Antiepileptic Drugs Flashcards
Epilepsy
-dogs (most common idiopathic epilepsy)
-cats
-horses (foals)
-birds (parrots common)
Rick characterization
=Hazard x Exposure
(Severity x likelihood)
Risks associated with anti epileptic drugs
-Adverse effects
- Cost (of medication and therapeutic monitoring/bloodwork)
-client effort (life long administration)
Risks associated without anti-epileptic drug therapy
-Progression of seizures and eventual euthanasia
Veterinarians role as risk Manager
- Discuss therapeutic options with client
- Understand what client is willing to accept
-Acceptance of seizures incidents (elimination is not feasible, but reduction of seizure frequency/severity is goal)
-Acceptance of adverse drug events, and TDM, cost, compliance
**note some owners more worried about one than the other - Tailor drug regimen to best manage risks
Communication of AED therapy
- Before therapy is started, discuss:
-Goals of AED therapy
-Expected adverse effects
-Schedule therapeutic drug monitoring and blood work - While on AED therapy:
-check on adverse events
-monitor
-adjust therapy
Objective of Anticonvulsants
**Pathogenesis not well understand
Objective is to raise the seizure threshold by stabilizing neuron membrane potential
Possible mechanisms of Anticonvulsant therapy
- enhance inhibitory neurotransmitters
eg. GABA, glycine - Reduce excitatory neurotransmitters
eg. Glutamate
Hyperpolarization
Occurs by:
- activating post synaptic K or Cl channels
OR
- Reducing pre and post synaptic Na/Ca channels
Why is anticonvulsant therapy challenging?
- Individual response is unpredictable
-subpopulation of dogs are refractory to therapy - No cure
-chronic administration
-side effects
-tolerance (PK or PD) - Poor compliance
- Therapeutic drug monitoring may be needed to ensure efficacy/safety
-tough sell to clients but also allows you the opportunity to optimize dose regimen for individual therapy
Tolerance to drug
-Work initially and then seizures begin to come back
“The animal is termed to have developed a tolerance to the drug”
Premature death and epilepsy
-epilepsy implies an increased risk of premature death (1-2 yrs after diagnosis)
-often the prognosis of epilespy depends on vet experience, therapeutic success, owners motivation
Vet used licensed Anticonvulsant drugs
- Phenobarbitol (Canada)
- Phenobarb, KBr, Primidone
Other drugs used as anti-convulsant
- Benzodiazepines- during seizures, not for prevention
- Levetiracetam (Kepra?), GABA-type drugs
- Imepitoin, Zonisamide, CBD
Efficacy of seizure control from drugs
Phenobarbitol: up to 85%
KBr: slightly lower
**no comparative studies; not sure if newer drugs are more effective
Phenobarbitol
*controlled drug; human generics available
-Barbiturate with anti-epileptic effects when used at sub-anesthetic doses
-Unknown mechanism: may be less excitatory (Ach, Glu, NE) or more inhibitory (GABA)
Other barbiturates
-Pentobarbital= euthanasia
-Thiopental= anesthesia
**All controlled drugs!
Adverse effects of Phenobarbitol in dogs
- Sedation/lethargy
-PU/PD from potentially decreased urinary smooth muscle tone
-Polyphagia (avoid obesity= PB distributes into fat)
-Ataxia (should diminish over 10-15days)
-Some Blood dyscrasias
-Decreased in T4 concentration…be aware of hyperthyroidism
-Hepatotoxicity
-Drug interactions (CYP enzyme induction… NOT INHIBITION)
Hepatotoxicity from Phenobarbitol
- Large increase in ALP and some increase in ALT
*Liver enzymes more than 3x normal - Abnormal bile acid stimulation test
- Decreased albumin, urea, cholesterol
Drug interactions with phenobarbitol
-Drug interactions (CYP enzyme induction… NOT INHIBITION)= increase clearance capacity because increase in cytochrome enzymes
Pathology of Phenobarbitol-induced hepatotoxicity
-Cirrhosis
-Fibrosis
-nodules
**chronic and dose-dependent hepatotoxicity
Adverse effects of phenobarbitol in cats
-sedation/lethargy
-polyphagia (avoid obesity)
-ataxia- dimished over next 10-15 days
-PU/PD
-Allergic reactions (blood dyscrasias= low platelet, WBC counts; and temporary facial swelling)
-blood clotting disorders
-drug interactions (CYP enzyme induction)
**HEPATOTOXICITY IS RARE IN CATS
Pharmacokinetics of phenobarbitol
Good oral bioavailability, moderate Vd
Dogs:
-Long half life in dogs (half life: 1.5-4days)
-induced cytochrome P450 enzymes (increase enzymes= increase clearance= decreased half life)
Cats:
-can become non linear PK
Cats non linear PK of phenobarbitol
Increased dose may not be proportional to increase in drug exposure
NOTE: minor dosage changes can result in large fluctuations in blood levels
-can make drug ineffective (blood level too low)
OR
-result in excessive sedation (blood level too high)
Expected Phenobarb accumulation
-dose interval (every 12hrs) is shorter than half life (1.5-4d) so accumulation occurs
-steady state concentrations reached after 5-7half lives (not doses)
Actual phenobarb accumulation (due to enzyme induction)
Due to hepatic enzyme induction over time, there is an increase in clearance and decrease in concentrations
Phenobarbitol in birds
-can’t take repeated blood samples in birds
-does work, absorbed, etc.
Generic phenobarbitol human drug and switching brands
-reported in human epileptics
-probably not an issue for most dogs if its an approved generic drug (not compounded!!!!)
-there is some minor difference in PK and can have significant clinical effect in some dogs
Compounded anticonvulsants
ex. small dog gets compounded version of phenobarb
-ended up needing increased dosing and were still getting poor effects
-lower plasma concentration of phenobarb present
found out that the solution used was a much lower strength
-Exp date was 3 months… if its a liquid, should only be 2 weeks so possibly lost potency over time
Potassium Bromide
-very old anti-epileptic drug
-likely hyperpolarizes neural cell membranes
-none approved for vet use in Canada but can get from compounding pharmacies
Adverse effects of Potassium Bromide
-sedation
-vomiting/diarrhea/constipation
-increased hunger and thirst
-pelvic limb weakness or stiffness (not ataxia)
-pancreatitis
-skin rxns (pruritic)
-occasional behavioural changes (depression, irritation/aggression, attention seeking or aimless pacing)
Potassium bromide pharmacokinetics
-drug interactions: none but food interactions
-long half life: 24days. Can use loading dose (4x regular dose) for first week to get steady state quicker
> once at steady state then missing single dose not critical
-Elimination: renal BUT reabsorbed with Cl. No hepatic metabolism (so decreased drug interactions)
Potassium bromide interactions with salt
Salty treats:
-high levels lead to decrease of Br reabsorption from renal tubule=more lost in urine because receptors are pulling in Cl (Cl competition for tubule transporters)
**Common!!
Low salt diets (cardio):
-increase Br resorption from renal tubule, will increase plasma KBr. Decreases clearance resulting in higher levels in the body
Treatment of overdose of KBr
Use IV 0.9% NaCl = Cl outcompetes and flushes any excess out!
Potassium bromide use in cats
not used in cats
-show adverse effects= coughing, bronchial asthma due to allergic rxn
Diazepam
-used to treat status epilepticus in cats and dogs
but not used for seizure prevention
**used in the moment!!
Diazepam administration
- IV- crosses BBB fast
2.Rectal- 50% bioavailability, administer 2x the IV dose
-must be kept in coloured glass vial
- Intranasal= 80% bioavailability
- Oral= very low bioavailability
Metabolism of diazepam
Hepatic
-2 active metabolites (nordiazepam and oxazepam which have 10% parent activity)
Other uses of Diazepam
-behavioural disorders
-appetite stimulant
-pre-anesthetic
Diazepam adverse effects
- lethargy, sedation, ataxia
*seizure will also cause these
-hyperactivity?
-increased appetite= weight gain
-seizures may occur if abruptly stopping chronic diazepam
-fulminant hepatic necrosis in cats
Fulminant hepatic necrosis in cats
-idiosyncratic
-oral formulation only
-rare; 11 cases documented
-not for chronic admin in cats
Newer anticonvulsants
-Keppra
-Gabapentin/Pregabalin
-Cannabidol
**not as effective of phenobarbitol or diazepam
What are the newer convulsants used for?
Usually add ons
-non controlled (no placebo for testing and small sample sizes, not blinded)
-imprecise outcome measures
Levetiracetum (Keppra)
-used with phenobarbitol or diazepam for seizures
*not as effective alone
-great for cluster seizures
>Keppra with phenobarb or diazepam saw increased response
-can be costly; frequent dosing, compliance may be issue, still need monitoring, and still need to add phenobarbitol or potassium bromide
Levetiracetum/Keppra dosing
-3x a day dosing
-3-4h half life (difficult for owners)
-high oral bioavailability
-renal excretion: therefore good if worried about hepatic disease, and can just decrease dose in renal impaired patients
Safety of Levetiracetum
-relatively safe
-no drug interactions
- tolerance may develop= honeymoon period of 4-8mths
-some studies showed link to behaviour changes
Keppra use in cats
-oral OR Transdermal product- unsure of absorption right now
-leads to increased hypersalivation, some sedation
-SAFE
Brivaracetam
-newer more potent analogue of levetiracetum
-lots of generic versions in Canada
-Study in cats: longer half life than Keppra, so may be possible for less frequency dosing. Efficacy not known!!
Gabapentin
-structural analogue of GABA that may blocks or modulates Ca channels
-used in vet med for pain and epileptic;
humans for partial seizures
**probably shouldnt use this instead of big name anti-epileptics
-not many formulations and need frequent dosing
Pregabalin (Bonqat)
-oral solution now approved as anxiolytic in cats before car transport BUT not approved as anticonvulsant
**older version used as anticonvulsant in humans in the past
GABA adverse effects
-uncommon
-sedation
-ataxia
-unpredictable efficacy
Cannabidiol for epilepsy
-decrease in seizure frequency in PB/KBr treated dogs with oral CBD oil
-no difference in overall therapeutic outcome… nothing confirmed!
-often studies are very high doses of cannabidiol and have serious adverse effects
Cannabis related issues
-neurological adverse events at higher doses= hyperesthesia/ataxia
-uniformity and bioavailability
-cannabis only legal in Canada for humans!
