A 52-year-old man comes to the office for an annual preventive visit. He has a history of seasonal allergies, and has recently started taking a medication that has improved his runny nose, sneezing, and watery eyes. Medical history is remarkable for diet-controlled type 2 diabetes mellitus and eczema. He is not on any other medications. He does not use tobacco, alcohol, or illicit drugs. Examination shows a well-appearing man with flushed cheeks and dilated pupils. This patient's physical examination findings are best explained by which of the following mechanisms?
Anticholinergic toxicity | |
Symptom | Mechanism |
"Hot as a hare" |
|
"Dry as a bone" |
|
"Red as a beet" |
|
"Blind as a bat" |
|
"Mad as a hatter" |
|
"Full as a flask" |
|
"Fast as a fiddle" Tachycardia |
|
This patient is likely taking a first-generation antihistamine (eg, diphenhydramine), which are commonly used for treating environmental allergies and mast cell-related disorders. First-generation antihistamines are nonspecific and act as antagonists to multiple receptors, including the muscarinic acetylcholine receptor. This leads to anticholinergic effects (eg, fever, urinary retention, decreased sweating, altered mental status). In this patient, the flushing is likely a compensatory response to dissipate excess body heat due to decreased sweating, and the pupillary dilation is due to inhibition of the iris sphincter.
Although commonly described as H1 receptor antagonists, antihistamines are actually inverse agonists that stabilize the receptor in the inactive state. H1 receptors are found in the vascular endothelium and bronchial smooth muscle, where they mediate vascular permeability and bronchoconstriction, as well as in the central nervous system where they are involved in alertness. Antihistaminic effects relieve nasal congestion, rhinorrhea, sneezing, and itching. First-generation antihistamines cross the blood-brain barrier and cause sedation. By contrast, second-generation antihistamines (eg, loratadine) are more specific to the histamine H1 receptor and have less permeability through the blood-brain barrier; they are generally less effective than first-generation antihistamines but have significantly fewer side effects.
(Choice A) Flushing and mydriasis are due to antagonism of the cholinergic receptor, not the H1 receptor.
(Choice B) H2 receptors are found on parietal cells in the gastric mucosa. H2 antagonists block gastric acid secretion by parietal cells.
(Choice D) Nicotinic cholinergic receptors are found in sympathetic and parasympathetic ganglia and on skeletal muscle cells at the neuromuscular junction. Nicotinic receptor antagonists (eg, rocuronium) are used to induce paralysis in preparation for surgery or endotracheal intubation. Adverse effects include hemodynamic instability (eg, hypotension) and respiratory insufficiency.
(Choice E) Alpha-1 adrenoreceptors are located on smooth muscle and neurons. Activation of these receptors increases smooth muscle tone of the iris dilator (causing mydriasis) and blood vessels (causing vasoconstriction); alpha-1 adrenergic agonists (eg, phenylephrine, oxymetazoline) can be used in patients with allergic rhinitis because their vasoconstrictive action reduces nasal congestion. However, vasoconstriction inhibits flushing.
Educational objective:
First-generation antihistamines are nonspecific and interact with multiple receptors, including the muscarinic receptor. This leads to anticholinergic effects (eg, fever, flushing, mydriasis, urinary retention, tachycardia, altered mental status).