Long-term Anticonvulsant Therapy in the Canine Idiopathic Epileptic

Transcription

Long-term Anticonvulsant Therapy in the Canine Idiopathic Epileptic
Long-term Anticonvulsant
Therapy in the Canine
Idiopathic Epileptic
Emily G. Davis, DVM
Neurology Section
Sugar Land Veterinary Specialists
DrDavis@SLVetSpecialists.com
November 16, 2014
Seizures
›  Paroxysmal depolarizing shifts within
the prosencephalon
›  Epilepsy
Epilepsy
1. 
Idiopathic
•  Estimated 2.0-5.0% canine population
•  1-5 years of age at onset
•  Normal inter-ictal neurologic examination and
diagnostics
•  Any breed (though some may be genetically
predisposed)
Epilepsy
2. 
Symptomatic
o  Intracranial or Extracranial
•  Any age
•  Neurologic examination abnormalities
•  +/- Lab abnormalities, +/- MRI abnormalities
Epilepsy
3. 
• 
• 
• 
Cryptogenic
>7 years old at onset
No neurologic abnormalities on exam
No cause for symptomatic epilepsy found on
complete neurologic work-up
Of dogs with seizures beginning >7 years of age, 21% were
cryptogenic and 79% found to be symptomatic epileptics.
PE and complete neuro exam:
• Chemistry, CBC, UA
• Bile acids (<1 yr old or suspect breeds)
• Lead levels if young and potentially exposed
• +/- T4
ž  Beware
over-interpretation of post-ictal
changes on neurologic examination
ž  May need to re-evaluate in 12-24 hours to
confirm if deficits are real or temporary
Common post-ictal symptoms
Ataxia
Loss of vision
Obtundation
Anxiety/
Behavioral
Changes
PU/PD,
changes in
appetite
Circling/
Pacing
ž 
Excessively severe obtundationàstuporàcoma
ž 
Any cranial nerve or UMN signs
ž 
Changes in vital parameters
ž 
Cushing’s reflex
›  Increased ICPà Systemic Hypertension
Bradycardia
ž  Look
for specific breeds prone
to life threatening immunemediated encephalitis rather
than idiopathic disease as underlying cause of
seizures
ž  Advanced
Imaging (Brain MRI)
ž  Cerebrospinal fluid analysis
ž  +/- Electroencephalography (EEG)
ž Brain
MRI (+/- CT)
CT
MRI
Ancillary Diagnostics
Who needs them?
ž  Dogs
<1 year or >5 years old
ž  At risk dog breeds
ž  Presenting in status epilepticus
ž  Any inter-ictal neurologic deficits
ž  Seizures refractory to appropriate drug
therapy
ž  Cats
ž  Goals
are important
We do NOT expect to completely eliminate all
seizure activity
ž  Frequency
ž  Severity
ž  Side
effects tolerable
1. 
2. 
3. 
4. 
5. 
Identifiable structural brain lesion (tumor,
inflammation, injury)
Status epilepticus
Two or more seizures within 24 hours
Two or more seizures within 6 months
Severe, prolonged or unusual post-ictal events
The top cause of death amongst IE pets is
euthanasia
1. inadequate seizure control
2. side effects of anticonvulsants
3. costs of medications and monitoring
Approximately 50% of dogs can be
controlled with monotherapy
ž  Approximately 75-85% can be
adequately controlled with multiple
drugs
ž 
% Patients with Seizures Controlled
Good
Luck
Monotherapy
2 drugs
Pheno + KBr
Pheno
Refractory
Drug resistant
epilepsy
Undiagnosed
brain disease
Ineffective
MOA
Drug related
mechanism
Tolerance
Genetics
Altered drug
metabolism
ž 
Excitatory neurotransmitters depolarize cells
• 
• 
ž 
Aspartate
Glutamate
Inhibitory neurotransmitters hyperpolarize cells
• 
• 
GABA
Glycine
Half-life
ž  Dose
Interval
›  Minimal fluctuation between peak and
trough serum levels
›  As half-life increases, frequency of
administration can be reduced
›  Long half-life drug with a short dosing interval
unlikely to provide added control
Steady-State
ž  When
drug eliminated = dose given
ž  Accumulation at steady-state allows
therapeutic concentrations through
peakàtrough
ž  87%
reach steady state after 3 x T ½
ž  95% reach steady state after 5 x T ½
Choosing an Anticonvulsant
ž Concurrent
medical conditions
ž Monotherapy if possible
ž Different MOAs if Multimodal
ž Dosing interval
ž Side effects
ž Cost
Newer drugs vs “older” drugs
ž  Tolerability
of side effects
ž  Costs of drug monitoring
ž  Emergency visit fees
ž  Cost of medications (Brand vs generics)
ž  Familiarity and comfort of clinician with
prescribing and monitoring
ž  Complications of interactions between
multimodal anticonvulsant therapies
ž  Phenobarbital
ž  Potassium
Bromide
ž  Diazepam
ž  Felbamate
ž  Gabapentin
ž  Zonisamide
ž  Levetiracetam
ž  Clorazepate
ž  Topiramate
ž  Rufinamide
ž  Lacosamide
Phenobarbital
ž  Unknown
MOA
›  Increased cell response to GABA
›  Antiglutamate effects
›  Decrease flow of Ca into channels
Phenobarbital
ž  Effective,
inexpensive, convenient dosing
ž  DEA Schedule IV
ž  Preferred medication in cats
ž  ~60% effective as monotherapy
Phenobarbital
Peak concentration 2-3 hours after ingestion
ž  86-96% absorbed orally
ž  T ½
›  40-90 hrs dogs
›  40-50 hrs cats
ž  Metabolized by liver, p-450 enzyme inducer
ž  25% excreted by kidneys unchanged
ž 
When to check drug concentrations?
1.  When SS reached, after changing a dose, or
immediately after loading dose*
2.  Break-through seizures occurring despite
adequate dosage and previously measured
therapeutic serum drug concentrations
3.  Signs of toxicity develop
4.  Every 6-12 months to verify changes in PK or
compliance have not altered drug concentrations
*Decision regarding whether to measure serum concentrations of a particular AED based upon
preference of veterinarian and available clinical veterinary data regarding effective serum
concentration in species in question
So I checked levels, now what?
ž  Treat
the patient, not the numbers
ž  Main
indications
Ø  avoid toxicity
Ø  calculation of new AED dosage
ž  If
levels are below the lab’s reported
therapeutic range and patient’s seizures are
clinically well controlled…
Phenobarbital Monitoring
ž  2.0-3.5
mg/kg PO BID
ž  Check serum levels 14 days following
initiation
ž  Peak & Trough sampling not important
ž  15-35 mcg/mL therapeutic dogs, 10-30 cats
ž  Avoid serum separator tubes
Loading
Loading dose 16-20 mg/kg/over 24 hours divided into 4
doses given q 6 hours IV
10 kg Beagle
20 mg/4 doses= 5 mg x 10= 50 mg each dose
50 mg IV x 4= 200 mg total loading dose over 24 hr
12 hours after the last loading dose, begin maintenance dose
2-3.5 mg/kg
Beagle: 32.4 mg (1/2 grain) PO BID
Phenobarbital Side Effects
Possible hyperactive reaction in dogs
ž  PU/PD/Polyphagia/Weight Gain
›  Blocks release ADH
›  Suppression on satiety center in
hypothalamus
ž  Sedation, Paresis and Ataxia pelvic limbs –
resolves after 2 weeks usually
ž 
Phenobarbital Side Effects
o 
Neutropenia, anemia and/or thrombocytopenia
›  Idiosyncratic or Immune-mediated
›  Resolves when discontinued
ž 
Superficial necrotizing dermatitis
Phenobarbital
o 
Hepatotoxicity is uncommon at
recommended dosages
most common at serum conc. above 35 mcg/mL
o 
o 
o 
o 
Potent inducer of cytochrome P-450*
ALKP should increase (3-4 x) but ALT
usually normal or only mildly increased
Bile acids, bilirubin, albumin should not be
affected
Very rarely recognized in cats
Phenobarbital
ž  Alters
thyroid hormone metabolism,
decreased T4 and fT4
ž  Little effect on adrenal tests
ž  Induces hepatic microsomal enzymesà
reduction in serum levels other drugs
metabolized by liver (doxycycline,
metronidazole, itraconazole, other AED)
Potassium Bromide
o 
First antiepileptic drug used in humans
with suitable efficacy starting in 1850’s
o 
Responsible for estimated 5-10% of all
psychiatric hospital
admissions
o 
Discontinued in US
1912
Potassium Bromide
ž  MOA Unknown
›  Believed to hyperpolarize neuronal
membrane passing through the Clchannel
ž  T ½ 21-24 days dogs, 11 days cats
ž  2-3 months until steady state
ž  Not protein bound
ž  Excreted by kidneys
ž  60% absorbed rectally
Potassium Bromide
ž  30-50
mg/kg/day monotherapy
ž  20-30
mg/kg/day with Phenobarbital
ž  Feed
with administration
›  Vomiting common
Potassium Bromide
ž  Loading
›  400–600 mg/kg à 1 – 1.5mg/mL serum conc.
ž  Load
over 1-5 days, add daily dosing
ž  Start maintenance early if too sedate
ž  Benny
3 year MC Beagle
ž  10.0 kg
ž  Adopted 2 years ago
ž  o report he experiences about 1
generalized seizure a month until past
two months
ž  Now having 1-2 seizures weekly
ž  Normal PE, neuro exam and bloodwork
KBr loading
Maintenance dose
500 mg/kg over 5 days + 30 mg/kg/day
10 kg Beagle
1000 mg/day + 300 mg/day=1300 mg
1300 mg/day x 5 days
Then begin maintenanceà 300 mg/day
Check serum KBr concentration in 2-4 weeks
after loading dose complete and at 3 mo. (SS)
Next year’s check up…
ž  300
mg KBr solution PO q 24 hr
ž  Current KBr level 1.1 mg/ml
ž  Seizure frequency past 3 months ~ 2-3
seizures/mo with no adverse drug side
effects
KBr dosage changes
Current dosage = New dosage
Current level
Desired level
30 mg/kg = New dosage
1.1 mg/ml
2.0 mg/ml
60 = 1.1 x New dosage à 60/1.1
New dosage= 54 mg/kg
Recheck serum KBr level in 3 months to confirm
desired level has been reached at new dosage
KBr monitoring
ž  Therapeutic
Range 1-3 mg/mL*
ž  Check 3 months after starting maintenance
dose
ž  Monitor serum levels and renal parameters
(BUN, Creatinine, UA) every 6 months – 1
year
Potassium Bromide
ž 
Common side effects
›  Sedation
›  PU/PD
›  Paresis and ataxia pelvic limbs
›  Vomiting
Polyphagia 25%
ž  Rarely aggressive behavior, coprophagia,
attention seeking, pancreatitis
ž  Bronchial pneumonitis in cats
ž 
Potassium Bromide
ž  Chloride
in diet
ž  Spurious elevation serum chloride levels
ž  Can withdrawal immediately, long T ½
ž  Saline diuresis treats KBr toxicity (+/- furosemide)
ž  Decrease dose in
dogs with renal disease
Pheno vs. KBr
ž  When
KBr is administered with
Phenobarbital, 34% can decrease dose of
Phenobarbital and 19% can have it
removed
Comparison of phenobarbital with bromide as a
first-choice antiepileptic drug for treatment of
epilepsy in dogs. (Boothe)
Phenobarbital treatment resulted in eradication
of seizures [85%] significantly more often than
did bromide [52%]
ž  Phenobarbital treatment also resulted in a
greater percentage decrease in seizure duration
(88%), compared with bromide (49%).
ž 
% pt. seizures eradicated
Pheno
KBr
85%
52%
% decrease in seizure duration
88%
49%
Benzodiazepines - Diazepam
ž  Daily AED
for cats
ž  Highly Lipid Soluble - Status Epilepticus
ž  Believed to enhance GABA
ž  Appetite stimulant
Diazepam
ž  IV,
IM (unreliable), PO, Rectal, Intranasal
ž  Metabolized by liver
ž  Crosses BBB
ž  Highly lipid soluble
ž  ~80% bioavailable IN
& per rectum
ž  T ½ dog- 2.5 hr
ž  T ½ cat- 5.5 hr
Diazepam
Status epilepticus 0.5 mg/kg IV
ž  CRI in 0.9% NaCl or 2.5% dextrose
›  Dogs 0.5 - 2 mg/kg/hr
›  Cats 0.25 - 1 mg/kg/hr
ž 
Add-on maintenance therapy in cats
›  0.5 – 2 mg/kg/day PO divided BID-TID
ž  Dogs short half-life and functional tolerance*
ž 
Diazepam
Sedation most common
ž  Skeletal muscle relaxant
ž  Fatal Hepatic necrosis 3 days -2 weeks after
initiation in cats
ž  Check liver enzymes 1 week and 1 month
following initiation of therapy
ž 
Felbamate
Dicarbamate
ž  Use in cases refractory to phenobarbital and KBr
ž  MOA
ž 
›  Potentiation GABA
›  NMDA blockade
›  Decrease Na currents
Added to phenobarbital without potentiating
sedation
ž  Add-on or sole therapy
ž 
Felbamate
ž 
ž 
T ½ 4-8 hrs dogs
MOA Unknown
›  Alter Na+ channels, antagonizing glutamate and
interfering with binding of glycine
70% excreted unchanged kidneys
Wide margin of safety
ž  Ataxia, limb rigidity, tremors, salivation,
vomiting, weight loss, decreased appetite
ž 
ž 
Treatment of partial seizures and seizure-like
activity with felbamate in six dogs.
(Ruehlmann, et al.)
ž 
Six dogs with partial seizures were treated with
felbamate.
ž 
All dogs experienced a reduction in seizure
frequency
ž 
Two dogs had an immediate and prolonged
cessation of seizure activity.
ž 
These results suggest that felbamate can be an
effective antiepileptic drug without life-threatening
complications when used as monotherapy for
partial seizures in the dog.
Felbamate
ž 
Idiosyncratic bone marrow suppression and
hepatotoxicity rarely reported in humans
ž 
Recommended monitoring CBC and chemistry
at one month and every 6 months
›  Especially if used concurrently w/
phenobarbital
Felbamate
ž  15
mg/kg PO q 8 hr, maximum 300 mg/kg/day
ž  Dose increased every 2 weeks by 15mg/kg
until controlled
ž  Rarely evaluate serum levels due to expense,
low toxicity, and wide safety margin
ž  Not evaluated in cats
ž  Very expensive
Gabapentin (Neurontin)
ž  Structural
analog to GABA
ž  MOA not completely understood
›  Enhance action of GABA
›  Inhibition of Calcium channels
ž  No
evidence of use in cats
Gabapentin
ž  T
½ 3-4 hr dogs
ž  80% bioavailability
ž  Minimal protein binding
ž  Primarily excreted through kidneys
ž  30% metabolized by liver without enzyme
induction
Gabapentin
ž  Sedation
common side effect
ž  Serum monitoring not common in dogs
ž  Not found to effectively reduce seizure
frequency as an add-on drug in dogs with
refractory IE
ž  20-30 mg/kg q 8 hr
ž  Less expensive now
Zonisamide (Zonegran)
ž  Sulfonamide-based
anticonvulsant
ž  MOA potentials
›  Blockade of T-type calcium and voltage-gated Na
channels
›  Enhancement of GABA
›  Inhibition of carbonic anhydrase - CSF
Zonisamide
ž  T
½ 15 hrs dog, 33 hrs cats
ž  Primarily metabolized by hepatic microsomal
enzymes
ž  High margin of safety
ž  Mild sedation, ataxia, vomiting dogs
ž  Anorexia, vomiting, diarrhea, lethargy cats
Idiosyncratic Reactions
ž 
Non-Antibiotic Sulfa
ž 
RARE- Renal tubular Acidosis, Hepatic
necrosis, KCS, Blood Dyscrasias
ž 
Hypersensitivity reaction rather than dose
related hepatotoxicity
ž 
Recheck CBC and liver profile one week after
treatment initiation
Zonisamide
ž  5-7.5
mg/kg PO BID as sole therapy
ž  Higher
doses needed as add on to
phenobarbital
ž  Moderately
Expensive
Zonisamide
ž  Efficacious
as add-on therapy to
phenobarbital/KBr therapy
ž  70%
reduction in seizure frequency (Klopmann, 2007)
ž  Often also used successfully as monotherapy
–  Contraindications to PhB
–  o concerns of side effects from other AED
Pharmacokinetics of zonisamide and drug
interaction with phenobarbital in dogs. (Orito)
ž 
5 dogs received zonisamide (5 mg/kg) before and during
repeated oral administration of phenobarbital.
ž 
Repeated phenobarbital decreased the maximum serum
concentration (Cmax) and elimination T ½ of zonisamide
ž 
Cmax and T ½ for zonisamide were restored to previous
levels 12 weeks after the discontinuation of phenobarbital.
ž 
Repeated administration of phenobarbital enhanced the
clearance of zonisamide
Dosage Considerations
ž If
using Zonisamide as add-on to PhB
Ø Increase starting dose to 10 mg/kg q 12h
Ø Consider checking trough serum levels in
1 week
Ø 15-40 mcg/ml human therapeutic range
Levetiracetam (Keppra)
ž  Pyrrolidine-based
anticonvulsant
ž  MOA
›  Binds to synaptic vesicle 2A (SV2A) in brain à
leads to alterations in Ca++ flow?
Levetiracetam
ž  100%
bioavailable
ž  T ½ 4 hr dogs, 2.9 hr cats but anticonvulsant
effects may persist longer
ž  70-90% eliminated unchanged in urine
ž  No hepatic metabolism
Levetiracetam
ž  Wide
margin of safety
ž  Side effects rare
ž  Salivation, restlessness, vomiting, ataxia
ž  Less expensive that previously (generic
available)
ž  Seems to be tolerated in cats with similar
side effects
The efficacy and tolerability of levetiracetam in
pharmacoresistant epileptic dogs. (Volk, et
al.)
ž 
14 dogs with IE which were pharmacoresistant to PhB
and KBr entered into prospective trial with Keppra as
an add-on medication.
ž 
8/14 dogs seizure frequency was reduced by 50%
ž 
However, 6/9 responders experienced a later
increase in seizure frequency after 4-8 months of tx
ž 
“Honey Moon” effect
ž 
Levetiracetam was well tolerated by all dogs
Levetiracetam
ž  20
mg/kg PO q 8 hr
ž  Due
to short T ½ dosage interval is important
ž  Keppra
XR?
The pharmacokinetics of levetiracetam in
healthy dogs concurrently receiving
phenobarbital (Moore, et al.)
o 
Six healthy dogs received a single oral dose of
LEV. Blood samples were collected at baseline
and intermittently for 24h. The study was
repeated after the dogs received oral PhB twice
daily for 21 days.
o 
PhB decreased the serum conc. and T ½ of LEV
Drug Monitoring
ž  Therapeutic
drug levels in veterinary patients
not established
ž  Human data 5-45 mcg/ml
ž  I check peak and trough levels only in severe
refractory cases/SE to calculate T ½
Clorazepate
ž  Benzodiazepine
ž  Dogs
T ½ 3-6 hr
ž  Extended release tablets available but offer
no advantage
Clorazepate in dogs: tolerance to the
anticonvulsant effect and signs of physical
dependence. (Scherkl)
ž 
Dogs were treated with clorazepate, 2 mg/kg t.i.d.
were given orally for 5-6 weeks.
ž 
One day after cessation of treatment, 2 out of 6
dogs showed withdrawal seizures, which, in 1
case, were lethal.
ž 
This shows that severe withdrawal symptoms,
even lethal seizures, may appear after abrupt
discontinuation of chronic clorazepate treatment
Clorazepate
ž  Long
term use can lead to development of
drug tolerance, increase serum
phenobarbital concentrations and/or
potential hepatotoxicity
ž  Abrupt
discontinuation after chronic
administration can cause severe withdrawal
symptoms
›  Status epilepticus
Clorazepate
ž  Reserved
for intermittent use at home in dogs
with a history of cluster seizures
›  2 or more seizures within a 24 hour time period with the patient
fully regaining consciousness between episodes
ž  0.5-1.0
mg/kg PO q 8h x 3 days
ž  Continue all other maintenance AED during
this time as well
ž  If seizures continue despite addition of
Clorazepate = Emergency Hospitalization
Topiramate (Topamax)
ž  Novel AED
ž  Not
well studied in vet med
ž  Na channel inactivation, enhanced GABA
activation, reduced glutamate excitation
ž  Dogs T ½ 2-4 hr
ž  Hepatic and renal excretion
Topiramate as an add-on antiepileptic
drug in treating refractory canine
idiopathic epilepsy. (Kiviranta)
ž 
Ten dogs were included. Five (50%) responded
to topiramate therapy during the short-term
follow-up showing a significant decrease of 66%
in seizure frequency.
ž 
SE- Weight loss, sedation and ataxia were the
most common adverse effects of topiramate
therapy
Topiramate
ž  2.5-5.0
mg/kg PO 8-12 hr?
ž  Generic
now available
ž  Clients
must be informed this is still
“investigational” in vet med
ž  “Dopamax”
Rufinamide (Banzel)
ž  No
clinical veterinary data
ž  Prolongs inactive state of Na channels
ž  Renal excretion
ž  Effective treatment for partial seizures in
humans
Pharmacokinetics of oral rufinamide in dogs.
(Wright, et al.)
ž 
No adverse effects were observed.
ž 
Results of this study suggest that rufinamide
given orally at 20 mg/kg every 12 h in healthy
dogs should result in a plasma concentration
and half-life sufficient to achieve the therapeutic
level extrapolated from humans without shortterm adverse effects.
Lacosamide (Vimpat)
ž  New
drug filed with FDA for use in epileptics
with focal seizures with secondary
generalization
ž  MOA unknown
ž  No clinical studies in vet med
ž  Well tolerated in dogs in FDA safety studies
ž  Most common SE- dizziness, ataxia
Lacosamide
ž  100-200
mg BID (humans)
50, 100, 150, 200 mg tablets
Summary
ž  Multiple AED
available for use in small
animal patients
ž  Many animals not controlled with
monotherapy
ž  Owners understanding of tx goals is very
important (Epilepsy is controlled most of the
time, not cured)
ž  If adding a tertiary AED, added seizure
control unlikely to be substantial
Don’t give up on your first AED choice too easily
Make sure the first and/or second choice AED drug is fully
utilized prior to adding/switching meds or labeling the dog a
refractory epileptic
Give the maximum dose and attain maximum serum blood concentrations without
serious adverse side effects or signs of toxicity for an appropriate amount of time
BEFORE declaring that drug/dog a failure
Questions?
Cases?