Controlling primary epilepsy (Proceedings)

1. Actions of anticonvulsant drugs: Prevent spread of the seizure focus; increase (raise) the seizure threshold; decrease electrical excitement of abnormal neurons without disrupting normal function.

2. If your overall goal of anticonvulsant therapy is to eliminate all seizure activity, there is a good chance you'll fail. A more reasonable goal: Reduce frequency, severity, and duration of seizures without intolerable or life-threatening adverse affects to the animal.c

3. Approximately 20-30% of epileptic dogs will not be controlled adequately using currently available antiepileptic drugs. Larger breeds of dogs are more difficult to control.

4. Treatment with a single drug should be attempted initially to simplify monitoring and management of adverse side effects.

5. Phenobarbital and bromide are usually the first anticonvulsant choices in the dog. Phenobarbital is first choice in the cat.

6. Successful therapy requires a basic knowledge of the pharmacology and deleterious effects of the medications as well as the ability to "fine tune" doses. For some owners, the side effects of anticonvulsants are not "worth" the seizure control.

7. When to start anticonvulsants: A. After 2nd or 3rd seizure in a dog with suspected primary epilepsy unless seizures are many months apart. B. During status epilepticus cases. C. After 2nd or 3rd seizure in same day unless there is a metabolic reason (hypoglycemia, hepatic encephalopathy, etc) or toxic cause of the seizures.

8. Before starting anticonvulsants, consider the owner's compliance and ability to medicate the pet, the owner's expectations, the pet's environment and use, the cost of the drug.

Dogs: Which Is Best To Start With: Phenobarbital(Pb) Or Bromide (Br)?

One study in 2002 (and the experiences of most neurologists) indicates that both PB and BR are reasonable first choices for control of epilepsy in dogs. In the 2002 study, Phenobarbital eradicated seizure activity in a greater percentage (85%) of patients compared to BR (65%). However, successful control (at least 50% reduction in seizure number) did not differ between the two drugs at 6 months. Both drugs caused abnormal behaviors (ex: weight increased by 10% in both groups). Changes in clinical pathology were limited to increased (but within normal) serum alkaline phosphatase and decreased (but within normal) serum albumin at 6 months for PB compared to baseline and compared to BR at 6 months. The incidence of obtundation and vomiting were greater in BR patients compared to PB patients at 6 months.

Mechanism

Phenobarbital (PB) potentiates the actions of GABA, an inhibitory neurotransmitter in the CNS. GABA stabilizes postsynaptic neurons by increasing chloride conductance into the cell. The increased intraneuronal chloride stabilizes the cell membrane. Dogs that have low CSF concentrations of GABA prior to therapy will have a reduced response to PB therapy. Barbiturates also decrease calcium influx into nerve cells, which decreases release of neurotransmitters.

Metabolism

Liver. Induces p450 enzymes, so may result in increased metabolism of concurrently administered drugs (digoxin, glucocorticoids, clorazepate, griesofulvin). Microsomal inhibiting drugs (chloramphenicol and tetracyclines) may inhibit phenobarbital metabolism so watch for signs of toxicity). Phenobarbital often results in increased ALP, GGT in dogs; less likely to increase ALT, AST. Increased liver enzymes do not equal hepatotoxicity! If there are questions as to liver function, perform pre- and post-prandial bile acids.

Pharmacokinetics

Half-life is about 30-70 hours for dog and 34-83 hours for cat. Steady state is reached in 10-14 days. Recommended therapeutic serum level in μg/ml: 15-40 dogs and 10-30 cats.

Adverse effects

PU/PD/PP (common). Sedation, ataxia (common, usually transient because pharmacokinetic and pharmacodynamic tolerance develop in about 2 weeks). Idiosyncratic excitement (rare). Hepatotoxicity is rare and the mechanism is unclear, but it is likely to be a dose- and duration-dependent toxicity. Dogs with hepatotoxicity usually have serum levels of 45 mcg/ml or greater. Blood dyscrasias are rare and include anemia (both nonregenerative and regenerative anemias reported), neutropenia, and/or thrombocytopenia. These often resolve with discontinuation of the medication.

Endocrine testing effects

Can result in decreased free and total T4 and increased TSH. Low free T4 and total T4 have been shown to normalize by 4-6 weeks after discontinuation of PB. May affect low dose dexamethasone suppression test.

Dosing

Oral maintenance dose is 2-5 mg/kg q 12 dog and cat. Loading dose: 16-20 mg/kg once IV.

Monitoring

CBC, chemistry, and blood level q 6-12 months, or sooner if problems develop. Efficacy is determined by seizure log, not by numbers but it is generally recommended that a serum concentration be done 2 weeks after starting. Since the elimination half-life of PB in most dogs is greater than 12 hours, serum drug levels are sustained well throughout a 12-hour period so there is rarely a need to check trough levels. Serum separator tubes should not be used for measurement of serum PB since the gel in these tubes can result in falsely low serum drug concentrations. An animal with a phenobarbital level less than therapeutic may be well-controlled so there isn't necessarily a need to increase the dose based on low therapeutic level.

Bromide

From a recent study, 83% of dogs have a decrease in seizure activity when Br was added to phenobarbital therapy. There may be a decrease in seizure intensity and less severe seizures. In some dogs, the addition of Br allows phenobarbital dose to be decreased.

Mechanism

Bromide exerts its anticonvulsant effects by passing through neuronal chloride channels and hyperpolarizing neurons.

Metabolism

Br is well absorbed from the GI tract, with peak absorption in 1.5 hours. It is excreted via kidneys. Maximal concentration in CSF occurs 2 hours after oral administration. Because Br- competes with Cl-, alterations of the salt (NaCl) content of the diet will change the serum Br levels (i.e. increased salt will decrease Br).

Commercial dry dog food diets vary in chloride content from 0.45 to 1.09% on a dry matter basis, and prescription diets may have even higher chloride content (Canine c/d dry 0.48%, Canine I/d dry 1.32%, Canine s/d dry 1.18%). Breakthrough seizures and reduced Br concentrations were described in a dog that was previously well controlled and was placed on a calculolytic diet (Canine s/d) to dissolve cystic calculi.

Pharmacokinetics

Half life in dog is about 25 days so it will take about 4 months to reach steady state kinetics. Half life in cat is about 10 days so steady state takes about 6-8 weeks. Recommended therapeutic serum level: 1-3 mg/ml.

Adverse effects

Sedation, ataxia (common). PU/PD/PP (common). Vomiting is sometimes associated with bromide-induced pancreatitis.

Bromide toxicity

Bromide toxicity is rare when serum concentrations are less than 1.5 mg/ml (15 mmol/L). Because of the great variability in therapeutic and toxic concentrations, bromide therapy must be titrated to the individual patient. Any reports of hind limb ataxia should be investigated as potential bromide toxicosis, by measuring serum bromide concentration and discontinuing therapy for 1 to 3 days. Severe signs of toxicity are easily treated by chloride loading the patient with IV 0.9% sodium chloride administered at a maintenance rate over 12 hours.

Pruritus has been reported in dogs and may be more likely to occur if there is underlying skin disease (e.g., flea bite dermatitis).

Personality change may require lowering the dose or discontinuing the therapy. Mental depression, irritability and aggression, attention-seeking behavior, aimless pacing.

Cats: Signs of asthma have been reported in about 1/3 of cats on bromide. Initial signs are cough, with marked cellular infiltrates seen on radiographs. In some cases, the airway disease is fatal, in others the cough resolves after many months.

Endocrine testing effects

No effects known. However Br can falsely elevate Cl- on some laboratory assays.

Dosing

Potassium bromide dose is 20-40 (may be able to go up to 60 in some cases) mg/kg PO q 24 hr dogs (can be divided). Because of minimal fluctuations in concentration, the bromide dose can be given once daily as long as the dog tolerates it. Dogs with renal insufficiency should be started on half of the recommended dose of bromide and serum concentrations should be monitored frequently.

Loading dose: 400-600 mg/kg divided over several days.

Sodium bromide: Reduce above calculated dose by 15 %.

Monitoring

CBC, chemistry, and blood level q 6-12 months, or sooner if problems develop. Efficacy is determined by seizure log, not by numbers!

"Newer" Or Alternative Anticonvulsants

Gabapentin

Mechanism of action: Interacts with the α2β subunit of neuronal voltage-gated calcium channels. Inhibition of these calcium channels is thought to decrease excitatory neurotransmission.

Metabolism: Renal excretion mostly.

Pharmacokinetics: Half-life in dog is 2-4 hr so requires tid dosing. Steady state: 1 day. Therapeutic level: 4-16 mg/L

Dose: Dogs: 10 mg/kg q 8 hr; can increase to 25-60 mg/kg q 8 hr. Cats: 5-10 mg/kg PO, q8-12 hr.

Clinical efficacy: In refractory epileptic dogs when GB is used as an add-on therapy, it is estimated that less than half of patients experience a 50% or more reduction in seizures.

Side effects: Mild minor sedation and pelvic limb ataxia at lower doses.

Generic source: Yes

Levetiracetam (Keppra)

Mechanism of action: have a unique intracellular binding site, a synaptic vesicle protein (SV2A), the affinity of binding to which appears to be correlated with the drug's anticonvulsant potency. Binding to SV2A affects neurotransmission via interactions between synaptotagmin and calcium ions, though the exact biochemical pathways involved remain undetermined.

Metabolism: Some hepatic metabolism but mostly renal excretion.

Pharmocokinetics: Half-life in dogs is about 4 hr; Steady state reached in 2 days. Therapeutic levels have been assumed to be similar to those in people: 5-45 μg/ml.

Dose: 20 mg/kg PO q 8 hours dogs and cats

Clinical efficacy:

Side effects: None to minimal (behavioral change; GI upset) ; no drug-drug interactions known at this time; 100% oral bioavailability;

Generic source: In Canada a lower-cost, generic form of oral levetiracetam is available.

Zonisamide

Mechanism of action: Multiple proposed ones: blockage of T-type calcium and voltage-gated sodium channels in the brain, facilitating dopaminergic and serotonergic neurotransmission, free-radical scavenging, enhancing GABA activity, and decreasing glutamate-mediated processes.

Metabolism: Majority excreted in urine; about 20% hepatic metabolism

Pharmocokinetics: Half-life in dogs:15 hr. Therapeutic level: 10-40 μg/ml. Steady state: 3 days

Dose: Dogs: 10 mg/kg, q 12 hrs in dogs on Phenobarbital; 5 mg/kg q 12 hr if monotherapy;

Clinical efficacy:

Side effects: Few; occasional sedation, ataxia, inappetance

Generic source: Yes

Felbamate

Mechanism of action: Likely potentiates GABA-mediated neuronal inhibition, mitigating NMDA-mediated neuronal excitation & inhibiting voltage-gated neuronal sodium & calcium channels.

Metabolism: Hepatic metabolism and renal excretion.

Pharmacokinetics: Half-life of 5-14 hrs. Therapeutic level: 30-10 μg/ml. Steady state in 3-5 days.

Dose: 15 to 50 mg/kg q 8 hours in dogs. Not used in cats.

Clinical efficacy: No reports available of its usefulness in refractory epileptic dogs as an add-on therapy.

Side effects: Uncommon, but hepatotoxicity (usually with concurrent high phenobarbital blood levels), reversible blood dyscrasias, and keratoconjunctivitis sicca have been reported with felbamate use in dogs. Occasional vomiting, nausea, tremors, agitation.

Generic source: yes