docLong-term Anticonvulsant Therapy in the Canine Idiopathic Epileptic
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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 [email protected] 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 Beware over-interpretation of post-ictal changes on neurologic examination 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 Excessively severe obtundationàstuporàcoma Any cranial nerve or UMN signs Changes in vital parameters Cushing’s reflex › Increased ICPà Systemic Hypertension Bradycardia Look for specific breeds prone to life threatening immunemediated encephalitis rather than idiopathic disease as underlying cause of seizures Advanced Imaging (Brain MRI) Cerebrospinal fluid analysis +/- Electroencephalography (EEG) Brain MRI (+/- CT) CT MRI Ancillary Diagnostics Who needs them? Dogs <1 year or >5 years old At risk dog breeds Presenting in status epilepticus Any inter-ictal neurologic deficits Seizures refractory to appropriate drug therapy Cats Goals are important We do NOT expect to completely eliminate all seizure activity Frequency Severity 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 Approximately 75-85% can be adequately controlled with multiple drugs % 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 Excitatory neurotransmitters depolarize cells • • Aspartate Glutamate Inhibitory neurotransmitters hyperpolarize cells • • GABA Glycine Half-life 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 When drug eliminated = dose given Accumulation at steady-state allows therapeutic concentrations through peakàtrough 87% reach steady state after 3 x T ½ 95% reach steady state after 5 x T ½ Choosing an Anticonvulsant Concurrent medical conditions Monotherapy if possible Different MOAs if Multimodal Dosing interval Side effects Cost Newer drugs vs “older” drugs Tolerability of side effects Costs of drug monitoring Emergency visit fees Cost of medications (Brand vs generics) Familiarity and comfort of clinician with prescribing and monitoring Complications of interactions between multimodal anticonvulsant therapies Phenobarbital Potassium Bromide Diazepam Felbamate Gabapentin Zonisamide Levetiracetam Clorazepate Topiramate Rufinamide Lacosamide Phenobarbital Unknown MOA › Increased cell response to GABA › Antiglutamate effects › Decrease flow of Ca into channels Phenobarbital Effective, inexpensive, convenient dosing DEA Schedule IV Preferred medication in cats ~60% effective as monotherapy Phenobarbital Peak concentration 2-3 hours after ingestion 86-96% absorbed orally T ½ › 40-90 hrs dogs › 40-50 hrs cats Metabolized by liver, p-450 enzyme inducer 25% excreted by kidneys unchanged 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? Treat the patient, not the numbers Main indications Ø avoid toxicity Ø calculation of new AED dosage If levels are below the lab’s reported therapeutic range and patient’s seizures are clinically well controlled… Phenobarbital Monitoring 2.0-3.5 mg/kg PO BID Check serum levels 14 days following initiation Peak & Trough sampling not important 15-35 mcg/mL therapeutic dogs, 10-30 cats 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 PU/PD/Polyphagia/Weight Gain › Blocks release ADH › Suppression on satiety center in hypothalamus Sedation, Paresis and Ataxia pelvic limbs – resolves after 2 weeks usually Phenobarbital Side Effects o Neutropenia, anemia and/or thrombocytopenia › Idiosyncratic or Immune-mediated › Resolves when discontinued 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 Alters thyroid hormone metabolism, decreased T4 and fT4 Little effect on adrenal tests 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 MOA Unknown › Believed to hyperpolarize neuronal membrane passing through the Clchannel T ½ 21-24 days dogs, 11 days cats 2-3 months until steady state Not protein bound Excreted by kidneys 60% absorbed rectally Potassium Bromide 30-50 mg/kg/day monotherapy 20-30 mg/kg/day with Phenobarbital Feed with administration › Vomiting common Potassium Bromide Loading › 400–600 mg/kg à 1 – 1.5mg/mL serum conc. Load over 1-5 days, add daily dosing Start maintenance early if too sedate Benny 3 year MC Beagle 10.0 kg Adopted 2 years ago o report he experiences about 1 generalized seizure a month until past two months Now having 1-2 seizures weekly 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… 300 mg KBr solution PO q 24 hr Current KBr level 1.1 mg/ml 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 Therapeutic Range 1-3 mg/mL* Check 3 months after starting maintenance dose Monitor serum levels and renal parameters (BUN, Creatinine, UA) every 6 months – 1 year Potassium Bromide Common side effects › Sedation › PU/PD › Paresis and ataxia pelvic limbs › Vomiting Polyphagia 25% Rarely aggressive behavior, coprophagia, attention seeking, pancreatitis Bronchial pneumonitis in cats Potassium Bromide Chloride in diet Spurious elevation serum chloride levels Can withdrawal immediately, long T ½ Saline diuresis treats KBr toxicity (+/- furosemide) Decrease dose in dogs with renal disease Pheno vs. KBr 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%] Phenobarbital treatment also resulted in a greater percentage decrease in seizure duration (88%), compared with bromide (49%). % pt. seizures eradicated Pheno KBr 85% 52% % decrease in seizure duration 88% 49% Benzodiazepines - Diazepam Daily AED for cats Highly Lipid Soluble - Status Epilepticus Believed to enhance GABA Appetite stimulant Diazepam IV, IM (unreliable), PO, Rectal, Intranasal Metabolized by liver Crosses BBB Highly lipid soluble ~80% bioavailable IN & per rectum T ½ dog- 2.5 hr T ½ cat- 5.5 hr Diazepam Status epilepticus 0.5 mg/kg IV CRI in 0.9% NaCl or 2.5% dextrose › Dogs 0.5 - 2 mg/kg/hr › Cats 0.25 - 1 mg/kg/hr Add-on maintenance therapy in cats › 0.5 – 2 mg/kg/day PO divided BID-TID Dogs short half-life and functional tolerance* Diazepam Sedation most common Skeletal muscle relaxant Fatal Hepatic necrosis 3 days -2 weeks after initiation in cats Check liver enzymes 1 week and 1 month following initiation of therapy Felbamate Dicarbamate Use in cases refractory to phenobarbital and KBr MOA › Potentiation GABA › NMDA blockade › Decrease Na currents Added to phenobarbital without potentiating sedation Add-on or sole therapy Felbamate 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 Ataxia, limb rigidity, tremors, salivation, vomiting, weight loss, decreased appetite Treatment of partial seizures and seizure-like activity with felbamate in six dogs. (Ruehlmann, et al.) Six dogs with partial seizures were treated with felbamate. All dogs experienced a reduction in seizure frequency Two dogs had an immediate and prolonged cessation of seizure activity. 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 Idiosyncratic bone marrow suppression and hepatotoxicity rarely reported in humans Recommended monitoring CBC and chemistry at one month and every 6 months › Especially if used concurrently w/ phenobarbital Felbamate 15 mg/kg PO q 8 hr, maximum 300 mg/kg/day Dose increased every 2 weeks by 15mg/kg until controlled Rarely evaluate serum levels due to expense, low toxicity, and wide safety margin Not evaluated in cats Very expensive Gabapentin (Neurontin) Structural analog to GABA MOA not completely understood › Enhance action of GABA › Inhibition of Calcium channels No evidence of use in cats Gabapentin T ½ 3-4 hr dogs 80% bioavailability Minimal protein binding Primarily excreted through kidneys 30% metabolized by liver without enzyme induction Gabapentin Sedation common side effect Serum monitoring not common in dogs Not found to effectively reduce seizure frequency as an add-on drug in dogs with refractory IE 20-30 mg/kg q 8 hr Less expensive now Zonisamide (Zonegran) Sulfonamide-based anticonvulsant MOA potentials › Blockade of T-type calcium and voltage-gated Na channels › Enhancement of GABA › Inhibition of carbonic anhydrase - CSF Zonisamide T ½ 15 hrs dog, 33 hrs cats Primarily metabolized by hepatic microsomal enzymes High margin of safety Mild sedation, ataxia, vomiting dogs Anorexia, vomiting, diarrhea, lethargy cats Idiosyncratic Reactions Non-Antibiotic Sulfa RARE- Renal tubular Acidosis, Hepatic necrosis, KCS, Blood Dyscrasias Hypersensitivity reaction rather than dose related hepatotoxicity Recheck CBC and liver profile one week after treatment initiation Zonisamide 5-7.5 mg/kg PO BID as sole therapy Higher doses needed as add on to phenobarbital Moderately Expensive Zonisamide Efficacious as add-on therapy to phenobarbital/KBr therapy 70% reduction in seizure frequency (Klopmann, 2007) 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) 5 dogs received zonisamide (5 mg/kg) before and during repeated oral administration of phenobarbital. Repeated phenobarbital decreased the maximum serum concentration (Cmax) and elimination T ½ of zonisamide Cmax and T ½ for zonisamide were restored to previous levels 12 weeks after the discontinuation of phenobarbital. Repeated administration of phenobarbital enhanced the clearance of zonisamide Dosage Considerations 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) Pyrrolidine-based anticonvulsant MOA › Binds to synaptic vesicle 2A (SV2A) in brain à leads to alterations in Ca++ flow? Levetiracetam 100% bioavailable T ½ 4 hr dogs, 2.9 hr cats but anticonvulsant effects may persist longer 70-90% eliminated unchanged in urine No hepatic metabolism Levetiracetam Wide margin of safety Side effects rare Salivation, restlessness, vomiting, ataxia Less expensive that previously (generic available) Seems to be tolerated in cats with similar side effects The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. (Volk, et al.) 14 dogs with IE which were pharmacoresistant to PhB and KBr entered into prospective trial with Keppra as an add-on medication. 8/14 dogs seizure frequency was reduced by 50% However, 6/9 responders experienced a later increase in seizure frequency after 4-8 months of tx “Honey Moon” effect Levetiracetam was well tolerated by all dogs Levetiracetam 20 mg/kg PO q 8 hr Due to short T ½ dosage interval is important 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 Therapeutic drug levels in veterinary patients not established Human data 5-45 mcg/ml I check peak and trough levels only in severe refractory cases/SE to calculate T ½ Clorazepate Benzodiazepine Dogs T ½ 3-6 hr Extended release tablets available but offer no advantage Clorazepate in dogs: tolerance to the anticonvulsant effect and signs of physical dependence. (Scherkl) Dogs were treated with clorazepate, 2 mg/kg t.i.d. were given orally for 5-6 weeks. One day after cessation of treatment, 2 out of 6 dogs showed withdrawal seizures, which, in 1 case, were lethal. This shows that severe withdrawal symptoms, even lethal seizures, may appear after abrupt discontinuation of chronic clorazepate treatment Clorazepate Long term use can lead to development of drug tolerance, increase serum phenobarbital concentrations and/or potential hepatotoxicity Abrupt discontinuation after chronic administration can cause severe withdrawal symptoms › Status epilepticus Clorazepate 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 0.5-1.0 mg/kg PO q 8h x 3 days Continue all other maintenance AED during this time as well If seizures continue despite addition of Clorazepate = Emergency Hospitalization Topiramate (Topamax) Novel AED Not well studied in vet med Na channel inactivation, enhanced GABA activation, reduced glutamate excitation Dogs T ½ 2-4 hr Hepatic and renal excretion Topiramate as an add-on antiepileptic drug in treating refractory canine idiopathic epilepsy. (Kiviranta) 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. SE- Weight loss, sedation and ataxia were the most common adverse effects of topiramate therapy Topiramate 2.5-5.0 mg/kg PO 8-12 hr? Generic now available Clients must be informed this is still “investigational” in vet med “Dopamax” Rufinamide (Banzel) No clinical veterinary data Prolongs inactive state of Na channels Renal excretion Effective treatment for partial seizures in humans Pharmacokinetics of oral rufinamide in dogs. (Wright, et al.) No adverse effects were observed. 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) New drug filed with FDA for use in epileptics with focal seizures with secondary generalization MOA unknown No clinical studies in vet med Well tolerated in dogs in FDA safety studies Most common SE- dizziness, ataxia Lacosamide 100-200 mg BID (humans) 50, 100, 150, 200 mg tablets Summary Multiple AED available for use in small animal patients Many animals not controlled with monotherapy Owners understanding of tx goals is very important (Epilepsy is controlled most of the time, not cured) 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?
