17 – Antiepileptic Drugs (AED) Flashcards
Who gets epilepsy?
- *Dogs
- Cats
- Foals
- Parrots
How can risk be characterized/’assessed (equation)?
- Hazard X exposure
- “severity X likelihood”
What are some risks/issues associated WITH AED therapy?
- Adverse effects
- Cost: medication, therapeutic monitoring/bloodwork
- Client effort: life-long administration
What are some risks/issues associated WITHOUT AED therapy?
- Progression of seizures
o Eventual euthanasia
What is the job of the vet as a RISK MANAGER?
- Discuss therapeutic options with client
- Understand what risk the client is willing to accept
- Tailor drug regimen to best manage the risks
- *COMMUNICATE!
What are some areas of the risks you need to figure of if the client is willing to accept?
- Acceptance of seizure incidents
o Complete elimination is NOT generally feasible
o Reduction of seizure frequency is REASONABLE - Acceptance of adverse drug events
- Acceptance of therapeutic drug monitoring (TDM), cost, compliance
What is the job of the vet before AED therapy is initiated?
- Set appropriate expectations of the goals of the AED therapy
- Expected adverse effects
- Schedule for therapeutic drug monitoring and bloodwork
What is the job of the vet while on AED therapy?
- Check on adverse events, monitor and ADJUST therapy
What is the ‘mechanism’ and objective of anti-convulsant therapy?
- Pathogenesis not well understood
- *objective is to raise “seizure threshold” by stabilizing neuron membrane potential
o Enhance inhibitory NTs (ex. GABA, glycine)
o Reduced excitatory NTs (ex. glutamate)
How can hyperpolarization occur? (ie. Channels)
- Activating post-synaptic K or Cl channels OR
- Reducing pre- and post- synaptic Na/Ca channels
Why is anticonvulsant therapy so challenging? (4 reasons)
- Individual response is UNPREDICTABLE
o Subpopulation of dogs (large breeds) are ‘refractory’ to therapy - Not a cure!
o Chronic administration, side effects, ‘tolerance’ (PK or PD) - POOR COMPLIANCE
- TDM may be required to ensure efficacy/safety
Therapeutic drug monitoring: ‘negative’ and positive
- Tough to sell to client
- OPPORTUNITY to optimize dose regimen for ‘individual’ therapy
What does the prognosis for dogs with epilepsy depend on? (combination of 3 things)
- Veterinary expertise
- Therapeutic success
- Owner’s motivation
*epilepsy=implies increased risk of premature death
Survival curve for an epileptic
- If epilepsy is cause of death, it will happen quicker
- 50% euthanized within 1-2 years
- *significant risk factor for early euthanasia
What anticonvulsant therapy is licensed for veterinary use?
- Not much
o Phenobarbital (Canada)
o Pheonobarb, KBr, Primidone (USA)
What other drugs are used in Canada? (even if not licensed)
- Benzodiazepines (during seizures=not for prevention)
- Levetiracetam, GABA-type drugs
- Others: Imepitoin, Zonisamide, CBD
What is the efficacy of Phenobarbital and KBr?
- PB: reported up to 85%
- KBr: maybe slightly lower, but similar?
- Newer drugs not as effective as previous drugs
What is phenobarbital?
- Barbiturate with anti-epileptic effects when used at sub-anesthetic doses
o Mechanism? Decreases Ach, Glu, NE OR increase GABA? - Human generics also available
- *don’t confuse with barbiturates (ex. pentobarbital: euthanasia)
- **CONTROLLED DRUG
What are the adverse effects of phenobarb in dogs?
- Sedation/lethargy
- Polyuria and polydipsia (decrease urinary smooth muscle tone), doesn’t usually persist
- Polyphagia (*avoid obesity: PB distributes into fat)
- Ataxia: should diminish over next 10-15 days
- Blood dyscrasias?
- Decrease in T4 concentration
- HEPATOTOXICITY
- Drug interaction: CYP enzyme INDUCTION
Drug interactions with Phenobarb
- Will get drug interactions as you are giving it CHRONICALLY
- *INDUCTION: produces more CYP (not immediately but increases pretty fast)
o Increases clearance capacity in the hepatocytes
o *drugs get cleared faster (including Phenobarb) - Be very CAREFUL, watch the concentrations!
How does Phenobarb cause hepatotoxicity in dogs?
- Increased ALP(++) and ALT(+)
o Liver enzymes>3x normal! - Abnormal bile acid stimulation test
- Decrease albumin, urea and cholesterol
- *if really bad or getting worse=change dose or switch to a different drug
- Typically DOSE dependent=we have control over the process
Phenobarbital-induced hepatotoxicity: gross changes
- Cirrhosis
- Fibrosis
- Nodules
- *generally chronic and DOSE-dependent
What are the adverse effects of Phenobarb in cats?
- Sedation/lethargy
- Polyphagia (must warn owners to avoid obesity)
- Ataxia: diminish over next 10-15 days
- Polyuria and polydipsia: doesn’t usually persist
- Allergic reaction
- Blood clotting disorders: due to platelet counts
- Drug interactions: CYP enzyme induction
- *hepatotoxicity is RARE in cats
Allergic reaction in cats on Phenobarb
- Blood dyscrasias: low platelet and WBC count
- Temporary facial swelling
What are the general PK of phenobarbital?
- Good oral bioavailability (F)
- Moderate volume of distribution (Vd)
What are the PK of phenobarbital in dogs?
- Long half-life (1.5-4 days) *measure in 2 weeks
- *induces cytochrome P450 enzymes
o Increase enzymes=increase clearance=decrease half-life later on
What are the PK of phenobarbital in cats?
- Non-linear kinetics can occur
o Increase dose may NOT be proportional to increase in drug exposure - BEWARE: minor dosage changes can result in large fluctuations in blood levels
o Can make drug ineffective (blood levels too low)
o OR result in excessive sedation (blood levels to high)
Example of Phenobarbital drug concentration vs. days graph: accumulation (predicted)
- Dose interval is SHORTER than half life=ACCUMULATION OCCURS
- *steady concentrations are reached after 5-7 HALF-LIVES (not doses!)
o Get plasma sample at 10-14 days
Example of Phenobarbital drug concentration vs. days graph: accumulation + INDUCTION
- *hepatic enzyme induction over time
o INCREASED CLEARANCE=DECREASED CONCENTRATIONS - *happen over MONTHS (not days)
Phenobarbital PK in birds
- Oral
- Gavage: tube
- *hard to take blood samples as they have a very small plasma volume
o Get individual animals and make an assumption for the population
Does it matter to switch between generic brands of Phenobarbital?
- NOT a big deal in humans
- DOGS: probably not
o But minor difference in PK may have significant clinical effect in some dogs
Compounded anticonvulsants examples
- Lower plasma concentrations of phenobarbital even when they were increasing the dose
- *assayed the phenobarbital=found it was half the strength it was supposed to be
o If solution=2 weeks from shelf life
o This one said: 3 months, and it was only 3 weeks old
o DEGRADED OVER TIME - *when used new batch=seizure control restored
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Potassium Bromide (KBr)
- VERY old anit-epileptic drug
- Likely, hyperpolarizes neural cell membranes
- *none approved for vet use in Canada
o But can get from compounding pharmacies - K-BroVet solution and tablets approved for dogs in USA
What are the adverse effects of KBr in DOGS?
- Sedation
- Vomiting/diarrhea/constipation
o Should go away quickly - Increased hunger/thirst : salty
- Pelvic limb weakness or stiffness (not really ataxia)
- Pancreatitis
- Skin reactions: pruritic lesions
- Occasional behavioural changes
o Depression, irritability/aggression, attention seeking or aimless pacing
What are the drug interactions of KBr?
- NONE documented
- *FOOD interactions
What is the half-life of KBr?
- EXTREMELY LONG (24d)
- Can use ‘loading’ dose for first week
- Once at steady state: missing single dose is NOT critical
What is the elimination of KBr?
- Renal
o But reabsorbed with Cl - NO hepatic metabolism: so decreased drug interactions
What is the influence of diet (SALT) with KBr? (IMPORTANT!)
- Watch out for salty treats
o Decrease Br reabsorption from renal tubule due to increased Cl competition for tubule transporters
o Increase Br excretion = decrease plasma Br - Watch out for cardiac diets (low salt)
o Increased Br reabsorption from renal tubule
Will increase plasma KBr
How do you treat overdose of KBr?
- Use Cl to flush it out
- *NaCl saline=flushes it out
KBr and cats
- NOT RECOMMENDED
- 50% showed adverse reactions
o Coughing
o Bronchial asthma due to allergic reaction=severe - *watch out with compounded drugs!
Diazepam (Valium)
- Used to treat STATUS EPILEPTICUS in cats and dogs
- NOT for seizure prevention
- Hepatic metabolism: 2 active metabolites
o Maybe problems if used chronically (ex. hepatotoxicity)
How do you give diazepam?
- IV: crossed BBB rapidly
o Hard to do when they are seizing - Rectally: 50% bioavailability
o Administer 2x the IV dose
o Owners: need to tell them it binds to plastic and inactivated by light - Intranasal: 80% bioavailability (hard to do=dangerous to go close to mouth)
- Oral: low bioavailability
What else can Diazepam be used for?
- Behavioural disorders
- Appetite stimulant
- Pre-anesthetic
What are some ‘newer’ anticonvulsants?
- Levetiracetam (Keppra)
- Brivaracetam?
- (Gabapentin)
- (CBD)
What are some warnings with ‘newer’ anticonvulsants?
- *most efficacy studies are:
- Typically administered as ADD-ONS
- NON-CONTROLLED
- Typically SMALL SAMPLE SIZE
- Often not BLINDED
- IMPRECISE OUTCOME MEASURES
Levetiracetam (Keppra) efficacy in dogs
- Usually used in combo with Phenobarbital +/- KBr
o Makes sense to use as ADD-ON - Monotherapy
o Doesn’t really work that well - *NEW: used for CLUSTER SEIZURES
o Use it with Diazepam/phenobarbital when having a seizure=big effect to stop the seizure more quickly!
Levetiracetam (Keppra) dosage regimen
- 3x/day=challenge for client (cost and compliance)
- Start at high dose: 20mg/kg
- Short half life: if miss dose=more of a problem
- High oral bioavailability
- *RENAL EXCRETION!
o Good if worried about hepatic disease
o Decrease dosage in renal impaired patients
Levetiracetam (Keppra) ‘safety’
- No drug interactions
- TOLERANCE may develop: ‘honeymoon period’ of 4-8months
- Often don’t do drug/blood monitoring
Levetiracetam (Keppra) in cats
- 3x/day orally
- Maybe transdermal will be something in FUTURE?
- Safe but
o Will get hypersalivation: makes sense (not a big deal)
Brivaracetam
- New more potent analogue of levetiracetam
o Longer half life
o Nothing about efficacy - *don’t recommend using it!
- Lots of human generic versions available
Gabapentin
- Structural analogue of GABA, but doesn’t impact GABA receptors
o Block Ca channels? - May be given in combination with Phenobarbital and/or KBr
- Safe and cheap (minimal side effects)
- *not many different formulations available (especially for cats and smaller dogs)
- NOT much evidence! Maybe works?
Pregabalin (Bonqat)
- Oral solution approved as anxiolytic in cats before car transport
o NOT approved as anticonvulsant - NOT much evidence to say it works. Maybe?
CBD for epilepsy?
- Decrease seizure frequency in Phenobarbitol/KBr treated dogs when oral CBD oil ADDED
- PROMISING: but smaller sample size
o Higher CBD plasma concentrations=lower seizure incidence
o HIGH DOSE: 9mg/kg=lots of side effects - *human results are very promising
