Lecture 19: Neuropharmacology (Anti-convulsants)

What are the two neurotransmitters involved in epilepsy?

GABA (inhibitory) and glutamate (excitatory); imbalance between them causes seizures.

What is the drug of choice for treating status epilepticus?

Diazepam; given IV every 15 minutes until seizures stop.

What are alternative drugs if diazepam fails?

Midazolam, phenobarbital, pentobarbital, propofol, levetiracetam.

What is the MOA of benzodiazepines?

Bind to GABAA receptor, enhancing chloride influx and neuronal inhibition.

What is the MOA of barbiturates?

Bind to GABAA receptor, prolonging chloride channel opening and enhancing inhibition.

What is the MOA of levetiracetam?

Inhibits SV2A, a synaptic vesicle protein, reducing glutamate release.

What drug is used to prevent feline epilepsy?

Phenobarbital; can be given orally or transdermally with PLO gel.

What is the active ingredient in most euthanasia solutions?

Pentobarbital; a potent barbiturate causing rapid CNS depression.

What is the major side effect in dogs receiving phenobarbital plus KBr?

Pancreatitis.

What is the major side effect in cats receiving KBr?

Bronchitis; coughing cat on KBr = warning sign.

What is the number one rule for combination anticonvulsant therapy?

Do not use two drugs with the same mechanism of action.

What is the MOA and use of levetiracetam?

Inhibits glutamate release via SV2A; used for refractory epilepsy or as adjunct.

What is the MOA and use of primidone?

Prodrug of phenobarbital; acts as GABA agonist for seizure prevention.

What is the preferred drug for euthanasia?

Pentobarbital; stable post-mortem and used in euthanasia solutions.

What is a generalized seizure?

Grand mal seizure; lasts 30 sec-3 min with loss of consciousness and motor activity.

What are cluster seizures?

Multiple seizures in 24 hours; requires medical intervention.

What is status epilepticus?

Continuous or repeated seizures without recovery; must treat within 1 hour to prevent damage.

What are the three drug targets for treating seizures?

Activate GABA receptors, block glutamate receptors, block glutamate release.

What is the role of propofol in seizure treatment?

Activates GABA receptors and blocks glutamate receptors; used as CRI.

Why is alfaxalone not a good anticonvulsant?

Requires endogenous GABA to work; poor efficacy during seizures.

What is the role of ketamine in refractory status epilepticus?

Used after other drugs fail; blocks NMDA receptor but can cause seizures alone.

What is the role of dexmedetomidine in refractory status epilepticus?

Used with ketamine and mild hypothermia in combination therapy.

When should seizure prophylaxis be started?

After status epilepticus, cluster seizures, or at owner's request due to safety concerns.

What is the goal of seizure prophylaxis?

Minimize seizure frequency and severity with minimal side effects.

What are the four drug targets for seizure prevention?

Activate GABA receptors, block glutamate receptors, block glutamate release, block ion channels.

Why are BDZs not used for long-term seizure prevention?

Tolerance develops; used only for emergency or bridging therapy.

What is the standard drug for seizure prevention?

Phenobarbital; inexpensive, effective, and available in multiple forms.

What monitoring is required for phenobarbital?

Serum levels at 2 weeks, 6 weeks, then every 6 months; monitor for hepatotoxicity.

What are side effects of phenobarbital?

Sedation, ataxia, polyphagia, polydipsia; induces hepatic enzymes.

Why must phenobarbital be tapered slowly?

Abrupt withdrawal can cause severe rebound seizures.

What is the MOA of bromide (KBr or NaBr)?

Unclear; likely facilitates chloride channel opening.

When is NaBr preferred over KBr?

In dogs with Addison's disease or potassium-related issues.

What is a major risk of KBr in dogs?

Pancreatitis, especially when combined with phenobarbital.

What is a major risk of KBr in cats?

Bronchitis; avoid in cats with respiratory issues.

What is the half-life of bromide in dogs?

25-46 days; allows for flexible dosing and missed doses.

What dietary factor affects bromide elimination?

High chloride diets (e.g., Hill's H/D, S/D, L/D) increase bromide clearance.

Can bromide be abruptly discontinued?

Yes, if side effects occur; unlike phenobarbital, no taper needed.

What is imepitoin and how does it work?

GABA receptor agonist; related to phenytoin but safe in dogs.

What is imepitoin used for?

Noise aversion (Pexion); used in Europe for epilepsy; not combined with phenobarbital.

What is zonisamide and how does it work?

Inhibits high-voltage calcium channels; minimal side effects; dosed twice daily.

What are side effects of zonisamide?

Same as sulfonamide antibiotics; monitor for hypersensitivity.

What is felbamate and how does it work?

Blocks voltage-gated sodium channels; used off-label; expensive with multiple side effects.

Why is phenytoin not used in dogs or cats?

Ineffective and toxic; used in humans and included in euthanasia solutions.

What is the mechanism of primidone?

Converted to phenobarbital; acts as GABA agonist.

What is the mechanism of gabapentin and pregabalin?

Block calcium channels; reduce excitatory neurotransmitter release.

What is the mechanism of topiramate and zonisamide?

Block sodium and calcium channels; used in refractory epilepsy.

What is the mechanism of perampanel?

Blocks AMPA receptors; reduces glutamate-mediated excitation.

What is the mechanism of ketamine in seizures?

Blocks NMDA receptors; used in refractory cases but can be pro-convulsant alone.

What is the mechanism of dexmedetomidine in seizures?

Alpha-2 agonist; used in combination with ketamine and hypothermia.