"For a Restful Night's Sleep", cross the blood-brain barrier

I think I set my personal record for consecutive hours asleep (13) and hours in bed (16) last night -- all thanks to the wonders of diphenhydramine, brand name Benadryl. Sleeping pills are a double-edged sword for depressives: they grant you the blissful escape of sleep but, with their induced morning grogginess, make it that much harder to get out of bed. Once I did get out of bed, I set out to figure out why antihistamines make you so sleepy -- why do they both cure your runny nose and your insomnia?

From www.rxlist.com, I learned that diphenhydramine (which I will mercifully abbreviate as DPH) has both anticholinergic (drying) and sedative side effects. The HCl salt form is quickly absorbed, with maximal activity occuring in about one hour and the duration of a normal dose lasting from four to six. This did not explain why I was still knocked out 13 hours after ingesting a "normal dose". DPH is also used to combat motion sickness (guess you can't be puking all over your car if you're fast asleep) and as an antiparkisonism. Interestingly, one of the listed side effects was insomnia. (I think sometimes they list every side effect just to cover their bases.) DPH has an additive effect with alcohol and other CNS depressants. So don't drink and Sleep-Aid.

Clicking on the word "antihistamine", I discovered more detailed information:

Antihistamine: A drug that opposes the action of histamine. Although there are two classes of histamine-blocking drugs, the term antihistamine is typically used to describe agents that block the action of histamines on H₁ receptors. These agents are used to treat allergies, hives, and other local and systemic hypersensitivity (allergic) reactions. Side effects of first-generation antihistamines (e.g, chlorpheniramine) include sedation, drying of mucous membranes, and urinary retention. Some first-generation antihistamines can also be used to treat insomnia, motion sickness, or vertigo. Second-generation agents (e.g., loratadine) tend to be less sedating, but still have beneficial effects in the treatment of allergies.

(The urinary retention might explain why my pee was orange-brown in the morning.) The answer to my question appears to lie in histamine recpetors, their different sub-types,where they are located in the body, and what functions they elicit.

But first, I wanted to learn a bit more about histamine, the foe of allergy- and insomnia-sufferers worldwide. A webpage for a biology course at Davdison College revealed the meaning behind the word histamine: hist- because it made of histidine, -amine because it's an amine. Clever. Histamine is released by mast cells during an allergic reaction and contributes to the inflammatory response of the immune system, specifically vasodialation -- the outpouring of fluids from your blood vessels into the surrounding tissues -- which is to blame for the itching, sneezing, and mucus-overproduction of allergies. Mmm, mucus. Histamine also causes constriction of smooth muscle -- which can be most bothersome when this smooth msucle happens to be around your airways and you've just inhaled an allergen.

Wikipedia proved to be a most useful source of detailed information. Histamine is in fact formed from the decarboxylation of the amino acid histidine, and some food poising is due to the conversion of histidine to histamine, such as in rotten fish. Histamine also regulates stomach acid and may function as a neurotrasmitter in the CNS (central nervous system). This seemed to be getting me closer to the sedative properties of DPH. Histamine receptors can be categorized into three subtypes:

• H1: resposible for bothersome allergy symptoms (vasodialation, smooth muscle contraction, hives) and also motion sickness
• H2: gastric acid secretion
• H3: neurotransmitter release
  

So, once pharmacologists figured out that there were different histamine receptors, the two most relevant ones conveniently located on different sides of the blood-brain barrier, all they had to do was devise a molecule that could not penetrate the brain yet still anatagonized the H1 histamine receptors and they had a non-drowsy antihistamine. That is exactly what Claritin (loratidine) and Allegra (fexofenadine) are -- selective H1 agonists. I've heard that one drug works better for some people than others because of genetic differences in our H1 histamine receptors. Perhaps one day we will be genotyped for our allergy medication, but for now, it's hit-and-miss (or find out which one works for your mom -- that's what I did).

From BioTrend I discovered that histamine is synthesized by neurons located in the posterior hypothalamus of the brain. These neurons then project to most cerebral areas and have been implicated in sleep and wakfeulness. This explains the sedative nature of old-school antihistamines!

My question now answered -- why do antihistamines treat both allergies and sleeplessness -- I feel I can end this post and tackle the next most pressing question: how shall I fall asleep tonight? Aided by Benadryl, induced by Budweiser, or come by naturally? I'm hoping for au naturel, but I've got a case chilling in the fridge just in case -- a hang-over from alcohol is far better than one from diphenhydramine.