Introduction

• Nature and Origin:

  • Bromide is an inorganic ion similar to chloride.
  • Naturally present in the environment, especially in seawater (approximately 65 mg/L).
  • Found in significant amounts in human blood due to seafood consumption.

• Historical Uses:

  • Widely used in the 19th and early 20th centuries as sedatives and for headaches.
  • Lithium bromide used for bipolar disorder treatment.
  • Current uses include low-concentration antiseptic agents in swimming pools.

• Relevance in Epilepsy:

  • Potassium bromide (KBr) was the first “modern” anticonvulsant.
  • Introduced in 1857 by Sir Charles Locock for hysterical (catamenial) epilepsy.
  • Remained the primary anticonvulsant until the discovery of phenobarbital in 1912.

Pharmacology

1. Chemical Structure and Characteristics:

   • Formula: Potassium bromide (KBr), a simple inorganic ion.
   • Mimics chloride and is handled similarly in the body.

2. Mechanism of Action:

   • Unclear but hypothesized mechanisms:
     • Facilitates hyperpolarization by replacing chloride in neuronal membrane channels, reducing neuronal excitability.
     • Potentiates GABAergic inhibition by acting on GABAA_AA​ receptors, enhancing chloride influx.
     • May inhibit carbonic anhydrase, affecting brain acid-base balance (similar to acetazolamide).

3. Pharmacokinetics:

   • Absorption: Rapid and complete absorption from the gastrointestinal tract.
   • Distribution:
     • Freely diffusible; volume of distribution: ~408 ± 17 mL/kg.
     • Present in body secretions (e.g., saliva, tears) and crosses the placenta.
   • Excretion:
     • Not metabolized; excreted primarily via kidneys.
     • Elimination half-life: 12–14 days (renal clearance: 267 ± 1.7 mg/kg/day).
     • Chloride intake inversely affects the half-life.
   • Steady-State Concentration: Takes ~7–8 weeks to achieve.

4. Drug Interactions:

   • CNS depressant; potentiates effects of other CNS-active drugs.
   • Does not induce/inhibit liver enzymes or affect protein binding.

5. Therapeutic Drug Monitoring:

   • Serum concentration range: 100–200 mg/mL (8.4–16.8 μmol/L).
   • Toxic effects occur above 150 mg/100 mL.
   • Requires close monitoring due to long half-life and potential for toxicity.

Clinical Indications

• Primary Indications:

  • Severe, drug-resistant childhood epilepsies, particularly generalized convulsive seizures.
  • Lennox-Gastaut Syndrome (LGS): Limited efficacy; may aggravate absences/tonic seizures.
  • Dravet Syndrome (DS): Effective against generalized tonic-clonic and complex partial seizures.
  • Malignant migrating partial seizures in infancy: Demonstrates notable efficacy.

• Additional Uses:

  • Useful in patients with epilepsy and porphyria (non-hepatic enzyme-inducing).
  • Last-resort option in intractable convulsive seizures resistant to conventional treatments.

• Dosage:

  • Starting dose: 10 mg/kg/day in divided doses (poor gastric tolerance).
  • Therapeutic dose: 30–80 mg/kg/day; steady state reached after 7–8 weeks.

Side Effects and Toxicity

1. Chronic Toxicity (“Bromism”):

   • CNS-related: Lethargy, ataxia, depression, tremor, psychosis, confusion, and seizures.
   • Dermatological: Acneiform dermatitis (bromoderma), aphthous stomatitis, panniculitis.
   • Gastrointestinal: Gastric irritation, vomiting.
   • Respiratory: Rhinitis, asthma aggravation.

2. Acute Toxicity:

   • Rare; includes nephrotoxicity, ototoxicity, and acute renal failure.

3. Monitoring:

   • Regular serum level assessments.
   • Adjust doses based on clinical response and side effects.

Limitations in Modern Use

• Declined use due to:

  • Significant chronic toxicity and long half-life.
  • Emergence of safer, more effective antiepileptic drugs.

• Current availability:

  • Licensed for severe epilepsy in children in limited regions (e.g., Dibro-Be® tablets in Germany).
  • Requires special prescription/import procedures.

Conclusion

• Legacy:

  • Historically pivotal as the first scientifically recognized anticonvulsant.
  • Contributions to early epilepsy research and treatment.

• Modern Context:

  • Reserved for specific, severe epilepsy cases unresponsive to conventional treatments.
  • Importance as a "third-line" option in intractable epilepsy conditions, particularly in pediatric populations.