The 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 activity.1 

Why is diphenhydramine more likely to cause anticholinergic side effects like xerostomia?
Antihistamines 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.  

Once diphenhydramine gets into the brain, how does it then decrease saliva production that results in xerostomia (dry mouth)?
It 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?
The 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.  

Conclusion:
Understanding 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). 

References:

1. Katzung BG.  Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids.  In: Basic & Clinical Pharmacology.  9^th Ed.  Katzung BG, eds.  Lange Medical Books/McGraw-Hill.  New York, NY.  2004:259-268.
2. Raphael 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.  
3. Junqueira LC, Careneiro J.  Chapter 16. Organs Associated with the Digestive Tract.  In: Basic Histology.  11^th Ed.  Junqueira LC, Careneiro J eds.  McGraw-Hill.  New York, NY.  2005:317-321.
4. Snell RS.  Chapter 11. The Cranial Nerve Nuclei and Their Central Connections and Distributions.  In: Clinical Neuroanatomy.  6^th Ed.  Snell RS eds.  Lippincott Williams and Wilkins.  Philadelphia, PA.  2006:325-364.
5. Costanzo LS.  Chapter 2.  Neurophysiology.  In: Physiology.  4^th Ed.  Costanzo LS eds.  Lippincott Williams & Wilkins.  Philadelphia, PA.  2007:33-37.

Antihistamine, Diphenhydramine, Allerdryl, Benadryl, Tylenol PM, Unisom, Xerostomia, Dry Mouth, Anticholinergic Side Properties of Benadryl