animal too sedated: further boluses at 3mg/kg to take total dose to 18-24mg/kg
Status epilepticus in animals currently 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); KBr loading dose
Bromide loading regime
Dogs going into status epilepticus in the presence of therapeutic levels of Pb
oral or rectal loading dose:
rectal loading may cause severe diarrhea
200mg/kg daily for 5 days, divided into 4 to 6 doses
single loading dose of 600 to 1000mg/kg divided into multiple doses
Monitor level post-load and one month later
If seizures continue
may need to sedate or GA for 12-36 hours
Constant diazepam infusion: 0.5-2mg/kg/hour
Constant midazolam infusion: 0.3mg/kg/hour
Levetiracetam infusion
Propofol coma
barbiturate coma
Maintain normal body temp, patent airway
turn patient every 2-4 hours
monitor vitals
broad spectrum ABX due to lying in hospitalized state.
