Jim Dimke
April Nichols
Socorro Valdez
Rob Crane
Psychopharmacology
Spring 05, Morgan
Jim Dimke
Chemistry of Benadryl (Diphenhydramine)
Diphenhydramine can be administered orally, injected, or applied
topically. It is an over the counter antihistamine and
sedative. I think it is interesting to note that it is used in
conjunction with antipsychotics to prevent tardive dyskinesia.
Patients with Parkinsons Disease also utilize the drug to
prevent dyskinesia. It is a member of ethanolamine class of
antihistaminergic agents and is a H1 receptor antagonist. Its
chemical formula is C17H21NO HCl. Antagonism is achieved through
blocking the effect of histamine more than blocking its
production or release. Diphenhydramine inhibits most responses
of smooth muscle to histamine and the vasoconstrictor effects of
histamine. The antagonism may also produce anticholinergic
effects, antiemetic effects, and significant sedative side
effects.
Once diphenhydramine is administered orally it is well absorbed
from the gastrointestinal tract, is widely distributed
throughout the body, and is able to pass though the blood-brain
barrier. The oral availability is 61%, and 78% is bound in
plasma. Peak plasma concentrations are reached in 2-3 hours.
Diphenhydramine is metabolized to nordiphenhydramine (active
metabolite), dinordiphenhydramine, and diphenylmethoxyacetic
acid. The plasma half-life is 8.53.2 hours; shorter and longer
half-lives have been reported for children and elderly subjects,
respectively. Urinary excretion of unchanged diphenhydramine is
1.9%. Less than 2% of an oral dose is excreted in the 24-hour
urine as unchanged parent drug, while approximately 11% is
eliminated as its glucuronide conjugate.
Diphenhydramine is metabolized via cytochrome P450 2D6
isoenzyme. Potential inhibitors of P450 2D6 could decrease the
rate of drug elimination if administered concurrently, while
potential inducers could increase the rate of drug elimination.
Urine test results suggest that first generation H 1 antagonists
can both stimulate and depress the CNS. Stimulation results in
restlessness, nervousness and inability to sleep, while
depressive effects include diminished alertness, and slowed
reaction time. Diphenhydramine is particularly prone to cause
marked sedation. Drowsiness, reduced wakefulness, altered mood,
impaired cognitive and psychomotor performance may also be
observed.
References:
Witek TJ Jr, Canestrari DA, Miller RD, Yang JY, Riker DK.
Characterization of daytime sleepiness and psychomotor
performance following H1 receptor antagonists. Allergy Asthma
Immunol 1995;74(5):419-26.
Hardman JG, Limbird LE (eds). Goodman & Gilmans The
Pharmacological Basis of Therapeutics. McGraw-Hill, NY, NY; 1996
http://www.nhtsa.dot.gov/people/injury/research/job185drugs/diph
enhydramine.htm
Socorro Valdez
Psychopharmacology
Benadryl Report 3
Chemistry of Diphenhydramine (continued)
Dephenhydramine (Benadryl) is an H1 histamine receptor
antagonist that produces local anesthetic effects; research has
shown that diphenhydramine inhibits the neuronal Na+ current and
the inhibition is stronger with more positive holding
potentials. The local anesthetic effect of dyphendydramine thus
is ascribable to inhibition of Na+ current by selective binding
of the drug to the inactivated channels (Kuo et al., 1994).
Dephenhydramine and many other H1 histamine receptor
antagonists, such chlorpheniramine, cyproheptadine, and
tripelennamine, have significant and clinical history of useful
local anesthetic effects (Steffen et al., 1957). Dipehgydramine
is only slightly inferior to lidocaine in the duration and depth
of anesthesia and has been successfully used as substituting
local anesthetic agent in caine-sensitive patients (Munsey,
1966; Pollack and Swindel, 1989). Furthermore,
diphenhydramine, chlorpheniramine, and cyproheptadine
significantly inhibited binding 3H batrachotocin to voltage
sensitive Na+ channels in vesicular preparations from guinea pig
cerebral cortex (McNeal et al., 1985).
Benadryl (Diphenhydramine) Diphenhydramine has been
available in the United States since 1945, and was approved by
the FDA in 1946. Diphenhydramine is used to treat allergic
reactions; because of its antihistamine with anticholinergic
(drying) and sedative properties. During several types of
allergic reactions, and during some viral infections such as a
common cold, the body releases histamine; when histamine binds
to its receptors on cells, it causes changes within the cells
that lead to sneezing, itching, and increased mucus production.
Antihistamines compete with histamine for cell receptors, and
once they bind to the receptors, they do not stimulate the
cells, but instead, they prevent histamine from binding and
stimulating the cells. Although, Diphenhydramine is used for
the relief of nasal and no-nasal symptoms of various allergic
conditions such as rhinitis, and patients with chronic
urticaria, they only reduce symptoms by 40-60 %. For active
cases of motion sickness, and mild cases of Parkinsonism,
including drug-induced Parkinsonism; Diphenhydramine is a
treatment used based on its anticholinergic effects, rather than
for its antihistamine effects. Diphenhydramine is also used to
treat insomnia, both by prescription and over the counter,
because of its efficacy as a sedative hypnotic. However, because
of its sedative effects, it is highly recommended to be taken at
bedtime and for patients 60 years of age or older, the dose
should be reduced because of their susceptibility to the
sedating and anticholinergic effects of diphenhydramine.
diphenhydramine
Benadryl
C17H21NO
antihistamine, used to treat allergies and motion sickness
DRUG INTERACTIONS: Diphenhydramine adds to (exaggerates) the
sedating effects of alcohol and other drugs than can cause
sedation such as the benzodiazepine class of anti-anxiety drugs
(e.g., Valium, Ativan, Klonopin, Xanax), the narcotic class of
pain medications and its derivatives (e.g., Percocet, Vicodin,
Dilaudid, Codeine, Darvon), the tricyclic class of
antidepressants (e.g., Elavil, Tofranil, Norpramin), and certain
antihypertensive medications (e.g., Catapres, Inderal).
Diphenhydramine can also intensify the drying effects of other
medications with anticholinergic properties (e.g., Bentyl,
Urecholine, Probanthine).
Reference:
Reference:
Kuo C. C; Chen R. S; Lu L. & Chen R.C. (1994b). Na+ channels mus
deactivate to recover from inactivation.
Http://molpharm.aspetjournals.org/cgi/content/full/57/1/35
Barman M.C. (1947). Danger with benadryl of self medication and
large dosage. Jama 1947; 133: 394-395.
Http://ajgp.psychiatryonline.org/sgi/content/full/11/2/05
Robert Crane
PHYSIOLOGICAL CHANGES FROM BENADRYL (DIPHENHYDRAMINE)
Benadryl is a fairly recent drug deemed so lacking in
serious side effects that it became available as an over-the-
counter medication. As an antihistamine it has a couple of uses
in that it blocks the secretion of bodily fluids in the GI tract
and mucus membranes creating a "dry mouth" experience that
decreases sweating and runny noses. A second use is as a
pruritis (itching) treatment. A scrape or cut, burn, or
allergic reaction can benefit from the topical or ingested use
of the drug.
It is easily understandable why diphenhydramine works for
colds or allergies. By blocking secretion of bodily fluids
throughout the body, this drug dries out the mucus membranes.
For someone with a runny nose and/or watery eyes this can seem
like a miracle! One should be aware that overdosing can easily
lead to toxicity that can contribute to seizures, racing
heartbeat and mental disturbances. See further discussion of
that later in this paper.
As a treatment for pruritus (itchiness), diphenhydramine is
less understood. It is thought that the sedation effect of this
anticholinergic is what relaxes the muscle tone, thus relieving
the uncomfortable sensations from bug bites, allergic reactions
and cuts or burns. Therefore, an antihistamine that has less
sedation effect seems to be less able to curb pruritus. This use
has been found to be so effective that many pet medications
dealing with itch from bug bites or allergies, motion sickness
and anxiety include this as the active ingredient.
A third use of the drug is as a treatment for sleep
disorders or as a substitute for traditional hypnotic
medications to treat insomnia. This definitely relates to the
sedation effect but does not work for all and must be moderated
in order to keep from overdose. Parents often think of this
drug as a helpful tool in treating their child's insomnia
inexpensively. While this medication is relatively safe when
used properly, little hard data has been gathered in the long-
term use in children or the elderly. Furthermore, care should
me taken to keep the dosage low so that the possibility of
seizures and/or hallucinations/delirium can be mitigated. In
the elderly, it was found that hospitalized patients over the
age of 70 were at significantly higher risk of deliriums or
cognitive decline when prescribed diphenhydramine.
It was found that some people used diphenhydramine as a way
of way of managing autism. Less than five percent of the people
surveyed used this drug and, it might be hypothesized, was yet
another way of inexpensively self medication for unwanted
behaviours.
Combined with cancer treatment, diphenhydramine has been
found to help improve dyskinesias. Dyskinesias are the
unintended (and usually unwanted) or involuntary, muscle spasms,
tics or movements. In the elderly, especially in sleep
disturbance from this muscle movement, dyphenhydramine seems to
lessen the severity and allow the patient to relax. Again, this
may have more to do with the sedation effect and care should be
taken to look for other long term treatment in order to mitigate
the chance of anticholinergic type syndrome.
Anticholinergic syndrome is the common symptom of
overuse/overdose. Palfai and Jankiewicz relate the description
used among medical professionals to describe the look of drug
action that in interfering with cholinergic systems:
Dry as a bone,
Red as a beet,
Hot as a furnace,
Mad as a hatter,
Blind as a bat.
These extremes should been watched for, especially by
caregivers of children and elderly so that medical attention can
me given. The dry as a bone thing is usually what we want when
using Benadryl. Unfortunately, at the toxic level it can effect
urination and the production of stomach fluids that are
necessary for good physical functioning. The flushed feeling or
look of the dilation of blood vessels and the increased
temperature of the patient can also indicate this syndrome. Mad
as a hatter describes what happens at the toxic level:
delusions, hallucinations, muscle spasms and anxiety. Blind as
a bat, with this drug, relates to the uncommon side effect of
blurred vision. Additional things to look for are constipation,
motor uncoordination and rapid heartbeat. The good news is that
there is effective treatment for this syndrom by using
medications that stimulate cholinergic sites (thus undoing many
of the symptoms).
This ability should in no way encourage overuse/abuse of
benadryl. Although safely used for many, excessive use without
treatment can permanently impair the user and can increase the
chance of seizures or death. Fortunately, this drug has a lower
rate of extended abuse because it does not produce the euphoric
feelings that other medications or drugs can elicit. It is more
commonly abused among young teens or adults who like the
feelings from the sedation effects and have not yet found
"better" highs.
Another caution, pregnant women or women who are trying to
get pregnant, should be careful to avoid this drug as the
correlation between usage in the first trimester of pregnancy
and birth defects has been established. Furthermore, women who
are breastfeeding should avoid this as it easily passes through
membranes, thus medicating the infant where toxicity levels are
much lower and the sedation effects increased.
Precautions should be taken to not use when dealing with
glocoma, prostate disease, urinary obstruction or high blood
pressure. Caution should also be taken when prescribed
barbiturates or other tranquilizer (sedation) medications.
Symptoms of overdose in dogs and cats are seizures, extreme
drowsiness, coma, respiratory depression and death. These same
symptoms, while extreme in otherwise healthy adults using
diphenhydramine for specific maladies, are also descriptive of
the impact this drug can have with infants, children and the
elderly.
References:
Aman, M.G., Lam, K.S.L., & Collier-Crespin, A. (2003).
Prevalence and patterns of use of psychoactive medications with
autism in the autism society of Ohio. Journal of Autism and
Developmental Disorders. 33(5), 527-534.
Brost, B.C., Scardo, J.A. & Newman, R.B. (1996).
Diphenhydramine overdosage during pregnancy: Lessons from the
past. American Journal of Obstetric Gynecology, 175(5), 1376-7.
Gadow, K.D. (1991). Clinical issues in child and adolescent
psychopharmacology. Journal of Consulting and Clinical
Psychology. 59(6), 824-852.
Levinson, A.J. (1979). Neuropsychiatric Side Effects of drugs in
the Elderly. New York: Raven Press.
Palfai, T., & Jankiewicz, H. (2001). Drugs and Human Behavior
(2nd ed). New York: McGraw-Hill Primis Custom Publishing.
Perinatology.com
Smith, H. (2003). Drugs for Pain. Philadelphia, PA: Hanley &
Belfus, Inc.
Stepanski, E., Rybarczyk, B., Lopez, M., & Stevens, S. (2003).
Assessment and treatment of sleep disorders in older adults: A
review for rehabilitation psychologists. Rehabilitation
Psychology 48(1), 23-36.
April Nichols
Diphenhydramine (trade name Benadryl) is an antihistamine with
anticholinergic (drying) and sedating properties generally used
to treat allergic reactions (1). Antihistamines act by
competing with histamine for cell receptors; yet unlike
histamine, do not stimulate the cells. The FDA originally
approved Diphenhydramine in 1946 (1).
Diphenhydramine relieves allergy symptoms such as sneezing,
itching, and red, irritated eyes. It is also used for the
treatment of hives and angioedema, sleep disturbance, Parkinsons
disease, cough, drug-induced extra pyramidal reactions and
certain skin disorders (1).
Side effects/toxicity
Off all antihistamine exposures reported to US poison control
centers in 1999, 7.4% resulted in moderate to major toxicity and
.05% resulted in death. 71% of these fatalities were associated
with Diphenhydramine (2).
Diphenhydramine affects multiple systems in the body. The
mnemonic, dry as a bone, red as a beet, hot as a hare, mad as a
hatter, and blind as a bat, summarizes the classic combination
of central and peripheral anticholinergic effects of
antihistamine poisoning (2).
Some of the most common adverse reactions include:
General: Rash, anaphylactic shock, photosensitivity, excessive
perspiration, chills, dryness of mouth, nose, and throat (4).
Cardiovascular System: Hypotension, headache, palpitations,
tachycardia (4).
Hematologic System: Hemolytic anemia, thrombocytopenia,
agranulocytosis (4).
Nervous System: Sedation, sleepiness, dizziness, disturbed
coordination, fatigue, restlessness, excitation, nervousness,
tremor, irritability, insomnia, euphoria, blurred vision,
diplopia, vertigo, tinnitus, neuritis, and convulsions (4).
GI System: Epigastric distress, anorexia, nausea, vomiting,
diarrhea, constipation (4).
GU System: Urinary frequency, difficult urination, urinary
retention, and early menses (4).
Peripheral manifestations include dry mucous membranes, and hot,
dry, flushed skin resulting from decreased secretions from the
salivary glands, bronchioles, and sweat glands (2).
Vasodilatation occurs in the blood vessels of the face and skin
surfaces. Individuals often appear flushed and warm without
sweat. This, in turn, causes body temperature to rise (2).
When used as a sleep aid, Diphenhydramine has been shown to
reduce REM sleep (9).
Also, tolerance has been shown to develop in as little as one to
two weeks, and rebound insomnia can occur after only one night
of use (9). Because of their addictive effects, Diphenhydramine
should be avoided or used with caution for patients with
substance abuse tendencies (9).
Seizures are not uncommon and coma occurs in roughly 55% of
reported overdoses (2).
Catatonic stupor and toxic psychosis have also been reported
(2).
Reports of chronic abuse (800 mg. twice a day to achieve
sedation and euphoria) resulted in withdrawal symptoms requiring
hospitalization (2).
Diphenhydramine should be used with caution in persons with
narrow-angle glaucoma, enlarged prostate gland, hyperthyroidism,
cardiovascular disease, hypertension, and asthma (3).
Children and older adults are particularly sensitive to the side
effects of antihistamines. Children are more likely to exhibit
convulsions and seizures as well as nightmares, excitement,
nervousness, restlessness, and irritability (5). Elderly
patients are more likely to exhibit confusion, difficult or
painful urination, drowsiness, and dryness of mouth, nose and
throat (5).
The use of antihistamines while breast-feeding is not
recommended since small amounts of the drug pass directly into
the breast milk. Babies are particularly sensitive to the
effects of antihistamines such as excitability and
irritability. Also, these drugs decrease the flow of breast
milk in some women (5).
Individuals of Asian descent can convert Diphenhydramine to a
non-toxic metabolite twice as rapidly as Caucasian individuals
making them much less sensitive to the psychomotor performance
and sedative side effects of the drug (2).
Diphenhydramine also exaggerates the sedating effects of
alcohol, benzodiazepines (Valium, Ativan, Klonopin, Xanax), the
narcotic class of pain medications and their derivatives
(Percocet, Vicodin, Dilaudid, Codeine, Darvon), the tricyclic
class of antidepressants ( Elavil, Tofranil,Norpramin), and
certain hypertensive medications (Catapres, Inderal) (3).
Reported side effects by users/survivors
As reported earlier, infants and young children are particularly
sensitive to the side effects of antihistamines. In January of
2003, one-year-old Dane Heggem died from an overdose of
Diphenhydramine while at day care. The day care provider
insists that the dosage was administered according to the
recommended levels on the package. The owner of the day care
center has filed a lawsuit against Costco Wholesale Corporation
for failing to label the drug with an adequate warning regarding
the potential risk of fatal toxicity in young children (6).
As a result of this and dozens of similar cases, it has come to
light that many day care providers administer Diphenhydramine to
sedate fussy children. Outraged parents and lawmakers across the
country are attempting to pass legislation making it a felony to
administer medication to young children without parental consent
except under cases of extreme emergency (7).
Most of the reported side effects involve adults between the
ages of 20 and 60 years of age, and the most reported reasons
for taking the drug are allergies and sleep disturbances. The
most commonly reported side effects among this group are
dehydration, excessive sedation, and drowsiness or grogginess
upon awakening. More serious side effects have been reported
however, including dizziness, irritability, tachycardia,
increased blood pressure, euphoria, hallucinations, nightmares,
memory loss and confusion, tinnitus, blurred vision, impaired
vision, and rebound insomnia (8). Males have reported
difficulties in getting and maintaining erections, and women
have reported early menstruation. Many of the more serious
side effects are a result of adverse drug interactions involving
other CNS depressants such as alcohol and benzodiazapines (8).
References
1. University of Maryland Medical Center (n.d.).
Diphenhydramine. Retrieved April 28, 2005 from
http://www.umm.edu/altmed/ConsDrugs/Diphenhydraminecd.html
2. Roth, B (2004). Antihistamine Toxicity. Retrieved April 28,
2005 from http://www.emedicine.com/emerg/topic.38.htm
3. Diphenhydramine (n.d.). Retrieved April 7, 2005 from
http://www.medicinenet.com/script/main/art.asp?articlekey=9142pf
=3
4. Antihistamines (Systemic) (n.d.). Retrieved April 7, 2005
from http://health.yahoo.com/drug/202060/overview
5. Drug Guide, Antihistamines (Systemic) (n.d.). Retrieved April
7, 2005 from http://health.yahoo.com.drug/202060/_precaution
6. Tanglen, L. (2005, March). Day care owner files suit against
Costco-Archives. Laurel Outlook. Retrieved April 7, 2005 from
http://www.laureloutlook.com/articles/2005/03/23/news/lbieber.tx
t
7. Fitzgerald, J. (2005, February). Students project aims to
save lives. Billings Gazette. Retrieved April 7, 2005 from
http://www.billingsgazette.com/index/php?id=1&display=rednews/20
05/02/18/build/local/4...
8. Benadryl: Side effects, ratings, and patient comments (n.d.).
Retrieved April 7, 2005 from
http://www.askapatient.com/viewrating.asp?drug=6146&name=BENADRY
L
9. Ringdahl, E., Periera, S., Delzell, J. (2004). Treatment of
primary insomnia. Journal of the American Board of Family
Practice, 17(3), 212-219.
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