14 Nov 2016
Holger Volk focuses on potassium bromide, an often forgotten second line treatment and the oldest antiepileptic drug, which is not always used to its full potential.
Holger Volk
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Canine epilepsy is often mentioned to be the most common chronic neurological condition encountered in first opinion practice. Despite it being the most common chronic neurological disease, practitioners will still only see a handful of patients a month.
The disease has a substantial impact on the quality of life of the dog and owners. It is, therefore, important to have a swift clinical reasoning approach and use the battery of antiepileptic drugs appropriately.
Canine epilepsy is often described as the most common chronic neurological condition, but can be difficult to treat and often requires more than one antiepileptic drug (AED) to control.
Large general population databases, such as VetCompass, show epilepsy has an estimated prevalence of 0.6% to 0.75% (Kearsley-Fleet et al, 2013; Heske et al, 2014).
The brain disease epilepsy is more often documented in male dogs (Van Meervenne et al, 2014) and pure-bred dogs (Bellumori et al, 2013), with 33% being the highest prevalence reported in single breeds (Berendt et al, 2008; Ekenstedt and Oberbauer, 2013).
As with any disease, first principles always come first, and establishing an accurate diagnosis prior to administering medication is the essential step in treating epilepsy. If clinicians can identify an underlying disease process, it needs to be treated with the seizures (Bhatti et al, 2015). When no underlying condition is identified, the diagnosis is idiopathic epilepsy (IE; Berendt et al, 2015).
Readers may want to read articles freely available online, published by the International Veterinary Epilepsy Task Force (IVETF), for more information (Berendt et al, 2015; Bhatti et al, 2015; De Risio et al, 2015; Hülsmeyer et al, 2015; Matiasek et al, 2015; Potschka et al, 2015; Rusbridge et al, 2015).
The IVETF’s main aim is “to provide the veterinary community, breeders and dog (and, in part, cat) owners with consensus statements on the key areas in the field of epilepsy”(Volk, 2015).
In addition, the American College of Veterinary Internal Medicine (ACVIM) published a complementary consensus statement about seizure management (Podell et al, 2016). Both statements also address treatment goals, stating: “How does successful seizure management look?”
The ultimate goal should be to get complete seizure remission when treating with an AED, which is defined as an at least “extension of the interseizure interval to three times the longest pre-treatment interseizure interval and for a minimum of three months”(Bhatti et al, 2015; Potschka et al, 2015).
Seizure freedom can only be achieved in 20% to 40% of patients with IE, so the IVETF defines partial treatment success as greater than, or equal to, “50% reduction in seizure frequency” and/or “seizure severity”.
The ACVIM’s consensus statement also cements that treatment is not to be seen as successful, and additional treatment options need to be considered if “seizure frequency increases more than 50% in a three-month period and/or there is a new onset of cluster seizures or status epilepticus”(Podell et al, 2016).
AED treatment should not only be efficient in controlling seizures; a balance also needs to be established with using a drug dose that is still well tolerated.
Treatment should be initiated in dogs with IE when they present with:
Evidence (Charalambous et al, 2014; Charalambous et al, 2016) is strongest for starting a drug-naïve, healthy dog with IE on imepitoin or phenobarbital (PB). However, the more interesting question is when to start the second AED.
When selecting a second AED, consider the interplay of the drugs in terms of their pharmacokinetic and pharmacodynamic effects (Podell et al, 2016); a risk factor for inadequate seizure control is a high seizure density (Packer et al, 2014) and patients with cluster seizures may need to be treated sooner, rather than later, with multiple AEDs.
Potassium bromide (KBr) was recommended as add-on medication (Bhatti et al, 2015) and is licensed as such in the UK for dogs that do not respond to first-line AEDs. Bhatti et al (2015) stated: “PB and KBr have a synergistic effect and add-on treatment with KBr in epileptic dogs improves seizure control in dogs poorly controlled with PB alone.”
KBr was the first AED used in humans and introduced by Sir Charles Locock in 1857. However, in human medicine, with the development of more effective and better-tolerated AEDs, the use of KBr is now limited to some drug-resistant epilepsies in children (Korinthenberg et al, 2007; Caraballo et al, 2014). KBr is better tolerated in dogs, but should not be used in cats as it can cause clinical signs suggestive of feline asthma.
Several studies in dogs have assessed the efficacy and tolerability of KBr as an add-on drug to PB and/or primidone, while one study evaluated KBr as monotherapy (Boothe et al, 2012; Rieck et al, 2006; Löscher et al, 2004; Schwartz-Porsche and Jürgens, 1991; Podell and Fenner, 1993; Pearce, 1990). Around half of the studies showed the majority of dogs with epilepsy treated with KBr responded adequately; most studies used the aforementioned partial response definition (Charalambous et al, 2014). KBr can be considered as a first-line treatment in dogs where treatment with PB or imepitoin is contraindicated.
KBr is a salt and needs to be considered when treating patients. The salt (NaCl) content in the diet, drugs and water should not fluctuate as it can influence clearance and absorption of KBr, leading potentially to inadequate seizure control. Renal insufficiency may also cause decreased clearance of bromide, while loop diuretics may enhance bromide elimination, thus lower serum concentrations (Dewey, 2006).
The body and biochemistry machine struggles to differentiate between bromide and chloride ions. This does explain KBr’s pharmacokinetic profile – it has a very long half-life – and the pseudohyperchloraemia frequently seen on routine biochemistry of dogs receiving KBr (De Risio, 2014; Trepanier, 1995).
KBr is not metabolised in the liver, does not bind to plasma proteins, diffuses freely across cellular membranes, is excreted unchanged in urine and undergoes tubular reabsorption.
As aforementioned, salt content in the diet can influence bromide’s bioavailability. Orally administered KBr has a bioavailability of around 46%. Its half-life in dogs ranges from 25 to 46 days (Trepanier and Babish, 1995; March et al, 2002; Podell, 1998; De Risio, 2014). The drug reaches steady state when given daily in around 50 to 75 days. The bromide anion dissociates, is quickly absorbed from the small intestine following ingestion and distributes rapidly, with Cmax typically seen after 90 minutes.
The bromide anion is thought to provide its anticonvulsant activity by competing with chloride ions for passage through chloride channels in the gamma-aminobutyric acidA (GABAA)-receptor and it appears to have a smaller hydrated diameter.
More bromide ions enter the cell than chloride ions, thereby hyperpolarising postsynaptic neuronal membranes and facilitating the action of inhibitory neurotransmitters. The exact mechanism of bromide’s action is, however, not fully understood (De Risio, 2014).
Barbiturates act on the same GABAA-receptors, prolonging their opening times and, therefore, may act synergistically with bromide – leading to an increase in the seizure threshold and prevention of further seizure activity.
Due to its long half-life, a loading dose can be used before starting maintenance dose therapy to achieve therapeutic concentrations more rapidly in patients requiring immediate seizure control (Figure 1). However, this can initially cause more severe side effects, such as ataxia.
The initial maintenance dose of 30mg/kg/day may be given without a loading dose to allow more gradual accommodation to effective serum concentrations. If significant side effects are seen, slowly titrate the dose from 15mg/kg/day up to 30mg/kg/day over the course of four weeks.
If KBr is being used as a first-line monotherapy, a higher starting dose – 30mg/kg/day to 40mg/kg/day – may be needed. The serum therapeutic range is 800mg/L to 2,300mg/L in drug-naïve dogs. However, 800mg/L to 1,500mg/L is recommended in dogs receiving PB.
When starting therapy, regular monitoring of serum drug concentration should be performed – for example, at 4, 8 and 12 weeks and then at 6 months.
As aforementioned, KBr is not recommended in cats as a bronchial-asthma like condition has been seen in a prohibitively high number of cases (Dewey, 2006). The most common side effects reported in dogs are polydipsia, polyphagia, sedation, ataxia, pancreatitis and erythematous dermatitis/pruritus.
KBr may cause vomiting due to its irritant nature on the gastric mucosa; this can be reduced by administration in multiple, smaller daily doses and by administering KBr with food. KBr should not be used in pregnant or lactating dogs and should be used with caution in dogs with hypoadrenocorticism or renal insufficiency.
In humans, bromide therapy is not as well tolerated and has been associated with side effects, such as severe skin lesions, gastrointestinal and neurological signs (Baird-Heinz et al, 2012). KBr should also not be used in cats, as aforementioned, as it can cause signs of coughing most likely secondary to feline asthma (Boothe et al, 2002; Volk et al, 2006).
Two systematic reviews about KBr’s safety give a good overview of all the reported side effects (Baird-Heinz et al, 2012, Charalambous et al, 2016). Most reports, however, are when KBr was used as an add-on, and data about its tolerability and safety as monotherapy are sparse.
Sedation, ataxia, weakness, polydipsia, polyuria and gastrointestinal signs, such as vomiting, are the most common reported type A side effects (Baird-Heinz et al, 2012; Boothe et al, 2012; De Risio, 2014).
Ataxia and sedation are the major dose-limiting side effects in dogs and have been shown to have an impact on the quality of life of owners looking after dogs with IE (Wessmann et al, 2016). As KBr is a salt, it can cause gastrointestinal irritations and is best given in two doses daily. Some larger dogs may tolerate KBr better when given in three doses. The side effects are most severe initially and improve over time until they stabilise. High KBr doses can affect thyroid function in humans and rats (Baird-Heinz et al, 2012).
Type B side effects formerly documented include increased risk of pancreatitis, behaviour changes – for example, irritability, hyperactivity and aggression – persistent cough, panniculitis and megaoesophagus (Boynosky and Stokking, 2014; March et al, 2002; Baird-Heinz et al, 2012; De Risio, 2014).
Bromide should be avoided in breeding animals as it readily passes the placenta. The author also advises KBr should be used with care in dogs with hypoadrenocorticism.
Epilepsy can be controlled effectively when AEDs are given at the right time, when appropriate and combined as necessary.
KBr is an effective and well-tolerated AED, and can help control seizures in the majority of the cases when added to first-line AED treatment with imepitoin or PB. Many of the side effects can be managed when the drug is given sensibly.
The more the owners are informed about what to expect, the more they will feel comfortable caring for an epileptic patient.
