How Do Histamine Antagonist-Inverse Agonists Work?

Histamine H3 (H3) antagonist/inverse agonist or histamine H3 receptor (H3R) antagonist/inverse agonists are used to treat excessive daytime sleepiness (EDS) in patients with narcolepsy---a chronic sleep disorder that causes overwhelming daytime drowsiness.

Histamine released from histaminergic neurons acts as a neurotransmitter and is responsible for the sleep-wake cycle where high levels of histamine promote wakefulness. H3R regulates histamine synthesis and releases histamine in the brain and even controls the activity of neurons through presynaptic autoinhibition. If histamine levels increase in the brain, they bind to H3 autoreceptors and inhibit histamine synthesis and its release, leading to low histamine levels and causing reduced wakefulness.

Pitolisant is the only novel therapeutic drug approved by the United States Food and Drug Administration for the treatment of EDS or cataplexy (a brain disorder that causes sudden and temporary muscle weakness, occasionally causing the patient to collapse while fully awake) in patients with narcolepsy. However, the mechanism of the therapeutic effect of the drug is unclear. Pitolisant binds to H3 autoreceptors and prevents histamine from binding to autoreceptors; this is called an antagonist effect. It also binds to H3 receptors and increases histamine synthesis and its release; this is called an inverse agonist effect. Antagonist and inverse agonist effects of pitolisant increase histamine levels in the neural synapses in the brain.

Histamine H3 antagonists/inverse agonists are administered orally to treat EDS in adult patients with narcolepsy with or without cataplexy.

Side effects associated with histamine H3 antagonists/inverse agonists include:

• Nausea
• Hallucinations
• Anxiety
• Insomnia (trouble sleeping)
• Fainting
• Headache
• Fatigue
• Irritability
• Increased heart rate
• Flu-like symptoms
• Muscle and joint pains
• Abdominal pain
• Decreased appetite
• Behavioral changes
• Mood disorders
• Anaphylaxis (life-threatening allergic reactions)

The information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of histamine H3 antagonists/inverse agonists include:

• Pitolisant
• Wakix