Histamine, its receptors and drugs acting on these receptors
Histamine
Autacoids is a general term that refers to a number
of compounds such as: histamine, serotonin, endogenous peptides,
prostaglandins, and leukotrienes.
The formal definition of autacoids is
"self-remedy”, referring to the action of local hormones
Histamine is a
biogenic amine found in many body tissues and cells. It is synthesized from the
amino acid L-histidine through mediation of the enzyme L-histidine
decarboxylase, while its metabolism is mediated by the enzyme histamine N-methyltransferase,
or alternatively by diamino-oxidase.
Chemistry
and Pharmacokinetics
The formation of histamine
occurs by the removal of a carboxyl group (decarboxylation) from amino
acid L-histidine.
One of the important issues associated with formation
of a biologically active compound is the mechanism that accounts for the
compounds inactivation.
Histamine is active biologically, but the first step
for its inactivation involves the addition of a methyl group (CH3)
followed by a chemical oxidation.
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.
The primary site for histamine localization is the
mast cell granules (or basophils)
Mast cells are important in that they release
histamine in response to potential tissue injury.
Other sites include the central nervous system where
histamine may function as a neurotransmitter and the fundus of the stomach
(enterochromaffin-like cells) which are major acid secretagogues (They promotes
accretion by activation of acid-producing mucosal parietal cells).
Immunologic Release: The most important mechanism for
histamine release is in response to an immunological stimulus. In Mast
cells, if sensitized by surface IgE antibodies, degranulate when exposed
specific antigen. Degranulation means liberation of the contents of the
mast cell granules, including histamine. Degranulation is involved in the
immediate (type I) allergic reaction.
Histamine Modulation is associated with the inflammatory
responses. Following local injury, histamine first produces a local
vasodilation (reddening of the area) followed by the release of acute
inflammation mediators. Inflammatory cells are involved in this process
and include neutrophils, eosinophils, basophils, monocytes &
lymphocytes. In
Mechanical/Chemical Release:
A second type of release occurs following chemical or mechanical injury to mast
cells. In these injuries caused degranulation as noted above including
again histamine release. Common drugs such as morphine or tubocurarine
can displace histamine from granule storage sites.
Pharmacodynamics-- Mechanism of Action -- Histamine mediates its effects by
interacting with receptors. In Receptor Types include H1,
H2, H3 and H4 types. We will focus
our attention on the first two types (H1, H2)
Different histamine receptors (Latest)
Histamine
receptor
|
Cell and tissue expression
|
Activated intracellular signals
|
G Proteins
|
HR1
|
Nerve cells, airway and vascular smooth muscles, endothelial
cells, hepatocytes, epithelial cells, neutrophils, eosinophils, monocytes,
DC, T and B cells.
|
Main signaling: enhanced Ca2+
Others: PhLC, PhLD, cGMP, PhLA, NFκ
B
|
Gq/11
|
HR2
|
Nerve cells, airway and vascular smooth muscles, hepatocytes,
chondrocytes, endothelial cells, epithelial cells, neutrophils, eosinophils,
monocytes DC, T and B cells.
|
Main signaling: enhanced AMPc
Others: Adenylate cyclase, c-Fos, c-Jun, PKC, p70S6K
|
G±S
|
HR3
|
Histaminergic neurons, eosinophils, DC, monocytes
low expression in peripheral tissues.
It inhibits histamine release and synthesis.
|
Main signaling: inhibition of cAMP
Others: enhanced Ca2+, MAP
kinase.
|
Gi/o
|
HR4
|
high expression on bone marrow and peripheral hematopoietic
cells, eosinophils, neutrophils, DC, T cells, basophils, mast cells, low
expression in nerve cells, hepatocytes peripheral tissues, spleen, thymus,
lung, small intestine, colon and heart. It stimulates chemotaxis of
eosinophils and mast cells.
|
Enhanced Ca2+, inhibition of cAMP
|
Gi/o
|
Eos, eosinophils; B cells, B lymphocytes; T cells, T
lymphocytes; PKC, protein kinase C; cAMP, cyclic adenosine monophosphate; PhLC,
phospholipase C; PhLD, phospholipase D; PhLA, phospholipase A; NF_B, nuclear
transcription factor Kappa.
Adapted source: Jutel
M, et al.
Localization
|
Receptor coupling
|
Antagonists (partially selective)
|
|
H1
|
Endothelium,
brain, smooth muscle
|
Receptor
activation causes and increased IP3, DAG (diacylglycerol)
production
|
N/A
|
H2
|
Mast
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
|
Receptor subtypes --H1, H2, and H3:
Intracellular
G protein interactions
H1:endothelial and smooth muscle cell
localization; H1 receptor activation causes can increase in
phosphoinositol hydrolysis and an increase in intracellular calcium.
H2: gastric mucosa, cardiac muscle cells,
immune cell localization; H2 receptor activation causes an
increase in cyclic AMP.
H3: primarily presynaptic; Activation
causes a decrease in transmitter release {transmitters: histamine, acetylcholine,
norepinephrine, serotonin)
Histamine is an
important chemical messenger with stimulatory action (agonism) upon atleast
four types of receptors, and with multiple regulatory functions in the nervous
system, gastrointestinal tract and immune system. All histamine receptors
transmit the corresponding extracellular signals via protein G systems coupled
to intracellular second messengers. The activation of one of these messengers,
specifically guanosine triphosphate (GTP) – binding protein, triggers a cascade
of events at intracytoplasmic level that ultimately induce activation of the
kappa nuclear factor (NF-κ). The latter is an
important proinfl ammatory transcription factor that exerts its function by
binding to the promoter regions of genes – thereby stimulating the synthesis of
a large number of mediators.
Organ
System Effects: Histamine
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)
Increase in vessel permeability due to separation of
endothelial cells, allowing transudation of fluid and molecules as large as
small proteins.
Responsible for urticaria (hives)
Endothelial
cell separation:
secondary to histamine-induced calcium influx causing intracellular
actin/myosin-mediated contraction
Direct
cardiac effects:
Increased contractility (positive inotropism)
Increased pacemaker rate (positive chronotropism)
Histamine promotes intestinal smooth muscle
contraction which is an H1 receptor mediated effect
Bronchiolar smooth muscle activation by histamine causes
bronchoconstriction (H1 receptor mediated )
It is not surprising that inhaled histamine is a
diagnostic, provocative test for bronchial hyperreactivity (asthma or cystic
fibrosis)
Nerve Endings: Sensory nerve endings are stimulated by
histamine, especially those endings which mediate pain and itching.
These effects are H1 receptor mediated
effect and represent part of the local reaction to insect stings (urticarial
responses)
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.
Histamine: Clinical Pharmacology-- Uses
Pulmonary
Function: histamine
aerosol may be used to test for bronchial hyperreactivity.
Flushing, hypotension,
tachycardia, headache, bronchoconstriction, gastrointestinal disturbances.
Should not be given to
asthmatics (except with extreme caution in pulmonary function testing).
Should not be given to
patients with active ulcer disease or gastrointestinal hemorrhage.
Physiologic
antagonists: example --
epinephrine, agents that produce opposing effects, acting and different
receptors
Release
inhibitors: reduced mast
cell degranulation: example: cromolyn and nedocromil
Receptor
antagonists: selective
blockade of histamine receptors (H1, H2, H3
types)
H1
antagonists include both
first-generation and second-generation compounds
Both categories of agents
are orally active and are metabolized by the liver using the cytochrome P450
drug-metabolizing system
The average duration of
pharmacological action is about 4-6 hours
Meclizine (Antivert) and
several second-generation drugs far longer acting, with effects lasting 12-24
hours.
First-generation
agents tend to be
relatively more sedating and more likely than second-generation drugs to block
autonomic receptors -- for example antimuscarinic effects (blockade of
cholinergic, muscarinic-type receptors)
Second-generation
agents are
relatively less sedating compared to the earlier first-generation agents and
exhibit less CNS penetration, which accounts for reduced sedation.
Some of the
second-generation agents are metabolized by a cytochrome P450 type that
is inhibited by other drugs, such as the antifungal agent ketoconazole
(Nizoral).
Therefore, plasma
concentrations of certain second generation H1 antagonists may
increase, even the toxic levels, if the patients also taking drugs such as
ketoconazole (Nizoral) or erythromycin estolate (Ilosone).
H1 receptor
blockers exhibit competitive antagonism for H1 receptor sites
whereas little effects at H2 receptor sites and negligible effects
of H3 sites are observed.
H1 receptor
blockers prevent bronchiolar or gastrointestinal smooth muscle
constriction
H1 receptor
blockers do not completely prevent cardiovascular effects (some of these
effects are mediated by H2 receptors)
H1 receptor
blockers cannot affect increases in gastric acid secretion or mast cell
histamine release because these effects are H2 receptor
site-mediated.
[Until recently, it
was believed that the H1 antihistamines were blockers (antagonists) of the H1 receptors.
However, recently it has been shown that the H1 receptors may present two
different conformational states: active and inactive. Histamine acts as an
agonist by binding to and stabilizing the active conformation of the receptor,
thereby deviating the balance in favor of an activation state. In the same way,
the H1 antihistamines combine with and stabilize the inactive form of the
receptor (inverse agonism), thereby deviating the balance in favor of the
inactive receptor conformation. According to this model, the receptor is
chronically “turned on” even in the absence of an agonist, and the degree of
activation under conditions of equilibrium constitute its baseline activity
level. Possibly some antihistamines that may be developed in future will behave
as neutral antagonists, i.e., they may combine with both H1 receptor
conformations without affecting baseline activity, but preventing the binding
of an agonist (neutral agonism). The relative number of receptors occupied by
histamine or by a given antihistamine depends on the relative concentrations of
these substances in the proximity of the receptor.]
Receptor Type: Sites of Action
H1 Endothelium, brain, smooth muscle
H2 Mast cells, gastric
mucosa, cardiac muscle, brain
Histamine
Pharmacodynamics continued:
Some important histamine promoted effects occur not true histamine's
interaction with histamine receptors but by histamine interaction with other
receptors. Many of these interactions are responsible for "side
effects" associated with antihistamines medications. One prominent
example is the side effect of sedation. The side effect is the basis for
antihistamine use as a sleep aid.
Non-Histamine
Receptor-Mediated Effects
First-generation H1 receptor blockers
cause effects mediated by many other receptor systems. These other effects in
the mediated by muscarinic cholinergic receptors, alpha adrenergic receptors,
serotonergic receptors and local anesthetic receptor sites.
Sedation: Sedation is a common side effect of
first-generation H1 antagonists and provided the rationale for these
agents to be used has sleep-aids, i.e. hypnotics. These agents may produce
a paradoxical excitement and children and toxic reactions can include
stimulation, agitation, or even coma. The newer H1 antagonists,
by contrast, cause minimal or no sedation.
Anti-emetic/Antinausea: Some first-generation H1
antagonists prevent motion sickness. In this application these agent
should be used as prophylaxis. Therefore they should be taken well in
advance of the activity which might be expected to induce
motion-sickness.
Anti-Parkinsonism: Certain first-generation H1
antagonists, because of their antimuscarinic properties, turn out to be
effective in suppressing Parkinsonian symptoms which are side-effects of some
antipsychotic medications. The antipsychotic drugs involved here tend to
be "first-generation" agents which have numerous neurological side
effects. The side effects are much less prevalent with newer
antipsychotic drugs, such as olanzapine (Zyprexa) or risperidone (Risperdal).
Anticholinergic effects: Some first-generation H1
antagonists have strong antimuscarinic actions (atropine-like effects).
Prominent anticholinergic effects include blurred vision (loss of
accommodation) and urinary retention. Therefore patients who may have
benign prostatic hypertrophy may exhibit significant worsening of their clinical
state due to antimuscarinic effects. Probably benign prostatic
hypertrophy would be one example of the syndrome for which there would be a
relative contraindications for these drugs.
Alpha adrenergic blocking
effects: Some first-generation H1 antagonists block alpha
adrenergic receptors. Alpha-adrenergic receptor blockade can cause orthostatic
(postural) hypotension.
Local Anesthetic effects: Many
first-generation H1 antagonists are local anesthetics, exhibiting
sodium channel blockade [similar in general to that caused by procaine
(Novocain) and lidocaine (Xylocaine)]. For
example, diphenhydramine (Benadryl) and promethazine (Pherergan) are more
potent than procaine (Novocain) as a local anesthetic.
CHEMICAL CLASSIFICATION OF H1 ANTIHISTAMINES
|
|||||
Alkylamines
|
Ethanolamines
|
Ethylenediamines
|
Phenothiazines
|
Piperazines
|
Piperidines
|
Bromopheniramine Chlorpheniramine Dexchlorpheniramine
Pheniramine
Dimethindene
Triprolidine
Acrivastine
|
Carbinoxamine Clemastine Dimenhydrinate Diphenhydramine
Doxylamine
Phenyltoxamine
|
Antazoline Pyrilamine Tripelenamine
|
Promethazine Mequitazine
Trimepazine
|
Buclizine
Cyclizine
Meclizine Oxatomide Hydroxyzine Cetirizine Levocetirizine
|
Azatadine Cyproheptadine Ketotifen
Loratadine Desloratadine Bilastine
Ebastine Terfenadine Fexofenadine Levocabastine Mizolastine
Rupatadine
|
Differences between first and second-generation H1
antihistamines
|
|
First-generation H1 antihistamines
|
Second-generation H1 antihistamines
|
Usually administered in three to four daily doses
|
Usually administered once or twice a day
|
Cross the blood-brain barrier (lipophilicity, low molecular
weight, lack of recognition by the P-glycoprotein efflux pump
|
Do not cross the blood-brain barrier(lipophobicity, high
molecular weight, recognition by the P-glycoprotein efflux pump)
|
Potentially cause side-effects (sedation / hyperactivity / insomnia / convulsions)
|
Do not cause relevant side-effects (sedation / fatigue /
hyperactivity / convulsions), in the absence of drug interactions
|
Case reports of toxicity are regularly published
|
No reports of serious toxicity
|
No randomized, double-blind, placebo-controlled in children
|
Some randomized, double-blind, placebo trials controlled
studies in children
|
Lethal dose identified for infants/young children
|
Do not cause fatality in overdose
|
Adapted source: de Benedictis FM, et al.
[Because first-generation H1-antihistamines derive
from the same chemical stem from which cholinergic muscarinic antagonists,
tranquilizers, antipsychotics, and antihypertensive agents were also developed,
they have poor receptor selectivity and often interact with receptors of other
biologically active amines causing antimuscarinic, anti-adrenergic, and
antiserotonin effects. But perhaps their greatest drawback is their ability to
cross the blood-brain barrier and interfere with histaminergic transmission.]
[A major advance in antihistamine development
occurred in the 1980s with the introduction of second-generation H1-antihistamines,
which are minimally sedating or nonsedating because of their limited
penetration of the blood brain barrier. In addition, these drugs are highly
selective for the histamine H1-receptor and have no anticholinergic effects.]
Clinical
Uses: H1 Histamine Receptor Blockers
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.
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.
Phenylephrine
(Neo-Synephrine) or oxymetazoline (Afrin) reduce nasal congestion/obstruction.
Efficacy duration:
limited due to rebound rhinitis and systemic effects which may include
insomnia, irritability, and hypertension -- the latter which is seen more
commonly with oral alpha adrenergic agonists.
Oral α-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 are the most potent drugs available for management of
established rhinitis (seasonal or perennial) and including vasomotor rhinitis.
Topical-to-systemic
activity greater for: flunisolide (AeroBid) or budesonide (Rhinocort), compared
to beclomethasone (Banceril) or triamcinolone (Aristocort).
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
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.
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.
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
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 inhibit
histamine-induced stomach acid secretion.
Interest in these drugs: based on the high incidence
of peptic ulcer disease (and related gastrointestinal disease).
H2 receptor antagonists: frequently
prescribed, available as over-the-counter preparations in some dosage forms.
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
Mechanism
of action: H2 Receptor Antagonists involves selective competitive
antagonism at H2 receptor sites.
The most important action is a reduction in gastric
acid secretion due to H2 receptor blockade.
Blockade of gastric acid secretion in the presence of
H2 receptor blockade following histamine, gastrin, cholinomimetics
(acetylcholine-like drugs such as bethanechol (Urecholine)) and vagal
stimulation.
Reduced gastric acid volume.
Decreased pepsin concentration.
Cimetadine (to lesser
degree ranitidine; not famotidine or nizatidine): inhibits cytochrome P450
microsomal drug metabolizing system
Cimetadine and ranitidine
inhibit renal clearance of basic drugs that use renal secretory transport
systems
Cimetadine, by binding to
androgen receptors, produce antiandrogen effects
H2 receptor antagonists (low toxicity) by
reducing gastric acidity has significantly advanced treatment of peptic ulcer
disease
Other agents that reduce gastric acid include:
Antimuscarinic drugs (at
high dosages required, side effects are significant).
Antacids which require
frequent dosing and may be associated therefore with poor patient
compliance.
Omeprazole (Prilosec) and
lansoprazole (Prevacid) (proton pump blockers and) are very effective in reducing
gastric acid by directly inhibiting an enzyme-pump which produce hydrogen ions
(protons) in the stomach thus decreasing pH.
Sucralfate (Carafate) (a
coating agent) promotes healing
Antibiotics are prominent
in current therapy because of the importance of H. pylori in gastric
ulcer disease.
H2 receptor
antagonists reduce symptoms and promote healing for benign gastric ulcers
Gastroesophageal Reflux Disorder (erosive esophagitis)
H2 receptor
antagonists, at higher dosages than for management of peptic or gastric ulcer
disease,are used as one component of treatment. Proton pump blockers (e.g.
omeprazole) are usually also administered.
Zollinger-Ellison syndrome
is associated with acid hypersecretion which is caused by gastrin-secreting
tumor. This disorder is often fatal; however, H2 receptor
antagonists often control symptoms.
Systemic mastocytosis and
multiple endocrine adenomas are hypersecretory conditions in which H2
receptor antagonists often control symptoms.
Overview: these agents are generally well
tolerated. The most common side effects include diarrhea, dizziness,
somnolence, headache and rash.
Cimetidine (Tagamet) has
the most adverse effects whereas, nizatidine (Axid) has the fewest adverse
effects.
CNS effects are
uncommon. However, in the elderly confusional of states, delirium, and
slurred speech may occur. These effects are often associate with
cimetidine (Tagamet) and are unusual with ranitidine (Zantac).
Endocrine effects are also
relatively uncommon. However cimetidine (Tagamet) does exhibit
antiantherogenic effects because the drug blinds to androgen receptors and
therefore can cause gynecomastia (men) and galactorrhea (women).
Endocrine effects not associated
with famotidine, ranitidine, nizatidine
Other uncommon side
effects include blood dyscrasias [cimetidine (Tagamet): granulocytopenia,
thrombocytopenia, neutropenia, aplastic anemia which is extremely rare],
hepatotoxicity with reversible cholestatic effects, reversible hepatitis,
liver enzyme test abnormalities.
Use
in pregnancy:
Harmful effects on the
fetus have not been observed when H2 blockers are prescribed to
pregnant women even though H2 blockers are secreted into
breast milk and may affect nursing infants.
The general rule, however
is that since these drugs across the placenta, they should only be prescribed
when absolutely required.
Since these drugs to cross
the placenta, the drugs should only be prescribed when absolutely
required.
Cimetidine (Tagamet) is
the prominent agent in this category for drug-drug interactions.
This observation occurs
because cimetidine (Tagamet) is particularly effective in inhibiting the
cytochrome P450 drug metabolizing system therefore influencing the metabolism
of other drugs.
Additionally, cimetidine
(Tagamet) reduces liver blood flow and the combination of effects on blood flow
and metabolism tend to decrease the clearance (removal from the body) of
certain drugs.
Cimetidine 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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