POTS Caused By Mast Cell Antihistamine Drugs?

How many of your patients right now have both MCAS (mast cell activation syndrome) and POTS (postural orthostatic tachycardia syndrome)? Many I’m sure! Have you determined which came first? You absolutely should. Why? Numerous antihistamine drugs are also anticholinergics. POTS is characterized by dysautonomia and an associated loss of vagus nerve function.

If POTS developed after MCAS, have you considered that MCAS medication may be the trigger for POTS?

Several antihistamine drugs are also: anticholinergics. This includes:

• Diphenhydramine (Benadryl) (2)
• Cyproheptadine (Periactin) (2)
• Promethazine (Phenergan) (2)
• Desloratidine (Clarinex) – strong muscarinic receptor antagonism (1)
• Loratadine (Claritin) (2)
• Diphenhydramine (Benadryl, Genahist, Sominex, Unisom) (2)
• Azelastine (Optivar) (1)
• Olopatadine (Patanol) – partial muscarinic receptor antagonism (1)
• Ketotifen (Zaditor) – strong muscarinic receptor antagonism (1)

Cetirizine, epinastine and fexofenadine are not believed to be anticholinergic (1, 2).

Vagus Nerve, POTS & Cholinergic Signaling

The vagus nerve is centrally involved in cholinergic signaling, through the use of the neurotransmitter acetylcholine and it’s muscarinic receptors. Vagus efferent (outward) signaling orchestrates key actions of the parasympathetic response. POTS is characterized by excessive sympathetic activity and ß-adrenergic receptor activation. POTS is linked to a loss of vagal function, and clinical trials are underway to investigate the efficacy of vagus nerve stimulation for POTS treatment (3, 4). To complicate matters is that muscarinic acetylcholine receptor antibodies have been found in a subset of POTS patients. Does this association involve antihistamine anticholinergic drugs?

It doesn’t stop there.
A recent Harvard edu blog made headlines describing how anticholinergics such as Benadryl are associated with increased dementia risk (5).

Important Immune-Modulating Mechanisms of Vagus Function That No One is Teaching

Aberrant efferent and afferent vagus signaling is likely a central player in chronic illness. What no one seems to be discussing is the important role acetylcholine and vagus signaling plays in the immune system. This includes GI mucosal and submucosal immunity, as well as important anti-inflammatory cytokine mechanisms. By inhibiting the action of histamine through the use of anticholinergics, is it possible these anti-inflammatory immune mechanisms are being inhibited or adversely affected in some way?

• Vagus innervation via acetylcholine is centrally involved in immune cell signaling (6, 7)
• Vagal-derived acetylcholine signaling critically inhibits hyper-inflammation of intestinal macrophages and dendritic cells (6, 7)
• Vagal-derived acetylcholine signaling inhibits autoimmune-promoting TH17 (6, 7)
• Vagal-derived acetylcholine signaling promotes mucosal and sub-mucosal immune tolerance through modulation of T-Regulatory Cells (TREGs) and FOXP3 (6, 7)
• Healthy vagal tone modulates immune tolerance via: TGFß, IL-10, CD103 (6, 7)
• Cell Danger Response (CDR) purinergic signaling directly inhibits vagus function (8)

Future research should be aimed at identifying safer alternatives for MCAS treatment, which does not interfere with the vagus nerve, or it’s cholinergic signaling.