Anticonvulsant therapy: the new and the old (Proceedings)
Successful control of seizures with anticonvulsant drugs reflects a balance in achieving seizure control while minimizing undesirable drug side effects. Variability in the disposition of anticonvulsants and interactions among them and other drugs are important confounders of successful therapy. This chapter reviews selected anticonvulsants, focusing on drugs most likely to control seizures in small animals. The proper use of anticonvulsants is discussed, with an emphasis on the differences in individual drug disposition, detection of these differences, and rational approaches to responding to these differences by dose modification. The primary topic of discussion is treatment of generalized, tonic-clonic seizures, the most common type afflicting small animals. Opinions regarding anticonvulsant therapy vary among clinicians. Most of the comments and recommendations offered in this discussion reflect personal observations in a therapeutic drug monitoring service and completed as well as ongoing clinical trials that focus on the use of anticonvulsants either alone or in combination with phenobarbital.
It is important to approach epilepsy as a clinical manifestation of an underlying disease. Thus, therapy is more likely to be effective if the underlying disease is treated. Such causes should be identified and appropriately treated, and if possible, before chronic anticonvulsant therapy is instituted. Undesirable side effects are often the limiting factor in the use of anticonvulsant drugs, and not all seizures necessarily need to be treated.
Certainly immediate, short-term anticonvulsant therapy is indicated for status epilepticus (see later definition) or cluster seizures. Chronic therapy is generally indicated for seizures that last more than 3 minutes, cluster seizures (for which there is no delineable interictal period), or seizures that occur more frequently than once a month. Seizures that are not sufficiently controlled can lead to additional seizuring (kindling) or to the development of a second "mirror" focus of seizure activity. This might be manifested as a decreasing interictal period or a worsening of seizure activity (including duration). Ideally, monotherapy is preferred to combination therapy; monotherapy should not be considered to have failed until either undesirable side effects emerge, or drug concentrations at the maximum acceptable range have been surpassed. Monitoring is indicated to confirm determine therapeutic failure, potential toxicity and to establish baseline concentrations such that proactive changes in anticonvulsants can be recognized. Monitoring at Auburn University can be found at http://www.vetmed.auburn.edu/home/departments/anatomy-physiology-pharmacology/diagnostic-services/clinical-pharmacology-lab/.THE OLD: Bromide.
Bromide continues to be a drug of choice for first choice or combination anticonvulsant therapy in dogs. For rapid response, a loading dose can be given but it is important to match the loading dose with an appropriate maintenance dose, otherwise, drug concentrations will slowly decline over 2-3 months (with the majority of the decline in 15-21 days). A load of 450 mg/kg should yield concentrations of 1 mg/ml (the minimum end of the therapeutic range); for each 0.5 mg/ml increase in blood concentrations desired (maxiumum end of the range is 3.5 mg/ml), an additional 225-250 mg/kg loading dose should be given. If this loading dose is split over 5 days, the maintenance dose should also be given (30 mg/kg/day for 1 mg/ml; 15 mg/kg/day for each 0.25 to 0.5 mg/ml increase above that). Patients should be monitored 1 to 3 days after the loading dose and again at one month; if the two samples do not match, the maintenance dose should be changed accordingly. Our lab will increase bromide concentrations well above the recommended range if necessary to control seizures as long as the animal is not groggy or otherwise is intolerant to the drug. If groggy, our choice is to decrease phenobarbital concentrations first. Phenobarbital can be completely eradicated in some animals; in contrast, some animals will be controlled only at concentrations of both bromide and phenobarbital at the maximum end of the therapeutic range. Bromide can be made by dividing a 1kg bottle of the salt into 4 equal 250 gm parts (store in zip lock back, protect from humidity).. One package can be added to a 1 liter bottle of commercial spring water.:draw a line at the 1 liter mark, remove about 0.5 liter, add the bromide, and enough water to make the bromide dissolve, and fill the remaining volume to the line with either water or corn syrup for flavoring. The final solution is 250 mg/ml. Potassium bromide can be loaded following rectal administration over a 24 hour period (divide the loading dose into 4 administrations). IV administration is not recommended because of the risk of potassium overload.
Bromide has been studied in cats (as the potassium salt) when used at the canine maintenance dose. Although concentrations are similar to those achieved in dogs, in a retrospective study of 17 cats, 38% of seizuring cats developed signs consistent with feline bronchial asthma. The time to onset varied from 3 to 24 months and did not seem to be related to dose. Treatment with glucocorticoids may be helpful. Combination anticonvulsant therapy is a powerful tool for control of refractory seizures (defined as unacceptable seizure activity despite anticonvulsant concentrations at the maximum end of the therapeutic range). Several options exist. We have studied bromide as an add-on anticonvulsant and found it to be effective in eradicating seizures in 60% of dogs refractory to phenobarbital. Bromide is also effective as a sole anticonvulsant. Efficacy and safety of bromide (BR) were compared to phenobarbital (PB) in 46 dogs with spontaneous epilepsy using a parallel, randomized double blinded study design. Acceptance was based on seizure history, physical and neurologic examinations and clinical pathology. Dogs were loaded over a 7 day period to achieve the minimum end of the therapeutic range of the assigned drug. PB (3.5 mg/kg) or BR (15 mg/kg) was administered every 12 hours. Data (clinical pathology and drug concentrations) were measured at baseline and at 30 days intervals for 6 months. All but 3 patients completed the study. Seizures initially worsened in 3 dogs on BR but not in any PB patient. Mean seizure number, frequency and severity were reduced at 6 months compared to baseline for both drugs; seizure duration was shorter for PB but not BR. Seizure activity was eradicated in a greater percent of PB (85%) compared to BR (65%) patients, but successful control (at least 50% reduction in seizure number) did not differ between drugs at 6 months. Mean bid dose and drug concentrations were dose 4.1 ± 1.1 mg/kg and 27 ± 6 µg/ml, respectively for PB and 31 ± 11 mg/kg and 1.9± 0.6 mg/ml for BR. Both drugs caused abnormal behaviors. 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. Side effects at one and six months, respectively for each drug were: ataxia (PB: 55 vs 5%;BR: 22 vs 9%), grogginess (PB: 50 vs 5%; BR: 35 vs 13%), polydypsia (PB: 40 vs 0%; BR: 39 vs 4%), polyuria (PB: 35 vs 0%; BR: 13 vs 0%), hyperactivity (PB: 35 vs 10%; BR 43 vs 4% [one failure]), polyphagia (PB: 30 vs 0%; BR: 43 vs 4%) and vomiting (PB: 20 vs 0%; BR: 57 vs 21% [one failure]). One PB dog failed due to neutropenia, a reported rare side effect (as is superficial necrolytic dermatitis in dogs.) The incidence of grogginess and vomiting were greater in BR compared to PB at 6 months. This study suggests that both PB and BR are reasonable first choices for control of epilepsy in dogs, although PB may provide better control. Side effects can be expected to be greater in BR following chronic dosing.