General
Preferred name
DIPHENHYDRAMINE
Synonyms
DIPHENHYDRAMINE HYDROCHLORIDE ()
DPH ()
Diphenhydramine hcl ()
DIMENHYDRINATE ()
Diphenhydramine Hydrochloride ()
dimenhydrinate CDT, SCOLR ()
Diphenhydramine (hydrochloride) ()
Alledryl ()
Caladryl ()
Nytol ()
Dibenil ()
Benylin ()
Hydramine ()
Diphen ()
Paxidorm ()
Tixylix Catarrh ()
Silphen ()
Benadryl Preservative Free ()
Gppe Cough Expect Paed ()
Benadryl ()
Histergan ()
Sleepia ()
Vicks Formula 44 ()
Beldin ()
Medinex ()
Dytuss ()
Diphenhydramine Hydrochloride Preservative Free ()
Dimedrol ()
Gppe Oral Soln ()
Nightcalm ()
Coltex ()
Belix ()
Syntedril ()
Dreemon ()
NSC-33299 ()
Nytol One-A-Night ()
Fedril ()
Diphenhdyra ()
Restamin ()
Diphenhydramine ()
Diphenhydramine Tannate ()
Diphenhydramine Laurylsulfate ()
DIPHENHYDRAMINE CITRATE ()
P&D ID
PD009823
CAS
147-24-0
58-73-1
88637-37-0
110491-04-8
Tags
natural product
drug
available
Approved by
FDA
First approval
2005
1946
Drug indication
Antitussive
Meniere disease
Antihistaminic
Drug Status
investigational
approved
Max Phase
4.0
Probe control
Probe control not defined
Orthogonal probes
0
No orthogonal probes found
Similar probes
0
No structurally similar probes found
Structure
P&D probe-likeness score
Structure formats
[[ format ]]
[[ compound[format === 'MOL' ? 'molblock' : format.toLowerCase()] ]]
Description
(extracted from source data)
HALF-LIFE
The elimination half-life ranges from 2.4-9.3 hours in healthy adults [F3394, L5287]. The terminal elimination half-life is prolonged in liver cirrhosis [L5287].
PHARMACODYNAMICS
Diphenhydramine has anti-histaminic (H1-receptor), anti-emetic, anti-vertigo and sedative and hypnotic properties [L5281]. The anti-histamine action occurs by blocking the spasmogenic and congestive effects of histamine by competing with histamine for H1 receptor sites on effector cells, preventing but not reversing responses mediated by histamine alone [L5281]. Such receptor sites may be found in the gut, uterus, large blood vessels, bronchial muscles, and elsewhere [L5281]. Anti-emetic action is by inhibition at the medullary chemoreceptor trigger zone [L5281]. Anti-vertigo action is by a central antimuscarinic effect on the vestibular apparatus and the integrative vomiting center and medullary chemoreceptor trigger zone of the midbrain [L5281].
MOA
Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors [L5263, L5266, L5269, F3379, A174541]. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons [L5263, L5266, L5269, F3379, A174541]. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response [L5263, L5266, L5269, F3379, A174541]. Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms [L5263, L5266, L5269, F3379, A174541]. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center [L5263, L5266, L5269, F3379, A174541]. Furthermore, H1 receptors are similar to muscarinic receptors [L5263, L5266, L5269, F3379, A174541]. Consequently, diphenhydramine also acts as an antimuscarinic [L5263, L5266, L5269, F3379, A174541]. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication [L5263, L5266, L5269, F3379, A174541]. Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties [L5263].
ROE
The metabolites of diphenhydramine are conjugated with glycine and glutamine and excreted in urine [L5281, L5287]. Only about 1% of a single dose is excreted unchanged in urine [L5281, L5287]. The medication is ultimately eliminated by the kidneys slowly, mainly as inactive metabolites [L5281, L5287].
ABSORPTION
Diphenhydramine is quickly absorbed after oral administration with maximum activity occurring in approximately one hour [A644, L5287]. The oral bioavailability of diphenhydramine has been documented in the range of 40% to 60%, and peak plasma concentration occurs about 2 to 3 hours after administration [A644, L5287].
MOA
Diphenhydramine predominantly works via the antagonism of H1 (Histamine 1) receptors [L5263, L5266, L5269, F3379, A174541]. Such H1 receptors are located on respiratory smooth muscles, vascular endothelial cells, the gastrointestinal tract (GIT), cardiac tissue, immune cells, the uterus, and the central nervous system (CNS) neurons [L5263, L5266, L5269, F3379, A174541]. When the H1 receptor is stimulated in these tissues it produces a variety of actions including increased vascular permeability, promotion of vasodilation causing flushing, decreased atrioventricular (AV) node conduction time, stimulation of sensory nerves of airways producing coughing, smooth muscle contraction of bronchi and the GIT, and eosinophilic chemotaxis that promotes the allergic immune response [L5263, L5266, L5269, F3379, A174541].; ; Ultimately, diphenhydramine functions as an inverse agonist at H1 receptors, and subsequently reverses effects of histamine on capillaries, reducing allergic reaction symptoms [L5263, L5266, L5269, F3379, A174541]. Moreover, since diphenhydramine is a first-generation antihistamine, it readily crosses the blood-brain barrier and inversely agonizes the H1 CNS receptors, resulting in drowsiness, and suppressing the medullary cough center [L5263, L5266, L5269, F3379, A174541].; ; Furthermore, H1 receptors are similar to muscarinic receptors [L5263, L5266, L5269, F3379, A174541]. Consequently, diphenhydramine also acts as an antimuscarinic [L5263, L5266, L5269, F3379, A174541]. It does so by behaving as a competitive antagonist of muscarinic acetylcholine receptors, resulting in its use as an antiparkinson medication [L5263, L5266, L5269, F3379, A174541].; ; Lastly, diphenhydramine has also demonstrated activity as an intracellular sodium channel blocker, resulting in possible local anesthetic properties [L5263].
INDICATION
Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea [L5263, L5266, L5269, F3379, A174541].; ; Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for:; i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated [F3352];; ii) the active treatment of motion sickness [F3352]; and; iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents [F3352].
DESCRIPTION
Diphenhydramine has anti-histamine action.
(GtoPdb)
INDICATION
Diphenhydramine is a first-generation histamine H1 receptor antagonist (H1 antihistamine) that is widely available as a non-prescription, over-the-counter (OTC) medication. As an OTC medication, diphenhydramine is typically formulated as tablets and creams indicated for use in treating sneezing, runny nose, itchy/watery eyes, itching of nose or throat, insomnia, pruritis, urticaria, insect bites/stings, allergic rashes, and nausea [L5263, L5266, L5269, F3379, A174541]. Additionally, when the use of oral diphenhydramine is impractical, there are also prescription-only formulations such as diphenhydramine injection products that are effective in adults and pediatric patients (other than premature infants and neonates) for: i) the amelioration of allergic reactions to blood or plasma, in anaphylaxis as an adjunct to epinephrine and other standard measures after acute allergic reaction symptoms have been controlled, and for other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated [F3352]; ii) the active treatment of motion sickness [F3352]; and iii) use in parkinsonism when oral therapy is impossible or contraindicated, as follows: parkinsonism in the elderly who are unable to tolerate more potent agents; mild cases of parkinsonism in other age groups, and in other cases of parkinsonism in combination with centrally acting anticholinergic agents [F3352].
TOXICITY
Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others [L5266, L5269, L5281, L5287, F3394]. Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes [L5287]. Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse [L5287]. Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow [F3394]. Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk [F3394]. This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant [F3394]. Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults [F3394]. Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects [L5287]. Avoid use in elderly patients with confusion [L5287]. The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR) [F3394]. After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease [F3394]. However, the mean plasma clearance and apparent volume of distribution were not significantly affected [F3394]. LD50=500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death.
METABOLISM
Diphenhydramine undergoes rapid and extensive first-pass metabolism [F3394, L5287, A174577]. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite) [F3394, A174577]. Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite [A174577]. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well [F3394, L5287, A174577]. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged [F3394, L5287, A174577]. The metabolites are further conjugated with glycine and glutamine and excreted in urine [L5287]. Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19 [A174574]. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified [A174574]. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine [A174574].
TOXICITY
Overdose is expected to result in effects similar to the adverse effects that are ordinarily associated with the use of diphenhydramine, including drowsiness, hyperpyrexia, and anticholinergic effects, among others [L5266, L5269, L5281, L5287, F3394]. Additional symptoms during overdose may include mydriasis, fever, flushing, agitation, tremor, dystonic reactions, hallucinations and ECG changes [L5287]. Large overdose may cause rhabdomyolysis, convulsions, delirium, toxic psychosis, arrhythmias, coma and cardiovascular collapse [L5287]. Moreover, with higher doses, and particularly in children, symptoms of CNS excitation including hallucinations and convulsions may appear; with massive doses, coma or cardiovascular collapse may follow [F3394].; ; Although diphenhydramine has been in widespread use for many years without ill consequence, it is known to cross the placenta and has been detected in breast milk [F3394]. This medication should therefore only be used when the potential benefit of treatment to the mother exceeds any possible hazards to the developing fetus or suckling infant [F3394].; ; Pharmacokinetic studies indicate no major differences in the distribution or elimination of diphenhydramine compared to younger adults [F3394]. Nevertheless, diphenhydramine should be used with caution in the elderly, who are more likely to experience adverse effects [L5287]. Avoid use in elderly patients with confusion [L5287].; ; The results of a review on the use of diphenhydramine in renal failure suggest that in moderate to severe renal failure, the dose interval should be extended by a period dependent on Glomerular filtration rate (GFR) [F3394].; ; After intravenous administration of 0.8 mg/kg diphenhydramine, a prolonged half-life was noted in patients with chronic liver disease which correlated with the severity of the disease [F3394]. However, the mean plasma clearance and apparent volume of distribution were not significantly affected [F3394].; ; LD50=500 mg/kg (orally in rats). Considerable overdosage can lead to myocardial infarction (heart attack), serious ventricular dysrhythmias, coma and death.
METABOLISM
Diphenhydramine undergoes rapid and extensive first-pass metabolism [F3394, L5287, A174577]. In particular, two successive N-demethylations occur wherein diphenhydramine is demethylated to N-desmethyldiphenhydramine (the N-desmethyl metabolite) and then this metabolite is itself demethylated to N,N-didesmethyldiphenhydramine (the N,N-didesmethyl metabolite) [F3394, A174577]. Subsequently, acetyl metabolites like N-acetyl-N-desmethyldiphenhydramine are generated via the amine moiety of the N,N-didesmethyl metabolite [A174577]. Additionally, the N,N-didesmethyl metabolite also undergoes some oxidation to generate the diphenylmethoxyacetic acid metabolite as well [F3394, L5287, A174577]. The remaining percentage of a dose of administered diphenhydramine is excreted unchanged [F3394, L5287, A174577]. The metabolites are further conjugated with glycine and glutamine and excreted in urine [L5287].; ; Moreover, studies have determined that a variety of cytochrome P450 isoenzymes are involved in the N-demethylation that characterizes the primary metabolic pathway of diphenhydramine, including CYP2D6, CYP1A2, CYP2C9, and CYP2C19 [A174574]. In particular, CYP2D6 demonstrates higher affinity catalysis with the diphenhydramine substrate than the other isoenzymes identified [A174574]. Consequently, inducers or inhibitors of these such CYP enzymes may potentially affect the serum concentration and incidence and/or severity of adverse effects associated with exposure to diphenhydramine [A174574].
DESCRIPTION
Muscarinic receptor agonist
(Tocris Bioactive Compound Library)
DESCRIPTION
H1 Histamine receptor antagonist
(LOPAC library)
DESCRIPTION
A histamine H1 antagonist used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as a hypnotic, an antiparkinson, and as an ingredient in common cold preparations. It has some undesired antimuscarinic and sedative effects.
(BOC Sciences Bioactive Compounds)
[[ p.pathway_name ]]
[[ compound.targets[tid].gene_name ]]
Cell lines
0
Organisms
1
Compound Sets
35
AdooQ Bioactive Compound Library
BOC Sciences Bioactive Compounds
ChEMBL Approved Drugs
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VGSC-DB
[[ a.name ]]
[[ ligand_id ]]
free of charge
External IDs
90
Molecular Weight
255.16
Hydrogen Bond Acceptors
2
Hydrogen Bond Donors
0
Rotatable Bonds
6
Ring Count
2
Aromatic Ring Count
2
cLogP
3.35
TPSA
12.47
Fraction CSP3
0.29
Chiral centers
0.0
Largest ring
6.0
QED
0.78
Structural alerts
0
No structural alerts detected
Related compounds
Custom attributes
(extracted from source data)
Selectivity
H1
Pathway
GPCR/G protein
Immunology/Inflammation
Neuroscience
Anti-infection
Membrane Transporter/Ion Channel
Metabolic Enzyme/Protease
Neuronal Signaling
Apoptosis
Target
H1 receptor
HRH1
Bacterial
Endogenous Metabolite
Histamine Receptor
iGluR
Primary Target
Histamine H1 Receptors
MOA
Antagonist
Histamine H1 Receptor Antagonists
Histamine Receptor antagonist
Member status
member
Indication
headache
Therapeutic Class
Antiallergic Agents
VGSC Target
Nav1.5
Solubility
Soluble in DMSO, not in water
Source data
