Introduction
-
Autacoids is a general term that
refers to a number of compounds such as:
histamine, serotonin, endogenous peptides, prostaglandins, and leukotrienes
-
Chemistry
and Pharmacokinetics
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The formation of histamine occurs
by the removal of a carboxyl group (decarboxylation) from
amino acid L-histidine
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One of the important issues
associated with formation of a biologically active
compound is the mechanism that accounts for the compounds inactivation.
-
Most of the time very
little histamine is excreted unchanged because of these
metabolic steps. One exception would be the case of
neoplastic disease (cancer). For instance,
significant histamine is excreted unchanged in the
presence of these diseases: (a) systemic mastocytosis,
(b) gastric carcinoid syndrome or (c) urticaria pigmentosa.
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Tissue Distribution:
Receptor
Subtype
|
Localization
|
Receptor
coupling
|
Antagonists
(partially selective)
|
H1
|
Endothelium,
brain, smooth muscle
|
receptor
activation causes and increased IP3,
DAG (diacylglycerol) production
|
N/A
|
H2
|
mass and cells, gastric mucosa, cardiac muscle, brain
|
receptor
activation causes an increase in cAMP production
|
ranitidine
(Zantac), cimetidine (Tagamet)
|
H3
|
presynaptic:
brain, mesenteric plexus (other neurons)
|
G
protein coupled
|
N/A
|
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Receptor subtypes --H1,
H2, and H3:
-
H1:endothelial and smooth muscle cell localization
-
H2 gastric mucosa, cardiac muscle cells, immune cell
localization:
-
H3: primarily
presynaptic
-
activation causes a
decrease in transmitter release
{transmitters: histamine,acetylcholine, norepinephrine,
serotonin)
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Organ System Effects:
Histamine
-
Cardiovascular:
-
Systolic
and diastolic blood pressure: Vasodilation of
arterioles and precapillary sphincters account for
histamine's vasodilating effects.
Vasodilation may be due in part to nitric oxide
liberation.
-
Following from the reduced blood
pressure, the heart
rate increases by autonomic reflex mechanisms and by
direct action.
-
Both H1
and H2
receptors involved in cardiovascular
responses.
-
Histamine-associated
edema:H1
receptor effects (postcapillary vessels)
-
Direct cardiac
effects:
-
increased
contractility (positive inotropism)
-
increased
pacemaker rate (positive chronotropism)
-
Gastrointestinal
tract: Histamine promotes
intestinal smooth muscle contraction which is an H1 receptor
mediated effect
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Bronchiolar smooth muscle
activation by histamine causes bronchodilation (H1 receptor mediated
)
-
Nerve
Endings: Sensory nerve endings
are stimulated by histamine, especially those endings which
mediate pain and itching.
-
Secretory
tissue:
-
Histamine cause the stimulation of
release by secretory tissues. For example, a
significant increase in gastric acid secretion is caused
by histamine. Other examples of increased release
include gastric pepsin.
-
Mechanism of Action: Considering the
gastric parietal cells, histamine interacts with H2
receptors and initiates a second messenger
response which proceeds by (1.) Increasing adenylyl
cyclase activity which (2.) Results in an increase in
the second messenger, cyclic AMP which (3.) Causes an
increase in intracellular calcium levels. The
increase in calcium triggers release. This releasing
characteristic of calcium applies broadly in physiology.
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Nursing
Implications: Antihistamines
Antihistamine Antiemetics (Dramamine,
Hydroxyzine (Atarax,Vistaril), Diphenhydramine
(Benadryl), Promethazine (Pherergan))
- Therapy is most effective
when given prophylactically for motion sickness.
- The most common side
effects are drowsiness, dry mouth, HA and
jitters.
- Antihistamines cause
additive depression with concurrent use of CNS
depressants and alcohol.
Antihistamines for
Allergies (Terfenadine (Seldane), Loratidine (Claritin), Temaril)
-
Monitor BP, HR, I &
O. Auscultate breath sounds; inspect for rash,
Monitor CBC, WBC with differential, platelent
count.
-
Warn patient to avoid
driving or operating hazardous equipment if
drowsiness blurred vision or dizziness occurs.
Notify MD if blurred vision occurs.
-
Do not crush or chew
sustained release forms, as this releases
the drug all at one time.
-
A potentially fatal drug interaction
exists between astemizole (Hismanal), loratidine
(Claritin), or terfenadine (Seldane) and
itraconazole (Sporanox) or ketoconazole (Nizoral)..
Histamine H2
Receptor Antagonists (Cimetidine (Tagamet),
Ranitidine (Zantac)
-
Cimetidine (Tagamet): is
incompatible with many other drugs for infusion.
Read medication labels carefully as pre-filled
syringes vary as to route, and may need to be
diluted IV. Give once daily doses at HS.
-
Ranitidine (Zantac): too
rapid IV administration has been associated with bradycardia, tachycardia and PVCs.
-
Monitor HR, BP, and LOC,
assess for constipation or diarrhea as SE.
Receptor Type:
Sites of Action
H1
|
endothelium,
brain, smooth muscle |
H2
|
mast cells,
gastric mucosa, cardiac muscle, brain |
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Clinical Uses: H1 Histamine Receptor
Blockers
-
Allergic Reactions:
-
The
pharmacological objective in the use of these medications
is to treat or prevent symptoms of allergic reaction.
-
H1 histamine receptor
blockers are drugs of choice to treat allergic
rhinitis and urticaria. In both cases, histamine
is the primary mediator of the symptoms
-
By contrast, in asthma
their multiple mediators and H1 histamine
receptor blockers are ineffective.
-
Angioedema (hives) may be initiated by
histamine but are maintained by bradykinins. In this
clinical setting H1
histamine receptor blockers are also ineffective.
-
For atopic dermatitis,
diphenhydramine which is a H1 histamine
receptor blocker proves effective in control of
itching and for sedation.
-
For allergic conditions, an
example being hay fever, the H1 histamine receptor
blockers are effective for symptomatic relief. The
goal is to minimize sedating effects while retaining
beneficial symptomatic relief.
-
The Second-generation H1 histamine
receptor blockers, for example terfenadine (Seldane)
or astemizole (Hismanal) are beneficial because they
exhibit minimal sedation while being effective in
management of allergic rhinitis and chronic urticaria.
At present, these medications tend to be more expensive
than first-generation histamine receptor
H1 antagonists.
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Allergic Rhinitis
-
H1
antihistamines are
effective for treating nasopharyngeal itching,
sneezing, watery rhinorrhea, and ocular itching,
tearing, erythema.
-
Side effects
associated with older H1
antihistamines include sedation, visual
disturbance, urinary retention, and arrhythmias
-
Newer H1
antihistamines:( terfenadine
(Seldane) astemizole (Hismanal))
-
These
agents exhibit less sedation associated
with their reduced ability
to cross the blood brain barrier.
-
However,
there are very important
drug-drug interactions associated with
this category.
-
For
example, macrolide
antibiotics such as
erythromycin,
clarithromycin (Biaxin), ketoconazole-class
broad-spectrum antifungal
drugs, inhibit terfenadine
(Seldane) or
astemizole (Hismanal)
metabolism.
-
Toxic
levels of terfenadine (Seldane) or astemizole
(Hismanal) may induce
potentially fatal cardiac
arrhythmias.
-
These
new H1
antihistamines are
contraindicated for
concurrent use with
macrolide antibiotics and
ketoconazole-class and
fungal drugs or in the
presence of impaired
hepatic function or
inpatients predisposed to
arrhythmias.
-
Topical alpha-adrenergic
agonists:
-
Oral alpha-adrenergic agonists
may be useful in diminishing antihistamine-mediated
sedation while improving antihistamine efficacy in
relieving congestion. However, there is a concern
that these agents due to their potentially hypertensive
effects, may precipitate adverse cardiovascular effects,
such as stroke. Recently, there has been an effort
to remove such "pressor" agents from common
over-the-counter cold medications.
-
Cromolyn sodium:
This agent is a liquid provided as a nasal
metered-does spray. Cromolyn sodium (Intal) is not
associated with side effects and typically is used
prophylactically to reduce episodic allergen nasal mast
cell activation. This agent may be used as part of a
anti-asthma drug regimen.
-
Intranasal
glucocorticoids:
-
Intranasal
glucocorticoids are the most potent drugs
available for management of
established rhinitis (seasonal or
perennial) and including
vasomotor rhinitis
-
Despite the
different route of administration,
intranasal-administered glucocorticoids exhibit
the same efficacy but with reduced systemic side
effects
compared to same agent
administered orally.
-
Side effects
include local irritation, which is the most
frequent side effect to Candida over-growth which
is an unusual side effect
-
Topical high
potency glucocorticoids exhibit
superior efficacy compared
antihistamines during pollen
season.
-
Immunotherapy
(hyposensitization): This approach is based
on repeated, subcutaneous injections of
gradually increasing allergen
(specific for the symptom
complex) over a period of 3-5 years.
-
Contraindications include significant
cardiovascular disease and unstable angina
-
Cautious use
applies to patients
receiving beta adrenergic
blockers (due to
difficulty in managing
possible anaphylactoid
responses to treatment)
-
Clinical Management
Sequence:
-
Identification
of allergens confirmed by
allergens-specific IgE
skin testing and/or serum
assay.
-
Avoidance
of offending allergen
-
Mild
symptoms: prophylaxis
with topical cromolyn
sodium or single
(bedtime) dose of chlorpheniramine
(Chlor-Trimeton) or
astemizole (Hismanal) or
terfenadine (Seldane)
(decision based on side
effects and presence of
other concurrent
medications or disease.
-
Prominent
symptoms: Topical
beclomethasone (Banceril)
or if needed budesonide (Rhinocort) or
flunisolide (AeroBid)
-
Management
failure: immunotherapy
|
Clinical
Uses: H1 Histamine Receptor Blockers
continued
- Motion Sickness:
- Scopolamine and certain
first-generation H1 blockers are among the most effective drugs for motion
sickness prevention
- Diphenhydramine and promethazine
are the H1 blockers with the greatest effectiveness
- Cyclizine (Marezine) and meclizine
are also effective agents and are less sedating than those
above.
- Nausea and Vomiting (Pregnancy)
- H1
blockers are not recommended for use in
management of nausea and vomiting
associate with pregnancy because:
- Difficulty in
assessment of possible birth
defects associated with certain H1
(benedictin) antagonists and
known teratogenic effects of
others (e.g., doxylamine) in
animal models.
-
H1
blockers: Toxicity
- Uncommon toxic effects following
systemic demonstration:
- excessive excitation and
convulsions in children
- orthostatic (postural)
hypotension
- Allergic responses
- Drug allergy -- relatively common,
following topical use of H1
antagonists
- First-generation overdosage:
similar to atropine overdosage
- Second-generation overdosage: may induce cardiac arrhythmias
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Drug-Drug Interactions
- Second-generation H1
blockers:
-
Myocardial
toxicity:
-
Toxicity follows
combination of terfenadine or
astemizole combined with ketoconazole (Nizoral),
itraconazole (Sporanox), or
macrolide antibiotics (e.g.,erythromycin) because-
-
Q-T (ECG)
prolongation
-
Ventricular
arrhythmias which may be potentially fatal.
-
Terfenadine
(Seldane)/astemizole (Hismanal) are contraindicated
in patients taking ketoconazole (Nizoral),
itraconazole (Sporanox), macrolide antibiotics,
and patients with diminished liver function.
-
patients
taking ketoconazole
(Nizoral), itraconazole
(Sporanox), macrolide
antibiotics, and patients
with diminished
-
Fexofenadine (Allegra),
a metabolite of terfenadine
(Seldane), is safer.
H2
Receptor Antagonists
H2
receptor blocker
|
Mechanism
of Elimination
|
Cimetidine
(Tagamet)
|
Mainly
renal
|
Ranitidine
(Zantac)
|
Mainly
renal
|
Famotidine
(Pepcid)
|
Mainly
renal
|
Nizatidine
(Axid)
|
Mainly
renal
|
Pharmacodynamics:H2 Receptor
Antagonists
Clinical
Uses: H2 Receptor Antagonists
Nursing
Implications: Antiulcer-antacids
-
Remind the patient to chew antacid
tablets, not to swallow them whole.
-
Encourage the patient to alternate
aluminum or calcium salts with magnesium salts to
prevent diarrhea or constipation unless a
specific antacid is ordered.
-
Instruct the patient to increase
fluid intake to 2500-3000 ml/day and to increase
dietary intake of fruits and fiber to prevent
constipation. The increased fluids also help to
prevent kidney stones.
-
Antacids may interfere with the
absorption of other medications. Review all
medications, and dose at appropriate times.
-
Remind the patient to take a small
amount of water after dose of antacid liquid to
ensure that the antacid dose is carried to the
stomach.
Nursing
Implications: Antiulcer other
- Watch for similar effects and side
effects as for other antiulcer drugs.
- Instruct the patient to avoid
administering antacids with tetracyclines, digoxin, or
quinidine. It is important to review
the complete list of medications as antacids may
interfere with the absorption of any other drugs.
- Teach patient on sodium
restriction to avoid antacids high in sodium.
Cimetadine
inhibits clearance of these agents (partial listing):
warfarin
|
phenytoin
(Dilantin)
|
propranolol
(Inderal)
|
metoprolol
(Lopressor)
|
labetalol
(Trandate, Normodyne)
|
Quinidine
gluconate (Quinaglute, Quinalan)
|
caffeine
|
lidocaine
(Xylocaine)
|
theophylline
|
alprazolam
(Xanax)
|
triazolam
(Halcion)
|
chlordiazepoxide
(Librium)
|
carbamazepine (Tegretol)
|
ethanol
|
tricyclic
antidepressants
|
metronidazole
(Flagyl)
|
calcium
channel blockers
|
sulfonylureas
|
diazepam
(Valium)
|
flurazepam
(Dalmane)
|
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-
Burkhalter, A, Julius, D.J. and
Katzung, B. Histamine, Serotonin and the Ergot Alkaloids
(Section IV. Drugs with Important Actions on Smooth
Muscle), in Basic and Clinical Pharmacology, (Katzung, B.
G., ed) Appleton-Lange, 1998, pp 261-286.
-
Friedman,
L. S. and Peterson, W.L. Peptic Ulcer and Related
Disorders In Harrison's Principles of Internal Medicine
14th edition, (Isselbacher, K.J., and Braunwald, E.,
Wilson, J.D., Martin, J.B., Fauci, A.S.
and Kasper, D.L., eds) McGraw-Hill, Inc (Health
Professions Division), 1998, pp. 1597-1616.
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