Dawn M. Boothe, DVM, PhD, DACVIM, DACVCP
Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University
Seizures can be a devastating experience for the pet, pet owner and veterinarian. Both acute and chronic control are often confounded by the lack of safe, yet effective anticonvulsant drugs. Anticonvulsant therapy is most likely to be successful if the underlying, causative disease can be treated. Clearly (e.g., idiopathic epilepsy) this is not always possible. Yet, not all seizures must be treated and the risk of undesirable side effects must be weighed in the context of the risk of damage if seizures are not treated. The likelihood of untreated seizures contributing to further seizure activity is controversial and probably variable. Prudence dictates that the more severe the seizure activity (number or presentation) the more important effective control becomes. Chronic therapy is generally indicated for seizures that occur more frequently than once a month or for cluster seizures, regardless of the interval. A decrease in seizure interval might be interpreted as a need for therapy, or better control with current therapy. Eradication of seizures should not be the expected goal; rather achieving a level acceptable to both the pet owner and the veterinarian is more reasonable. The mechanisms of seizures and their treatment are complex and not well understood. However, clearly altered neurotransmitters (increasing inhibitory such as gamma amino butyric acid [GABA] which increases receptor mediated chloride influx; or decreasing excitatory such as glutamate, acetylcholine, others), ion fluxes (calcium, sodium, decreased chloride or altered potassium) and receptors (GABA, T-type calcium, potassium and n-methylaspartate [NMDA]) are examples of potential targets of therapy.
Enhancing Control. Monitoring is a tool that identifies the therapeutic range for a patient. An animal should not be considered refractory to therapy with a chosen anticonvulsant simply because unacceptable seizures still occur despite serum drug concentrations in the therapeutic range. The therapeutic range is a population statistic: a large proportion (e.g., 95%) of the population can be expected to respond to the drug somewhere in that range; however, where the individual patient responds in the range is not predictable. Some will respond at the low end of the range; some at the higher end, and some (up to 5%) will respond outside of the range. Thus, the dose of drug does not necessarily have to be increased if an animal has responded even if concentrations are "subtherapeutic." Further, an animal should not be considered refractory to any combination of drugs unless seizures occur at an unacceptable level despite drug concentrations in the maximum end of the therapeutic range, or the animal can not tolerate any drug at the current dose. Finally, if the drug does not cause life threatening side effects, the maximum range can be exceeded if doing so is likely to add to control of seizures. With TDM as a tool, using monotherapy, seizures can be expected to be eradicated in 65% (bromide [BR]) to 90% (Phenobarbital [PB]) of canine epileptics. For patients that truly are refractory to the first anticonvulsant drug (seizuring unacceptably despite drug concentrations at the maximum end of the range, or exhibiting unacceptable side effects), the addition of a second anticonvulsant to can be expected to eradicate seizures in up to 60% nonresponders and decrease the severity or number of seizures by 50% or more in another 20%.
BROMIDE AS AN ANTICONVULSANT
Clinical Pharmacology. Bromide is an old anticonvulsant that was used in the 1800's for control of seizures and as a sedative. However, it has enjoyed a resurgence in veterinary medicine and, to some degree, in human medicine. The mechanism of action of BR is not completely understood. Replacement of negatively charged chloride with BR has been implicated as the mechanism; the neuron becomes hyperpolarized (i.e., the resting membrane potential becomes more negative in relation to the threshold potential). However, it is unlikely that this is the mechanism of action of BR, in part because chloride is more electronegative than BR. Studies focusing on membrane ion (probably Na+) fluxes are currently underway. Regardless of the mechanism of action, the anticonvulsant effects of BR appear to complement that of other anticonvulsants. Additionally, effects correlate with plasma concentration as long as the method of monitoring is well validated for concentrations in serum. The pharmacokinetics of BR have not been well established in either dogs or cats. The half-life in dogs is 21 to 24 days. Steady-state concentrations is achieved at 2.5 to 3 months. Distribution is to extracellular fluid yet sufficient quantities penetrate the CNS. Bromide is eliminated slowly (perhaps due to marked reabsorption) in the kidney. The effect of renal disease on BR excretion has not been established, but prudence dictates that monitoring accompany disease a longer time to steady-state be anticipated. Further, compared to normal renal function, higher serum concentrations at equivalent doses should be anticipated. Bioavailability of BR following rectal administration is approximately 100 %, suggesting that loading rectally in the refractory patient is a viable route for status epilepticus patients. KBr (or NaBr) can be administered rectally over a 24 hour period in 4 equal--split doses. IV administration of the potassium salt should be avoided because of the risk of hyperkalemia (it can be safely done but only over a 24 hour period), but IV administration of the sodium salt appears to be safe even if give as a loading dose. KBR has been studied in cats following bid oral administration at 15 mg/kg. Elimination is faster than in dogs (mean half-life approximately 10 days) and steady-state concentrations (1.2 mg/ml compared to 1.0 mg/ml in dogs) occur in about 6 weeks.
Safety. The long term effects of BR have not been established in dogs or cats. Central nervous system (CNS) adverse reactions to BR tend to be dose dependent and most often are related to the expected general sedative properties of the drug manifested as ataxia, grogginess and hind-end weakness. Up to 3 months may be required for accommodation to these effects. CNS effects are more likely if the drug is used in combination with PB. Gradual reduction of PB in 25% increments may resolve some of the side effects. Alternatively, the BR dose can be decreased by 25%, although 1 to 2 weeks may elapse before a response is seen and 3 months must elapse before the full effect can be evaluated. Fluids containing sodium chloride can be used to treat acute "bromide toxicity"; monitoring should occur after saline treatment to establish a new baseline. Hyperactivity is an occasional side effect (to PB as well) and may or may not be dose dependent. Gastrointestinal side effects occurred in about 50% of dogs loaded with BR over a 7 day period. Vomition appears to reflect the hypertonicity of the salt and direct gastric irritation; diarrhea may reflect a direct irritant or ionic osmotic effect in the lumen. Solutions may be better tolerated than capsules, although this may vary. Dividing the daily dose into smaller, more frequent doses or feeding before or with the medication sprinkled in food may decrease gastrointestinal side effects. Sodium BR may be more tolerated than other BR salts. Pancreatitis has been associated with the use of BR but only when combined with PB; in deed, it is not clear which drug might be increasing the incidence of pancreatitis as neither drug by itself is associated with an increased incidence. Like other anticonvulsants, BR tends to increase the appetite of dogs, and--although less than PB--polyuria and polydypsia. Pruritic skin lesions may occur, particularly in patients with pruritic disorders prior to starting therapy. A short period of glucocorticoid therapy may control pruritis. Cats treated experimentally with BR developed no adverse reactions although they were studied only for 12 weeks. However, in clinical patients receiving KBr alone or in combination with PB, therapy in about 50% of cats (n=17) was associated with side effects. 40% of 17 cats receiving the drug in a two retrospective studies developed signs typical of feline bronchial asthma. Thus, its use in cats should be accompanied by close monitoring for signs consistent with this illness. Glucocorticoids might control signs.
Drug Interactions. Because BR is not a human drug, little information is available regarding drug interactions. As a renally-eliminated drugs, few should be suspected and interactions with hepatically metabolized drugs should not occur. However, BR competes with chloride for renal excretion and drugs which alter chloride excretion (i.e., diuretics, fluids containing sodium chloride) should be used cautiously and in conjunction with therapeutic drug monitoring for BR before, during and after the drug is used. Because forced chloride excretion may alter BR elimination, remember that the drug elimination half-life may also change, although in which direction (faster or longer) is not clear. Thus, the 3 month period to steady-state may not be relevant. Ideally, patients should be monitored before diuretics are used or discontinued and one month into the change in therapy. Drugs which improve renal function (i.e., afterload reducers in patients with congestive heart failure or hypertension associated with renal disease) may also alter BR excretion. Dietary salt content will have a similar effect and clients should be instructed to not change the diet (including converting from the moist to dry or vice versa version of the same diet). In generally, a proportional increase (or decrease) in BR can be anticipated with the amount of sodium chloride decrease (or increase) that occurs. Finally, when monitoring serum chloride, note that some assays can not discriminate between BR and chloride and chloride concentrations may be markedly artifactually increased.
Compounding Bromide. Bromide is available as a potassium or sodium salt. Triple BR salt preparations (Na, K and NH4) also are available through some human pharmacies. The cation accompanying BR does not appear to alter efficacy, although NaBR is more difficult to solubilize in water compared to KBR. In addition, since potassium weighs less than sodium, a gram of NaBR contains more BR than does a gram of KBR. Thus, the amount of NaBR used to make an equivalent solution should be less (2ll mg/ml) than KBR (250 mg/ml) in order to achieve equivalent amounts of BR in the solution. The accompanying cation does not appear to present a health risk unless give extremely rapidly (potassium salt), although prudence would dictate that the sodium salt be avoided in patients with cardiac disease and the potassium in cases of hypoaldosteronism. Bromide also can be prescribed through a number of pharmacies that cater specifically to veterinarians. However, the cost of drugs through these pharmacies can be expensive. Bromide should be mixed to a convenient concentration in water or administered in a gelatin capsule. That most easily tolerated (e.g., solution vs capsule) varies among animals. Bromide can be easily and inexpensively (and legally) compounded by veterinarians as a solution. Potassium BR can be purchased through chemical companies (search the internet and request medicinal or ACS grade: Curtis Matheson, Scientific & Industrial Sales [e.g., 800 332 0525; 25 lbs for $480 versus 1 lb for $75 or 5 lbs for $289). In the US, particularly with the most release of the most recent (2003) Compliance Policy Guidelines for Compounding for Animals by the Food and Drug Administration, chemical companies may refuse to sell potassium BR for medicinal purposes without an investigational new animal drug application (INADA). If necessary for purchase, the Food and Drug Administration (Division of Drug Compliance; phone number 240-276-9220) will grant regulatory discretion. If 1 kg of potassium bromide (KBR) is purchased from a chemical company, the packaged can be divided into 4 equal packets containing 250 gm. These should be stored in a dry environment. A liter bottle of distilled water can be purchased from a local grocery store. Prior to mixing the BR, a line should be drawn on the bottled water at the 1 liter volume mark and approximately 25% of the water removed and set aside. A 250 gm packet of KBR can be added and the bottle shaken well to dissolve the BR (this may take a little aggressive shaking). Once dissolved, the volume should be returned to 1 liter using either water or corn syrup or another water soluble flavoring agent. The final solution will be 250 mg/ml KBR (remember that if sodium BR is used, approximately 20% more BR will be in each ml). The solution should be stable for at least 6 months but refrigeration should minimize microbial growth in the solution. Refrigerating the solution may cause the salt to crystallize; warming the solution should cause the drug to redissolve. Note that while this solution can be used to fill a prescription, in the USA, it cannot be sold to other veterinarians legally. If compounded by a pharmacist, the drug also should not be resold (i.e., a markup) to clients by the veterinarian.
Clinical Use. Bromide generally is administered orally once to (divided) twice daily, depending on animal gastric tolerance of the drug. Because of the long half-life of the drug, an animal can miss several days of dosing with minimal impact on serum drug concentrations. Missed doses should be given when convenient. On the other hand, if BR is better tolerated when broken into smaller, frequent doses, no disadvantages are apparent with this approach other than owner inconvenience. Recommended target ranges may vary with the lab (but probably should not). Although some variation reflects whether PB also is being given, our laboratory (http://www.vetmed.auburn.edu/index.pl/clinpharmlab - 334 844 7187); used our Airborne Express contract [cost of shipment overnight is $6.50; tag must be marked less than 3 lbs]. The therapeutic range can be exceeded if drug concentrations are increased beyond the maximum if side effects are tolerable.
Two dosing approaches can be taken to achieve BR concentrations in the targeted therapeutic range: administration of either a maintenance dose, which will require 2-3 months to be complete, or a loading dose followed by a maintenance dose. Which method depends upon the rapidity with which therapeutic concentrations must be achieved and tolerability of the patient and owners to the side effects (generally gastrointestinal with loading). The target varies with the patient: a target as low as 1 mg/ml may be sufficient for some animals but may be insufficient for others. For animals converting from PB to BR, the target can be based on the PB: if controlled at high PB concentrations, high BR also should be anticipated. In general, we prefer a BR of at least 1.5 mg/ml if converting from PB to BR.
The loading dose is designed to rapidly achieve the targeted therapeutic concentration; the maintenance dose is intended to maintain what a loading dose achieves, or, if no loading dose is given, achieve the targeted therapeutic concentration at steady-state. Proactive monitoring is important for BR because of its long steady-state. For those patients only receiving a maintenance dose, we monitor at 3 to 4 weeks and then at steady state (2.5 to 3 months). The first sample at 3-4 weeks indicates about 50% of what will be achieved at steady-state and allows adjustment of the dose early. For loading, an immediate (day 6 or 7) post load sample is recommended, followed by a sample at 1 month and then 3 months. The immediate sample indicates what was achieved with loading; the 1 month indicates the success of the maintenance dose to maintain what was achieved with loading, and allows proactive adjustment, particularly for maintenance doses that are too low. Without this paired post-load and 1 month sample, plasma concentrations may gradually decline as steady-state on the maintenance dose is achieved, leading to seizures 3 to 6 weeks after the loading dose was given. The 3 month post load dose simply establishes the new baseline.
Maintenance Dose. In general, a maintenance dose of 30 mg/kg/day (15 mg/kg twice daily) of KBR (25 mg/kg/day NaBr) will achieve a one month concentration of about 0.5 to 0.6 mg/ml at 3 to 4 weeks and a steady-state concentration of about 1 mg/ml in dogs (1.25 mg/ml in cats). For each 0.5 mg/ml increase in targeted therapeutic BR concentration desired above 1 mg/ml, the maintenance dose must be increased 15 mg/kg/day. Thus, to achieve a targeted BR concentration of 2 mg/ml at steady-state, a daily maintenance dose of about 60 mg/kg must be given.
Loading Dose. A 450 mg/kg loading dose will achieve the lowest end of the therapeutic BR concentration, 1 mg/ml. For each 0.5 mg/ml increase in targeted therapeutic concentration desired above 1 mg/ml, approximately 225 mg/kg must be given. Thus, to target 2 mg/ml, approximately 900 mg/kg of a loading dose must be given. Some clinicians have administered a loading dose quite successfully over one 24 hour period.
However, because of GI side effects, the loading dose often is spread over 5 days (particularly if higher BR concentrations are targeted). If this approach is taken, the loading dose must then be ADDED to the appropriate maintenance dose. For example: To target 1.5 mg/ml with a 5 day loading period, the patient should receive 650 to 675 mg/kg over 5 days, or 130 mg/kg a day load PLUS a maintenance dose of 45 mg/kg/day. The total daily dose during the loading period will be 130 plus 45 or 175 mg/kg. On day 6 or 7, blood is monitored and the daily dose is decreased to 45 mg/kg. Three to four weeks later, blood is monitored again. If the month post-load sample does not match the immediate post load sample, the maintenance dose is adjusted accordingly. For example, a post load concentration of 1.3 mg/ml followed 3 to 4 weeks later by a concentration of 0.9 mg/ml indicates that the maintenance dose is too low. If monitoring had not occurred immediately post load and 3 weeks later, the decline in plasma BR concentrations would not have been detected, and BR concentrations would have continued to decline to approximately another 0.5 mg/ml by steady-state. The decrease in BR concentrations suggest that the maintenance dose should be increased approximately 25%. The importance of postload monitoring is particularly critical if a goal of therapy is to decrease PB. Veterinarians often collect a 1 month post-load sample without the immediate post-load sample. However, this sample can only indicate what concentrations are at the time of sample collection and can not predict if drug concentrations are increasing or decreasing (i.e., can not predict the appropriateness of the maintenance dose).
In a patient at steady-state and still not adequately controlled, BR concentrations can be increased either by 1. Simply increasing the maintenance dose by 25% (monitor before the increase, at one month [to allow pro-active adjustment of the new maintenance dose] and at steady-state) or 2. By giving "mini" loading doses. Mini loading doses (225-250 mg/kg total for each 0.5 mg/ml increase in BR) can be given to rapidly adjust subtherapeutic concentrations of BR in patients suffering from severe seizures. The mini-loading dose can be given over 5 days as previously described (however, remember to add the new maintenance dose to the daily dose) or it can be given as a single dose on top of the daily dose for the animal. However, if the seizure history does not warrant rapid achievement of (new) steady-state concentrations, maintenance dose can simply be increased and the patient can be gradually brought to steady-state.
Adding to or converting from PB. We generally do not recommend decreasing PB concentrations until therapeutic concentrations of BR have been confirmed. The targeted concentration depends on the amount of PB required to control the patient; the higher the PB concentrations, the higher the BR should be. Weaning off PB might begin as early as half-way into the loading dose of BR, or one month into therapy if a loading dose is not given. We generally do not decrease PB more than 25% at a time (waiting until steady-state for PB [2 weeks] plus one seizure interval have elapsed before the next 25% is reduced). An exception occurs for patients on PB that have developed liver disease (severe) or bone marrow dyscrasias. In such situations, loading of BR at adequate concentrations (greater than 1.5 mg/ml) is followed by a decrease in PB over a 2 week period. Post-load monitoring (immediate and one month) is critical in such patients to assure that they remain controlled as the BR is discontinued. BR is indicated in patients suffering from unacceptable PB induced side effects. This includes liver disease. Patients with liver disease severe enough to cause hepatic encephalopathy have markedly improved and survived for another 3 years following rapid conversion from PB to BR. We target at least 1.5 to 2.0 mg/ml of BR when rapidly converting from PB. Phenobarbital-induced pancytopenia or leukopenia has been another indication for rapid loading with BR accompanied by rapid discontinuation of PB. In such cases, we attempt to decrease PB by 50% as we approach the half-way point for BR loading.
Clinical Response. The primary indication of BR in veterinary medicine has been in combination with PB in refractory epileptics or in patients that have developed liver disease and in whom PB concentrations must be reduced. However, increasingly BR is being recommended as the first choice antiepileptic in dogs. Studies documenting its efficacy compared to PB currently are underway. Bromide has been used as the sole drug in patients whose seizure history is limited to mild seizure episodes. Because of its long t2, BR may be the drug of choice in dogs whose owners are noncompliant since plasma drug concentrations are not easily manipulated.
Efficacy and safety of BR (BR) were compared to PB (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 mg/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 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. Candidates for BR as first choice therapy might be older dogs which will require other drug therapies and dogs requiring long term non-steroidal therapy.
We also have studied BR as an add-on anticonvulsant and found it to be effective in eradicating seizures in 60% of dogs refractory to PB. When compared to using felbamate and clorazepate as add-on anticonvulsants, response to BR was clinically (not statistically) better. Further, PB were statistically lower in the BR group compared to the felbamate and clorazepate group. This reflected both a decreased incidence of drug interactions between PB and BR compared to PB and clorazepate or PB and felbamate, but also a better response that allowed a dose reduction for PB in the BR group. Further, BR was able to reduce the incidence of seizures in another 15-20% of animals.