Respiratory: Antihistamines Flashcards
Types of Respiratory Drugs:
Bronchodilators: Beta2-Receptor Agonists:
Basic Understanding:
Antihistamines are used in primary care to treat a variety of
allergic conditions. This chapter addresses the antihistamines
used to treat allergic symptoms specific to the respiratory
tract. Antihistamines are also called H1 receptor antagonists,
which describes the action the medication has at the cellular
level. This text uses antihistamine, the more commonly used
name in clinical practice.
The first antihistamines became available in the 1940s,
with the still widely used diphenhydramine first available in
the 1950s. They are referred to as the first-generation antihistamines. The 1980s brought a new generation of nonsedating antihistamines that provided relief to allergy sufferers
without causing the drowsiness of the earlier medications.
They are referred to as second-generation antihistamines.
New antihistamines that are longer acting and have better
adverse-effect profiles continue to be developed.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacodynamics:
Antihistamines are H1 receptor antagonists that reduce or
prevent most of the physiological effects of histamine at the
H1 receptor site. Antihistamines compete with histamine for
H1 receptor sites on the effector cells. They do not prevent
histamine release or bind with histamine that has already
been released. They prevent, but do not reverse, responses
mediated by histamine. The effects of antihistamines include
inhibition of respiratory, vascular, and GI smooth muscle
constriction by antagonism of the constrictor action on
smooth muscle. Antihistamines strongly block the action of
histamine that results in increased capillary permeability and
formation of edema and wheal. They also decrease the flare
and itch responses of histamine on peripheral nerve endings.
Histamine-activated exocrine secretions (salivary, lacrimal)
are decreased with the use of systemic antihistamines. Antihistamines with strong anticholinergic (atropine-like) properties may have an increased drying effect by decreasing
secretions from cholinergically innervated glands.
The first-generation antihistamines competitively antagonize the effects of histamine at the peripheral H1 receptor sites
in the GI tract, uterus, large blood vessels, and bronchial muscle. First-generation antihistamines bind nonselectively to the
central H1 receptors and can cause both CNS stimulation and
depression. CNS depression is found even with therapeutic
doses of the first-generation antihistamines. Some of them are
more likely than others to depress the CNS, and patients vary
in their sensitivity to the different preparations. Commonly
prescribed first-generation antihistamines include the
ethanolamine drugs diphenhydramine (Benadryl) and clemastine (Tavist), the alkylamines brompheniramine (Dimetane)
and chlorpheniramine (Chlor-Trimeton), the piperazine hydroxyzine (Atarax, Vistaril), the piperidine cyproheptadine
(Periactin), and carbinoxamine maleate (Arbinoxa).
Second-generation antihistamines are selective for peripheral H1 receptors and therefore as a group are less sedating.
They do not cross the blood–brain barrier in appreciable
amounts; consequently, very little of the second-generation
antihistamines gets into the brain. Their effects on perfor -
mance and on objective measures of sedation vary little from
those of a placebo. Second-generation antihistamines that are
commonly prescribed include the piperazine drug cetirizine
(Zyrtec) and the piperidines desloratadine (Clarinex), fexofenadine (Allegra), and loratadine (Claritin).
Antihistamines have other pharmacodynamic properties
related to their central action rather than their histaminereceptor blockade action. Several first-generation antihistamines
have significant antiemetic and antinausea properties owing
to strong anticholinergic properties caused by the antihistamine’s binding to the muscarinic receptors. Diphenhydramine
can be used to reverse the extrapyramidal adverse effects
caused by phenothiazines. Probably because of their anticholinergic actions, some of the antihistamines (diphenhydramine) have effects on Parkinson’s symptoms and may be
effective in the early stages of treatment.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacokinetics: Absorption and Distribution:
The first-generation antihistamines are stable, lipid-soluble
amines that are well absorbed from the GI tract. Diphenhydramine is widely distributed throughout the body tissues
and fluids, including the CNS. It crosses the placenta and is
found in breast milk. The distribution of clemastine is unknown, but the drug does cross the placenta and is distributed
in breast milk. Chlorpheniramine is approximately 72% protein bound and is widely distributed in body tissue and fluids.
Chlorpheniramine crosses the placenta and is found in breast
milk. Distribution of hydroxyzine has not been fully described, and it is unknown whether it crosses the placenta or
is distributed in breast milk. The distribution of cyproheptadine, dimenhydrinate, and brompheniramine is unknown.
The second-generation antihistamines are rapidly absorbed
from the GI tract, although concurrent food ingestion can decrease or delay absorption. Fexofenadine is rapidly absorbed,
and absorption is not affected by food intake. Administration
of loratadine with food decreases absorption up to 40% for the
syrup or tablet and 48% for the rapid-disintegrating tablet.
Desloratadine is well absorbed, and food intake dose not affect
absorption. Absorption of cetirizine is slightly reduced by food
intake. Cetirizine is widely distributed, except in the CNS,
where concentrations are less than 10% of the peak serum concentration. It is unknown whether cetirizine crosses the placenta, but it has been measured in breast milk. Fexofenadine
distribution is unknown. Loratadine is 97% protein bound and
is excreted in breast milk. It is not known if loratadine crosses
the placenta. Desloratadine is highly (82% to 87%) protein
bound, it is not known whether it crosses the placenta, and only
minimal amounts are excreted in breast milk.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacokinetics: Metabolism and Excretion:
The first-generation antihistamines are metabolized primar -
ily in the liver. Diphenhydramine is metabolized in the liver,
with the unchanged portion of the dose and metabolites
excreted in the urine in 24 to 48 hours. Clemastine is extensively metabolized by an unknown mechanism. Clemastine
and its metabolites are excreted primarily in the urine. Metabolism of chlorpheniramine is extensive, occurring first in
the gastric mucosa and then on the first pass through the
liver. Metabolites of chlorpheniramine are excreted in
the urine, with the excretion rate dependent on the pH of the
urine and urinary flow. Cyproheptadine is metabolized in the
liver into several conjugated metabolites, with excretion in the
urine and feces. Hydroxyzine is completely metabolized by
the liver. Metabolism and excretion of brompheniramine and
dimenhydrinate are unknown.
Most of the second-generation antihistamines are metabolized by the liver to active metabolites by the hepatic microsomal P450 system. Consequently, metabolism of these drugs
can be affected by competition for the P450 enzymes by other
drugs. Cetirizine is minimally metabolized by the P450
enzymes and is primarily excreted unchanged in the urine.
Approximately 5% of the dose of fexofenadine is metabolized,
with 80% excreted in the feces and 11% excreted in the urine.
Loratadine has a high first-pass effect and is metabolized in
the liver to the active metabolite descarboethoxyloratadine.
Patients with chronic liver disease have higher peak plasma
concentrations (double the normal levels) of loratadine than
do healthy patients. Elimination of loratadine is through the
urine and feces.
See Table 17-10 for the pharmacokinetics.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics: Precautions and Contraindications:
The precautions and contraindications differ between the
first-generation and second-generation antihistamines.
First-Generation Antihistamines
Although first-generation antihistamines are available without prescription and all antihistamines are widely prescribed,
the provider must be aware of the precautions and absolute
contraindications to the antihistamines.
The first-generation antihistamines are generally safe
and effective. Antihistamines are contraindicated in patients
with narrow-angle glaucoma, lower respiratory tract symptoms (they thicken secretions and impair expectoration),
stenosing peptic ulcer, symptomatic prostatic hypertrophy,
bladder neck obstruction, pyloroduodenal obstruction, and
MAOI use.
There are few but significant precautions to the firstgeneration antihistamines. Because of the anticholinergic effects, caution is required for patients with a predisposition
to urinary retention, history of bronchial asthma, increased
intraocular pressure, hyperthyroidism, cardiovascular disease,
or hypertension. Antihistamines cause varying degrees of sedation and drowsiness and reduce mental alertness; therefore,
patients should not drive or perform other tasks requiring
mental alertness while taking the first-generation antihistamines. Children should be supervised when they are taking
these medications and performing potentially unsafe activities
such as swimming or bicycling.
The first-generation antihistamines—chlorpheniramine,
brompheniramine, diphenhydramine, clemastine, and cyproheptadine—are Pregnancy Category B. Hydroxyzine and
carbinoxamine are the only first-generation antihistamines
classified as Pregnancy Category C.
First-generation antihistamines are contraindicated in newborns and premature infants, who may have severe reactions
(convulsions). Breastfeeding is also a contraindication for the
use of first-generation antihistamines because all of the medications are excreted in breast milk and they may decrease
milk production.
Caution should be exercised with the use of first-generation
antihistamines in young children because a paradoxical
CNS stimulation can occur. Do not exceed recommended
dosages for each age group of children. Chlorpheniramine,
brompheniramine, cyproheptadine, dimenhydrinate, and
diphenhydramine are all labeled to be used in children over
the age of 2 years. Hydroxyzine syrup may be prescribed for
infants and children for pruritus, althought cetirizine may be
a safer choice. Carbinoxamine is not recommended for children younger than 2 years of age.
The first-generation antihistamines—carbinoxamine,
chlorpheniramine, diphenhydramine, clemastine, and
cyproheptadine—are all on the Beers criteria list of medications that should be avoided in geriatric patients.
Second-Generation Antihistamines
The second-generation antihistamines have only a few
contraindications. Two second-generation antihistamines,
astemizole (Hismanal) and terfenadine (Seldane), have been
voluntarily removed from the market because of potentially
life-threatening drug interactions and increased prolonged
QT interval associated with their use.
The second-generation antihistamines are generally not
recommended during pregnancy, especially during the third
trimester, because of a seizure risk to the fetus. Loratadine and
cetirizine are classified Pregnancy Category B. The other
second-generation antihistamines—loratadine, desloratadine,
and fexofenadine—are Pregnancy Category C, and their use
should be avoided.
Fexofenadine are not recommended for children under
age 6. Loratadine may be prescribed to children as young as
age 2. Cetirizine syrup and desloratadine syrup may be used
in children as young as 6 months.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics: Adverse Drug Reactions:
As described previously, the major adverse reaction to firstgeneration antihistamines is sedation, which can interfere with
a patient’s ability to function at work or school. Other central
adverse effects include dizziness, tinnitus, lassitude, disturbed
coordination, fatigue, headache, irritability, nervousness, blurred
vision, diplopia, and tremors. The next most common adverse
effects are GI and include increased or decreased appetite, nausea, epigastric distress, vomiting, constipation, and diarrhea.
Dry mouth, urinary retention, and dysuria are also adverse effects reported in patients taking first-generation antihistamines.
The concurrent ingestion of alcohol or other CNS depressants
produces an additive effect that further impairs function.
The second-generation antihistamines have few central adverse effects. The major improvement in the second-generation
antihistamines is that the incidence of drowsiness is greatly
reduced. They are well tolerated by the GI system and have
t
recommended during pregnancy, especially during the third
trimester, because of a seizure risk to the fetus. Loratadine and
cetirizine are classified Pregnancy Category B. The other
second-generation antihistamines—loratadine, desloratadine,
and fexofenadine—are Pregnancy Category C, and their use
should be avoided.
Fexofenadine are not recommended for children under
age 6. Loratadine may be prescribed to children as young as
age 2. Cetirizine syrup and desloratadine syrup may be used
in children as young as 6 months.
Adverse Drug Reactions
As described previously, the major adverse reaction to firstgeneration antihistamines is sedation, which can interfere with
a patient’s ability to function at work or school. Other central
adverse effects include dizziness, tinnitus, lassitude, disturbed
coordination, fatigue, headache, irritability, nervousness, blurred
vision, diplopia, and tremors. The next most common adverse
effects are GI and include increased or decreased appetite, nausea, epigastric distress, vomiting, constipation, and diarrhea.
Dry mouth, urinary retention, and dysuria are also adverse effects reported in patients taking first-generation antihistamines.
The concurrent ingestion of alcohol or other CNS depressants
produces an additive effect that further impairs function.
The second-generation antihistamines have few central adverse effects. The major improvement in the second-generation
antihistamines is that the incidence of drowsiness is greatly
reduced. They are well tolerated by the GI system and have
a minimal incidence of dry mouth (less than or equal to 5%).
Overall, when patients have adverse reactions to the firstgeneration antihistamines, a change to a second-generation
drug often alleviates the problem.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics: Drug Interactions:
The first-generation antihistamines should be used with caution concurrently with any medication that has CNS depressant effects. All of the first-generation antihistamines exhibit
additive CNS sedation effects if coadministered with ethanol,
anxiolytics, sedatives, hypnotics, and barbiturates. The anticholinergic effects of antihistamines may be enhanced if
coadministered with tricyclic antidepressants and pheno -
thiazines.It is recommended that H 1 agonists not be used
within 2 weeks of MAOIs because of increased anticholinergic effects. Cyproheptadine may reverse the antidepressant
effects of selective serotonin reuptake inhibitors (SSRIs). Two
antihistamines should not be prescribed at the same time to
avoid additive anticholinergic and sedative effects.
The second-generation antihistamines, although not sedating when used singly, may have additive CNS sedation effects
if used with other CNS depressants (barbiturates, anxiolytics,
sedatives, hypnotics, ethanol, and benzodiazepines). Concurrent use with another H1 blocker may cause sedation.
Desloratadine and loratadine are extensively metabolized by
the CYP450 enzymes, and coadministration of other medications
that are also metabolized by these enzymes should be avoided,
such as are erythromycin, cimetidine, and ketoconazole.
Table 17-11 presents drug interactions.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics: Rational Drug Selection:
First- Versus Second-Generation Antihistamines
Although many of the first-generation antihistamines are
readily available without prescription, the common adverse
effect of sedation prevents their use during the day by patients who need to be alert for work or school. The secondgeneration antihistamines are well tolerated and do not
impair daytime functioning. They are also longer acting,
allowing for convenient once- or twice-a-day dosing
Cost
The second-generation antihistamines used to be more
expensive than the first-generation antihistamines, but with
many second-generation drugs now available in generic form,
cost has less impact on decision making. Most insurance companies will not pay for the cost of the more expensive, brandname, second-generation antihistamines. For the patient, the
cost is offset by the ability to perform daily functions more
easily when taking the second-generation medications.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics: Monitoring
No specific laboratory monitoring is necessary with anti -
histamines.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics:
Patient Education:
Patient education focuses on proper use of the medication,
adverse reactions, and safety precautions while using the
medications.
Types of Respiratory Drugs:
Bronchodilators: B2RAs:
Pharmacotherapeutics:
Patient Education:
Patient education focuses on proper use of the medication,
adverse reactions, and safety precautions while using the
medications.
Administration
Patients should be instructed regarding the proper dosing of
the drug. Especially if patients are switching from a shorteracting first-generation to a longer-acting second-generation
antihistamine, they need to be aware of the dosing schedule.
Doses should not be doubled or increased unless prescribed
by the health-care provider. The long-acting second-generation
antihistamines should not be taken closer together than prescribed, so missed doses need to be held until the time of the
next dose (every 12 or 24 hours).
Some antihistamines cause GI upset and need to be taken
with food. Loratadine should be taken on an empty stomach
because absorption may be decreased by as much as 60%.
Patients should be instructed not to crush or chew
sustained-release tablets.
Adverse Reactions
Some antihistamines (first generation) may cause drowsiness,
and patients should observe caution while driving or performing other tasks requiring alertness. Patients should avoid alcohol
and other CNS depressants while taking antihistamines and
should be instructed to report excessive drowsiness to their
health-care provider to determine whether another medication
would provide therapeutic effects without sedation.
Patients taking loratadine should be aware of the serious
interaction between the antihistamines and macrolide antibiotics and the oral azol antifungals. Written instructions regarding the specific medications to avoid are the most
effective and safest method of ensuring that patients do not
accidentally get placed on any new medication that would
cause a serious adverse reaction. The additive CNS depression that occurs with the antihistamine and other CNS depressants (e.g., alcohol) should be addressed and the patient
cautioned regarding driving or operating heavy machinery.
Lifestyle Management
Lifestyle management related to the disease process needs to
be discussed with the patient. Points to discuss often include
avoidance of known allergens and using environmental
methods to control dust mites and other common allergens.
Available dosage forms are presented in Table 17-12.
