Thread by @angryhacademic

Antihistamines


4 histamine receptors which have different actions: H1, H2, H3, H4

Note that over the counter antihistamines target H1. Famotidine and similar (often used for stomach protection) targets H2
🧵sciencedirect.com/science/articl…

All histamine receptors are GPCRs - a hot topic in #longcovid!

H1 mainly implicated in immediate hypersensitive reactions - wheezing, itching, coughing, blood pressure drop

H2 mainly affects gastric mucosa, vascular smooth muscle, brain, fat cells, basophils, neutrophils, etc

H3 mainly found in the central nervous system, e.g. hippocampus, thalamus, amygdala, hypothalamus. Also found in vascular beds

H4 mainly found in peripheral blood cells, but also bone marrow, colon, small intestines, lungs. Possibly implicated in regulating immune responses

Vascular bed: main histamine effect is dilation = flushing and low blood pressure. Plus capillary permeability.

Vasodilation = H1 & H2. H1 is typically quicker than H2 to induce vasodilation.
H1 & 2 works on smooth muscle and H1 via endothelial stimulation too

Endothelial stimulation = NO and possibly prostaglandin I2

H3 works on the nerves that regulate the vasculature

Heart: histamine effects on heart mainly mediated through H2, but also H1. Vasodilation = tachycardia

Extravascular smooth muscle: H1 = contraction of smooth muscle of uterus; H2 = uterine relaxation. Gastrointestinal contraction seems mediated through H1

Glandular secretion: mucus stimulated vis H1 & H2. H2 = more secretion; H1 = more viscosity

Immune: immune/inflammatory response mediated by H2 = negative feedback loop on basophil (not mast cell) histamine release. Also has broader effect on T cells, monocytes, etc

H4 receptors found on leukocytes, & may help recruit mast cells, contributing to allergic reactions

Antihistamines: act on both mast cell AND basophil degranulation

Different drugs can cause different reactions (including release of mediators) depending on tissue and dose (in vitro), e.g. ketotifen = weak histamine release inhibitor, and only induced release in skin mast cells

cetirizine = inhibited histamine and prostaglandin D2 release from all tested tissues and did not induce release at ↑ concentrations

In vitro evidence of broader anti-inflammatory effects too

In vitro, desloratadine blocks IL4 & IL13 release (implicated in allergic reactions)

Unknown mechanisms how antihistamines prevent mast cell and basophil degranulation, but these effects do not appear to be from H1 receptor blockade, some ideas are described in the paper

Most 1st gen ("sedating") antihistamines look similar to histamine

But 2nd gen antihistamines (e.g. loratadine, cetirizine, fexofenadine, etc) do not look similar to histamine, i.e. antihistamine activity doesn't require a shared structure.

Most/all antihistamines are not competitive agonists, but inverse agonists

1st gen antihistamines can impair performance even without apparent sedation.

2nd gen antihistamines are called "non-sedating" (they don't pass the blood brain barrier) but can still cause sedation, esp in higher doses 🙃 but they don't interfere with performance so much

2nd gen = much more specific to (peripheral) H1 receptors compared to 2nd gen (which also have other effects like anti-cholinergic)

Erythromycin and ketoconazole ↑ bioavailability of fexofenadine by > 100 %!!😯

Loratadine has a similar structure to tricyclic antidepressants, but doesn't affect the nervous system so much. it has no structural resemblance to histamine, but is quite specific for H1 receptors. higher doses can = other effects like anticholinergic

Desloratadine is a loratadine metabolite and may be particularly helpful for asthma and rhinitis

Cetirizine is not heavily metabolised by the liver so may be good for those with liver problems or certain P450-affecting drugs

You poop most fexofenadine out, and a good chunk of the rest is peed out 💩



lots of other interesting bits, but those were my highlights!

#MCAS

https://twitter.com/angryhacademic/status/1695139178655162612

Woops typo, should read:

2nd gen = much more specific to (peripheral) H1 receptors compared to 1st gen...

https://twitter.com/angryhacademic/status/1695928902797959404