Antihistamine's effect on insulin secretion and tiredness?

Question

Antihistamines are known to cause tiredness. The essential hormones of the body are insulin (glucose), parathyroid hormone (calcium) and aldosterone (Na-K ATPase, sodium). I am thinking how this tiredness symptom can come. There are so many different antihistamines so I am confused about the mechanism how they cause tiredness.

1. Histamine acts on parietal cells of stomach via H2 receptors to stimulate hydrogen ion secretion - cephalic phase. Excess of antihistamines can lead to decreased acidity of stomach so change in conversion of pepsinogen into pepsin. So less pepsin breaking down peptides and proteins. Body has to do something else to break those components - and this consumes much energy and makes you tired.

2. Small mucus food mass stays in the intestines. Delayed absorption. Nutrients needed so liver has to work and make essential things - amino acids and something else. Some waste management also may happen - because of tiredness.

Changes in blood sugar level. Delayed most probably after food intake. Very fast and fast insulin secretion mechanism starting during wrong times - all of the sudden. So less insulin secretion cumulatively:

• very fast mechanism - change of permeability of membranes (Na-K ATPase and sodium channels) reacting during times when not suitable - long after food intake
• fast mechanism (phosphorylation of different things) happening more, since sympaticus apparently is not so inhibiting here
• slow and very slow mechanisms however preferable (increased permeability of amino acids and mitoses)

So I think the tiredness of antihistamines is because of the increased amount of active fast mechanisms of insulin secretion, while less very fast mechanisms. To carry the raw food mass in the intestines also require much energy.

What is the physiological mechanism behind the tiredness of excess antihistamines?

Answer 1

Thanks to studies on animal behavior and on histamine dection in the Central Nervous System, researchers found out the "histaminergic system". It's thought that histamine-containing neurons regulate sleep-wake cyrcle, immunity, memory, body temperature, drinking, feeding rhythms. By the way, knockout rats who lack of histamine system don't show big defects in any function.

H1-Receptors for Histamine are distributed in the CNS and in the rest of the body. H1-antagonists (such as Promethazine, Chlorcyclizine, Loratadine...) have different effects on CNS, depending on dose. At conventional doses central depression appears and patients are sedated. They can even experience an antihistamine "hangover" in the morning, even if they take these drugs at bedtime. By the way, antihistamine overdose typically shows with convulsions.

The "non-sedating" H1-antagonists, or "second generation" have a lot less effects on CNS. They have polar chemical structure: they can not cross the blood-brain barrier. By the way, a lot of typical and atypical anti-psychotic drugs have H1-antagonism effects on the brain (with H2 and H4 antagonism): their main goal is sedation to stop the patient from hurting himself (or others) during manic episodes.

So I think the last two sentences explain that sedation is almost a totally CNS-mediated side effect of antihistamine drugs.

H1-antagonists don't suppress gastic secretion, do not inhibit salivary, lacrimal or other exocrine secretions. Older H1-antagonists have an anti-colinergic effect on muscarinic receptors: they may reduce ACh-mediated secretions, typically in mouth and in the respiratory tree.

H2-antagonists are used to treat acid-peptic desease (as PPIs, proton pump inhibitors). CNS-related side effects are not commons, and include: confusion, delirium, hallucinations, slurred speech and headaches. These effects are mostly related with IV infusion of the H2-antagonist.

I just made a very small research on PubMed. I found this: http://www.ncbi.nlm.nih.gov/pubmed/3529778 as you can see it is a study (on only 9 patients, in 1986), about insuline-glucose-Cpeptide and ranitidine (H2-antagonist) relations. Their conclusion is "Ranitidine significantly increased the area under concentration/time curves for glucose and insulin but not that of C-peptide. Our data indicate that ranitidine does not affect pancreatic insulin release nor peripheral glucose utilization and are consistent with the hypothesis that ranitidine influences the hepatic clearance of glucose and insulin both of which undergo high first-pass liver extraction."

I think that tiredness is a typical CNS-mediated side effects of H1-antagonists (anti-allergic) but is not a side effect of H2-antagonists (anti-acid). Maybe H2-antagonists affects insulin action via hepatic effects.

*I'm italian (sorry for any english mistake) and I am a last-year medicine college student. I wrote trying to summarize some chapters (8, 32 and 45) of: - "Goodman & Gilman's The Pharmacological Basis of Therapeutics" - L. Brunton, B. Chabner, B. Knollman - 12th edition; McGrawth Hill 2011