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62 Cards in this Set
- Front
- Back
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What are epileptic seizures? |
Disturbance of the neuronal environment lowering the threshold for electrical activity. - 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 |
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Intracranial versus extracranial epileptic seizures? |
INTRACRANIAL: - Functional - no abnormalities can be detected on investigation. - Structural - abnormality within the brain (e.g. tumor, encephalitis, etc)
EXTRACRANIAL: - Metabolic- e.g. hypoglycemia, hepatic disease, electrolyte disturbance - Toxic - e.g. organophosphates, carbamates, lead, ivermectin, etc |
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How do epileptic seizures arise? |
Either: 1. INADEQUATE Neuronal Inhibition: - Abnormality of inhibitory NTs (e.g. GABA = major inhibitory NT) - Loss of inhibitory neurons - Decreased neuromodulation by serotonin, dopamine or noradrenaline. 2. EXCESSIVE NEURONAL EXCITATION: - Abnormality of excitatory NTs (L-glutamate = major excitatory NT) - Too many excitatory neurons - Increased acetylcholin |
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What are the two mechanisms thought to be involved with termination of seizures? |
1. Input from subcortical areas 2. Development of LACTIC ACIDOSIS
* LACTIC ACIDOSIS is thought to inhibit neuronal excitability. |
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In some patients there may be a failure to terminate seizure activity resulting in: |
1. Cluster seizure activity 2. Status epilepticus * In addition to maintenance therapy, these cases also need EMERGENCY INTERVENTION! |
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Purposes of Anti-epileptic drugs? |
1. Prevent excessive neuronal activity 2. Avoid the spread of seizure activity within the brain 3. Protects the brain from the excitotoxic effects of seizures and neuronal damage 4. Stop the progression of seizures over time |
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What are the major CNS Targets for Anti-epileptic drugs (AED)? |
1. GABA (major CNS inhibitory NT) 2. Glutamate (major CNS excitatory NT) 3. Voltage gated ion channels: - Sodium - Calcium - Chloride |
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AEDs need to be highly ________ soluble to penetrate the CNS. |
LIPID |
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What is the MAJOR EFFECT of AEDs? |
The major effect of anti-epileptic drugs is to HYPERPOLARIZE THE INSIDE OF THE CELL, with the help of major anticonvulsant medications and GABA. |
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What are the two main groups of epileptic seizure types? |
1. Occasional Brief Seizures - Few minutes long and rarely occur - Most common 2. Severe, Emergency Seizures - Clusters of short seizures (>1 in 24 hour period) - Status epilepticus (prolonged; >20-30 mins) |
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Management protocol for epileptic seizures? |
1. Address any underlying cause (functional, structural, metabolic or toxic?) 2. Symptomatic control of seizures with medication, which may consist of: - Chronic ongoing therapy = dogs with occasional, brief seizures - Immediate, short-term emergency therapy = status epilepticus or severe cluster seizure doggies |
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What are the AIMS of epileptic treatment? |
1. Reduce frequency, severity, & duration 2. Delay progression 3. Minimize side effects 4. Minimize demands on owner * Unlikely to totally abolish all seizures. |
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Anti-epileptic drug clinical effects are based on maintaining an effective ________________________. |
SERUM CONCENTRATION - So drugs that are eliminated slowly are ideal! |
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What are suitable AEDs for chronic therapy? |
1. Phenobarbital (or phenobarbitone) - Dogs & cats 2. Imepitoin - Dogs 3. Potassium bromide - Contraindicated for cats 4. Diazepam - Chronic for cats; emergency medication for dogs! |
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What are suitable AEDs for chronic therapy, REFRACTORY CASES? |
1. Levetiracetam 2. Zonisamide - Dogs & cats 3. Gabapentin |
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What are the important EXTRA-CRANIAL CASES for which standard AEDs will either have no effect or could be contra-indicated? |
1. Hepatic encephalopathy 2. Hypoglycemia 3. Multiple toxic causes: carbamates, methaldehyde (slug bate), organophosphates 4. Ion imbalance: hypocalcemia, etc |
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Describe which AEDs you'd choose INITIALLY to give for chronic therapy epilepsy in a DOG. If refractory to initial choice? If refractory to this combination therapy? |
INITIALLY: - Phenobarbital (Pb) - Imepitoin INITIAL REFRACTORY: - Potassium bromide (KBr) in addition to Pb REFRACTORY TO COMBO: - Add or change to Levetiracetam, Zonisamide or gabapentin |
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What initial chronic therapy AED would you give a dog with hepatic impairment? |
Potassium Bromide or Levetiracetam |
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Describe which AEDs you'd choose INITIALLY to give for chronic therapy epilepsy in a CAT. If refractory to initial choice? If refractory to this combination therapy? |
INITIALLY: - Phenobarbital or diazepam INITIAL REFRACTORY: - Try combination of the two IF REFRACTORY TO THAT: - Levetiracetam
* DON'T USE POTASSIUM BROMIDE IN CATS! |
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When to start MAINTENANCE TREATMENTS for epilepsy? |
Ideally as soon as the animal develops epileptic seizures, but DEFINITELY if there's >1 per month! |
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What are the important facts about AEDs that a vet should inform the client of before starting maintenance treatments? |
Absence of seizures is hard to achieve. - Medication is aimed at controlling seizures - Side effects common initially - Sometimes side effects are more severe than seizures - Owners must keep diary of seizure events - Withdrawal effects: may precipitate seizures, so important to maintain drug once started! |
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Most common FIRST CHOICE anticonvulsant? |
PHENOBARBITAL - Enhances activity of GABA, increasing neuronal inhibition - Reduces neuronal excitability through interaction with glutamate receptors - Inhibits voltage-gated calcium channels - Competitive binding of chloride channel picrotoxin site |
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Mechanism of action of Phenobarbital? |
FIRST CHOICE ANTICONVULSANT for Chronic therapy. - Enhances activity of GABA, increasing neuronal inhibition - Reduces neuronal excitability through interaction with glutamate receptors - Inhibits voltage-gated calcium channels - Competitive binding of chloride channel picrotoxin site |
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Pharmacokinetics of Phenobarbital? |
- Rapid oral absorption - High bioavailability - Low lipid solubility, so slower penetration - Primarily hepatic metabolism - Serum concentrations will decrease with chronic therapy & therefore doses will need to increase; check every 1-2 weeks! |
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With AEDs, the serum concentration is most important, not the administered dose.
True or false? |
TRUE - serum concentrations provide optimal seizure control while minimizing side effects when within the THERAPEUTIC RANGE. * Different drums have different "steady serum state" = date range at which serum should be checked - Phenobarbital = 1-2 weeks - Bromide = 3-6 months |
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Used to increase serum concentration of AED to a steady state faster. |
LOADING DOSE - Requires 5x the maintenance dose - Must take into account possible side effects associated - Because of side effects, restricted to EMERGENCY CASES ONLY! |
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Initial adverse effects of phenobarbital? Long term therapy adverse effects? |
INITAL ADVERSE EFFECTS: - Polyuria, polydipsia, polyphagia (inc appetite) - Transient sedation (or less commonly, hyperexcitability) - Transient ataxia (uncoordinated, unbalanced, disorientated) - Less commonly: blood dyscrasia (neutropenia, anemia); usually a idiosyncratic or allergic response that resolves LONG TERM THERAPY EFFECTS: - Hepatic toxicity - Induction of hepatic enzymes (ALP, ALT); not in cats - Mild reduction in serum albumin - Increased metabolism of thyroid hormones & suppression of TSH - Induction of hepatic microsomal P450 enzyme systems |
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In dogs, phenobarbital half-life increases with time.
True or False? |
FALSE - Pb half-life DECREASES with time. - Hepatic enzyme induction decreases the half-life, meaning that the drug doesn't last as long in the system, so must increase the dose. |
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How would one monitor hepatic function when using phenobarbital as AED? |
Because of induction of hepatic enzymes these would be a poor guide to hepatic impairment. * BILE ACID ASSAY is best guide to hepatic function. |
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During routine monitoring of serum phenobarbital levels, when is consistency in timing of blood sample collection important? |
When phenobarbital is used at HIGH ORAL DOSES! * Not relevant for a dose <8mg/kg/day. |
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What routine monitoring of patients receiving chronic AEDs must be performed and how often? |
1. Regular monitoring of serum phenobarbital levels = every 6 months 2. Regular monitoring of hepatic and bone marrow function = every 6-12 months - Hematology, biochemistry, & bile acid assay |
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What are common causes for phenobarbital treatment failure? |
1. Low serum concentration - Dose too low (below therapeutic range) - Poor owner compliance - Interference with absorption 2. Drug interaction 3. Incorrect diagnosis 4. Second disease causing seizures 5. Refractory to phenobarbital (25-40% of dogs) - Add another maintenance drug (imepitoin, bromide) |
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Mechanism of action of Potassium Bromide? |
INTERACTION WITH CHLORIDE CHANNELS - Cl- channels modulated by GABA & function to hyperpolarize the neuronal cell membrane, making it more stable - Bromide crosses the chloride channels in preference to chloride, as it's smaller - Facilitates the effect of NTs acting on the GABA channel by hyperpolarizing the cell membrane - May also act synergistically with phenobarbital |
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Potassium Bromide - Initial Adverse Effects? - Long Term Adverse Effects? |
INITIAL ADVERSE EFFECTS: - Vomiting & Anorexia (often resolved by changing formulation or mixing with food)
LONG TERM THERAPY ADVERSE EFFECTS: - Ataxia & sedation - Asthma in over 50% of cats & can be fatal so CONTRAINDICATED FOR CATS! - Pancreatitis - Pruritis |
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Why is potassium bromide contraindicated in cats? |
Long term therapy results in asthma in over 50% of cats and can be fatal! |
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Describe the use of Potassium Bromide (KBr) in Dogs. |
1. SOLE ANTICONVULSANT (if Pb is contraindicated) - Approx 50% of cases
2. WITH Pb = in refractory epilepsy |
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Mechanism of action of PEXION? |
Partial agonist at Benzodiazepin recognition site of GABA receptor - Potentiates GABA receptor-mediated inhibitory effects of neurons - Also has a week Calcium channel blocking effect |
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Pexion serum concentrations are not measured, typically.
True or False? |
TRUE |
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Adverse effects of pexion? |
- Polyphagia, polyuria, polydipsia, hyperactivity, hypersalivation, vomiting, ataxia, diarrhea, and few others have been reported at beginning of treatment - BUT when compared to phenobarbital, fewer adverse effects were noted with pexion. |
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Uses of pexion? |
Reducing frequency of generalized seizures due to idiopathic (unknown) epilepsy in dogs. - After 20 weeks, treatment considered as effective as phenobarbitone with no loss of anticonvulsant activity & no increase in liver enzymes! *Efficacy as an add-on has not been demonstrated.. |
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Use of Levetiracetam? |
Add-on medication in refractory dogs - Sole anticonvulsant in cats - Useful in animals with hepatic impairment (90% renal excretion) |
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Use of Zonisamide? |
Add-on medication in refractory dogs |
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Use of Gabapentin? |
Add-on medication in refractory dogs - Particularly those with SEVERE CLUSTERS OF SEIZURES |
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Status Epilepticus vs Cluster Seizures? |
STATUS: - 1 epileptic seizure lasting more than 30 minutes or, - 2 or more seizures without a break, lasting more than 30 minutes in total
CLUSTER: - 2 or more generalized epileptic seizures within 24 hours |
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Main aim of emergency therapy for severe seizures? |
TOTALLY ABOLISH THE ACUTE SEIZURE EPISODE - Emergency treatment only for duration of severe episode - Must then determine underlying cause if possible and start chronic therapy if required. |
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What medications are most effective for EMERGENCY THERAPY? |
Relatively short-acting medications, meaning that a higher dose can be used with a lower risk of overdose - These drugs AREN'T suitable for maintenance (except Diazepam in cats). |
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List the suitable medications for EMERGENCY THERAPY: |
1. DIAZEPAM - Orally, IV (bolus & constant infusion) or rectally - Dogs and cats - Also used for maintenance in cats! - 2-3 mins to clinical effect; repeated up to 3 times 2. MIDAZOLAM - IV (bolus & constant infusion) - Can be used with Diazepam 3. LEVETIRACETAM - IV (bolus & constant infusion) - Particularly used for CLUSTER SEIZURES 4. Propofol - only used with continued seizures despite treatments above - Dogs & cats given slowly via IV to effect. 5. Potassium Bromide loading dose - not in cats! |
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Pharmacokinetics of Diazepam? |
- Only used as emergency med in dogs - Can be used as maintenance med in cats - Wide margin of safety = can dose multiple times - Anticonvulsant effect follows 2-3 mins after IV administration, with effects lasting about 20 mins in dogs; treatment therefore needs to be repeated. |
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Pharmacokinetics of MIDAZOLAM? |
- Wide margin of safety and broad therapeutic index - RAPID ELIMINATION (half-life of around 53-77 mins) |
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In severe clusters, then in addition to maintenance therapy, you can use additional pulse therapy during the cluster with: |
1. LEVETIRACETAM (most common!) 2. Long-acting Benzodiazepams 3. Rectal diazepam 4. Gabapentin 5. Slow release phenytoin formulations |
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Aim of treatment of cluster seizures? |
Reduce number of seizures in a cluster - At the end of the cluster must stop additional drug, but keeping the dog on normal maintenance therapy |
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_____________ epilepticus is a life threatening emergency. |
STATUS EPILEPTICUS! |
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Aims of management of status epilepticus? |
1. Stop the seizures, using short-acting anticonvulsants (DIAZEPAM) 2. Supportive care - fluids, electrolytes, etc 3. Follow-up maintenance anticonvulsant therapy 4. Obtain diagnostic samples |
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How would you approach achieving phenobarbital blood levels in a status epilepticus patient that is phenobarbital naive? Presently on Pb therapy? |
Pb NAIVE: - Give initial loading dose (12 mg/kg IV) - If animal isn't too sedated: further boluses at 3 mg/kg to take total dose to 18-24 mg/kg
PRESENTLY ON Pb THERAPY: - First, get serum levels! - Single bolus of 3 mg/kg to slightly increase levels - Potassium bromide dose... |
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Describe the Bromide Loading Regime for a dog in status epilepticus, in the presence of therapeutic levels of Pb: |
ORAL OR RECTAL LOADING DOSE: - Rectal may cause severe diarrhea - 200 mg/kg daily for 5 days, divided into 4-6 doses - Single loading dose of 600-1000 mg/kg, divided into multiple doses * Monitor levels post-load and one month later! |
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When would a Bromide Loading Regime be required/appropriate? |
DOGS GOING INTO STATUS EPILEPTICUS IN THE PRESENCE OF A THERAPEUTIC LEVEL OF PHENOBARBITAL! |
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What if the seizures continue in a status epilepticus patient initial emergency doses of anticonvulsants? |
May need to sedate or GA for 12-36 hours via: 1. Constant diazepam infusion 2. Constant midazolam infusion 3. Levetiracetam infusion 4. Propofol coma 5. Barbiturate coma |
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What type of supportive care must be provided to sedated status epilepticus patients? |
1. Maintain normal body temp 2. Maintain patent airway 3. Turn patient every 2-4 hours 4. Monitor vital parameters 5. Broad-spectrum antibiotic therapy |
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What is the major inhibitory NT? |
GABA |
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What is the therapeutic range of a drug? |
Serum concentration level providing optimal seizure control while minimizing side effects |
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Name a drug used as an initial therapy in dogs? Cats? |
Dogs = Phenobarbital or Imepitoin
Cats = Phenobarbital or Diazepam |
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Name a drug used as an adjunctive therapy in dog? Cat? |
Dog = Potassium bromide + Pb or change to Levetiracetam
Cat = Combining Pb and Diazepam or switch to Levetiracetam |
