insomnia (part II)

I get seasick. I get carsick. I get sick from rollercoasters. I get sick on buses. I get sick on trains. I get sick on subways. This may be a contributing factor to why I love human-powered transportation so much! Bicycling never makes me sick.

This semester was so stressful! (see previous posts eLearning then Checking in) I was so self-involved trying to be extrordinary that I forgot it's more important to keep it simple. In 2018, I hope to leave at least 6 hours each day for empty space and see what happens (how the time gets filled in). Last semester, I was scheduled so tightly that I really had no time that wasn't already spoken for.  It was actually quite ridiculous. Anyway, that's a long way of making an excuse for how I would come home at 11pm (after night lab) and then have to teach at 8am the next morning. So I would dissolve Alka Seltzer Plus Night Cold & Flu in 4 oz of water and crash out. It would help me sleep no matter what.

Then, on dear husband's birthday (see previous post behind the curtain) we boarded the Catalina Express and spent the weekend out driving around in a golf cart and in cars throughout Los Angeles, Riverside, and Orange counties. My mother-in-law gave me Dramamine so that I wouldn't get motion-sick. I took the maximum recommended dose in the morning, and then took another dose 6 hours later. I felt just like I had drank an entire bottle of red wine. But also, I felt a similar feeling the next day as I felt when I had taken the Alka-Seltzer Plus Night Cold & Flu, which made me wonder about the active ingredients in each.

Antihistamines and the endogenous ligand

Doxepin at low doses used to treat insomnia due to its binding to the histamine H1 receptor. Meclizine is sold under the name Dramamine II (Less Drowsy Formulation). Doxylamine is a first-generation antihistamine, part of the formulation NyQuil. Chlorphenamine is part of Kirkland Signature Day/Night Time Cold Multisymptom Relief Rapid Release Gelcaps (from Costco). Dimenhydrinate (a combination of diphenhydramine and 8-chlorotheophylline) is Dramamine I. Diphenhydramine alone is sold under the trade name Benadryl among others. In college, after the 9/11/2001 terrorist attacks on the World Trade Center, I had a hard time sleeping. The student health center recommended Benadryl as a sleep-aid.

Dale discovered histamine,1910

Antihistamines, including diphenhydramine, were introduced in the 1940s. Dale isolated histamine and discovered its role in nerve signal transduction. Bouvet together with his student Anne-Marie Staub synthesized and tested the first antihistamines. These compounds were too toxic; not until 1942 were the first medically useful antihistamines developed by Bernard Halpern.

I have written about the histamine H2 receptor in a previous post. There are histamine H3 and H4 receptors also, but this post is going to stay on the topic of compounds that block the histamine H1 receptor.

Bouvet discovered antihistamine, 1937

Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first-generation antihistamines. Their main benefit is they primarily affect peripheral histamine receptors and therefore are less sedating.  These are newer drugs, but this post will continue to focus on the first-generation antihistamines, which are available over-the-counter at an affordable cost.

An advantage to the use of antihistamines for treatment of insomnia is that tolerance does not occur during regular use. A disadvantage to the use of antihistamines for treatment of insomnia is impairment of alertness, cognition, learning and memory. Overdose is possible, leading to death via respiratory depression. Diphenhydramine overdoses (0.5-1 g) whether accidental, suicide or homicide, are a common event in the United States. Therefore, poison control centers have guidelines for triage and management for antihistamine toxicity after overdose.

This research and writing has inspired me to devote my next chemistry-related post to drugs that are stimulants of the xanthine class. Dimenhydrinate, for example, is a combination of diphenhydramine and 8-chlorotheophylline. The stimulant counteracts the calming effects of the antihistamine.

Anne-Marie Staub wins Ehrlich Prize, 1969

References

Church, M. K. and Church, D. S. Pharmacology of Antihistamines, Indian Journal of Dermatology, Volume 58, Issue 3, 2013, Pages 219–224.

Mahdy, Amr M. and Webster, N. R. Histamine and antihistamines, Anaesthesia & Intensive Care Medicine, Volume 12, Issue 7, 2011, Pages 324 - 329.

Mitchell, H. A. and Weinshenker, D. Good night and good luck: norepinephrine in sleep pharmacology, Biochemical Pharmacology,Volume 79, Issue 6, 2010, Pages 801-809.

Simons, F. E. R. and Simons, K. J. Histamine and H1-antihistamines: Celebrating a century of progress, Journal of Allergy and Clinical Immunology, Volume 128, Issue 6, 2011, Pages 1139-1150.

Stojković, N., Cekić, S., Ristov, M., et al. Histamine and Antihistamines / Histamin i antihistamini. Acta Facultatis Medicae Naissensis, Volume 32, Issue 1, 2015, pp. 7-22.

Yanai, K; Yoshikawa, T.; Yanai, A.; Nakamura, T; Iida, T.; Leurs, R and Tashiro, M. The clinical pharmacology of non-sedating antihistamines, Pharmacology & Therapeutics, Volume 178, 2017, Pages 148-156.

insomnia (part I)

Valium launched in 1963. Ativan opened for US sales in 1977. Klonopin opened for US sales in 1975. Rohypnol launched in 1974, but was never marketed in the US. Xanax launched in 1981. 

In the mid-1950s, chemists at Hoffman-LaRoche intended to discover new tranquilizers. Valium was among the first pharmacological and commercial successes. By 1980s, it was known that this class of molecules resulted in chemical dependence (addiction). However, use of these compounds for short-term relief from anxiety have not significantly dropped. Dependence and tolerance, coupled with dosage escalation and withdrawal symptoms, may appear after as little as 3 weeks.

Benzodiazepines work by binding to the GABAA receptor, at a site adjacent to the binding sites for GABA. The native ligand, GABA, inhibits nerve action by flooding the cell with chloride ions so that the nerve cannot "fire." Binding of benzodiazepines opens the ion channel even more, letting in more chloride ions, assisting in hyperpolarization, shutting the neuron "off." This is why benzodiazepines have the effect of a general nervous system depressant, muscle relaxant, and interfere with the formation of memories.

Treatment of insomnia can be achieved using benzodiazepines, however there are significant adverse-effects. Benzodiazepines are controlled substances and can lead to cognitive impairment, falls/fractures, delirium/dementia, anterograde amnesia, altered sleep activities (e.g., sleep-eating, sleepdriving, sleep-walking), and carryover sedation. Lack of memory formation is a contributing factor for Rohypnol's use as a date rape drug.

Long term use can result in permanent changes in the quantity of GABAA receptors and/or the configuration of GABAA receptors. This may be why rebound anxiety or rebound insomnia is a common withdrawal symptom. Overdose is possible, resulting in death by cessation of breathing. Benzodiazepines may cause or worsen depression. Upon cessation, seizures similar to delirium tremens are observed.

This class of drugs is still in use to alleviate pre-surgical nervousness, as they are fast-acting and potent. All are available as generic versions, but all require a prescription.

References
Wietholter, J. P. and Coetzee, R. "FDA-Approved Nonbenzodiazepine Receptor Agonists for the Management of Insomnia." US Pharm. 2017;42(1):29-32.