antihistamine, diphenhydramine (Allerdryl; Benadryl; Tylenol PM; Unisom) has
been used for many years for a variety of conditions that include such things
as allergies, sleep aid, and motion sickness.1,2 Most clinicians and even
patients know very well that older antihistamines (such as diphenhydramine)
cause xerostomia (dry mouth).1,2 In fact, xerostomia is one of many side
effects associated with the use of diphenhydramine that are collectively called
"anticholinergic" side effects which also includes such things as
drowsiness, blurry vision, constipation and urinary retention. This means
that older antihistamines, like diphenhydramine, block some of the actions
mediated by the cholinergic system and thus are described as having
anticholinergic effects in addition to their histamine (H1) antagonist
Why is diphenhydramine more likely to cause anticholinergic
side effects like xerostomia?
differ in their chemical structure and these differences have a direct impact
on their ability to cross the blood brain barrier.1Diphenhydramine is one of a
group of antihistamines with ethanolamine subgroups.1 This chemical
structure allows it to penetrate the blood brain barrier and enter the brain
where it exerts its anticholinergic effects.
gets into the brain, how does it then decrease saliva production that results
in xerostomia (dry mouth)?
is important to note that saliva is produced by 3 separate glands in the oral
cavity. These are the parotid, submandibular, and sublingual glands.3
Each of these glands receives autonomic nerve innervation via the
parasympathetic nervous system (i.e., cholinergic nervous system).3,4 The
primary neurotransmitter of the parasympathetic nervous system is acetylcholine
and upon release will activate either nicotinic or muscarinic receptors
(depending on the target organ or tissue).5 Nicotinic and muscarinic
receptors are G-coupled protein receptors that exert their biological (or
physiologic) effect via a number of different intracellular signaling pathways.5 As
it relates to the activation of the salivary glands, the parasympathetic fibers
that innervate the parotid gland travel with cranial nerve IX (CNXII; glossopharyngeal
nerve) and the parasympathetic nerve fibers that innervate the submandibular
and sublingual glands travel with cranial nerve VII (CNVII; facial nerve).4
Therefore, anything that interrupts cholinergic transmission to these glands
(such as the anticholinergic activity of diphenhydramine) would decrease saliva
production and ultimately result in xerostomia.
What are the
details for this drug side effect?
autonomic innervation to various organs/tissues in the body is in part
regulated or mediated by the hypothalamus (one component of the diencephalon)
in the brain.4 Nerve cell bodies in the hypothalamus send out afferent
nerve fibers which travel along the dorsal longitudinal fasciculus (DLF; or
descending autonomic pathway) in the brain stem. At certain points in its
descent the afferent autonomic nerve fibers branch off at the level of various
cranial nerves where they will ultimately travel to their target tissue or
organ. The first branch occurs at the level of CNVII (facial nerve) at
the level of the pons in the brain stem where they activate parasympathetic
nuclei located in the superior salivatory nucleus. The activated
preganglionic nerve fibers then exit the brainstem along with other fibers on
CNVII at the level of the pons and the medulla. These fibers then (along
with CNVIII (vestibulocochlear nerve)) enter the internal acoustic meatus where
they pass through the geniculate ganglion without synapsing. Prior to the
exit of CNVII through the stylomastoid foramen, the preganglionic
parasympathetic nerve fibers branch off onto the chordae tympani from which
they will branch off again onto to the lingual nerve. Once on the lingual
nerve, the preganglionic parasympathetic nerve fibers will then release
acetylcholine (Ach) within the submandibular ganglion where it will bind to
nicotinic-2 receptors (N2) thereby resulting in the opening of the Na+/K+
channels on the postganglionic parasympathetic nerve fibers thus causing
depolarization.5 The depolarized postganglionic parasympathetic nerve
fibers then travel to the sublingual and submandibular glands where they also
release Ach which activates Gq-protein coupled muscarinic-3 receptors (M3)
found on the salivary glands thereby resulting in salivation.5 The
parotid gland is activated in a similar manner when the remaining afferent
nerve fibers from the hypothalamus continue to descend within the DLF to exit
and synapse on preganglionic parasympathetic nerve cell bodies within the
inferior salivatory nucleus. Of note, nerve fibers from the olfactory
system can also activate the preganglionic parasympathetic nerve fibers at this
location. Regardless of the activation, the depolarized preganglionic
parasympathetic nerve fibers then travel on the tympanic branch of CNIX
(glossopharyngeal nerve). After a short distance, the nerve fibers then
exit onto the tympanic plexus and then onto the lesser petrosal nerve where
they will eventually release Ach in the otic ganglion. The released Ach
then binds to N2 receptors thereby causing depolarization of the postganglionic
parasympathetic nerve fibers that innervate the parotid gland.5 Once the
impulse reaches the parotid gland, the postganglionic parasympathetic nerve
fibers release Ach which also binds to Gq-coupled protein M3 receptors on the
parotid gland thereby resulting in salivation. It is the binding of Ach
at the M3 receptors that is the primary stimulatory effect on salivation.
Stimulation of the M3 receptors results in an increase in inositol 1,4,5-triphosphate
(IP3) and intracellular calcium (Ca++) concentrations.5 This is also where
diphenhydramine's anticholinergic activity is likely to be most influential in
the development of xerostomia. The increase in salivary activity by Ach
is a result in both increased transport mechanisms by the acinar and ductal
cells as well as an increase in blood flow (vasodilation).4,5 While the
sympathetic nervous system also contributes to saliva production, the
parasympathetic activity predominates.
the anatomy and physiology can easily allow a clinician to see how
diphenhydramine's anticholinergic properties can cause xerostomia. While
xerostomia can be a mild aggravation for the patient and may not appear to be
clinically relevant, chronic xerostomia can increase the risk for dental caries
as well as worsen symptoms of gastroesophageal reflux disease (GERD).
- Katzung BG. Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids. In: Basic & Clinical Pharmacology. 9th Ed. Katzung BG, eds. Lange Medical Books/McGraw-Hill. New York, NY. 2004:259-268.
GD, Angello JT, Wu MM et al. Efficacy of diphenhydramine vs
desloratadine and placebo in patients with moderate-to-severe seasonal
allergic rhinitis. Ann Allergy Asthma Immunol 2006;96:606-14.
- Junqueira LC, Careneiro J. Chapter 16. Organs Associated with the Digestive Tract. In: Basic Histology. 11th Ed. Junqueira LC, Careneiro J eds. McGraw-Hill. New York, NY. 2005:317-321.
- Snell RS. Chapter 11. The Cranial Nerve Nuclei and Their Central Connections and Distributions. In: Clinical Neuroanatomy. 6th Ed. Snell RS eds. Lippincott Williams and Wilkins. Philadelphia, PA. 2006:325-364.
- Costanzo LS. Chapter 2. Neurophysiology. In: Physiology. 4th Ed. Costanzo LS eds. Lippincott Williams & Wilkins. Philadelphia, PA. 2007:33-37.