Allergic rhinitis is a group of symptoms affecting the nose.

These symptoms occur when you breathe in

something you are allergic to, such as dust, dander, insect venom, or pollen.
This article focuses on allergic rhinitis due to outdoor triggers, such as plant pollen. This type of allergic
rhinitis is commonly called hay fever.
Causes, incidence, and risk factors
An allergen is something that triggers an allergy. When a person with allergic rhinitis breathes in
an allergen such as pollen or dust, the body releases chemicals, including histamine. This causes allergy
symptoms.
Hay fever involves an allergic reaction to pollen. A similar reaction occurs with allergy to mold, animal
dander, dust, and other allergens that you breathe in.
The pollens that cause hay fever vary from person to person and from area to area. Tiny, hard-to-see
pollens often cause hay fever. Examples of plants that cause hay fever include:
Trees
Grasses
Ragweed
The amount of pollen in the air can affect whether hay fever symptoms develop. Hot, dry, windy days are
more likely to have increased amounts of pollen in the air. On cool, damp, rainy days most pollen is
washed to the ground.
Some disorders may be linked to allergies. These include eczema and asthma.
Allergies are common. Your genes and environment may make you more likely to get allergies.
Allergies often run in families. If both your parents have allergies, you are likely to have allergies too. The
chance is greater if your mother has allergies.
Symptoms
Symptoms that occur shortly after you come into contact with the substance you are allergic to may
include:
Itchy nose, mouth, eyes, throat, skin, or any area
Problems with smell
Runny nose
Sneezing
Tearing eyes
Symptoms that may develop later include:
Stuffy nose (nasal congestion)
Coughing
Clogged ears and decreased sense of smell
Sore throat
Dark circles under the eyes
Puffiness under the eyes
Fatigue and irritability
Headache
People with allergic rhinitis often have allergy symptoms that also involve the eyes.
Signs and tests
The health care provider will perform a physical exam and ask you questions about your symptoms. Your
history of symptoms is important in diagnosing allergic rhinitis. You will be asked whether your symptoms
vary by time of day or season, and exposure to pets or other allergens.
Allergy testing may reveal the substances that trigger your symptoms. Skin testing is the most common
method of allergy testing. See the article on allergy testing for detailed information.
If your doctor determines you cannot have skin testing, special blood tests may help with the diagnosis.
These tests can measure the levels of allergy-related substances, especially one called immunoglobulin
E (IgE).
A complete blood count (CBC) test called the eosinophil white blood cell count may also help diagnose
allergies.
Treatment
LIFESTYLE AND AVOIDING ALLERGENS
The best treatment is to avoid what causes your allergic symptoms. It may be impossible to completely
avoid all your triggers. However, you can often take steps to reduce your exposure to triggers such as:
Dust
Mold
Pollen
There are many different medicines to treat allergic rhinitis. Which one your doctor prescribes depends on
the type and severity of your symptoms, your age, and whether you have other medical conditions (such
as asthma).
For mild allergic rhinitis, a nasal wash can help remove mucus from the nose. You can buy a saline
solution at a drug store or make one at home using one cup of warm water, half a teaspoon of salt, and
pinch of baking soda.
Treatments for allergic rhinitis include:
ANTIHISTAMINES
Antihistamines work well for treating allergy symptoms. They are often used when symptoms do not
happen very often or do not last very long.
Many antihistamines taken by mouth can be bought over the counter, without a prescription.
Older antihistamines can cause sleepiness. They may affect a child's learning and make it unsafe
to drive or operate machines.
Newer antihistamines cause little or no sleepiness. They usually do not interfere with learning.
Antihistamine nasal sprays work well for treating allergic rhinitis. You may try these medicines
first.
CORTICOSTEROIDS
Nasal corticosteroid sprays are the most effective treatment for allergic rhinitis.
They work best when used nonstop, but they can also be helpful when used for shorter periods of
time.
Many brands are available. You will need a prescription from your doctor.
Corticosteroid sprays are safe for children and adults.
DECONGESTANTS
Decongestants may also be helpful for reducing symptoms such as nasal stuffiness.
Do not use nasal spray decongestants for more than 3 days.
OTHER TREATMENTS
The leukotriene inhibitor Singulair is a prescription medicine approved to help control asthma and
relieve the symptoms of seasonal allergies.
Certain illnesses that are caused by allergies (such as asthma and eczema) may need other treatments.
ALLERGY SHOTS
Allergy shots (immunotherapy) are sometimes recommended if you cannot avoid the allergen and your
symptoms are hard to control. This includes regular injections of the allergen. Each dose is slightly larger
than the dose before it. Allergy shots may help your body adjust to the substance that is causing the
reaction (antigen).
Expectations (prognosis)
Most symptoms of allergic rhinitis can be treated. More severe cases need allergy shots.
Some people (especially children) may outgrow an allergy as the immune system becomes less sensitive
to the allergen. However, once a substance causes allergies, it usually continues to affect the person over
the long term.
Calling your health care provider
Call for an appointment with your health care provider if:
You have severe allergy or hay fever symptoms
Treatment that once worked for you no longer works
Your symptoms do not respond to treatment
Prevention
You can sometimes prevent symptoms by avoiding known allergens. During pollen season, people with
hay fever should stay indoors where it is air conditioned, if possible.
Most trees produce pollen in the spring.
Grasses usually produce pollen during the late spring and summer.
Ragweed and other late-blooming plants produce pollen during late summer and early autumn.




Rhinitis is defined as inflammation of the nasal membranes
[1]
and is characterized by a symptom
complex that consists of any combination of the following: sneezing, nasal congestion, nasal
itching, and rhinorrhea.
[2]
The eyes, ears, sinuses, and throat can also be involved. Allergic rhinitis
is the most common cause of rhinitis. It is an extremely common condition, affecting
approximately 20% of the population.
Although allergic rhinitis is not a life-threatening condition, complications can occur and the
condition can significantly impair quality of life,
[3, 4]
which leads to a number of indirect costs. The
total direct and indirect cost of allergic rhinitis was recently estimated to be $5.3 billion per
year.
[5]
A 2011 analysis determined that patients with allergic rhinitis averaged 3 additional office
visits, 9 more prescriptions filled, and $1500 in incremental healthcare costs in 1 year than similar
patients without allergic rhinitis.
[6]


Allergic rhinitis involves inflammation of the mucous membranes of the nose, eyes, eustachian tubes,
middle ear, sinuses, and pharynx. The nose invariably is involved, and the other organs are affected in
certain individuals. Inflammation of the mucous membranes is characterized by a complex interaction of
inflammatory mediators but ultimately is triggered by an immunoglobulin E (IgE)mediated response to an
extrinsic protein.
[7]

The tendency to develop allergic, or IgE-mediated, reactions to extrinsic allergens (proteins capable of
causing an allergic reaction) has a genetic component. In susceptible individuals, exposure to certain
foreign proteins leads to allergic sensitization, which is characterized by the production of specific IgE
directed against these proteins. This specific IgE coats the surface of mast cells, which are present in the
nasal mucosa. When the specific protein (eg, a specific pollen grain) is inhaled into the nose, it can bind
to the IgE on the mast cells, leading to immediate and delayed release of a number of mediators.
[7, 8, 9]

The mediators that are immediately released include histamine, tryptase, chymase, kinins, and heparin.
[8,
9]
The mast cells quickly synthesize other mediators, including leukotrienes and prostaglandin D2.
[10, 11,
12]
These mediators, via various interactions, ultimately lead to the symptoms of rhinorrhea (ie, nasal
congestion, sneezing, itching, redness, tearing, swelling, ear pressure, postnasal drip). Mucous glands
are stimulated, leading to increased secretions. Vascular permeability is increased, leading to plasma
exudation. Vasodilation occurs, leading to congestion and pressure. Sensory nerves are stimulated,
leading to sneezing and itching. All of these events can occur in minutes; hence, this reaction is called the
early, or immediate, phase of the reaction.
Over 4-8 hours, these mediators, through a complex interplay of events, lead to the recruitment of other
inflammatory cells to the mucosa, such as neutrophils, eosinophils, lymphocytes, and
macrophages.
[13]
This results in continued inflammation, termed the late-phase response. The symptoms
of the late-phase response are similar to those of the early phase, but less sneezing and itching and more
congestion and mucus production tend to occur.
[13]
The late phase may persist for hours or days.
Systemic effects, including fatigue, sleepiness, and malaise, can occur from the inflammatory response.
These symptoms often contribute to impaired quality of life.


Allergic rhinitis affects approximately 40 million people in the United States.
[14]
Recent US figures suggest
a 20% cumulative prevalence rate.
[15, 16]

International
Scandinavian studies have demonstrated a cumulative prevalence rate of 15% in men and 14% in
women.
[17]
The prevalence of allergic rhinitis may vary within and among countries.
[18, 19, 20, 21]
This may be
due to geographic differences in the types and potency of different allergens and the overall aeroallergen
burden.
Mortality/Morbidity
While allergic rhinitis itself is not life-threatening (unless accompanied by severe asthma or anaphylaxis),
morbidity from the condition can be significant. Allergic rhinitis often coexists with other disorders, such
as asthma, and may be associated with asthma exacerbations.
[22, 23, 24]

Allergic rhinitis is also associated with otitis media, eustachian tube dysfunction,sinusitis, nasal
polyps, allergic conjunctivitis, and atopic dermatitis.
[1, 2, 25]
It may also contribute to learning difficulties,
sleep disorders, and fatigue.
[26, 27, 28]

Numerous complications that can lead to increased morbidity or even mortality can occur secondary to
allergic rhinitis. Possible complications include otitis media, eustachian tube dysfunction, acute sinusitis,
and chronic sinusitis.
Allergic rhinitis can be associated with a number of comorbid conditions, including asthma, atopic
dermatitis, and nasal polyps. Evidence now suggests that uncontrolled allergic rhinitis can actually
worsen the inflammation associated with asthma
[22, 23, 24]
or atopic dermatitis.
[25]
This could lead to further
morbidity and even mortality.
Allergic rhinitis can frequently lead to significant impairment of quality of life. Symptoms such as fatigue,
drowsiness (due to the disease or to medications), and malaise can lead to impaired work and school
performance, missed school or work days, and traffic accidents. The overall cost (direct and indirect) of
allergic rhinitis was recently estimated to be $5.3 billion per year.
[5]

Race
Allergic rhinitis occurs in persons of all races. Prevalence of allergic rhinitis seems to vary among different
populations and cultures, which may be due to genetic differences, geographic factors or environmental
differences, or other population-based factors.
Sex
In childhood, allergic rhinitis is more common in boys than in girls, but in adulthood, the prevalence is
approximately equal between men and women.
Age
Onset of allergic rhinitis is common in childhood, adolescence, and early adult years, with a mean age of
onset 8-11 years, but allergic rhinitis may occur in persons of any age. In 80% of cases, allergic rhinitis
develops by age 20 years.
[29]
The prevalence of allergic rhinitis has been reported to be as high as 40% in
children, subsequently decreasing with age.
[15, 16]
In the geriatric population, rhinitis is less commonly
allergic in nature.
Previous

istory
Obtaining a detailed history is important in the evaluation of allergic rhinitis. Important elements include
an evaluation of the nature, duration, and time course of symptoms; possible triggers for symptoms;
response to medications; comorbid conditions; family history of allergic diseases; environmental
exposures; occupational exposures; and effects on quality of life. A thorough history may help identify
specific triggers, suggesting an allergic etiology for the rhinitis.
Symptoms that can be associated with allergic rhinitis include sneezing, itching (of nose, eyes, ears,
palate), rhinorrhea, postnasal drip, congestion, anosmia, headache, earache, tearing, red eyes, eye
swelling, fatigue, drowsiness, and malaise.
[2]

Symptoms and chronicity
Determine the age of onset of symptoms and whether symptoms have been present continuously since
onset. While the onset of allergic rhinitis can occur well into adulthood, most patients develop symptoms
by age 20 years.
[29]

Determine the time pattern of symptoms and whether symptoms occur at a consistent level throughout
the year (ie, perennial rhinitis), only occur in specific seasons (ie, seasonal rhinitis), or a combination of
the two. During periods of exacerbation, determine whether symptoms occur on a daily basis or only on
an episodic basis. Determine whether the symptoms are present all day or only at specific times during
the day. This information can help suggest the diagnosis and determine possible triggers.
Determine which organ systems are affected and the specific symptoms. Some patients have exclusive
involvement of the nose, while others have involvement of multiple organs. Some patients primarily have
sneezing, itching, tearing, and watery rhinorrhea (the classic hayfever presentation), while others may
only complain of congestion. Significant complaints of congestion, particularly if unilateral, might suggest
the possibility of structural obstruction, such as a polyp, foreign body, or deviated septum.
Trigger factors
Determine whether symptoms are related temporally to specific trigger factors. This might include
exposure to pollens outdoors, mold spores while doing yard work, specific animals, or dust while cleaning
the house.
Irritant triggers such as smoke, pollution, and strong smells can aggravate symptoms in a patient with
allergic rhinitis. These are also common triggers of vasomotor rhinitis. Many patients have both allergic
rhinitis and vasomotor rhinitis.
Other patients may describe year-round symptoms that do not appear to be associated with specific
triggers. This could be consistent with nonallergic rhinitis, but perennial allergens, such as dust mite or
animal exposure, should also be considered in this situation. With chronic exposure and chronic
symptoms, the patient may not be able to associate symptoms with a particular trigger.
Response to treatment
Response to treatment with antihistamines supports the diagnosis of allergic rhinitis, although sneezing,
itching, and rhinorrhea associated with nonallergic rhinitis can also improve with antihistamines.
[30]

Response to intranasal corticosteroids supports the diagnosis of allergic rhinitis, although some cases of
nonallergic rhinitis (particularly the nonallergic rhinitis with eosinophils syndrome [NARES]) also improve
with nasal steroids.
Comorbid conditions
Patients with allergic rhinitis may have other atopic conditions such as asthma
[22, 23]
or atopic
dermatitis.
[25]
Of patients with allergic rhinitis, 20% also have symptoms of asthma. Uncontrolled allergic
rhinitis may cause worsening of asthma
[24]
or even atopic dermatitis.
[25]
Explore this possibility when
obtaining the patient history.
Look for conditions that can occur as complications of allergic rhinitis. Sinusitis occurs quite frequently.
Other possible complications include otitis media, sleep disturbance or apnea, dental problems (overbite),
and palatal abnormalities.
[31]
The treatment plan might be different if one of these complications is present.
Nasal polyps occur in association with allergic rhinitis, although whether allergic rhinitis actually causes
polyps remains unclear. Polyps may not respond to medical treatment and might predispose a patient to
sinusitis or sleep disturbance (due to congestion).
Investigate past medical history, including other current medical conditions. Diseases such as
hypothyroidism or sarcoidosis can cause nonallergic rhinitis. Concomitant medical conditions might
influence the choice of medication.
Family history
Because allergic rhinitis has a significant genetic component,
[32]
a positive family history for atopy makes
the diagnosis more likely.
In fact, a greater risk of allergic rhinitis exists if both parents are atopic than if one parent is atopic.
However, the cause of allergic rhinitis appears to be multifactorial, and a person with no family history of
allergic rhinitis can develop allergic rhinitis.
Environmental and occupational exposure
A thorough history of environmental exposures helps to identify specific allergic triggers. This should
include investigation of risk factors for exposure to perennial allergens (eg, dust mites, mold, pets).
[33,
34]
Risk factors for dust mite exposure include carpeting, heat, humidity, and bedding that does not have
dust miteproof covers. Chronic dampness in the home is a risk factor for mold exposure. A history of
hobbies and recreational activities helps determine risk and a time pattern of pollen exposure.
Ask about the environment of the workplace or school. This might include exposure to ordinary perennial
allergens (eg, mites, mold, pet dander) or unique occupational allergens (eg, laboratory animals, animal
products, grains and organic materials, wood dust, latex, enzymes).
Effects on quality of life
An accurate assessment of the morbidity of allergic rhinitis cannot be obtained without asking about the
effects on the patient's quality of life. Specific validated questionnaires are available to help determine
effects on quality of life.
[3, 4]

Determine the presence of symptoms such as fatigue, malaise, drowsiness (which may or may not be
related to medication), and headache.
Investigate sleep quality and ability to function at work.
The physical examination should focus on the nose, but examination of facial features, eyes, ears,
oropharynx, neck, lungs, and skin is also important. Look for physical findings that may be consistent with
a systemic disease that is associated with rhinitis.
General facial features
"Allergic shiners" are dark circles around the eyes and are related to vasodilation or nasal congestion.
[2, 35]

"Nasal crease" is a horizontal crease across the lower half of the bridge of the nose that is caused by
repeated upward rubbing of the tip of the nose by the palm of the hand (ie, the "allergic salute").
[2, 35]

Nose
The nasal examination is best accomplished with a nasal speculum or an otoscope with nasal adapter. In
the specialist's office, a rigid or flexible rhinolaryngoscope may be used.
The mucosa of the nasal turbinates may be swollen (boggy) and have a pale, bluish-gray color. Some
patients may have predominant erythema of the mucosa, which can also be observed with rhinitis
medicamentosa, infection, or vasomotor rhinitis. While pale, boggy, blue-gray mucosa is typical for
allergic rhinitis, mucosal examination findings cannot definitively distinguish between allergic and
nonallergic causes of rhinitis.
Assess the character and quantity of nasal mucus. Thin and watery secretions are frequently associated
with allergic rhinitis, while thick and purulent secretions are usually associated with sinusitis; however,
thicker, purulent, colored mucus can also occur with allergic rhinitis.
Examine the nasal septum to look for any deviation or septal perforation, which may be present due to
chronic rhinitis, granulomatous disease, cocaine abuse, prior surgery, topical decongestant abuse, or,
rarely, topical steroid overuse.
Examine the nasal cavity for other masses such as polyps or tumors. Polyps are firm gray masses that
are often attached by a stalk, which may not be visible. After spraying a topical decongestant, polyps do
not shrink, while the surrounding nasal mucosa does shrink.
Ears, eyes, and oropharynx
Perform otoscopy to look for tympanic membrane retraction, air-fluid levels, or bubbles. Performing
pneumatic otoscopy can be considered to look for abnormal tympanic membrane mobility. These findings
can be associated with allergic rhinitis, particularly if eustachian tube dysfunction or secondary otitis
media is present.
Ocular examination may reveal findings of injection and swelling of the palpebral conjunctivae, with
excess tear production. Dennie-Morgan lines (prominent creases below the inferior eyelid) are associated
with allergic rhinitis.
[36]

The term "cobblestoning" is used to describe streaks of lymphoid tissue on the posterior pharynx, which is
commonly observed with allergic rhinitis. Tonsillar hypertrophy can also be observed. Malocclusion
(overbite) and a high-arched palate can be observed in patients who breathe from their mouths
excessively.
[37]

Neck
Look for evidence of lymphadenopathy or thyroid disease.
Lungs
Look for the characteristic findings of asthma.
Skin
Evaluate for possible atopic dermatitis.
Other
Look for any evidence of systemic diseases that may cause rhinitis (eg, sarcoidosis, hypothyroidism,
immunodeficiency, ciliary dyskinesia syndrome, other connective tissue diseases).

The causes of allergic rhinitis may differ depending on whether the symptoms are seasonal, perennial, or
sporadic/episodic. Some patients are sensitive to multiple allergens and can have perennial allergic
rhinitis with seasonal exacerbations. While food allergy can cause rhinitis, particularly in children, it is
rarely a cause of allergic rhinitis in the absence of gastrointestinal or skin symptoms.
Seasonal allergic rhinitis is commonly caused by allergy to seasonal pollens and outdoor molds.
Pollens (tree, grass, and weed)
Tree pollens, which vary by geographic location, are typically present in high counts during the spring,
although some species produce their pollens in the fall. Common tree families associated with allergic
rhinitis include birch, oak, maple, cedar, olive, and elm.
Grass pollens also vary by geographic location. Most of the common grass species are associated with
allergic rhinitis, including Kentucky bluegrass, orchard, redtop, timothy, vernal, meadow fescue, Bermuda,
and perennial rye. A number of these grasses are cross-reactive, meaning that they have similar
antigenic structures (ie, proteins recognized by specific IgE in allergic sensitization). Consequently, a
person who is allergic to one species is also likely to be sensitive to a number of other species. The grass
pollens are most prominent from the late spring through the fall but can be present year-round in warmer
climates.
Weed pollens also vary geographically. Many of the weeds, such as short ragweed, which is a common
cause of allergic rhinitis in much of the United States, are most prominent in the late summer and fall.
Other weed pollens are present year-round, particularly in warmer climates. Common weeds associated
with allergic rhinitis include short ragweed, western ragweed, pigweed, sage, mugwort, yellow dock,
sheep sorrel, English plantain, lamb's quarters, and Russian thistle.
Outdoor molds
Atmospheric conditions can affect the growth and dispersion of a number of molds; therefore, their
airborne prevalence may vary depending on climate and season.
For example, Alternaria and Cladosporium are particularly prevalent in the dry and windy conditions of the
Great Plains states, where they grow on grasses and grains. Their dispersion often peaks on sunny
afternoons. They are virtually absent when snow is on the ground in winter, and they peak in the summer
months and early fall.
Aspergillus and Penicillium can be found both outdoors and indoors (particularly in humid households),
with variable growth depending on the season or climate. Their spores can also be dispersed in dry
conditions.
Perennial allergic rhinitis is typically caused by allergens within the home but can also be caused by
outdoor allergens that are present year-round.
[38]
In warmer climates, grass pollens can be present
throughout the year. In some climates, individuals may be symptomatic due to trees and grasses in the
warmer months and molds and weeds in the winter.
House dust mites
In the United States, 2 major house dust mite species are associated with allergic rhinitis. These
are Dermatophagoides farinae and Dermatophagoides pteronyssinus.
[33]

These mites feed on organic material in households, particularly the skin that is shed from humans and
pets. They can be found in carpets, upholstered furniture, pillows, mattresses, comforters, and stuffed
toys.
While they thrive in warmer temperatures and high humidity, they can be found year-round in many
households. On the other hand, dust mites are rare in arid climates.
Pets
Allergy to indoor pets is a common cause of perennial allergic rhinitis.
[33, 34]

Cat and dog allergies are encountered most commonly in allergy practice, although allergy has been
reported to occur with most of the furry animals and birds that are kept as indoor pets.
Cockroaches
While cockroach allergy is most frequently considered a cause of asthma, particularly in the inner city, it
can also cause perennial allergic rhinitis in infested households.
[39, 40]

Rodents
Rodent infestation may be associated with allergic sensitization.
[41, 42, 43]

Sporadic allergic rhinitis causes
Sporadic allergic rhinitis, intermittent brief episodes of allergic rhinitis, is caused by intermittent exposure
to an allergen. Often, this is due to pets or animals to which a person is not usually exposed. Sporadic
allergic rhinitis can also be due to pollens, molds, or indoor allergens to which a person is not usually
exposed. While allergy to specific foods can cause rhinitis, an individual affected by food allergy also
usually has some combination of gastrointestinal, skin, and lung involvement. In this situation, the history
findings usually suggest an association with a particular food. Watery rhinorrhea occurring shortly after
eating may be vasomotor (and not allergic) in nature, mediated via the vagus nerve. This often is called
gustatory rhinitis.
Occupational allergic rhinitis
Occupational allergic rhinitis, which is caused by exposure to allergens in the workplace, can be sporadic,
seasonal, or perennial. People who work near animals (eg, veterinarians, laboratory researchers, farm
workers) might have episodic symptoms when exposed to certain animals, daily symptoms while at the
workplace, or even continual symptoms (which can persist in the evenings and weekends with severe
sensitivity due to persistent late-phase inflammation). Some workers who may have seasonal symptoms
include farmers, agricultural workers (exposure to pollens, animals, mold spores, and grains), and other
outdoor workers. Other significant occupational allergens that may cause allergic rhinitis include wood
dust, latex (due to inhalation of powder from gloves), acid anhydrides, glues, and psyllium (eg, nursing
home workers who administer it as medication).
Previous
Testing for reaction to specific allergens can be helpful to confirm the diagnosis of allergic rhinitis and to
determine specific allergic triggers. If specific allergic triggers are known, then appropriate avoidance
measures can be recommended. It is essential to know which allergens a patient is sensitive to in order to
perform allergen immunotherapy (desensitization treatment). To an extent, allergy testing provides
knowledge of the degree of sensitivity to a particular allergen. The most commonly used methods of
determining allergy to a particular substance are allergy skin testing (testing for immediate
hypersensitivity reactions) and in vitro diagnostic tests, such as the radioallergosorbent test (RAST),
which indirectly measures the quantity of specific IgE to a particular antigen.
Allergy skin tests (immediate hypersensitivity testing) are an in vivo method of determining immediate
(IgE-mediated) hypersensitivity to specific allergens. Sensitivity to virtually all of the allergens that cause
allergic rhinitis (see Causes) can be determined with skin testing.
By introducing an extract of a suspected allergen percutaneously, an immediate (early-phase) wheal-and-
flare reaction can be produced. Percutaneous introduction can be accomplished by placing a drop of
extract on the skin and scratching or pricking a needle through the epidermis under the drop. Depending
on the exact technique used, this testing is referred to as scratch, prick, or puncture testing.
The antigen in the extract binds to IgE on skin mast cells, leading to the early-phase (immediate-type)
reaction, which results in the release of mediators such as histamine (see Pathophysiology). This
generally occurs within 15-20 minutes. The released histamine causes the wheal-and-flare reaction (A
central wheal is produced by infiltrating fluid, and surrounding erythema is produced due to vasodilation,
with concomitant itching.). The size of the wheal-and-flare reaction roughly correlates with the degree of
sensitivity to the allergen.
The extract can also be introduced intradermally (ie, injected into the dermis with an intradermal [TB]
needle). With this technique, the extract is allowed to contact the underlying dermal tissues, including skin
mast cells. Intradermal testing is approximately 1000-fold more sensitive than percutaneous testing. This
should be performed with care by qualified specialists. The rate of false-positive results may be high.
In vitro allergy tests, ie, RAST, allow measurement of the amount of specific IgE to individual allergens in
a sample of blood. The amount of specific IgE produced to a particular allergen approximately correlates
with the allergic sensitivity to that substance. These tests allow determination of specific IgE to a number
of different allergens from one blood sample, but the sensitivity and specificity are not always as good as
accurate skin testing (depending on the laboratory and assay used for the RAST). As with skin testing,
virtually all of the allergens that cause allergic rhinitis (see Causes) can be determined using the RAST,
although testing for some allergens is less well established compared to others.
Testing every patient for sensitivity to every allergen known is not practical. Therefore, select a limited
number of allergens for testing (this applies to both skin testing and RAST). When selecting allergens,
select from among the allergens that are present locally and are known to cause clinically significant
allergic disease. A clinician who is specifically trained in allergy testing should select allergens for testing.
Total serum IgE
This is a measurement of the total level of IgE in the blood (regardless of specificity). While patients with
allergic rhinitis are more likely to have an elevated total IgE level than the normal population, this test is
neither sensitive nor specific for allergic rhinitis. As many as 50% of patients with allergic rhinitis have
normal levels of total IgE, while 20% of nonaffected individuals can have elevated total IgE levels.
Therefore, this test is generally not used alone to establish the diagnosis of allergic rhinitis, but the results
can be helpful in some cases when combined with other factors.
Total blood eosinophil count
As with the total serum IgE, an elevated eosinophil count supports the diagnosis of allergic rhinitis, but it
is neither sensitive nor specific for the diagnosis. The results can sometimes be helpful when combined
with other factors.

While radiographic studies are not needed to establish the diagnosis of allergic rhinitis, they can
be helpful for evaluating possible structural abnormalities or to help detect complications or
comorbid conditions, such as sinusitis or adenoid hypertrophy.
A 3-view sinus series (Caldwell, Waters, and lateral views) can be helpful in evaluating for
sinusitis of the maxillary, frontal, and sphenoid sinuses. The ethmoid sinuses are difficult to
visualize clearly on x-ray films. Plain x-ray films can be helpful for diagnosing acute sinusitis,
but CT scanning of the sinuses is more sensitive and specific. For chronic sinusitis, plain x-ray
films are often inconclusive, and CT scan is much preferred.
A lateral view of the neck can be helpful when evaluating for soft tissue abnormalities of the
nasopharynx, such as adenoid hypertrophy.
CT scanning
Coronal CT scan images of the sinuses can be very helpful for evaluating acute or chronic
sinusitis. In particular, obstruction of the ostiomeatal complex (a confluence of drainage
channels from the sinuses) can be seen quite clearly. CT scanning may also help delineate
polyps, turbinate swelling, septal abnormalities (eg, deviation), and bony abnormalities (eg,
concha bullosa).
MRI
For evaluating sinusitis, MRI images are generally less helpful than CT scan images, largely
because the bony structures are not seen as clearly on MRI images. However, soft tissues are
visualized quite well, making MRI images helpful for diagnosing malignancies of the upper
airway.
Previous
Nasal cytology: A nasal smear can sometimes be helpful for establishing the diagnosis of allergic rhinitis.
A sample of secretions and cells is scraped from the surface of the nasal mucosa using a special
sampling probe. Secretions that are blown from the nose are not adequate. The presence of eosinophils
is consistent with allergic rhinitis but also can be observed with NARES. Results are neither sensitive nor
specific for allergic rhinitis and should not be used exclusively for establishing the diagnosis.

Rhinoscopy: While not routinely indicated, upper airway endoscopy (rhinolaryngoscopy) can be
performed if a complication or comorbid condition may be present. It can be helpful for evaluating
structural abnormalities (eg, polyps, adenoid hypertrophy, septal deviation, masses, foreign bodies) and
chronic sinusitis (by visualizing the areas of sinus drainage).
Nasal provocation (allergen challenge) testing: This procedure is essentially a research tool and is rarely
indicated in the routine evaluation of allergic rhinitis. The possible allergen is inhaled or otherwise
inoculated into the nose. The patient can then be monitored for development of symptoms or production
of secretions, or objective measurements of nasal congestion can be taken. Some consider this test the
criterion standard test for the diagnosis of allergic rhinitis.
[44]
However, it is not a practical test to perform
routinely, and only an appropriately trained specialist should perform this test.


The management of allergic rhinitis consists of 3 major categories of treatment, (1) environmental control
measures and allergen avoidance, (2) pharmacological management, and (3) immunotherapy.
Environmental control measures and allergen avoidance involve both the avoidance of known allergens
(substances to which the patient has IgE-mediated hypersensitivity) and avoidance of nonspecific, or
irritant, triggers. Consider environmental control measures, when practical, in all cases of allergic
rhinitis.
[45]
However, global environmental control without identification of specific triggers is inappropriate.
Pollens and outdoor molds
Because of their widespread presence in the outdoor air, pollens can be difficult to avoid. Reduction of
outdoor exposure during the season in which a particular type of pollen is present can be somewhat
helpful. In general, tree pollens are present in the spring, grass pollens from the late spring through
summer, and weed pollens from late summer through fall, but exceptions to these seasonal patterns exist
(see Causes).
Pollen counts tend to be higher on dry, sunny, windy days. Outdoor exposure can be limited during this
time, but this may not be reliable because pollen counts can also be influenced by a number of other
factors. Keeping the windows and doors of the house and car closed as much as possible during the
pollen season (with air conditioning, if necessary, on recirculating mode) can be helpful. Taking a shower
after outdoor exposure can be helpful by removing pollen that is stuck to the hair and skin.
Despite all of these measures, patients who are allergic to pollens usually continue to be symptomatic
during the pollen season and usually require some other form of management. As with pollens, avoidance
of outdoor/seasonal molds may be difficult.
Indoor allergens
Depending on the allergen, environmental control measures for indoor allergens can be quite helpful. For
dust mites, covering the mattress and pillows with impermeable covers helps reduce exposure.
[46]
Bed
linens should be washed every 2 weeks in hot (at least 130F) water to kill any mites present.
[47,
48]
Thorough and efficient vacuum cleaning of carpets and rugs can help, but, ultimately, carpeting should
be removed. The carpet can be treated with one of a number of chemical agents that kill the mites or
denature the protein, but the efficacy of these agents does not appear to be dramatic. Dust mites thrive
when indoor humidity is above 50%, so dehumidification, air conditioning, or both is helpful.
[49]

Indoor environmental control measures for mold allergy focus on reduction of excessive humidity and
removal of standing water. The environmental control measures for dust mites can also help reduce mold
spores.
For animal allergy, complete avoidance is the best option. For patients who cannot, or who do not want
to, completely avoid an animal or pet, confinement of the animal to a noncarpeted room and keeping it
entirely out of the bedroom can be of some benefit.
[50]
Cat allergen levels in the home can be reduced with
high-efficiency particulate air (HEPA) filters and by bathing the cat every week (although this may be
impractical). Cockroach extermination may be helpful for cases of cockroach sensitivity.
Occupational allergens
As with indoor allergens, avoidance is the best measure. When this is not possible, a mask or respirator
might be needed.
Nonspecific triggers
Exposure to smoke, strong perfumes and scents, fumes, rapid changes in temperature, and outdoor
pollution can be nonspecific triggers in patients with allergic rhinitis. Consider avoidance of these
situations or triggers if they seem to aggravate symptoms.
Pharmacotherapy
See Medication.
Immunotherapy (desensitization)
A considerable body of clinical research has established the effectiveness of high-dose allergy shots in
reducing symptoms and medication requirements.
[51]
Success rates have been demonstrated to be as high
as 80-90% for certain allergens. It is a long-term process; noticeable improvement is often not observed
for 6-12 months, and, if helpful, therapy should be continued for 3-5 years. Immunotherapy is not without
risk because severe systemic allergic reactions can sometimes occur. For these reasons, carefully
consider the risks and benefits of immunotherapy in each patient and weigh the risks and benefits of
immunotherapy against the risks and benefits of the other management options.
Sublingual immunotherapy (SLIT) is currently increasing in use, particularly in Europe. It is not yet
approved in the United States but clinical trials are underway, with plans for application for FDA approval.
Differences between SLIT and subcutaneous immunotherapy (SCIT) need further study, including
research on differences in efficacy, durability, and safety. Thus far, the data on SLIT has focused largely
on pollen allergens. Whether SLIT will be effective for non-pollen allergens as well as pollens also needs
additional study. A 2012 meta-analysis of existing studies of SLIT for grass pollen reported that SCIT is
more effective than SLIT in controlling symptoms and in reducing the use of allergy medications in
patients with seasonal allergic rhinoconjuntivitis to grass pollen.
[52]

Indications: Immunotherapy may be considered more strongly with severe disease, poor response to
other management options, and the presence of comorbid conditions or complications. Immunotherapy
is often combined with pharmacotherapy and environmental control.
Administration: Administer immunotherapy with allergens to which the patient is known to be sensitive
and that are present in the patient's environment (and cannot be easily avoided). The value of
immunotherapy for pollens, dust mites, and cats is well established.
[53, 54, 55, 56, 57]
The value of
immunotherapy for dogs and mold is less well established.
[51, 53]

Contraindication: A number of potential contraindications to immunotherapy exist and need to be
considered. Immunotherapy should only be performed by individuals who have been appropriately
trained, who institute appropriate precautions, and who are equipped for potential adverse events.




ALLERGIC RHINITIS OVERVIEW
Rhinitis refers to inflammation of the nasal passages. This inflammation can cause a variety of annoying
symptoms, including sneezing, itching, nasal congestion, runny nose, and post-nasal drip (the sensation
that mucus is draining from the sinuses down the back of the throat).
Brief episodes of rhinitis are usually caused by respiratory tract infections with viruses (eg, the common
cold). Chronic rhinitis is usually caused by allergies, but it can also occur from overuse of certain drugs,
some medical conditions, and other unidentifiable factors.
For many people, rhinitis is a lifelong condition that waxes and wanes over time. Fortunately, the
symptoms of rhinitis can usually be controlled with a combination of environmental measures,
medications, and immunotherapy (also called allergy shots).
Other forms of rhinitis are discussed separately. (See "Patient information: Nonallergic rhinitis (runny or
stuffy nose) (Beyond the Basics)".)
WHO GETS ALLERGIC RHINITIS?
Allergic rhinitis, also known as hay fever, affects approximately 20 percent of people of all ages. The risk
of developing allergic rhinitis is much higher in people with asthma or eczema and in people who have a
family history of asthma or rhinitis.
Allergic rhinitis can begin at any age, although most people first develop symptoms in childhood or young
adulthood. The symptoms are often at their worst in children and in people in their 30s and 40s. However,
the severity of symptoms tends to vary throughout life; many people experience periods when they have
no symptoms at all.
ALLERGIC RHINITIS CAUSES
Allergic rhinitis is caused by a nasal reaction to small airborne particles called allergens (substances that
provoke an allergic reaction). In some people, these particles also cause reactions in the lungs (asthma)
and eyes (allergic conjunctivitis).
The allergic reaction is characterized by activation of two types of inflammatory cells, called mast cells
and basophils. These cells produce inflammatory substances, such as histamine, which cause fluid to
build up in the nasal tissues (congestion), itching, sneezing, and runny nose. Over several hours, these
substances activate other inflammatory cells that can cause persistent symptoms.
Seasonal versus perennial allergic rhinitis Allergic rhinitis can be seasonal (occurring during
specific seasons) or perennial (occurring year round). The allergens that most commonly cause seasonal
allergic rhinitis include pollens from trees, grasses, and weeds, as well as spores from fungi and molds
(figure 1).
The allergens that most commonly cause perennial allergic rhinitis are dust mites, cockroaches, animal
dander, and fungi or molds. Perennial allergic rhinitis tends to be more difficult to treat.
ALLERGIC RHINITIS SYMPTOMS
The symptoms of allergic rhinitis vary from person to person. Although the term "rhinitis" refers only to the
nasal symptoms, many patients also experience problems with their eyes, throat, and ears. In addition,
sleep can be disrupted, so it is helpful to consider the entire spectrum of symptoms.
Nose: watery nasal discharge, blocked nasal passages, sneezing, nasal itching, post-nasal drip,
loss of taste, facial pressure or pain.
Eyes: itchy, red eyes, feeling of grittiness in the eyes, swelling and blueness of the skin below the
eyes (called allergic shiners) (see"Patient information: Allergic conjunctivitis (Beyond the
Basics)").
Throat and ears: sore throat, hoarse voice, congestion or popping of the ears, itching of the throat
or ears.
Sleep: mouth breathing, frequent awakening, daytime fatigue, difficulty performing work.
When an allergen is present year round, the predominant symptoms include post-nasal drip, persistent
nasal congestion, and poor-quality sleep.
ALLERGIC RHINITIS DIAGNOSIS
The diagnosis of allergic rhinitis is based upon a physical examination and the symptoms described
above. Medical tests can confirm the diagnosis and identify the offending allergens.
Identify allergens and other triggers It is often possible to identify the allergens and other triggers
that provoke allergic rhinitis by:
Recalling the factors that precede symptoms
Noting the time at which symptoms begin
Identifying potential allergens in a person's home, work, and school environments
Skin tests may be useful for people whose symptoms are not well controlled with medications or in whom
the offending allergen is not obvious.
ALLERGIC RHINITIS TREATMENT
The treatment of allergic rhinitis includes reducing exposure to allergens and other triggers, in
combination with medication therapy. In most people, these measures effectively control the symptoms.
Reduce exposure to triggers Some simple measures can reduce a person's exposure to allergens
and triggers that provoke allergic rhinitis. These measures are discussed in detail in a separate topic
review. (See "Patient information: Trigger avoidance in allergic rhinitis (Beyond the Basics)".)
Several different classes of drugs counter the inflammation that causes symptoms of allergic rhinitis. The
severity of symptoms and personal preferences usually guide the selection of specific drugs.
Nasal irrigation and saline sprays Rinsing the nose with a salt-water (saline) solution is called nasal
irrigation or nasal lavage. Saline is also available in a standard nasal spray, although this is not as
effective as using larger amounts of water in an irrigation.
Nasal irrigation is particularly useful for treating drainage down the back of the throat, sneezing, nasal
dryness, and congestion. The treatment helps by rinsing out allergens and irritants from the nose. Saline
rinses also clean the nasal lining and can be used before applying sprays containing medications, to get a
better effect from the medication.
Nasal lavage with warmed saline can be performed as needed, once per day, or twice daily for increased
symptoms. Nasal lavage carries few risks when performed correctly and with sterilized water. Saline
nasal sprays and irrigation kits can be purchased over-the-counter. Saline mixes can also be purchased
or patients can make their own solution.
A variety of devices, including bulb syringes, Neti pots, and bottle sprayers, may be used to perform nasal
lavage; instructions for nasal lavage are provided in the table (table 1). At least 200 mL (about 3/4 cup) of
fluid (salt solution made with distilled or boiled water or sterile saline, not tap water) is recommended for
each nostril.
Nasal glucocorticoids Nasal glucocorticoids (steroids delivered by a nasal spray) are the first-line
treatment for the symptoms of allergic rhinitis. These drugs have few side effects and dramatically relieve
symptoms in most people. Studies have shown that nasal glucocorticoids are more effective than oral
antihistamines for symptom relief [1].
There are a number of nasal glucocorticoids available by prescription. Specific medications include
fluticasone, mometasone, budesonide, flunisolide, triamcinolone, beclomethasone, fluticasone furoate,
and ciclesonide. These drugs differ with regard to the frequency of doses, the spray device, and cost, but
all are similarly effective for treating all the symptoms of allergic rhinitis.
People with severe rhinitis may need to use a nasal decongestant for a few days before starting a nasal
glucocorticoid to reduce nasal swelling, which will allow the nasal spray to reach more areas of the nasal
passages (see 'Decongestants' below).
Some symptom relief may occur on the first day of therapy with nasal glucocorticoids, although their
maximal effectiveness may not be noticeable for days to weeks. For this reason, nasal glucocorticoids are
most effective when used regularly. Some people are able to use lower doses when symptoms are less
severe.
How to use a nasal spray Nasal sprays work best when they are used properly and the medication
remains in the nose rather than draining down the back of the throat. If the nose is crusted or contains
mucus, it should be cleaned with a saline nasal spray before a nasal spray that contains medication.
The head should be positioned normally or with the chin slightly tucked. The spray should be directed
away from the nasal septum (the cartilage that divides the two sides of the nose). The spray is dispensed
and then sniffed in slightly to pull it into the higher parts of the nose. Sniffing too hard will result in the
medicine draining down the throat, and should be avoided.
Some people find that holding one nostril closed with a finger improves their ability to draw the spray into
the upper nose. Medicine that drains into the throat should be spit out, since it is not effective unless it
remains in the nose.
Side effects The side effects of nasal steroids are mild and may include a mildly unpleasant smell or
taste or drying of the nasal lining. In some people, nasal steroids cause irritation, crusting, and bleeding of
the nasal septum, especially during the winter. These problems can be minimized by reducing the dose of
the nasal steroid, applying a moisturizing nasal gel or spray to the septum before using the spray, or
switching to a water-based (rather than an alcohol-based) spray.
Studies suggest that nasal steroids are generally safe when used for many years. However, people who
use these drugs for years should have periodic nasal examinations to check for rare side effects, such as
nasal infection.
Steroids taken as a pill or inhaled into the lungs can have side effects, especially when taken for long
periods of time. However, the doses used in nasal steroids are low and are NOT associated with these
side effects. However, clinicians usually recommend using the lowest effective dose.
Antihistamines Antihistamines relieve the itching, sneezing, and runny nose of allergic rhinitis, but
they do not relieve nasal congestion. Combined treatment with nasal steroids or decongestants may
provide greater symptom relief than use of either alone.
Oral medications Several antihistamines have been available for many years without a prescription,
including brompheniramine (Dimetapp allergy, Nasahist B), chlorpheniramine (Chlor-Trimeton),
diphenhydramine (Benadryl), and clemastine (Tavist). These drugs often cause sedation and should
not be used before driving or operating machinery. Even if the person does not feel excessively drowsy,
these drugs can have a sedating effect. Thus, patients should use caution.
Less-sedating oral antihistamines include Loratadine (Claritin, Alavert), desloratadine (Clarinex),
cetirizine (Zyrtec), levocetirizine (Xyzal), and fexofenadine (Allegra). Loratadine and cetirizine are
available without a prescription. These drugs work as well as the sedating antihistamines for rhinitis, but
they are less sedating and are available in long-acting formulas. However, they may be more expensive.
Nasal sprays Azelastine (Astelin, Astepro) and olopatadine (Patanase) are prescription nasal
antihistamine sprays that can be used daily or when needed to relieve symptoms of post-nasal drip,
congestion, and sneezing. These sprays start to work within minutes after use. The most common side
effect with azelastine is a bad taste in the mouth immediately after use. This can be minimized by keeping
the head tilted forward while spraying, to prevent the medicine from draining down the throat (see 'How to
use a nasal spray' above).
Decongestants Decongestants (like pseudoephedrine or phenylephrine [Sudafed, Actifed,
Drixoral]) are often combined with antihistamines in oral, over-the-counter allergy drugs. In the United
States, pseudoephedrine has been used to make illegal drugs, which caused many companies to
substitute phenylephrine for pseudoephedrine. However, phenylephrine is not effective for treating
allergic rhinitis.
Oral decongestants elevate blood pressure and are not appropriate for people with high blood pressure or
certain cardiovascular conditions. Men with an enlarged prostate who have difficulty urinating may notice
a worsening of this symptom when they take decongestants. (See"Patient information: Benign prostatic
hyperplasia (BPH) (Beyond the Basics)".)
Decongestants in the form of nasal sprays are also available, including oxymetazoline (Afrin) and
phenylephrine (Neo-synephrine). Nasal decongestant sprays should not be used for more than two to
three days at a time because they may cause a type of rhinitis called rhinitis medicamentosa, which
causes the nose to be congested constantly UNLESS the medication is used repeatedly. This condition
can be difficult to treat. To avoid it, do not use decongestant sprays for more than 3 days. (See "Patient
information: Nonallergic rhinitis (runny or stuffy nose) (Beyond the Basics)".)
Cromolyn sodium Cromolyn sodium (Nasalcrom) prevents the symptoms of allergic rhinitis by
interfering with the ability of allergy cells to release natural chemicals that cause inflammation. This drug
is available as an over-the-counter nasal spray that must be used three to four times per day, preferably
before symptoms have begun, to effectively prevent the symptoms of allergic rhinitis.
Allergy shots Allergy shots, also known as allergen immunotherapy, are injections given to reduce a
person's sensitivity to allergens. Allergy shots are only available for common allergens, such as pollens,
cat and dog dander, dust mites, and molds. These shots contain solutions of the allergens to which a
specific person is allergic, and are made up individually for each person. The process of immunotherapy
changes the person's immune response to the allergens over time. As a result, being exposed to the
allergen causes fewer or even no symptoms.
Immunotherapy can help many people with allergic rhinitis. In children, immunotherapy can help prevent
developing allergic asthma later in life. However, immunotherapy is relatively time-consuming and is often
reserved for people who have a poor response to medication, or want to avoid taking medications long-
term. Immunotherapy can be expensive, but many insurance plans cover the therapy because long-term
use of allergy medications is also costly.
Immunotherapy is usually started by an allergist. Treatment begins with several months of weekly
injections of gradually increasing doses, followed by monthly maintenance injections.
Immunotherapy is usually administered for a minimum of three to five years. If immunotherapy is
discontinued, the benefits gradually diminish over time, although some patients have several more years
of symptom relief [2].
Immunotherapy injections carry a small risk of a severe allergic reaction. These reactions occur with a
frequency of 6 of every 10,000 injections. The symptoms usually begin within 30 minutes of the injection.
For this reason, patients are required to remain in the office after routine injections so that such a reaction
could be quickly treated. Because drugs called beta-blockers may interfere with the ability to treat these
reactions, people who take beta-blockers are often advised to avoid immunotherapy.
Other treatments Other drugs may be recommended for some people with allergic rhinitis.
Ipratropium Nasal atropine is effective for the treatment of severe runny nose. This drug,
available as ipratropium bromide (Atrovent), is not generally recommended for people with
glaucoma or men with an enlarged prostate.
Leukotriene modifiers Release of substances called leukotrienes may contribute to the
symptoms of allergic rhinitis. Drugs that block the actions of leukotrienes, called leukotriene
modifiers, can be very useful in patients with asthma and allergic rhinitis. However, nasal steroids
are more effective than leukotriene modifiers for treating allergic rhinitis; thus, leukotriene
modifiers are generally reserved for patients who cannot tolerate nasal sprays (due to nose
bleeds) or azelastine (see 'Antihistamines' above).
PREGNANCY AND ALLERGIC RHINITIS
Women who have allergic rhinitis before pregnancy may have worsening, improvement, or no change in
their symptoms during pregnancy. Most women notice some nasal congestion in the later stages of
pregnancy, even if they did not have rhinitis before. This is called rhinitis of pregnancy, and is related to
hormone levels. Rhinitis of pregnancy does not respond to medications and goes away after delivery. The
discussion below applies only to allergic rhinitis.
As a general rule, medications should be avoided or used at the lowest dose that controls symptoms
during pregnancy. A woman should always review any medication (over-the-counter or prescription)
before taking it during pregnancy. However, several of the drugs used to treat allergic rhinitis are thought
to be safe.
Saline sprays and nasal irrigation Women with mild rhinitis may be able to control symptoms
using only saline nasal sprays or irrigation, which do not contain any medications. (See 'Nasal
irrigation and saline sprays' above.)
If medication for rhinitis is needed during pregnancy, the following are considered to be safer choices:
Nasal sprays Certain nasal sprays are a sensible option for pregnant women, because much
less drug is required to control symptoms when it is sprayed directly into the nose, compared to
taking that same medication by mouth.
Cromolyn nasal sprays are safe for use during pregnancy. Only a very small amount of drug
is absorbed into the blood stream with this medication and no serious side effects are known
to occur. (See 'Cromolyn sodium' above.)
Nasal glucocorticoids are considered safe for use in pregnancy, and women who are already
taking these can simply continue during pregnancy (table 1). Although no safety differences have
been identified among the different nasal glucocorticoids, budesonide (Rhinocort Aqua) has
been approved for use in pregnancy for a longer time than the others. (See 'Nasal
glucocorticoids' above.)
Antihistamines Chlorpheniramine (Chlor-Trimeton and others), loratadine (Claritin), or
cetirizine (Zyrtec) are the antihistamines of choice during pregnancy.
Decongestants Pseudoephedrine should be avoided during the first trimester of pregnancy if
possible, because its safety has not been confirmed. After the first trimester, it should be used
only when needed and only as directed. However, it should not be used at all by women with high
blood pressure or pre-eclampsia. Phenylephrine should be avoided altogether during pregnancy.
Allergy shots Women already taking allergy shots who have not had allergic reactions to the
shots in the past may safely continue treatment through pregnancy. However, the dose should
not be increased during pregnancy due to the risk of a serious allergic reaction (anaphylaxis),
which could potentially reduce the blood supply to the fetus. For the same reason, allergy shots
are not started during pregnancy.
WHERE TO GET MORE INFORMATION
Your healthcare provider is the best source of information for questions and concerns related to your
medical problem.
This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for
patients, as well as selected articles written for healthcare professionals, are also available. Some of the
most relevant are listed below.
Patient level information UpToDate offers two types of patient education materials.
The Basics The Basics patient education pieces answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and who
prefer short, easy-to-read materials.
Patient information: Seasonal allergies in adults (The Basics)
Patient information: Giving your child over-the-counter medicines (The Basics)
Patient information: Allergy shots (The Basics)
Patient information: Allergy skin testing (The Basics)
Patient information: Rinsing out your nose with salt water (The Basics)
Patient information: Seasonal allergies in children (The Basics)
Beyond the Basics Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are best for patients who want in-depth information and are comfortable
with some medical jargon.
Patient information: Nonallergic rhinitis (runny or stuffy nose) (Beyond the Basics)
Patient information: Allergic conjunctivitis (Beyond the Basics)
Patient information: Trigger avoidance in allergic rhinitis (Beyond the Basics)
Patient information: Benign prostatic hyperplasia (BPH) (Beyond the Basics)
Professional level information Professional level articles are designed to keep doctors and other
health professionals up-to-date on the latest medical findings. These articles are thorough, long, and
complex, and they contain multiple references to the research on which they are based. Professional
level articles are best for people who are comfortable with a lot of medical terminology and who want to
read the same materials their doctors are reading.
Allergen avoidance in the treatment of asthma and allergic rhinitis
An overview of rhinitis
Chronic nonallergic rhinitis
Clinical manifestations, pathophysiology, and diagnosis of chronic rhinosinusitis
Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis
Occupational rhinitis
Pathogenesis of allergic rhinitis (rhinosinusitis)
Pharmacotherapy of allergic rhinitis
The following organizations also provide reliable health information.
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
Allergy, Asthma, and Immunology Online

(www.acaai.org/public/advice/rhin.htm)
American Academy of Allergy, Asthma, and Immunology

(www.aaaai.org/patients/publicedmat/tips/rhinitis.stm)
[1-4]




NONALLERGIC RHINITIS CAUSES
The cause of nonallergic rhinitis is not usually known. However, many triggers of symptoms are known,
and include tobacco smoke, traffic fumes, or strong odors and perfumes. People with nonallergic rhinitis
are not bothered by pollen or furred animals (the common triggers in allergic rhinitis), although about one-
half of people with this condition also have allergic rhinitis. (See "Patient information: Allergic rhinitis
(seasonal allergies) (Beyond the Basics)".)
NONALLERGIC RHINITIS TREATMENT
Treatment of nonallergic rhinitis includes trigger avoidance, medications, and/or nasal rinsing or irrigation.
Trigger avoidance Exposure to tobacco smoke can be reduced if household members stop smoking
or smoke only outside of the home. It is also important to avoid smoke exposure in the workplace.
Exposure to pollutants and irritants can be reduced by avoiding wood-burning stoves and fireplaces;
properly venting other stoves and heaters; and avoiding cleaning agents and household sprays that
trigger symptoms.
Exposure to strong perfumes and scented products may be more difficult. People who are bothered by
these items should avoid using them and may need to request that coworkers, family, or friends do the
same. Some workplaces have policies regarding the use of strongly scented personal products.
Nasal rinsing and irrigation Simply rinsing the nose with a salt water (saline) solution one or more
times a day is helpful for many patients with nonallergic rhinitis, as well as for other rhinitis conditions.
Nasal rinsing is particularly useful for symptoms of postnasal drainage. Nasal rinsing can be done before
use of nasal medication so that the lining is freshly cleansed when the medication is applied.
The nose can be rinsed with small amounts of saline by using over-the-counter saline nasal sprays, or
with larger amounts of saline. The latter technique is called nasal irrigation or nasal lavage. Nasal sprays
are easy to use but do not rinse the nasal passages as thoroughly as nasal irrigation. However, nasal
irritation is less convenient and takes more time.
A variety of devices, including bulb syringes, irrigation pots (which look like small kettles), and bottle
sprayers, may be used to perform nasal irrigation; instructions for the technique are provided in the table
(table 1). At least 200 mL (about 3/4 cup) of fluid is recommended for each nostril. Patients can make
their own solution or buy commercially-prepared solutions. All are available without a prescription.
Nasal irrigation with warmed saline can be performed as needed, once per day, or twice daily for
increased symptoms. Nasal irrigation carries few risks when performed correctly. Very rare brain
infections have been reported from the use of water that was not sterile.
Medications that worsen symptoms Certain medications can cause or worsen nasal symptoms
(especially congestion). These include the following: birth control pills, some drugs for high blood
pressure (eg, alpha blockers and beta blockers), antidepressants, medications for erectile dysfunction,
and some medications for prostatic enlargement. If rhinitis symptoms are bothersome and one of these
medications is used, ask the prescriber if the medication could be aggravating the condition.
Nonallergic rhinitis medications Daily use of a nasal glucocorticoid and/or an antihistamine nasal
spray can be helpful for people with nonallergic rhinitis. These medications may be used alone or in
combination.
Nasal antihistamines A prescription nasal antihistamine spray, such as azelastine (eg, Astelin,
Astepro), can relieve symptoms of postnasal drip, congestion, and sneezing. These sprays start to work
within minutes after use and can be used to treat symptoms after they develop. However, they are most
effective when used on a regular basis.
The most common side effect of nasal antihistamines is a bad taste in the mouth immediately after use.
This can be minimized by keeping the head tilted forward while spraying, to prevent the medicine from
draining down the throat. The usual dose of azelastine is two sprays in each nostril twice per day.
Nasal glucocorticoids A nasal glucocorticoid, fluticasone (eg, Flonase, generic equivalents), has
been shown to be effective for symptoms of nonallergic rhinitis. The dose is one squirt in each nostril
twice per day. Other glucocorticoid nasal sprays may also be effective, although these have not been
directly studied in people with nonallergic rhinitis.
Some symptom relief may occur on the first day of treatment, although the maximal effect may not be
noticeable for days to weeks. For this reason, fluticasone is most effective when used regularly. Some
people are able to use lower doses when symptoms are less severe. (See'How to use a nasal
spray' below.)
Nasal ipratropium A runny nose with profuse, watery discharge from the nose (rhinorrhea) can be
treated with ipratropium bromide (0.03 percent or 0.6 percent) nasal spray. Ipratropium is the best
treatment for gustatory rhinitis. (See 'Gustatory rhinitis' below.)
How to use a nasal spray Nasal sprays work best when they are used properly and the medication
remains in the nose, rather than draining down the back of the throat. Some people find that holding one
nostril closed with a finger improves their ability to draw the spray into the upper nose. Medicine that
drains into the throat should be spit out, since the medicine is only effective when it remains in the nose.
The head should be positioned normally or with the chin slightly tucked. The spray should be directed
away from the nasal septum (the cartilage that divides the two sides of the nose). The spray is dispensed
and then sniffed in slightly to pull it into the higher parts of the nose. Sniffing too hard will result in the
medicine draining down the throat, and should be avoided.
Decongestants Oral decongestant medications (like pseudoephedrine or phenylephrine) help to
relieve symptoms of congestion (stuffiness) in some people. However, this treatment is not usually
recommended unless nasal antihistamines and nasal glucocorticoids do not improve symptoms.
Several decongestant nasal sprays also are available, including oxymetazoline (Afrin) and
phenylephrine (Neo-synephrine). Nasal decongestants should not be used for more than two to three
days at a time because they may cause a type of rhinitis called rhinitis medicamentosa. (See 'Rhinitis
medicamentosa' below.)
Oral decongestants elevate blood pressure and may not be appropriate for people with high blood
pressure or certain cardiovascular conditions. In addition, oral decongestants can cause nervousness and
difficulty sleeping. Men with an enlarged prostate who have difficulty urinating may notice a worsening of
this problem when they take decongestants. (See "Patient information: Benign prostatic hyperplasia
(BPH) (Beyond the Basics)".)
How long will I need treatment? The dose or frequency of medications can be reduced in some
patients over time. However, in most patients, symptoms are lifelong and some medication is usually
needed on a daily and long-term basis.
OTHER TYPES OF NONALLERGIC RHINITIS
Gustatory rhinitis Gustatory rhinitis is a type of nonallergic rhinitis that causes a sudden onset of
watery nasal discharge with eating, especially foods that are spicy or heated (such as soup).
Rhinitis medicamentosa Rhinitis medicamentosa is a type of rhinitis that develops as a result of
overuse of over-the-counter decongestant nasal sprays or from snorting cocaine (this does not happen
with use of nasal glucocorticoid sprays). Oral medications can also cause rhinitis medicamentosa.
(See 'Medications that worsen symptoms' above.)
Rhinitis medicamentosa is treated by discontinuing the drug that is causing the condition. Steroid nasal
sprays can speed the recovery from this condition [1].
WHERE TO GET MORE INFORMATION
Your healthcare provider is the best source of information for questions and concerns related to your
medical problem.
This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for
patients, as well as selected articles written for healthcare professionals, are also available. Some of the
most relevant are listed below.
Patient level information UpToDate offers two types of patient education materials.
The Basics The Basics patient education pieces answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and who
prefer short, easy-to-read materials.
Patient information: Cough, runny nose, and the common cold (The Basics)
Beyond the Basics Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are best for patients who want in-depth information and are comfortable
with some medical jargon.
Patient information: Allergic rhinitis (seasonal allergies) (Beyond the Basics)
Patient information: Benign prostatic hyperplasia (BPH) (Beyond the Basics)
Professional level information Professional level articles are designed to keep doctors and other
health professionals up-to-date on the latest medical findings. These articles are thorough, long, and
complex, and they contain multiple references to the research on which they are based. Professional
level articles are best for people who are comfortable with a lot of medical terminology and who want to
read the same materials their doctors are reading.



ALLERGIC CONJUNCTIVITIS OVERVIEW
Conjunctivitis, also called "pink eye," is defined as an inflammation of the conjunctiva. The conjunctiva is
the thin membrane that lines the inner surface of the eyelids and the whites of the eyes (called the sclera)
(figure 1). Conjunctivitis can affect children and adults. The most common symptoms of conjunctivitis
include a red eye and discharge.
There are many potential causes of conjunctivitis, including bacterial or viral infections and allergies. All
types of conjunctivitis cause a red eye, although not everyone with a red eye has conjunctivitis. The term
pink eye refers primarily to conjunctivitis caused by viruses (such as adenoviruses), rather than other
causes. Therefore, this term should not be used when the underlying cause of the conjunctivitis is
unknown or is not thought to be viral.
This topic review discusses the signs and symptoms, evaluation, and treatment of allergic conjunctivitis.
Other types of conjunctivitis are discussed separately. (See "Patient information: Conjunctivitis (pinkeye)
(Beyond the Basics)".)
ALLERGIC CONJUNCTIVITIS CAUSES
Allergic conjunctivitis is caused by airborne allergens that come in contact with the eye. Symptoms may
be sudden in onset (acute), seasonal, or present year-round (perennial), depending upon the allergen.
Acute allergic conjunctivitis Acute allergic conjunctivitis is a sudden-onset reaction that occurs when
a person comes in contact with a known allergen, such as cat dander. Symptoms include intense
episodes of itching, redness, tearing, and swelling of the eyelid. Symptoms can be severe, although they
usually resolve within 24 hours of removal of the allergen.
Seasonal allergic conjunctivitis Seasonal allergic conjunctivitis (SAC) is a form of eye allergy that
usually causes milder but more persistent symptoms during a particular pollen season(s).
Seasonal allergens include tree pollens in the spring, grass pollens in the summer, and weed pollens in
the late summer and fall, although there is some variation based upon geographic location (figure 2).
Perennial allergic conjunctivitis Perennial allergic conjunctivitis (PAC) is a mild, chronic, allergic
conjunctivitis related to year-round environmental, usually indoor, allergens such as dust mites, animal
danders, and molds.
ALLERGIC CONJUNCTIVITIS SYMPTOMS
The most common symptoms of allergic conjunctivitis include redness, watery discharge, and itching of
both eyes. Other symptoms can include burning, sensitivity to light, and swelling of the eyelids. Both eyes
are usually affected, although symptoms may be worse in one eye. Rubbing the eyes can worsen
symptoms.
People with allergic conjunctivitis often have a history of other allergic conditions, such as eczema,
seasonal allergies, or a specific allergy (eg, to cats).
ALLERGIC CONJUNCTIVITIS TREATMENT
There are a number of treatments available for the symptoms of allergic conjunctivitis. In addition, basic
eye care is important.
Basic eye care
Avoid rubbing the eyes. If itching is bothersome, use artificial tears, a cool compress, or
antihistamine eye drops (see'Medications' below).
Minimize exposure to pollen by staying inside when possible, using air conditioning, and keeping
car and home windows closed during the peak allergy seasons (figure 2). (See "Patient
information: Allergic rhinitis (seasonal allergies) (Beyond the Basics)".)
People with year round allergic conjunctivitis should consider consulting an allergy specialist to
determine which allergens are responsible for their symptoms (eg, dust mites, cat dander,
others).
Medications
People with sudden-onset symptoms can use a combination antihistamine/vasoconstrictor eye
drop four times daily for up to two weeks. These are available without a prescription.
People with seasonal or year round symptoms are usually treated with a combination
antihistamine/mast cell stabilizer eye drop. Most of these require a prescription. Ketotifen is an
eye drop in this category that is available without a prescription.
An oral antihistamine may be most helpful when it is taken preventively (before symptoms
develop). However, antihistamines may also be used to treat symptoms after they have started,
although the greatest benefit may not be seen for several days.

Non-sedating oral antihistamines include fexofenadine (generic, Allegra), loratadine (generic,
Claritin), desloratadine (Clarinex), cetirizine (generic, Zyrtec), and levocetirizine (Xyzal).
Loratadine and cetirizine are available in the United States without a prescription.

Diphenhydramine (Benadryl) is a short-acting, sedating antihistamine that can be taken at
bedtime to reduce night-time itching.
If symptoms of allergic conjunctivitis do not improve after two to three weeks of the above treatments, the
person should see an ophthalmologist for evaluation.
Treat dry eyes People with allergic conjunctivitis often produce an inadequate amount of tears, which
can cause dryness of the eye. This can worsen symptoms of allergic conjunctivitis. However, it is not
always possible to know if a person has inadequate tear production unless an eye examination is
performed.
If inadequate tear production is diagnosed, treatment often includes use of a lubricant eye drop or
ointment. These products are available without a prescription in most pharmacies. Preservative-free
preparations are more expensive and are necessary only for people with a severe case of dry eye and
those who are allergic to preservatives.
Lubricant drops can be used as often as hourly with no side effects. The ointment provides longer lasting
relief but blurs vision temporarily. For this reason, some people use ointment only at bedtime. It may be
worthwhile to switch brands if one brand of drop or ointment is irritating, since each preparation contains
different active and inactive ingredients and preservatives


ALLERGIC RHINITIS TRIGGER OVERVIEW
Allergic rhinitis, also known as hay fever, affects approximately 20 percent of people of all ages. The most
common symptoms include nasal itching, watery nasal discharge, sneezing, itchy red eyes, sore throat,
or hoarse voice.
Allergic rhinitis is caused by a nasal reaction to small airborne particles called allergens (substances that
cause an allergic reaction). In some people, these particles also cause reactions in the lungs (asthma),
and eyes (allergic conjunctivitis).
One of the first steps in treating any allergic condition is to avoid or minimize exposure to the allergens
that cause the condition [1]. The evaluation and treatment of allergic rhinitis is discussed in a separate
topic review. (See "Patient information: Allergic rhinitis (seasonal allergies) (Beyond the Basics)".)
IDENTIFYING THE ALLERGEN
There are four major categories of allergens that trigger allergic rhinitis:
Pollens (spring and summer: trees, grass; fall: ragweed, tumbleweed)
Insects (house dust mites, cockroaches, lady bugs)
Animal allergens (skin, fur, feathers, saliva)
Molds
In some cases, it is easy to identify a person's triggers, based upon when symptoms develop (eg, during
a particular season, after exposure to a dog or cat, etc). In people with year-round symptoms, it may be
more difficult to pinpoint the allergen(s).
The first step in the treatment of allergic rhinitis is to reduce exposure to allergens. The most common
indoor allergens are dust mites and cat and dog dander [2]. However, with indoor allergens, it may take
three to six months to see an improvement in symptoms once triggers are removed; steps to reduce
allergens are discussed later in this topic review. (See 'Reduce exposure to triggers' below.)
First-line treatment also usually includes one or more medications (eg, nasal glucocorticoid sprays,
antihistamines). Medications for allergic rhinitis and allergic conjunctivitis are discussed in separate topic
reviews. (See "Patient information: Allergic rhinitis (seasonal allergies) (Beyond the Basics)" and "Patient
information: Conjunctivitis (pinkeye) (Beyond the Basics)".)
If symptoms are severe or persist despite avoidance of the allergen, the person may be referred to an
allergy specialist for further testing and treatment. Allergy specialists can identify each person's triggers,
so that he or she can focus on reducing exposure to the triggers that are important for them.
REDUCE EXPOSURE TO TRIGGERS
Once a person trigger(s) have been identified, the next step is to reduce exposure to those specific
allergens. Triggers may be present at work or at home, although for most people, the home environment
is the primary source. It is especially important to reduce exposure to triggers in the bedroom because
most people spend a significant number of hours there. However, to be effective, changes must be made
throughout the entire home (table 1).
Dust mites Dust mites are a microscopic type of insect that lives in bedding, sofas, carpets, or any
woven material. Dust mites do not bite and do not cause harm to humans, other than by triggering
allergies.
Mites absorb humidity from the atmosphere (ie, they do not drink) and feed on organic matter (including
shed human and animal skin). They require sufficient humidity and nests to live in (which are not visible
with the naked eye). Dust mite infestation is less common in dry climates, such as the southwestern
United States.
Exposure to dust mites can be reduced by encasing pillows, mattresses, box springs, comforters, and
furniture in mite-impermeable barriers. When covering crib mattresses and childrens mattresses and
pillows, only tight-fitting, commercial covers intended for this purpose should be used. Home-made
covers (for example, plastic sheeting fastened with duct tape) should not be used in childrens beds, as
these can come apart and children can become trapped or suffocate. Tightly woven fabrics with a pore
size of 6 microns or less are very effective at controlling the passage of mite (as well as cat allergens).
Fabrics with a pore size greater than 2 microns or greater still permit airflow [3,4].
Mites can be eliminated by washing sheets and blankets weekly in warm water with detergent or by
drying them in an electric dryer on the hot setting (table 2). Exposure can be further reduced by
vacuuming with a vacuum cleaner equipped with a HEPA filter, dusting regularly, and not sleeping on
upholstered furniture (eg, couches). However, studies have yet to show that physical or chemical cleaning
methods reduce mite levels to a degree that improves symptoms [5].
Indoor humidity levels should be kept between 30 and 50 percent; inexpensive humidity monitors can be
purchased at most hardware stores. Humidifiers make the problem worse and are not recommended.
When possible, the amount of clutter, carpet, upholstered furniture, and drapes should be minimized and
horizontal blinds should be eliminated in the rooms where the person spends the most time (bedroom,
study, TV room). Washable vinyl, roller-type shades are optimal. For children, the number of stuffed toys
in the bedroom should be minimized.
Animal dander Animal dander is made up of the dead skin cells or scales (like dandruff) that are
constantly shed by animals. Any breed of dog or cat is capable of being allergenic, although the levels
given off by individual animals may vary to some degree. In cats, the protein that causes most people's
allergies is found in the cat's saliva, skin glands, and urinary/reproductive tract. Accordingly, short-haired
cats are not necessarily less allergenic than long-haired animals, and furless cats have allergen levels
similar to furred cats.
Other animals, such as rodents, birds, and ferrets can also trigger symptoms in an allergic individual. Pets
without feathers or fur, such as reptiles, turtles, and fish rarely cause allergy, although deposits of fish
food that build up under the covers of fish tanks are an excellent source of food for dust mite colonies.
If a person is found to be allergic to a pet, the most effective option is to remove the pet from the home.
Limiting an animal to a certain area in the house is not effective because allergens are carried on clothing
or spread in the air. Once a pet has left a home, careful cleaning (or removal) of carpets, sofas, curtain,
and bedding must follow. This is particularly true for cat allergens because they are "sticky" and adhere to
a variety of indoor surfaces. Even after a cat has been removed from a home and it has been thoroughly
cleaned, it can take months for the level of cat allergen to drop. For this reason, it may take months for
the person's symptoms to fully reflect the absence of the pet.
If it is not possible to remove the animal, measures can be taken to decrease exposure to the animal
dander (table 3), although none of these methods is as effective as removing the animal. Vacuum
cleaners with a HEPA filter are effective in reducing cat and dog allergen levels in the home and can
reduce symptoms [5]. (See 'Air filters' below.)
Rodents Mice and rats have proteins in their urine that can cause allergies. This applies to rodents
that live in a laboratory setting as well as rodents that live in the wild.
To reduce rodent allergen levels significantly, a combination of pest control methods, in combination with
pesticides (eg, poison baits), are usually necessary. This includes keeping food and trash in covered
containers, cleaning food scraps from the floor and countertops, and sealing cracks in the walls, doors,
and floors.
Cockroaches Cockroach droppings contain allergens that can trigger asthma and allergic rhinitis in
sensitive individuals. Cockroaches thrive in warm, moist environments with easily accessible food and
water. Unfortunately, efforts to control cockroach populations in infested areas are often less than
successful. Still, certain measures are recommended, including:
Use multiple baited traps or poisons
Remove garbage and food waste promptly from the home
Wash dishes and cooking utensils immediately after use
Remove cockroach debris quickly
Eliminate any standing water from leaking faucets or drains
Keep humidity levels less than 50 percent with a dehumidifier or air conditioner
Consult a professional exterminator for large or recurrent infestations
Asian ladybugs Asian ladybugs were previously imported to the United States as a biological means
of controlling aphids. It was anticipated that the insects would not survive the cold of winter; however,
they adapted by moving inside houses when temperatures drop in the early fall. Allergies to Asian
ladybugs have been increasingly reported as a source of seasonal indoor respiratory symptoms,
particularly chronic cough, rhinitis, and asthma. Most cases have been reported in rural areas of the
central, mid-western, and southern United States. The insects can also bite and cause local reactions.
Asian ladybugs enter homes through external cracks and crevices, and then infest spaces within walls.
They secrete a brown liquid that may stain walls and produce an unpleasant smell.
Treating the exterior of the house with a chemical (pyrethroids) before cold weather arrives can prevent
swarming of the ladybugs inside the home. Pyrethroids are similar to pyrethrins, which are derived from
marigold flowers. Pyrethrins are broken down by the sun and do not significantly affect groundwater
quality. More information about Asian ladybugs is available from the Ohio State University Office of
Integrated Pest Management (http://ipm.osu.edu/lady/lady.htm).
Indoor molds Mold spores can trigger symptoms of allergic rhinitis in allergic patients. Mold thrives in
damp environments. Area such as air conditioning vents, water traps, refrigerator drip trays, shower
stalls, leaky sinks, and damp basements are particularly vulnerable to mold growth if not cleaned
regularly. Most of the mold spores enter the home from the outside air. However, under certain
circumstances, mold growth in the home can be significant and worsen allergy symptoms.
To reduce the growth of mold in the home, it is necessary to remove existing mold and also to reduce
humidity to prevent future growth of mold. Humidity can be reduced by removing sources of standing
water and persistent dampness. Removing house plants, fixing leaky plumbing, correcting sinks and
showers that do not drain completely, removing bathroom carpeting that is exposed to steam and
moisture, using exhaust fans in the bathroom when bathing, and dehumidifying damp areas to levels
below 50 percent are a few steps that can help to reduce or prevent growth of indoor mold.
Indoor garbage pails should be regularly disinfected, and an electric dehumidifier should be used to
remove moisture from wet or humid basements. Old books, newspapers, and clothing should be
discarded or donated rather than stored. Water damaged carpets and wall or ceiling boards should be
thrown out because it is difficult or impossible to eliminate mold in this situation, even with thorough
cleaning.
Mold thrives on soap film that covers tiles, sinks, and grout. Sinks, tubs, and other surfaces with visible
mold growth should be cleaned at least every four weeks with dilute bleach [one ounce (30 mL) bleach
diluted in one quart (one liter) of water].
Air filters Air filtering devices, including HEPA filters, other mechanical filters, and electrostatic filters,
are widely advertised to reduce indoor allergens. These may be marketed as components of heating or
cooling systems, as individual units for use in a room or area, or as units that are worn by individuals.
These devices are expensive and none have been scientifically proven to significantly improve allergy
symptoms. Certain types of air filters (eg, ionizers) produce ozone, which is a respiratory irritant for some
people. These devices have not been proven safe or effective and are not recommended
(www.epa.gov/iaq/pubs/ozonegen.html).
There are several factors that interfere with how well air filters work, and these may partly explain why
studies have shown mixed results:
Air filters do not remove dust mite allergens effectively because these allergens are relatively
heavy and do not stay airborne for more than a few minutes, for example, after making a bed or
disturbing a dusty cushion.
Most air filters probably remove pollens and pet danders from the air because these allergens are
light and remain airborne. However, if there is a pet, carpeting, upholstered furniture, access to
outside air, or some other reservoir of allergen in the vicinity, the allergen is continuously
released from these items as people move around the house. There are far more allergens in
these reservoirs then an air filter can remove. Therefore, allergens continuously enter the air,
even as it is being filtered, and the benefit of an air filter is minimal.
In contrast, in a room where there are no carpets, drapes, upholstered furniture, access to
outside air, and pets are not allowed, an air filter may improve air quality.
In addition, a vacuum cleaner with a HEPA (high-efficiency particulate air) filtration system and a double
thickness vacuum bag can help to reduce allergen levels. This is recommended to avoid rebreathing the
debris that is captured by vacuuming. A controlled trial has reported a reduction in cat and dog, but not
dust mite allergen levels, and a clinical improvement in asthma and allergic rhinitis symptoms in homes
cleaned with vacuums equipped with HEPA filters, compared to vacuums without specialized filters [5].
OUTDOOR ALLERGENS
Allergic rhinitis symptoms that worsen when outdoors and at certain times of year are likely to be
triggered by an allergy to pollen, other plant material, or molds.
Affected individuals should close the windows of the car and home, stay indoors when possible, and use
air conditioners to filter the air during times of peak symptoms. Use of a high quality mask may be helpful
for activities, such as grass cutting or wood cutting. These are also helpful in avoiding nonspecific
irritants, such as dust and fumes, which can trigger sneezing. Showering before bed removes allergens
from hair and skin and can help reduce contamination of the bedding. Over-the-counter saline sprays and
rinses can be used after being outdoors to wash away allergens from the nasal lining.
The American Academy of Allergy, Asthma, and Immunology has a toll free number (1-800-976-5536)
and website (www.aaaai.org/nab/index.cfm) that monitors pollen and mold spore counts.
WHERE TO GET MORE INFORMATION
Your healthcare provider is the best source of information for questions and concerns related to your
medical problem.
This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for
patients, as well as selected articles written for healthcare professionals, are also available. Some of the
most relevant are listed below.
Patient level information UpToDate offers two types of patient education materials.
The Basics The Basics patient education pieces answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and who
prefer short, easy-to-read materials.
Patient information: Avoiding asthma triggers (The Basics)
Patient information: Asthma in adults (The Basics)
Patient information: Asthma in children (The Basics)
Patient information: Seasonal allergies in adults (The Basics)
Beyond the Basics Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are best for patients who want in-depth information and are comfortable
with some medical jargon.
Patient information: Allergic rhinitis (seasonal allergies) (Beyond the Basics)
Patient information: Conjunctivitis (pinkeye) (Beyond the Basics)
Professional level information Professional level articles are designed to keep doctors and other
health professionals up-to-date on the latest medical findings. These articles are thorough, long, and
complex, and they contain multiple references to the research on which they are based. Professional
level articles are best for people who are comfortable with a lot of medical terminology and who want to
read the same materials their doctors are reading.
Allergen avoidance in the treatment of asthma and allergic rhinitis
An overview of rhinitis
Chronic nonallergic rhinitis
Clinical manifestations, pathophysiology, and diagnosis of chronic rhinosinusitis
Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis
Pathogenesis of allergic rhinitis (rhinosinusitis)
Pharmacotherapy of allergic rhinitis
Primary prevention of allergic disease: Maternal avoidance diets in pregnancy and lactation
Recognition and management of allergic disease during pregnancy
The following organizations also provide reliable health information.
National Library of Medicine


INTRODUCTION
Allergic rhinitis is associated with a symptom complex characterized by paroxysms of sneezing,
rhinorrhea, nasal obstruction, and itching of the eyes, nose, and palate. It is also frequently associated
with postnasal drip, cough, irritability, and fatigue [1-3].
The pathogenesis of allergic rhinitis is presented in this topic review. The clinical manifestations,
diagnosis, and treatment of this condition are discussed separately. (See "Clinical manifestations,
pathophysiology, and diagnosis of chronic rhinosinusitis" and "Allergic rhinitis: Clinical manifestations,
epidemiology, and diagnosis" and "Pharmacotherapy of allergic rhinitis".)
MECHANISMS OF UPPER AIRWAY ALLERGIC REACTIONS
Upon exposure to an allergen, atopic individuals respond by producing allergen-specific IgE. These IgE
antibodies bind to IgE receptors on mast cells in the respiratory mucosa and to basophils in the peripheral
blood. When the same allergen is subsequently inhaled, the IgE antibodies are bridged on the cell
surface by allergen, resulting in activation of the cell. Mast cells in the nasal tissues release preformed
and granule-associated chemical mediators, which cause the symptoms of allergic rhinitis.
Models of nasal allergen challenge in patients with allergic rhinitis have provided information about the
pathogenesis of allergic rhinitis [4,5]. In this model study system, individuals known to have allergic
rhinitis on exposure to a particular allergen are exposed to incremental doses of that allergen placed in
the nose. The subsequent reaction is then monitored over time with nasal biopsies or washes. This allows
direct quantitation of cell types by stains and surface markers and assessment of message for
transcription or direct measurement of cellular cytokines and other mediators of inflammation [6].
Rhinomanometry, the measurement of nasal airway resistance, permits measurement of both resistance
and airflow following allergen provocative challenge [7]. (See "Occupational rhinitis", section on
'Rhinomanometry techniques'.)
Immunogenetics The expression of allergic diseases of the upper airways reflects an autosomal
dominant pattern of inheritance with incomplete penetrance. This inheritance pattern is manifested as a
propensity to respond to inhalant allergen exposure by producing high levels of allergen specific
immunoglobulin E (IgE). The IgE response appears to be controlled by immune response genes located
within the major histocompatibility complex (MHC) on chromosome 6. (See "Major histocompatibility
complex (MHC) structure and function".)


INTRODUCTION
Allergic rhinitis is characterized by paroxysms of sneezing, rhinorrhea, nasal obstruction, and itching of
the eyes, nose, and palate. It is also frequently associated with postnasal drip, cough, irritability, and
fatigue.
The pharmacologic management of allergic rhinitis is presented in this topic review. The clinical
manifestations, diagnosis, differential diagnosis, and pathogenesis of allergic rhinitis are discussed
elsewhere. (See "Clinical manifestations, pathophysiology, and diagnosis of chronic
rhinosinusitis" and "Allergic rhinitis: Clinical manifestations, epidemiology, and
diagnosis" and "Pathogenesis of allergic rhinitis (rhinosinusitis)".)
OVERVIEW
The management of allergic rhinitis involves the following components:
Allergen avoidance, which is reviewed separately. (See "Allergen avoidance in the treatment of
asthma and allergic rhinitis".)
Pharmacotherapy, which is discussed here.
Allergen immunotherapy (when appropriate), which is reviewed elsewhere. Of note,
immunotherapy helps prevent the development of asthma in children with allergic rhinitis, and
thus should be given special consideration in the pediatric population. (See "Subcutaneous
immunotherapy for allergic disease: Indications and efficacy".)
AVAILABLE MEDICATIONS
Most patients with allergic rhinitis require pharmacotherapy, in addition to allergen avoidance, for
satisfactory symptom control. As more medications become available without a prescription, patients can
extensively self-treat, although the side effects of some over-the-counter allergy medications, particularly
excessive sedation and anticholinergic effects, can be significant. Therefore, the current challenge for
clinicians is to assure that patients with moderate to severe allergic rhinitis are adequately treated with
medications that do not cause undue side effects.




Although allergic rhinitis (AR) is a common disease, the impact on daily life cannot be underestimated.
Some patients find allergic rhinitis to be just as debilitating and intrusive as severe asthma. Employees
with untreated allergies are reportedly 10% less productive than coworkers without allergies, whereas
those using allergy medications to treat allergic rhinitis were only 3% less productive.
[1]
This suggests that
effective medications may reduce the overall cost of decreased productivity.
Allergic rhinitis is caused by an immunoglobulin E (IgE)mediated reaction to various allergens in the
nasal mucosa. The most common allergens include dust mites, pet danders, cockroaches, molds, and
pollens. For example, tree pollen allergen binds to IgE antibodies that are attached to a mast cell via Fce
receptor. When 2 IgE molecules bind to the same tree pollen allergen, they cause the mast cell to fire off
(degranurate), leading to release of various inflammatory mediators that cause the symptoms we feel as
allergic rhinitis, including sneezing; nasal congestion; stuffiness; rhinorrhea (runny nose); cough; itching
of the nose, eyes, and throat; sinus pressure; headache; and epistaxis (bloody nose).
The allergens present in the outdoor environment vary with the time of year and location. Knowing what
allergens are in the environment at a specific time of year helps in diagnosing and treating allergic rhinitis
and helps in excluding allergy as a cause of the patient's symptoms. For example, a patient who presents
with nasal congestion in November in Boston, Massachusetts cannot have allergic rhinitis attributed to
tree pollen allergy, which is prevalent in spring.
Allergen exposure likely causes both upper and lower airway inflammation, meaning that both the nose
and the lungs may be involved. Many experts believe that a patient's airway needs to be evaluated as a
total entity, not as individual parts. Studies have shown that most patients with asthma also have allergic
rhinitis. Guidelines regarding the impact of allergic rhinitis on asthma have been established.
[2]
Allergic
reactions of the upper airway can trigger lower airway symptoms and vice versa. One study showed that
patients with untreated allergic rhinitis and asthma have an almost 2-fold greater risk of having an
emergency department visit and almost a 3-fold greater risk of being hospitalized for an asthma
exacerbation, respectively.
[3]
Similarly there are studies that reveal treatment of one disease entity
improves the other.
The graphs below detail the significant impact of nasal allergies.
Impact of nasal allergies. How patient feel
when they have allergy symptoms. Nasal symptoms and affect on work
performance.


Pediatric sinusitis is a common problem treated by primary care physicians and otolaryngologists.
Although this disorder has been addressed for many centuries, full appreciation for its scope,
pathophysiology, diagnosis, treatment, and complications has been realized only relatively recently.
Children with occasional episodes of acute sinusitis following a routine cold are treated with short courses
of antibiotic therapy with good results. However, treatment of chronic and recurrent sinusitis can be more
challenging for physicians and frustrating for families. In these cases, the physician must not only treat
with an appropriate antibiotic but must also address the associated conditions contributing to the problem.
The goal in treating these children is to combine antibiotic therapy with treatment of associated conditions
for a time sufficient to allow resolution of symptoms with return of normal sinus physiology and
mucociliary clearance. This article addresses the medical management of pediatric sinusitis.
See the image below.
Preseptal cellulitis of the left eye. Courtesy of Dwight Jones, MD.




Pathophysiology
The ostiomeatal complex (OMC) is believed to be the critical anatomic structure in sinusitis and is entirely
present, although not at full size, in newborns. Present within the middle meatus, the OMC is composed
of the uncinate process, infundibulum ethmoidalis, hiatus semilunaris, ethmoid bulla, and frontal recess.
Although obstruction of the OMC has not been proven to be the primary source for pediatric sinusitis,
changes occurring in the anterior ethmoids are known to impair drainage through the OMC, resulting
in chronic maxillary sinusitis and, occasionally, frontal sinusitis.
The normal metachronous movement of mucous toward the natural ostia of the sinuses and eventually to
the nasopharynx can be disrupted by mucosal inflammation. This most commonly occurs secondary to
routine viral upper respiratory tract infections (URTIs) or nasal allergies and the host response to these
insults. In addition, many other predisposing factors to chronic disease exist, including allergic rhinitis,
anatomical abnormalities, gastroesophageal reflux(GER), immune deficiency, and disorders of ciliary
function.


pidemiology
Frequency
United States
Although the exact incidence of sinusitis in the pediatric population is unclear, it is diagnosed commonly,
most often following a viral URTI. The number of URTIs that an individual has per year may be as high as
25 (children will have on average 6-8 per year); the number depends on a several factors, including age,
day care attendance, and number of siblings. Approximately 5-13% of URTIs are complicated by bacterial
sinusitis. Many viral URTIs are mislabeled early in their course as acute sinusitis and are inappropriately
treated with antibiotics.
International
International incidence is similar to that in the United States.
Mortality/Morbidity
Recent health-related quality of life measures showed a poor result in children with chronic rhinosinusitis.
Because quantifying the morbidity caused by pediatric conditions is difficult, it must also be viewed in
other terms. A child with an acute episode of sinusitis may lead the caregiver to experience emotional
distress and lack of sleep and miss days from work. Chronic illness may have a negative impact on a
child's quality of life in many ways, including complications of chronic antibiotic therapy, school absences,
poor sleep patterns, impaired school performance, and irritability.
[1]

Children are also susceptible to more serious sequelae from a complication of sinusitis such as orbital
cellulites (in about 9.3% of the cases) and intracranial complications (in 3.7-11% of patients). With close
follow-up care, counseling of the family, and proper medical treatment, morbidity from this disease should
be very low.
Race
No race predilection exists.
Sex
No sex predilection exists.
Age
The ethmoid and maxillary sinuses are present at birth. The sphenoid sinuses are pneumatized by age 5
years, and the frontal sinuses appear by age 7 years but are not completely developed until adolescence.
Thus, children are predisposed to sinus infection at an early age. In young children, the most common
sinuses involved are the ethmoid and maxillary sinuses. Acute sinusitis is much less common in young
children than routine URTI or adenoiditis.
In an older child, the sphenoid and frontal sinuses are more likely to be involved with disease. Allergic
rhinitis is also more common in older children. It affects only 1% of infants and 5% of children aged 5-9
years, while 15% of the adolescent population is affected. Allergic rhinitis is one of the most common
predisposing factors for sinusitis, second only to viral URTIs.


History
Any condition that alters mucociliary clearance, decreases ventilation through a patent sinus ostium, or
interferes with local or systemic defense mechanisms can lead to a cycle of sinus infection that can be
very difficult to clear without concurrently addressing the associated condition.
Acute sinusitis
o Signs and symptoms normally clear within 30 days.
o URTI symptoms persisting longer than 7-10 days suggest acute sinusitis.
o Daytime cough and rhinorrhea are the 2 most common symptoms.
o Other common signs and symptoms include the following:
Nasal congestion
Infrequent low-grade fever
Otitis media (50-60% of patients)
Irritability
Headache
o Signs and symptoms of severe infection include the following:
Purulent rhinorrhea
High fever (ie, >39C)
Periorbital edema
o Uncomplicated sinusitis spontaneously resolves in 40% of patients.
Recurrent acute sinusitis: This condition is defined as episodes each lasting fewer than 30 days and
separated by intervals of at least 10 days during which the patient is asymptomatic.
Subacute sinusitis: This condition is defined as signs and symptoms lasting between 30-90 days.
Chronic sinusitis
o Chronic sinusitis is defined as low-grade persistence of signs and/or symptoms lasting longer than 90
days without improvement.
o The patient may have 6 or more recurrent episodes per year.
o The patient may have a history of acute exacerbations without ever being completely well between
episodes.
o Nighttime cough is more prevalent.


Physical
Perform a thorough head and neck examination on patients with sinusitis, with emphasis on otoscopy,
anterior rhinoscopy, and nasal endoscopy to examine the middle meatus, nasopharynx, and adenoids.
[2]

Anterior rhinoscopy
o This study can be difficult to perform in young children.
o Examine the middle turbinate and middle meatus for evidence of purulence or sinus discharge.
o Using a nasal spray mixture of a vasoconstrictive agent, such as oxymetazoline and lidocaine, is
helpful.
o Polyps, if present, should prompt an evaluation for cystic fibrosis.
Nasal endoscopy
o This study provides an excellent look at the middle meatus and provides the most accurate
examination results outside the operating room.
o Nasal endoscopy can be difficult to perform in young and uncooperative children.
Transillumination of the sinuses: This study is not usually helpful.



Causes
Causes of rhinosinusitis are best organized according to microbiological agents and associated
conditions.
Acute and subacute pathogens
o Streptococcus pneumoniae - 20-30%
o Nontypeable Haemophilus influenzae - 15-20%
o Moraxella catarrhalis - 15-20% (not as common in adults)
o Streptococcus pyogenes (beta-hemolytic) - 5%
Chronic pathogens
o No well-defined bacterial pathogen population
o Chronic sinusitis more commonly a polymicrobial infection
o Commonly cultured bacteria
Alpha-hemolytic streptococci
Staphylococcus aureus
Coagulase-negative staphylococci
Nontypeable H influenzae More common than acute sinusitis
Moraxella catarrhalis
Anaerobic bacteria, including Peptostreptococcus, Prevotella,
Bacteroides, and Fusobacterium species
Pseudomonads - More common after multiple courses of antibiotics; consider immunodeficiency
Viral URTI
o This is the most significant predisposing factor for sinusitis.
o Day care attendance is associated with a 3-fold increase in overall incidence of URTIs. Hand-to-hand
contact is the primary method of spread. Hand washing and decreased numbers of children in day
care have been demonstrated to aid in prevention of URTI transmission. To break the cycle of chronic
infection, removing the child from day care for a time may be required.
o No criterion standard treatment exists for viral URTIs, despite multiple trials. Antiviral agents currently
under investigation are promising. A vaccine is difficult to develop because of the multiple viruses
responsible for URTIs.
Allergic rhinitis
o This is the second most common predisposing factor for sinusitis after viral URTIs.
o Viral URTI affects 10-15% of the pediatric population older than 9 years.
o Eosinophilia with resultant increase in major basic protein is toxic to mucosa and disrupts mucociliary
clearance.
o In a 1991 study by Shapiro et al, 60% of patients with refractory sinusitis had increased total
immunoglobulin E (IgE) or marked skin reactivity.
o IgE testing is not as reliable in children younger than 4 years.
o Physicians must aim therapy at decreasing allergic mucosal edema to stop recurrent sinusitis
symptoms.
o Allergy testing is recommended in all patients with unresponsive symptoms, particularly in children
with a strong family history and in children showing other signs of atopy such as skin manifestations.
Anatomical abnormalities: Several anatomical abnormalities of the lateral nasal wall can predispose to
sinusitis.
o Concha bullosa, an aerated middle turbinate, can cause blockage of the OMC.
o Haller cells, infra-orbital cells that cause narrowing of the maxillary sinus ostium, predispose to
maxillary sinusitis.
o Deviated septum in the area of the middle turbinate can cause lateralization of the middle turbinate
with blockage of the OMC.
o Other variations include an agger nasi, hypoplastic maxillary sinus, and a large ethmoidal bulla.
[3]

Immune deficiency
o Immune deficiencies are present in 0.5% of the population.
o Humoral immune response matures to a level near that of adults by approximately age 7 years, and
the prevalence of chronic sinusitis decreases accordingly by this age.
o As many as one third of cases of refractory rhinosinusitis may involve immune deficiencies, especially
if the patient has a history of frequent bacterial infections or becomes ill soon after antibiotics are
stopped.
o Immune deficiencies are more common in the general population than cystic fibrosis or ciliary
disorders. In order of decreasing prevalence, the most common types are common variable,
immunoglobulin G (IgG) subclass, and selective antibody.
o Symptoms may be more severe in patients with immune deficiency.
o Recurrent URTIs are the most common manifestations of an immune disorder.
o Always consider immune deficiency in cases refractory to proper courses of aggressive medical
therapy.
o Initial evaluation includes total immunoglobulin levels and IgG subclasses, as well as response to
pneumococcal, tetanus toxoid, and diphtheria vaccines.
Asthma
o Impaired nasal function increases postnasal drip and irritant burden on the lower airways, which can
exacerbate asthma symptoms.
o Chronic rhinitis is present in 80% of individuals with asthma, and viral URTIs are implicated in
exacerbation of reactive airway disease.
o Treatment of chronic sinusitis can aid in normalization of pulmonary function tests and ability to
decrease long-term use of bronchodilators.
Gastroesophageal reflux disease
o Clinicians are becoming more aware of GER as an etiologic agent in patients with asthma symptoms,
chronic cough, and hoarseness.
o GER may lead to inflammation of the eustachian tube orifices or sinus ostia secondary to mucosal
irritation.
o Silent GER has respiratory manifestations in as many as 60% of patients.
o GER is especially likely in children with a history of poor weight gain, chronic reactive airway disease,
or reflux as infants.
o An empiric trial of antireflux medications in children with chronic sinusitis symptoms not responsive to
medical management has been proposed but has not gained widespread acceptance.
Allergic fungal sinusitis
Polypoid mass or mucosal changes associated with allergic fungal sinusitis are commonly unilateral.
Nasal and sinus secretions of allergic mucin the consistency of peanut butter are present.
o Histologic examination of sinus secretions shows the presence of abundant eosinophils and Charcot-
Leyden crystals.
o The most common causative organisms are in the Aspergillus genus.
o Treatment is surgical.
o Immunotherapy has also been demonstrated to be helpful as an adjuvant treatment. Limited trials of
immunotherapy with a 3-year follow-up period have shown no recurrence of disease after surgery for
allergic fungal sinusitis.
Biofilms
o Biofilms have recently been associated with 80% of patients with chronic rhinosinusitis compared with
none in control subjects.
o Work is still in progress to define the exact role of biofilms and how to treat those patients.


KARTAGENER
Siewert first described the combination of situs inversus, chronic sinusitis, andbronchiectasis in 1904.
However, Manes Kartagener
[1]
first recognized this clinical triad as a distinct congenital syndrome in 1933.
Because Kartagener described this syndrome in detail, it bears his name. Kartagener syndrome (KS) is
inherited via an autosomal recessive pattern. Symptoms result from defective cilia motility.
Also see Primary Ciliary Dyskinesia.

Camner and coworkers
[2]
first suggested ciliary dyskinesia as the cause of Kartagener syndrome
in 1975. They described 2 patients with Kartagener syndrome who had immotile cilia and
immotile spermatozoa. These patients had poor mucociliary clearance because the cilia that lined
their upper airways were not functioning.
Later, Afzelius
[3]
discovered that bronchial mucosal biopsy specimens from patients with similar
respiratory complaints showed cilia that appeared abnormal, were poorly mobile, and were
missing dynein arms. In 1977, Eliasson and coworkers
[4]
used the descriptive phrase immotile
cilia syndrome to characterize male patients with sterility and chronic respiratory infections.
In 1981, Rossman and coworkers
[5]
coined the term primary ciliary dyskinesia (PCD) because
some patients with Kartagener syndrome had cilia that were not immobile but exhibited an
uncoordinated and inefficient movement pattern. Current nomenclature classifies all congenital
ciliary disorders as primary ciliary dyskinesias in order to differentiate them from acquired types.
Kartagener syndrome is part of the larger group of disorders referred to as primary ciliary
dyskinesias. Approximately one half of patients with primary ciliary dyskinesia have situs
inversus and, thus, are classified as having Kartagener syndrome. Afzelius proposed that normal
ciliary beating is necessary for visceral rotation during embryonic development. In patients with
primary ciliary dyskinesia, organ rotation occurs as a random event; therefore, half the patients
have situs inversus and the other half have normal situs.
Ciliated epithelium covers most areas of the upper respiratory tract, including the nasal mucosa,
paranasal sinuses, middle ear, eustachian tube, and pharynx. The lower respiratory tract contains
ciliated epithelium from the trachea to the respiratory bronchioles. Each ciliated cell gives rise to
approximately 200 cilia that vary in length from 5-6 m and decrease in size as the airway
becomes smaller.
The typical ciliary axoneme consists of 2 central microtubules surrounded by 9 microtubular
doublets. Each doublet has an A subunit and a B subunit attached as a semicircle. A central
sheath envelops the 2 central microtubules, which attach to the outer doublets by radial spokes.
The outer doublets are interconnected by nexin links, and each A subunit is attached to 2 dynein
arms that contain adenosine triphosphatase; one inner arm and one outer arm. The primary
function of the central sheath, radial spokes, and nexin links is to maintain the structural integrity
of the cilium, whereas the dynein arms are responsible for ciliary motion.
The cilium is anchored at its base by cytoplasmic microtubules and a basal body comprised of a
basal foot and rootlet. The orientation of the basal foot indicates the direction of the effective
cilial stroke. Just above the base, the cilium is composed of microtubular triplets (previously
doublets) without associated structures, but at the tip, only the B subunits remain.
Cilia propel overlying mucus via a 2-part ciliary beat cycle. First, the power stroke occurs when
a fully extended cilium moves perpendicular to the cell surface in an arclike manner. Then, the
recovery stroke follows, in which the entire cilium bends and returns to its starting point near the
cell surface. Once a cilium starts to move, the complete beat cycle is obligatory.
The cycle is mediated by dynein arms from the A subunit that attach to the B subunit of the
adjacent microtubule. Adenosine triphosphate is hydrolyzed by the dynein arms and the 9
microtubule doublets as they slide against each other.
Patients with primary ciliary dyskinesia exhibit a wide range of defects in ciliary ultrastructure
and motility, which ultimately impairs ciliary beating and mucociliary clearance. The most
common defect, first described by Afzelius, is a reduction in the number of dynein arms, which
decreases the ciliary beat frequency.
Sturgess et al
[6]
described how the radial spoke, which serves to translate outer microtubular
sliding into cilial bending, was absent in some patients with primary ciliary dyskinesia. Cilia in
other patients lacked central tubules; however, instead of the central tubules, an outer
microtubular doublet transposed to the cell of the axoneme was present that displayed an
abnormal 8+1 doublet-to-tubule pattern. Both the radial spoke and the transposed doublet defects
impaired mucociliary clearance.
Other ciliary defects include an abnormal basal cell apparatus with giant roots and double feet,
cilia lacking all internal microtubular structures, and even cilia twice the normal length that beat
in an uncoordinated undulating fashion. Pedersen
[7]
compared the type of ultrastructural defect to
ciliary motility and found that dynein defects caused hypomotility and microtubular defects
caused asynchrony. He also found that normal ciliary ultrastructure occasionally was associated
with hypermotility or inefficient ciliary trembling.
Some patients with clinical features of primary ciliary dyskinesia have a ciliary ultrastructure
that appears normal, but their arrangement and beat direction is disoriented, which causes
inefficient mucociliary transport. These findings illustrate the importance of analyzing ciliary
motility and ultrastructure when considering a diagnosis of primary ciliary dyskinesia.
PCD tissues have also been characterized by impaired chloride ion transport currents. This
impaired current has been shown to persist even after application of a cAMP-elevating agonist.
[8]

Previous

Frequency
United States
The frequency of Kartagener syndrome is 1 case per 32,000 live births. Situs inversus occurs randomly in
half the patients with primary ciliary dyskinesia; therefore, for every patient with Kartagener syndrome,
another patient has primary ciliary dyskinesia but not situs inversus.
Mortality/Morbidity
Clinical manifestations include chronic upper and lower respiratory tract disease resulting from ineffective
mucociliary clearance. Males demonstrate infertility secondary to immotile spermatozoa.
Upper airway
Patients may exhibit chronic, thick, mucoid rhinorrhea from early in childhood. Examination usually
reveals pale and swollen nasal mucosa, mucopurulent secretions, and an impaired sense of smell. Nasal
polyps are recognized in 30% of affected individuals.
The recurrent chronic sinusitis typically produces sinus pressure headaches in the maxillary and
periorbital regions. Sinus radiographs (which largely have been supplanted by CT scans) typically
demonstrate mucosal thickening, opacified sinus cavities, and aplastic or hypoplastic frontal and/or
sphenoid sinuses.
[9]
Symptoms usually improve with antibiotic therapy but have a propensity for rapid
recurrence. It has been shown that up to 59% of patients have recurring problems at the paranasal
sinuses and 69% of these patients need corresponding surgical intervention.
[10]

Recurrent otitis media is a common manifestation of primary ciliary dyskinesia. Examination may reveal a
retracted tympanic membrane with poor or absent mobility and a middle-ear effusion. Further testing
usually demonstrates a flat tympanogram and bilateral conductive hearing loss secondary to thick middle-
ear effusion. Many patients undergo repeated tympanostomy tube insertion, often complicated by chronic
suppurative otitis media. Other associated otologic disorders may include tympanosclerosis,
cholesteatoma, and keratosis obturans.
Lower respiratory tract
Chronic bronchitis, recurrent pneumonia, and bronchiectasis are common conditions associated with
primary ciliary dyskinesia. Patients presenting with bronchiectasis should be evaluated for Kartagener
syndrome. Chest radiographs may illustrate bronchial wall thickening (earliest manifestation),
hyperinflation, atelectasis, bronchiectasis, and situs inversus (in 50% of patients with primary ciliary
dyskinesia). Bronchiectasis usually occurs in the lower lobes in patients with Kartagener syndrome, while
patients with cystic fibrosis have bronchiectasis predominantly in the upper lobes.
Obstructive lung disease may be another component of Kartagener syndrome symptomatology. It
probably results from elevated levels of local inflammatory mediators in a chronically irritated airway.
Other features
Other features include digital clubbing and diminished female fertility. Primary ciliary dyskinesia has been
associated with esophageal problems and congenital cardiac abnormalities.
Sex
No sex predilection exists.
Age
Clinical manifestations of chronic sinusitis, bronchitis, and bronchiectasis are more severe during the first
decade of life but remit somewhat by the end of adolescence.
Previous

Kartagener syndrome is characterized by the clinical triad of chronic sinusitis, bronchiectasis, and situs
inversus. The majority of patients are seen by a physician more than 50 times before the diagnosis is
made at an average age of 10-14 years.
[10]

Upper airway
Patients may exhibit chronic, thick, mucoid rhinorrhea from early in childhood. Examination usually
reveals pale and swollen nasal mucosa, mucopurulent secretions, and an impaired sense of smell. Nasal
polyps are recognized in 30% of affected individuals.
[11]

The recurrent chronic sinusitis typically produces sinus pressure headaches in the maxillary and
periorbital region. Symptoms usually improve with antibiotic therapy but have a propensity for rapid
recurrence.
[11]

Recurrent otitis media is a common manifestation of primary ciliary dyskinesia. Examination may reveal a
retracted tympanic membrane with poor or absent mobility and a middle-ear effusion. Other associated
otologic disorders may include tympanosclerosis, cholesteatoma, and keratosis obturans.
[11]

Middle ear symptoms in PCD patients tend to remain severe throughout childhood, with improvement
only after age 18 years, and, in a recent study, grommet tympanostomy tube placement did not improve
the middle ear condition. In this study, half the patients with a history of grommet placement eventually
developed tympanic perforation, which is much more frequent than in the general pediatric population.
These patients, therefore, should be closely followed and a specific treatment approach may be required,
especially in the treatment of persistent middle ear effusion, as repeated grommet placement can
predispose patients to chronic otitis and worsen the prognosis.
[12]

Lower respiratory tract
Chronic bronchitis, recurrent pneumonia, and bronchiectasis are common conditions in patients with
primary ciliary dyskinesia and are often caused by pseudomonal infection.
[13]
Thus, upon physical
examination of the patient's chest, increased tactile fremitus, rhonchi, crackles, and, occasionally,
wheezes may be present.
Obstructive lung disease may be another component of Kartagener syndrome symptomatology. It
probably results from elevated levels of local inflammatory mediators in a chronically irritated airway.
Therefore, wheezing may occur. The lung examination may be normal during intercurrent periods when
the airway is not actively inflamed.
Other features
Cardiovascular examination of a patient with KS demonstrates a point of maximal impulse, and the heart
sounds are heard best on the right side of the chest.
Extremities may exhibit digital clubbing.
Previous
Next Section: Causes

Kartagener syndrome is characterized by the clinical triad of chronic sinusitis, bronchiectasis, and situs
inversus. The majority of patients are seen by a physician more than 50 times before the diagnosis is
made at an average age of 10-14 years.
[10]

Upper airway
Patients may exhibit chronic, thick, mucoid rhinorrhea from early in childhood. Examination usually
reveals pale and swollen nasal mucosa, mucopurulent secretions, and an impaired sense of smell. Nasal
polyps are recognized in 30% of affected individuals.
[11]

The recurrent chronic sinusitis typically produces sinus pressure headaches in the maxillary and
periorbital region. Symptoms usually improve with antibiotic therapy but have a propensity for rapid
recurrence.
[11]

Recurrent otitis media is a common manifestation of primary ciliary dyskinesia. Examination may reveal a
retracted tympanic membrane with poor or absent mobility and a middle-ear effusion. Other associated
otologic disorders may include tympanosclerosis, cholesteatoma, and keratosis obturans.
[11]

Middle ear symptoms in PCD patients tend to remain severe throughout childhood, with improvement
only after age 18 years, and, in a recent study, grommet tympanostomy tube placement did not improve
the middle ear condition. In this study, half the patients with a history of grommet placement eventually
developed tympanic perforation, which is much more frequent than in the general pediatric population.
These patients, therefore, should be closely followed and a specific treatment approach may be required,
especially in the treatment of persistent middle ear effusion, as repeated grommet placement can
predispose patients to chronic otitis and worsen the prognosis.
[12]

Lower respiratory tract
Chronic bronchitis, recurrent pneumonia, and bronchiectasis are common conditions in patients with
primary ciliary dyskinesia and are often caused by pseudomonal infection.
[13]
Thus, upon physical
examination of the patient's chest, increased tactile fremitus, rhonchi, crackles, and, occasionally,
wheezes may be present.
Obstructive lung disease may be another component of Kartagener syndrome symptomatology. It
probably results from elevated levels of local inflammatory mediators in a chronically irritated airway.
Therefore, wheezing may occur. The lung examination may be normal during intercurrent periods when
the airway is not actively inflamed.
Other features
Cardiovascular examination of a patient with KS demonstrates a point of maximal impulse, and the heart
sounds are heard best on the right side of the chest.
Extremities may exhibit digital clubbing.


The cause of primary ciliary dyskinesia is genetic, with an autosomal recessive inheritance pattern.
Genome analysis has found primary ciliary dyskinesia to be genetically heterogenous.
Genes DNAH5 and DNA11 on bands 5p15.1 and 9p13,3 respectively, are known to cause primary ciliary
dyskinesia. Both genes encode for dynein.
[14]
There are more than 200 genes, however, that are predicted
to be involved in cilia biology and may play a role in primary ciliary dyskinesia and other ciliopathies.
[15]

Recently a gene protein, CCDC40, has been characterized as playing an essential role in correct left-right
patterning in mouse, zebrafish, and humans. In mouse and zebrafish, CCDC40 is expressed in tissues
that contain motile cilia. Mutations in this protein result in cilia with reduced ranges of motility and likely
result in a variant of primary ciliary dyskinesia characterized by misplacement of the central pair of
microtubules and defective assembly of inner dynein arms and dynein regulatory complexes.
[16]

Adenylate kinase type 7 (AK7), the mediator of the reaction of ADP to ATP and AMP, is also diminished
significantly in patients with primary ciliary dyskinesia compared with healthy controls. AK7 expression
has also been correlated with ciliary beat frequency in this patient population.
[17]

Previous

D-CUL DIFERENTIAL
Alpha1-Antitrypsin Deficiency
Immunosuppression
Proceed to Workup


Fistula de lichid cefalorahidian reprezint o condiie potenial fatal, al crei tratament
de succes necesit n primul rnd nelegerea etiopatogeniei, a originii anatomice i a
fiziopatologiei sale. Acesta este subiectul articolului semnat de dnii dr. Marian Stroi, dr.
Corneliu Toader i prof. dr. Alexandru Vlad Ciurea.

Fistula de lichid cefalorahidian (LCR) reprezint un traiect de comunicare direct a LCR ntre
spaiile subarahnoidiene i exterior, avnd ca substrat anatomic o bre ntre arahnoid, dura mater
i craniu, aprut spontan, posttraumatic sau n urma interveniilor neurochirurgicale.
Fistula LCR este o condiie serioas, frustrant, potenial fatal, al crei management de succes
necesit nelegerea fundamental a anatomiei i a substratului fiziopatologic. n ultimul deceniu,
chirurgia endoscopic funcional a contribuit substanial la arsenalul chirurgical, devenind, pentru
unii chirurgi, standardul de tratament (1). Cauza fundamental a scurgerii de LCR este fistula
meningeal, cu numeroi factori etiologici i facilitat de presiunea intracranian crescut, de orice
natur (2). Aceasta se poate manifesta ca rinolicvoree, otolicvoree, oculolicvoree, scurgere de LCR
la nivelul plgilor craniocerebrale sau operatorii. Cel mai important aspect n tratamentul fistulei LCR
este reprezentat de localizarea exact a defectului dural ce constituie cauza scurgerii de LCR,
permind repararea acestuia i oprirea scurgerii de LCR. O bun colaborare ntre orelist,
neurochirurg i neuroimagist reprezint cheia succesului.
Clasificare
Fistulele LCR transcraniene se mpart n:
Traumatice (6777%) acute (apar n prima sptmn de la traumatism) i tardive (apar dup
luni sau ani de la traumatism). Fistulele LCR iatrogene sau postoperatorii sunt incluse n categoria
fistulelor traumatice. Cea mai frecvent cauz de fistul LCR nazal postoperatorie este dup
chirurgia hipofizar transsfenoidal, iar calea de scurgere este prin sinusul sfenoid.
Netraumatice sau spontane se asociaz cu procese expansive intracraniene, defecte
congenitale ale bazei de craniu, osteomielit, radionecroz, atrofie cerebral focal,
meningoencefalocel, a turceasc goal (1). 84% din scurgerile de LCR spontane sunt asociate cu
obstruciile tumorale (3). Fistulele LCR spontane se mpart n categorii cu presiune nalt i categorii
cu presiune joas (1). Fistule LCR cu presiune crescut reprezint 45% din totalul celor
netraumatice (3).
Fistulele LCR spinale se pot clasifica similar, iar majoritatea sunt traumatice (postoperatorii).
Anomaliile congenitale pot da natere fistulelor meningopleurale sau meningoperitoneale (1).
Etiologie i epidemiologie
Cea mai frecvent cauz de fistul LCR este traumatismul craniocerebral (TCC), n particular
fracturile de baz de craniu. Acestea apar la 23% din pacienii cu TCC. 60% apar tipic n primele
48 de ore de la TCC i 95% n primele trei luni (1). 70% din cazurile de fistule LCR nazale se opresc
n prima sptmn i n ase luni restul de 30% (4). 5% se asociaz cu traumatisme craniofaciale,
9% cu traumatisme penetrante de mare energie i 1230% cu fracturi de baz de craniu (1). Cel mai
frecvent loc pentru fistulele LCR posttraumatice este lama cribriform a osului sfenoid (5). La copii,
incidena fistulei LCR traumatice este mai mic de 1% din TCC nchise, probabil ca urmare a
diferenelor de fragilitate i a slabei dezvoltri a sinusurilor aerice. n chirurgia hipofizar
transsfenoidal, fistula LCR nazal are o inciden de 1,46,4%, iar incidena fistulei LCR
intraoperatorii este de 25%. Dup abordul endoscopic, incidena este mai mic: 0,022,9% (1).
Fistula LCR dup chirurgia neurinomului de acustic este cea mai frecvent complicaie, alturi de
parezele de nervi cranieni (2), iar incidena raportat dup anul 2000 a sczut de la 515% la 2,2
5,7% (6); cele mai multe fistule apar n prima sptmn postoperator (7).
Posibile ci de scurgere n fistulele LCR (4): prin celulele mastoidiene, dup intervenii
chirurgicale pentru tumori de fos cerebral posterioar (neurinom de acustic) LCR trece n
celulele mastoidiene, de aici n urechea medie i, prin trompa lui Eustachio, n nazofaringe i fosele
nazale prin sinusul sfenoidal, n special dup chirurgia hipofizar transsfenoidal prin lama
cribriform (tavanul osului etmoid), ce reprezint podeaua fosei cerebrale anterioare (n TCC) prin
sinusul osului frontal (fractura peretelui posterior al sinusului, cu disrupia durei subiacente), n TCC
hernieri ale meningelui (a goal) i, de aici, n sinusul sfenoidal pe traiectul arterei carotide
interne, prin canalul determinat de aceasta prin foseta Rosenmller situat imediat inferior de
sinusul cavernos, ce poate fi deschis cnd se perforeaz clinoida anterioar pentru anevrismele
paraclinoide la nivelul deschiderii canalului faringeal, n cazul persistenei acestuia percutan, prin
plgi traumatice sau chirurgicale la nivelul stncii osului temporal sau al conductului auditiv intern,
dup fracturi ale osului temporal sau dup intervenii chirurgicale pentru neurinomul de acustic; se
manifest cu rinoree, cnd LCR trece n urechea medie trompa lui Eustachio nazofaringe, sau
cu otoree, cnd, din urechea medie, LCR perforeaz membrana timpanic i ajunge n conductul
auditiv extern.
Meningitele survenite n contextul fistulelor LCR
Meningita bacterian reprezint o complicaie redutabil a fistulei LCR, fiind principala cauz de
mortalitate i morbiditate. Incidena meningitei n fistula LCR posttraumatic este de 510% i crete
dac perioada de persisten a fistulei depete apte zile (8). Este recomandat nchiderea pe
cale chirurgical a fistulei, dac aceasta nu s-a nchis spontan dup una-dou sptmni.
nchiderea chirurgical a fistulei LCR dup acest interval nu previne apariia meningitei. Riscul de
meningit este mai mare dup interveniile neurochirurgicale dect n fistulele posttraumatice, ca
urmare a creterii presiunii intracraniene.
Meningita determin fenomene inflamatorii la nivelul orificiului de scurgere al LCR i poate
determina nchiderea fistulei (8). Cel mai frecvent germene implicat este pneumococul (83%),
mortalitatea este ns mai sczut dect n meningita pneumococic survenit n absena fistulei
(10% vs. 50%), probabil deoarece aceasta din urm apare la pacienii vrstnici, cu patologie
asociat (8). La copil, prognosticul este prost.
Incidena meningitei n cadrul fistulei LCR nazale dup chirurgia hipofizar transsfenoidal este de
0,51,9%. Tratamentul antibiotic al fistulei LCR nazale nu este recomandat, iar administrarea
antibioticelor trebuie fcut cu pruden, deoarece pot modifica flora nazofaringian i crea condiiile
dezvoltrii unor germeni agresivi. Opinia general este abinerea de la tratamentul antibiotic n
fistula LCR nazal, pn la confirmarea meningitei (9). n schimb, inseria de rutin a unui drenaj
lombar extern (10) postoperator, la pacienii la care s-a remarcat intraoperator prezena fistulei,
scade semnificativ riscul apariiei meningitei. Incidena meningitei dup operaiile pentru neurinom
de acustic este de 3,35,5% (11).
Simptome i semne clinice
Scurgerea unui lichid incolor, clar ca apa, din fosele nazale, atunci cnd bolnavul este n poziie
eznd, sau senzaia de scurgere la nivelul nazofaringelui, urmat de reflexul de deglutiie, atunci
cnd bolnavul st culcat, sunt suficiente pentru a suspiciona o fistul LCR nazal. Dac LCR este
amestecat cu snge, semnul inelului este relevant: pe lenjerie va aprea o pat de snge
nconjurat de un inel de lichid clar. Pacienii cu fistul LCR nazal pot simi un gust srat sau uneori
dulce, deoarece LCR conine dou treimi din concentraia sanguin de glucoz.
Cefaleea poate fi ntlnit n formele acute i cronice de fistul LCR. Cnd aceasta este
intermitent diagnosticul este dificil i trebuie efectuat manevra Valsalva sau se procedeaz la
schimbarea poziiei pacientului, deoarece sinusurile frontal sau sfenoidal se pot comporta ca nite
rezervoare.
Dac fistula LCR se nsoete de pneumocefalie, apar semne i simptome de hipertensiune
intracranian.
Febra cu fotofobie, accentuarea cefaleei, meningismul sau alterarea statusului neurologic al
pacientului (pn la com) trdeaz apariia meningitei. Pacienii care prezint episoade repetitive
de meningit, fr a avea deficiene imunologice, trebuie cutai de fistul LCR (12). Pacienii cu
TCC i fractur de baz de craniu pot prezenta meningite recurente oricnd n intervalul dintre dou
luni i 21 de ani de la traumatism. TCC este cea mai frecvent cauz de pneumocefalie (74%), iar
prezena acesteia anuleaz tendina la nchidere spontan a fistulei, 85% din aceste cazuri
complicndu-se cu meningit (13, 14).
Pot aprea tinitus, tulburri de cmp vizual, cefalee i, uneori, fenomene de insuficien hipofizar,
prin compresia sacului dural lichidian pe glanda hipofiz (la pacienii cu a turceasc goal). Acetia
pot dezvolta fenomene de HIC benign, ce determin o rat crescut de eecuri n tratamentul
fistulei LCR (15).
Fistula LCR dup chirurgia neurinomului de acustic apare ca urmare a persistenei comunicrii
ntre spaiul subarahnoidian i osul temporal sau celulele mastoidiene, ca urmare a diseciei i
expunerii chirurgicale, i se poate exterioriza prin urmtoarele ci de scurgere: fistul LCR la nivelul
plgii operatorii, rinoree sau otoree, iar majoritatea sunt diagnosticate n prima sptmn
postoperator (4).
Determinri de laborator
Investigaiile de laborator constau n determinarea glucozei din LCR (este singura scurgere
orificial care conine glucoz) sau, n cazuri incerte, determinarea beta-2 transferinei prin tehnici de
imunofixare. Ultima este o metod valoroas, deoarece are sensibil
PUBLICITATE
itate i specificitate crescute n diagnosticul fistulei LCR (16). Cnd un pacient este suspect de
fistul LCR postoperator, se face un test de provocare, cu pacientul aplecat n fa timp de cinci
minute. Dac pacientul nu prezint rinoree, testul este considerat negativ. Dac prezint rinoree, se
face testul la glucoz. Un rezultat pozitiv (peste 30 mg/100 ml) face probabil fistula LCR; un rezultat
neclar presupune testarea pentru beta-2 transferin sau pentru beta-trace protein (6). Administrarea
topic intranazal de fluorescein este o metod simpl, sigur i rapid, ce are o acuratee de
100% n diagnosticul fistulei LCR nazale preoperator (17), se poate utiliza i intra- sau postoperator,
cnd exist dubii asupra recurenei fistulei.
Diagnosticul imagistic
Cheia succesului n tratamentul fistulei LCR o constituie localizarea defectului dural.
Radiologia clasic presupune surprinderea pe o radiografie simpl de craniu a pneumocefalului
sau a unui sinus sfenoidal cu nivel hidroaeric, coroborat cu diagnosticul de fractur de baz de
craniu.
CT cerebral de nalt rezoluie, n seciuni coronare i axiale, este investigaia de prim alegere
pentru localizarea defectelor osoase ale craniului. Exclude prezena altei patologii cerebrale cu
implicaii terapeutice importante (hidrocefalia). Are 9,5% rezultate fals pozitive n fistulele LCR
inactive (18). Asocierea cu administrarea de fluorescein intratecal crete ansele de identificare a
defectului osos (19).
Cisternografia CT (CTC) este complementar tomografiei computerizate i demonstreaz
trecerea substanei de contrast prin defectul fistulos cu o precizie de 85%. Dezavantajele sunt date
de imposibilitatea evidenierii fistulelor LCR inactive, este invaziv i cu expunere intens la radiaii
(4).
Cisternografia radioizotopic cu techneiu 99 administrat intratecal este util n special cnd
fistula are un volum mic sau este intermitent. Prezint mai multe dezavantaje: are o proporie mare
de rezultate fals pozitive (33%), sensibilitatea sa de diagnostic este de doar 6276%, este invaziv,
presupune personal calificat i nu are acurateea CTC n ceea ce privete detaliile anatomice (20).
IRM i cisternografia IRM sunt alternative neinvazive ce ofer detalii ale esuturilor moi de la
nivelul bazei craniului i nazofaringelui. Sensibilitatea sa este de 8592%, iar specificitatea de 100%
(21). Este o investigaie esenial la pacienii cu fistule LCR inactive (18).
Tratamentul conservator al fistulei LCR
Tratamentul conservator vizeaz scderea presiunii intracraniene i implic (4): repaus la pat, cu
capul ridicat la 1520 de grade evitarea constipaiei, a suflrii nasului, a tusei, a strnutului i a
manevrelor Valsalva reducerea moderat a ingestiei de lichide scderea produciei de LCR (se
administreaz acetazolamid 250 mg/zi) puncii lombare repetate sau drenajul lombar continuu.
Exist multe controverse cu privire la utilizarea drenajului lombar ca metod terapeutic. n
general, n cazul fistulelor LCR posttraumatice, nu se vor executa puncii lombare din cauza riscului
mare de inversare a gradientului de presiune, cu modificarea direciei de curgere a lichidului i
inducerea meningitei (Ommaya, 1996). Exist studii mai noi (Rocchi i colab., 2005) care consider
c managementul conservator al fistulei LCR prin drenaj lombar continuu, repaus la pat, ad-
ministrarea de inhibitori de anhidraz carbonic i profilaxie antibiotic reprezint o opiune
terapeutic excelent doar n cazuri selectate i c repararea defectului dural scade riscul de
meningit n urmtorii zece ani de la 85% la 7%.
n cazul fistulelor LCR postchirurgie hipofizar transsfenoidal, dac fistula LCR nu se nchide
dup 72 de ore de tratament conservator, drenajul zilnic a 150 ml de LCR, timp de patru zile naintea
interveniei chirurgicale, poate fi benefic. Drenajul lombar genereaz un proces de granulaie ce
poate nchide fistula i scdea rata fistulelor LCR postoperator, dar i incidena meningitei de la
3,1% la 0,7% (22).
n cazul fistulelor LCR dup chirurgia neurinomului de acustic, drenajul lombar se menine apte
zile, n combinaie cu tratament antibiotic profilactic, evacundu-se 150240 ml de LCR pe zi (6). La
fiecare dou zile, se trimit probe de LCR pentru testare microbiologic i celular. Dup apte zile,
se suprim drenajul i se face testul de provocare. n cazul persistenei fistulei, se trece la
intervenia chirurgical. Majoritatea fistulelor LCR rspund la drenajul lombar continuu (7).
n cazul rinoreei, drenajul lombar nu este la fel de eficient ca n cel al fistulei LCR de la nivelul
plgii operatorii, probabil pentru c defectul este la nivelul osului (1). Indiferent de tipul lor,
majoritatea fistulelor LCR se remit spontan n primele apte-zece zile posttraumatism (23),
otolicvoreea mai frecvent dect rinolicvoreea.
Tratamentul chirurgical
n general, ineficiena tratamentului conservator impune intervenia chirurgical. n cazul fistulelor
LCR posttraumatice, indicaiile operatorii sunt urmtoarele (Ommaya, 1996): lipsa nchiderii fistulei
dup apte-zece zile de la debut diminuarea iniial a debitului fistulei, cu meninerea unei scurgeri
sczute timp de 1012 zile fistula cu pneumocefal fistula cu meningit (dup recuperarea
pacientului n urma meningitei) fistule produse de fracturi extensive, dehiscente de baz de craniu
prezena encefalocelelor sau a meningocelelor fistula recurent.
n funcie de localizarea i de caracterele fistulei, precum i de extensia i mrimea defectului
osos, se folosesc mai multe tehnici.
Abordul extracranian utilizeaz instrumentaie endoscopic i tehnici de microneurochirurgie.
Abordul endoscopic este preferat astzi, cu o rat mare de succes i morbiditate sczut,
comparativ cu abordurile transcraniene.
Fracturile peretelui posterior al sinusului frontal sunt soluionate prin sinusotomie osteoplastic
frontal endoscopic.
Fistula LCR situat la nivelul platoului cribriform sau al labirintului etmoidal aste abordat printr-o
incizie orbital medial, etmoidectomie, iar defectul dural este reparat cu substituent mucoperiostal.
Un abord paraseptal direct, cu sau fr deschiderea celulelor etmoidale, etmoidotomie
anteroposterioar cu prezervarea cornetului mijlociu i etmoidosfenoidotomie cu rezecia complet a
cornetelor etmoidale sunt utilizate n fistula LCR dat de existena unui defect la nivelul anului
olfactiv.
Sinusul sfenoid este abordat transseptosfenoid, transnazal sau sublabial. n funcie de anatomia
sinusului sfenoid, un abord endonazal paraseptal cu sfenoidotomie sau un abord transetmoid
pterigosfenoidal pot fi utilizate pentru fistula LCR dat de defectele osului sfenoid.
Fistula LCR de la nivelul osului petros poate fi rezolvat extradural prin mastoidectomie, menajnd
cohleea i funcia nervilor cranieni facial i acusticovestibular.
Abordul clasic intracranian. Fosa cerebral anterioar poate fi abordat prin mai multe tehnici
chirurgicale, de la volet osos frontal uni- sau bilateral, pn la abord transfrontal suprasinusal, cu
extensie lateral. Fosa frontal poate fi abordat att intradural, ct i extradural. Deschiderea
sinusului frontal printr-un volet osos bazal poate obliga la exenteraia mucoasei sinusului, urmat de
plombarea acestuia cu muchi sau grsime. Cranializarea sinusului frontal este un pas important n
tratarea fistulei LCR secundare fracturilor sinusului frontal. Dac nchiderea primar a durei nu este
fezabil, se utilizeaz substitueni durali: pericraniu, fascie de muchi temporal sau fascia lata.
Cnd fistula este otic, voletul se dimensioneaz pentru a expune dura care acoper poriunea
petroas a osului temporal. Recomandarea general este de a aborda fistula intradural. Se pot
utiliza fascie temporoparietal, muchi temporal vascularizat, fascie de muchi temporal. Cnd
fractura bazei craniului este dehiscent (peste 2 mm), este necesar abordul extradural, cu
plombarea defectului osos cu grsime, muchi, cear sau ciment acrilic (23). O nou tehnic n
repararea fistulei de fos cerebral medie const n combinarea cimentului de hidroxiapatit cu
substitueni durali din matrice de colagen i polietilenglicol hidrogel, cu o rat de nchidere etan de
100%.
Tratamentul fistulelor LCR nazale dup chirurgia hipofizar transsfenoidal presupune
reintervenia pe cale transsfenoidal microchirurgical sau endoscopic. Scopul este suprimarea
fistulei i prevenia meningitei ascendente. Paii realizai n tratamentul fistulei LCR nazale sunt:
localizarea fistulei, crearea unei suprafee brute pentru plasarea grefelor i formarea de sinechii care
s ajute la vindecare, dar i mpachetarea defectului cu diverse materiale: grsime abdominal,
fascia lata, fragment de os pentru reconstrucia planeului selar, adeziv de fibrin autolog
(crioprecipitat autolog cu soluie de trombin i calciu), muchi, dura liofilizat sau burete de
colagen.
n cazul fistulei LCR dup operaii pentru neurinomul de acustic, este indicat reexplorarea inciziei
i reocluzionarea mastoidei sau a conductului auditiv intern cu cear, muchi sau grsime. Cnd
urechea este nefuncional, abordul extradural via mastoidectomie combinat cu obliterarea urechii
interne i medii asigur maxim detecie i obliterare a fistulei. Fistulele LCR de la nivelul plgii se
rezolv prin drenarea LCR i resutura plgii. n aceast situaie, trebuie excluse tulburrile de
dinamic LCR i hipertensiunea intracranian crescut (1).
Concluzii
Existena unui numr mare de soluii terapeutice atest dificultatea tratamentului fistulei. Fistula
LCR poate fi manageriat numai dup nelegerea etiopatogeniei, a originii anatomice i a
fiziopatologiei acesteia. Utilizarea procedurilor de diversie a LCR trebuie avut n minte cnd fistula
LCR treneaz. Progresele realizate de neuroimagistic i tehnicile endoscopice sau
microchirurgicale care se utilizeaz complementar au determinat creterea anselor de reuit n
diagnosticarea i localizarea precis a defectului i, implicit, n tratarea cu succes a fistulelor LCR.


S C O A L A P O S T L I C E A L A
D I M I T R I E C A N T E M I R
T G - M U R E S

I O A N R A D



FARMACOTOXICOLOGIE SI
FARMACOEPIDEMIOLOGIE
GENERAL
S U P O R T D E C U R S
( t e o r i e s i l a b o r a t o r t e h n o l o g i c )






2 0 0 8

C U P R I N S

CAPITOLUL I
FARMACOTOXICOLOGIA GENERALA........................................................... 3
1.1. Aspecte introductive..........................................................................................3
1.2. Efecte secundare................................................................................................4
1.3. Efecte toxice......................................................................................................5
1.4. Reacii adverse de tip mutagen..........................................................................8
1.5. Reacii adverse de tip teratogen.........................................................................9
1.6. Efecte adverse de tip cancerigen......................................................................13
1.7. Reacii adverse de tip idiosincrazic (intoleran medicamentoas).................13
1.8. Reacii adverse produse de medicamente imunosupresive.............................24
1.9. Tolerana (tahifilaxia)......................................................................................27
1.10. Farmacodependena (dependena medicamentoas)......................................29
1.11. Intoxicaiile medicamentoase.........................................................................32
1.12. Dopajul medicamentos...................................................................................35
1.13. Reacii adverse rezultate la ntrerupereaFarmacoterapiei..............................35
CAPITOLUL II
FARMACOEPIDEMIOLOGIA.............................................................................39
2.1. Generaliti.......................................................................................................39
2.2. Prezentarea din punct de vedere statistic a rezultatelor unor studii privind prevalena i
incidena reaciilor adverse [9]..........................................................40
2.3. Elemente (Aspecte) de studiu ale procesului epidemiologic.......................... 41
2.4. Formele activitii farmacoepidemiologice.....................................................43
2.5. Sistemul de farmacovigilen..........................................................................45
BIBLIOGRAFIE....................................................................................................47









CAPITOLUL I

FARMACOTOXICOLOGIA GENERALA

1.1. Aspecte introductive
Este ramura farmacologiei care studiaz aspecte diverse legate de manifestri
nedorite nocive rezultate n urma administrrii medicamentelor i numite n general
reacii adverse, dar i alte aspecte legate de lipsa de reactivitate sau rspuns al
organismului la administrarea substanelor medicamentoase.
Organizaia Mondial a Sntii definete reaciile adverse ca reacii
nedorite, duntoare i care apar la doze terapeutice.
Desigur, pentru apariia reaciilor adverse sau a altor forme de manifestare care
fac obiectul de studiu al farmacotoxicologiei, exist anumii factori favorizani,
dintre care amintim:
- polimedicaia;
- administrarea de substane medicamentoase cu indicaii terapeutice
necunoscute;
- diveri poluani (chimici, fizici etc.);
- stri fiziologice particulare (sarcin, alptare, vrst naintat, copii de vrst
mic etc.);
- complian deficitar;
- ali factori (subnutriia, fumatul, consumul de alcool, droguri etc.).
n funcie de mecanismul incriminat n producerea lor, reaciile adverse pot fi de
mai multe tipuri, i anume:
- reacii adverse produse ca efecte secundare ale unui efect farmacologic de baz;
- reacii adverse produse prin mecanism idiosincrazic;
- reacii adverse produse prin mecanism imunologic (reacii alergice);
- reacii adverse produse ca urmare a unei adaptri fiziologice, i anume
sensibilizare sau up regulation, i desensibilizare sau down regulation.
n continuare vom prezenta principalele manifestri nedorite sau neateptate
care fac obiectul de studiu al farmacotoxicologiei.



1.2. Efecte secundare

Mecanismul de producere a efectelor secundare este de tip farmacodinamic.
Intensitatea i frecvena de apariie a acestora este n general dependent de doz,
factorul favorizant fiind supradozarea.
Ca exemple de efecte secundare amintim:
- uscciunea gurii, datorat reducerii secreiei salivare, provocat de
parasimpatolitice;
- hipotonicitate digestiv sau chiar constipaie, produs de parasimpatolitice;
- sindrom de blocare excesiv a S.N.C. cu manifestri depresive, produse de
simpatolitice etc.;
- somnolen produs de medicamente deprimante ale S.N.C., ca de exemplu
hipnotice;
- sindrom neurologic extrapiramidal produs de neurolepticele clasice prin
blocarea excesiv a transmisiei neuronale dopaminergice (D2);
- sindrom astmatic (bronhoconstricie) provocat sau agravat de -
adrenolitice neselective (propranolol);
- insuficien cardiac produs de medicamente cu efect inotrop negativ, ca de
exemplu: 1 adrenolitice, antiaritmice blocante ale canalelor de sodiu
(chinidina) sau de calciu (verapamil);
- aritmii rezultate prin creterea excitabilitii miocardului contractil (efect
batmotrop pozitiv), ca de exemplu :1 adrenergice, glicozide cardiotonice etc.;
- reacia Herxheimer determinat de cantitile mari de toxine eli- berate prin
moartea masiv a spirochetelor speciei Treponema
palidum n urma utilizrii unor doze mari de atac, din antibioticul
utilizat;
- carene vitaminice aprute n urma tratamentului cu antibiotice cu spectru
larg de tipul Tetraciclinei i fr un tratament auxiliar cu vitamine din
complexul B sau alte modaliti,
- gastrite hiperacide sau chiar ulcer gastrointestinal ca rezultat al administrrii
medicamentelor antiinflamatoare nesteroidiene sau steroidiene n urma blocrii
prostaglandinelor E2 etc.


1.3. Efecte toxice

Ca i n cadrul efectelor secundare, acest tip de reacii adverse cresc
proporional cu doza administrat.
Acest tip de reacii sunt frecvente la persoanele hiperreactive, care sunt situate
n partea stng a curbei Gauss, obinut n urma nregistrrii pe un grafic cartezian
a modului de apariie a efectului farmacodinamic, ca urmare a creterii treptate a
dozelor.
Dintre factorii favorizani putem sublinia pe cei amintii la nceput, la care
putem aduga substanele medicamentoase cu toxicitate intrinsec mare i indice
terapeutic mic, ca de exemplu: cardiotonice, amonoglicozide etc.
Efectele toxice pot fi uoare sau grave, pn la efecte mortale, i pot fi ntlnite
n funcie de medicamentul administrat, la nivelul diferitelor sisteme i aparate din
organism.
n continuare se va prezenta, n mod succint, modul n care diferite clase de
medicamente pot prezenta efecte toxice la diferite niveluri ale organismului, i anume:
a) Medicamente cu efect toxic asupra S.N.C.
La nivelul S.N.C. pot aprea diferite tulburri de ordin neurologic sau psihic, n
funcie de medicamentul administrat sau de reactivitatea individual a pacientului
tratat, i anume:
- efecte psihice de tip psihotic, n cazul supradozrii corticosteroizilor;
- manifestri psihotice, halucinaii, la administrarea medicamentelor
antiinflamatoare nesteroidiene (A.I.N.S);
- tulburri de memorie la pacienii tratai cu anticolinergice.
b) Medicamente cu efect toxic la nivelul aparatului cardiovascular
La acest nivel pot aprea:
- leziuni degenerative n urma administrrii antibioticelor citostatice (
daunorubicina etc.);
- aritmii rezultate n urma administrrii de cardiotonice etc.;
- leucopenie i trombopenie dup administrarea de citostatice;
- risc de tromboembolie sau tromboze datorate creterii coagulabilitii sngelui
n urma administrrii de contraceptive perorale;
- methemglobinemie n urma administrrii de substane cu caracter oxidant care
transform Fe
2+
hemoglobinic n Fe
3+
inactiv din punct de vedere al legrii
oxigenului, ca de exemplu: paracetamol, fenacetin etc.
- anemie megaloblastic provocat de antiepileptice de tip fenitoin etc.
c) Reacii adverse de tip toxic la nivelul aparatului respirator
- alveolit, fibroz pulmonar n urma administrrii de citotoxice (bleomicin,
ciclofosfamid etc.);
- sindrom astmatic etc.
d) Reacii adverse la nivelul aparatului digestiv
- diaree, colici, hiperperistaltism provocat de medicamente propulsive, iritante ale
mucoasei tractului digestiv etc.;
- ulcer gastric provocat de medicamentele care stimuleaz secreia acid sau
iritante, ca de exemplu: antiinflamatoarele nesteroidiene etc.
e) Reacii adverse la nivelul principalului organ epurator (ficatul)
- citoliz produs de medicamente cum sunt: rifampicina, izoniazida,
paracetamolul, antimalarice, IMAO, citostatice etc.;
- steatoz hepatic provocat de: tetracicline, corticosteroizi etc.;
- granulomatoz provocat de: chinidin, hidralazin etc.;
- carcinom-hepato-celular produs de steroizi androgeni;
- sindrom de hepatit virotic produs de: IMAO, halotan etc., care este rar
ntlnit, dar letal n procent de pn la 20%;
- ciroz produs de metotrexat administrat n cantiti mari;
- adenom i tromboz suprahepatic produs de contraceptive perorale;
- colestaz intrahepatic i icter produse de: contraceptive perorale, estrogeni,
fenotiazine, antidiabetice perorale, steroizi anabolizani etc.;
- hepatit subacut i acut cu leziuni cronice, produs de: paracetamol,
rifampicin, izoniazid, sulfonamide, IMAO etc.;
f) Reacii adverse de tip toxic produse la nivelul rinichiului
La nivelul rinichiului pot aprea diferite tipuri de reacii adverse n urma
administrrii unor medicamente, ca de exemplu:
- cristaluria n urma administrrii sulfamidelor cu eliminare rapid;
- nefropatii provocate de aminoglicozide, n special, dar i de unele cefalosporine,
ca de exemplu: cefaloridina;
- tubulopatii cronice nsoite de poliurie provocate de: tetracicline, sruri de litiu
etc.
g) Reacii adverse de tip toxic la nivelul analizatorilor
g1) Reacii adverse de tip toxic la nivelul ochiului
La acest nivel s-au nregistrat efecte adverse de tip toxic cum sunt:
- glaucom, prin creterea presiunii intraoculare n urma administrrii de
glucocorticoizi;
- retinit pigmentar provocat de neuroleptice fenotiazinice, ca de exemplu:
tioridazina, clorpromazina etc.
g2) Reacii adverse de tip toxic la nivelul urechii
- tulburarea auzului pn la surditate, provocate de: aminoglicozide, glicopeptide
(vancomicina), diuretice ca furosemid, acid etacrinic n doze mari;
- tulburarea echilibrului i vertij produse de aminoglicozide etc.
h) Reacii adverse de tip toxic produse la nivelul sistemului muscular sau
esutului conjunctiv
- distrucii musculare (rabdomiolize) produse de: anestezice generale de tip
halotan, analgezice antipiretice (paracetamol, salicilai), antiinflamatoare
nesteroidiene, antiinflamatoare steroidiene, IMAO, curarizante, neuroleptice
anti D
2
, antibiotice (peniciline) etc.;
- miopatii fr mialgie, produse de corticosteroizi;
- miastenii produse de polimixine, -blocante, aminoglicozide, benzodiazepine
etc.;
- miopatii cu mialgii produse de: fluorochinolone etc.;
- polimiozite cu mialgie produse de: antiulceroase anti H2 (ranitidina);
- tremor, produs de neuroleptice etc.;
- colagenoz la indivizi acetilatori leni datorit deficienei de N acetiltransferaz
n urma administrrii de izoniazid etc.
i) Reacii adverse de tip toxic la nivelul pielii
Efectele toxice la acest nivel sunt diferite ca intensitate, fiind de la cele mai
simple pn la cele mai grave, ca de exemplu: necroliza epidermic toxic etc., unele
chiar cu sfrit letal.
Afeciunile toxice la nivelul pielii sunt ntlnite cu frecven mai mare la
persoane n vrst i la femei. n continuare se vor prezenta cteva dintre reaciile
adverse de tip toxic cu manifestare la nivelul pielii, i anume:
a. pruritul poate fi provocat de medicamente ca: barbiturice, opiacee,
contraceptive perorale etc.;
b. erupii cutanate care sunt de mai multe feluri i pot fi provocate de:
contraceptive orale, steroizi, bromuri, ioduri, antituberculoase cloramfenicol,
aminoglicozide, sulfamide, penicilin, antihistamini-ce antimalarice, fenitoin,
-adrenolitice, fenilbutazon etc.;
c. Eritem, care este de asemenea de mai multe feluri i poate fi provocat de:
barbiturice, acid acetilsalicilic, paracetamol, tetracicline, peniciline, sulfamide,
fenitoin, pirazolone, salicilai, bromuri, ioduri etc.
d. Porfirie produs de: rifampicin, sulfamide, griseofulvin, barbiturice,
fenitoin, androgeni, estrogeni, contraceptive orale etc.;
e. Tulburri pigmentare de diferite culori, produse de: antimalarice, citostatice,
contraceptive orale, tetracicline, fenitoin etc.;
f. Alopecii, produse de: citostatice (ciclofosfamid etc.), contraceptive orale,
retinol, sruri de aur, antitiroidiene, anticoagulante etc.;
g. Necroliz epidermic toxic, care poate fi produs de barbiturice,
cloramfenicol, rifampicin, sulfamide, fenilbutazon etc.

1.4. Reacii adverse de tip mutagen

Reaciile adverse de acest tip sunt rezultat al alterrii genotipului care, mai rapid
sau n timp, dau modificri fenotipice.
Modificrile genotipului pot rezulta n urma aciunii a diferii factori din mediul
extern, i anume:

- factori fizici, ca de exemplu: radiaiile etc.;
- factori chimici: substane mutagene.
Dintre farmaconii incriminai n producerea reaciilor adverse de tip
mutagen, amintim: medicamente citostatice, fungicide etc.

1.5. Reacii adverse de tip teratogen

Substanele cu efect teratogen acioneaz asupra dezvoltrii biologice
intrauterine a fiinei umane, afectnd anumite organe, sisteme, esuturi
etc., n funcie de faza de dezvoltare.
Substanele cu efect teratogen produc malformaii, cuvntul teraton deriv din
limba greac i nseamn monstru.
Foarte multe medicamente pot produce malformaii la ft, chiar dac pentru
organismul matern nu sunt toxice.
Placenta este o membran lipidic cu pori mari, care este uor permeabil pentru
substane liposolubile cu GMR<1000, dar datorit prezenei porilor i a sistemelor
membranare de transport activ spre ft pot penetra i diferite substane hidrosolubile
polare sau disociate. Riscul teratogen cel mai mare este n primele 3 luni, dar
posibilitatea producerii reaciilor adverse de tip teratogen exist i n alte faze ale
dezvoltrii intrauterine.
Efectele adverse asupra procesului reproducerii pot avea loc n diferite
faze de dezvoltare i anume:
a) Efecte adverse asupra gametogenezei
Gametogeneza are loc n organele sexuale masculine i feminine. Exist puine
informaii privind reacii adverse produse de medicamente care s afecteze n acest
stadiu.
b) Efecte adverse asupra blastogenezei
Aceast etap are loc n primele 2 sptmni de la fecundare. Substanele
toxice care afecteaz zigotul sau blastomerul n aceast faz au efect letal asupra
acestuia, urmnd expulzarea acestuia.
n aceast perioad se difereniaz din celulele mugurelui embrionar dou
straturi, i anume: endoblastul i ectoblastul, ulterior difereniindu-se i mezoblastul.
c) Reacii adverse asupra embriogenezei
Embriogeneza cuprinde perioada de timp din dezvoltarea intraute-rin a
embrionului cuprins ntre sptmnile 3 i 8.
Diferitele substane toxice sau medicamentoase pot afecta embrio-nul, avnd ca
urmare:
- efect letal i expulzarea embrionului;
- sau efect teratogen etc.
Efectul teratogen poate avea loc asupra diferitelor organe, n funcie de perioada
n care afectarea poate fi maxim.
n perioada embriogenezei, din cele trei membrane se difereniaz diferitele organe, i
anume:
- din ectoblast: sistemul nervos, tegumentele;
- din mezoblast: sistemul osos, esut conjunctiv, muscular, aparatul circulator, renal etc.;
- din endoblast: aparatul digestiv, aparatul respirator etc.
Afectarea maxim a diferitelor organe, sisteme sau aparate poate
avea loc ntr-un anumit interval de timp, ca de exemplu:
- S.N.C. ntre zilele 15 25;
- ochii ntre zilele 24 42;
- urechile ntre zilele 20 36;
- gonadele ntre zilele 37 45 etc.
n continuare se vor prezenta cteva exemple de substane contraindicate
pentru a fi administrate femeii nsrcinate datorit riscului teratogen, i anume:
- antineoplazice (metotrexat) care pot produce malformaii cranio-faciale;
- androgeni i progesteroni pot duce la masculinizarea ftului feminin;
- estrogeni care pot duce la feminizarea ftului masculin;
- glucocorticoizi care pot da: malformaii cardiovasculare, cranio-faciale, ale
membrelor etc.;
- medicamentele antiepileptice (fenitoin, acid valproic) pot produce malformaii:
cardio-vasculare, cranio-faciale etc.;
- medicamentele antidepresive triciclice pot da malformaii ale membrelor;
- litiul malformaii cardiace;
- tranchilizantele benzodiazepinice;
- anticoagulante cumarinice;
- derivai de vitamina A (izotretinoina)
d ) Efecte adverse produse n perioada fetogenezei
Fetogeneza este perioada de timp ncepnd cu sptmna a IX-a i pn la
sfritul vieii intrauterine. n aceast perioad sunt posibile ur-mtoarele tipuri de
efecte adverse:
- defecte fiziologice;
- tulburri de histogenez ale sistemului nervos;
- malformaii minore asupra aparatului genital extern;
- efect letal etc.
n continuare se vor prezenta cteva grupe de medicamente contraindicate la
gravide (n timpul sarcinii), datorit potenialului fetotoxic, i anume:
- neuroleptice fenotiazinice - pot produce deprimare respiratorie, sindrom
extrapiramidal, sedare etc.;
- anestezice locale (lidocaina) - produc deprimare respiratorie, efect cronotrop
negativ (bradicardie), convulsii etc.;
- salicilai - pot produce hemoragii;
- antitiroidiene (ioduri, carbimazol) - pot produce hipotiroidism;
- antidiabetice perorale (tolbutamida) - pot produce hipoglicemie;
- anticoagulante cumarinice - risc de hemoragii;
- -adrenolitice - pot produce deprimare respiratorie, bradicardie, hipoglicemie
etc.;
- cloramfenicol - sindrom cenuiu;
- tetracicline - dentiie anormal, colorat n galben;
- aminoglicozide - pot produce ototoxicitate manifestat prin surdi-tate
congenital, tulburri vestibulare etc.;
- antimalarice;
- sulfamide - pot produce icter nuclear, anemiile hemolitice datorate deficitului
de glucozo 6 fosfatdehidrogenaz etc.
e ) Efecte adverse produse n perioada prenatal i obstetrical
Medicamentele care pot produce tulburri n aceast perioad sunt substanele
medicamentoase cu efect ocitocic i tocolitic.
Suferinele produse n aceast perioad pot afecta fetusul imediat sau tardiv.
Dintre medicamentele stimulante ale motilitii uterine care pot produce
accidente obstetricale, ca: avort, asfixie, natere prematur, amintim: ocitocina,
ergometrina, prostaglandine, 1-adrenolitice neselective (propranolol), purgative de
contact (antrachinona etc.), parasimpatomimetice (neostigmina, pilocarpina etc.) etc.
Dintre medicamentele inhibitoare ale motilitii uterine, care pot produce accidente
obstetricale, ca iniierea naterii, oprirea travaliului, amintim: tocolitice (izoxuprina), 2-
adrenomimetice (salbutamol etc.), antiinflamatoare nesteroidiene blocante ale sintezei
prostaglandinei PGT2 (indometacin, fenilbutazon etc.), anestezice generale,
deprimante ale S.N.C. (sulfat de magneziu), analgezice opioide, ca de exemplu: morfina
etc.
f ) Medicamente care pot produce efecte adverse asupra sugarilor
Sugarul poate fi afectat de medicamentele utilizate de mam i care sunt
eliminate prin secreia lactat.
Pentru a ajunge n laptele matern substanele medicamentoase tre-buie s
traverseze bariera snge/lapte, care este o membran semiper-meabil lipidic cu
pori mari, permind astfel ptrunderea multor sub-stane nedisociate att lipo- ct i
hidrosolubile.
Datorit pH-ului laptelui matern de ~ 7, n lapte se pot concentra substane
bazice.
Reaciile adverse manifestate la sugar pot fi diferite ca mecanism, i anume:
- ca efect secundar al aciunii farmacodinamice principale;
- mecanism toxic;
- mecanism imunoalergic etc.
Exist medicamente care, n timpul administrrii lor trebuie ntrerupt
alptarea, i anume:
- antibiotice sau chimioterapice ca: tetraciclina, cloramfenicolul, aminoglicozide,
metronidazol (tulburri neurologice, deprimare medular);
- antitiroidiene pot produce hipotiroidism;
- antiinflamatoare nesteroidiene (indometacin, acid acetilsalicilic), care pot
produce: acidoz, hemoragii, tulburri respiratorii, convulsii etc.;
- analgezice-antipiretice derivai de anilin (paracetamol), care pot produce
methemglobinemie;
- anticoagulante orale pot provoca sngerri;
- glucocorticoizi pot produce insuficien corticosuprarenal i ncetinirea
creterii;
- opiacee pot produce deprimare respiratorie, dependen etc.;
- purgativele antrachinonice pot produce diaree;
- sedativele pot da somnolen;
- antihipertensivele neurosimpatolitice (reserpina) pot da dispnee, stimularea
secreiilor bronice etc.;
n continuare se vor prezenta cteva grupe de medicamente care pot suprima
lactaia, i anume:
- alcaloizii din ergot (bromocriptina);
- contraceptive orale;
- estrogeni;
- diuretice (furosemid) datorit hipohidremiei;
- parasimpatolitice produc hiposecreie exocrin etc.

1.6. Efecte adverse de tip cancerigen

Exist substane care pot induce proliferarea i dezvoltarea celu-lelor
canceroase. Timpul de laten pentru apariia tumorilor poate fi uneori de 20
30 de ani.
Dintre substanele cu potenial cancerigen amintim: amine aromatice,
nitrozamine, rezultate n urma transformrii aminofena-zonei n pH-ul acidului
gastric, azocolorani, aflatoxine produse de mucegaiuri, substane alchilante
(citostatice), hidrocarburi policiclice coninute n fumul de igar sau n gudronul
de crbune etc.

1.7. Reacii adverse de tip idiosincrazic (intoleran
medicamentoas)

Intolerana este un gen de reacie advers caracterizat printr-un rspuns
farmacodinamic anormal att din punct de vedere calitativ, ct i cantitativ, avnd
la baz un deficit enzimatic, care poate caracteriza un individ sau chiar
colectiviti.
Acest tip de reacii adverse pot avea dou tipuri de etiologii:
- congenital (nnscut)
- sau dobndit etc.

1.7.1. Intolerana congenital

Acest tip de intoleran apare la prima doz administrat dintr-un medicament
sau dup primele administrri. Cauza determinant este o enzimopatie (deficit
enzimatic) care se datoreaz unei anomalii genetice (gen absent). Aceast deficien
enzimatic poate fi latent mult timp, declanarea intoleranei manifestndu-se n
momentul n care se administreaz un medicament care este biotransformat de ctre
enzima deficitar sau absent.
n ultimii ani a aprut o nou tiin numit farmacogenetica, tiin care
studiaz aceste aspecte cu determinare genetic.
Cnd exist un teren pentru manifestri idiosincrazice, pot fi evideniate dou
tipuri de manifestri, i anume:
- manifestri farmacocinetice;
- manifestri farmacodinamice etc.
1.7.1.1. Manifestri idiosincrazice de tip farmacocinetic
Manifestrile farmacocinetice vizeaz devierea de la traseul normal
pe care medicamentul l are n organism, cu afectarea uneia sau mai multor etape
farmacocinetice. Consecinele acestor manifestri pot fi datorate tipului de distribuie
respectiv metabolizare (rapid sau lent) i modului de eliminare. Acest tip de
manifestri sunt de dou feluri i anume:
- farmacoterapice, care pot conduce la ineficien terapeutic, cnd
medicamentul se administreaz la subieci metabolizatori rapizi;
- farmacotoxicologice, cnd medicamentul se administreaz la subieci
metabolizatori leni, cnd creterea concentraiei plasmatice poate atinge
niveluri superioare domeniului terapeutic etc.
n continuare vor fi prezentate principalele tipuri de enzimopatii responsabile de
reacii adverse de tip idiosincrazic cu manifestri farmacocinetice, i anume:

a. Deficit de pseudocolinesteraz
Aceast enzim este biosintetizat n ficat i este ntlnit n plasm. Enzima
are rolul de a biotransforma medicamente cum sunt suxametoniul etc. Datorit
structurii anormale a enzimei, capacitatea de metabolizare a acestei substane este
mic, conducnd la creterea dozei plasmatice de suxametoniu pn n domeniul
toxic. Acest deficit enzimatic este ntlnit cu frecven crescut n ri din Asia Mic,
de exemplu: Iran, Irak etc.
b. Tulburri de acetilare
N-acetiltransferaza hepatic prezint mai multe forme polimorfe care difer n
privina vitezei cu care se acetileaz diferitele medicamente n procesul
biotransformrilor. Din acest punct de vedere, persoanele care prezint anomalii
genetice de acest tip se pot ncadra n dou grupe, i anume:
- persoane la care acetilarea se face rapid;
- persoane la care acetilarea se face lent etc.
Distribuia celor dou categorii este dependent i de apartenena rasial,
procentul primei categorii fiind mai ridicat la rasa galben, ajungnd pn la 90 % n
Japonia sau 95 100 % la eschimoii canadieni.
Prin acetilare sunt metabolizate diferite medicamente, ca de exemplu: izoniazida,
hidralazina, procainamida, fenalazina, dapsona, sulfazolina etc.
Timpul de njumtire al izoniazidei, de exemplu, este de 2 3 ori mai mare la
acetilare lent, conducnd la concentraii plasmatice de pn la 10 ori mai mari la
aceast categorie de persoane. Datorit acetilrii lente, procentul de izoniazid
nemetabolizat este de aproximativ 10 ori mai mare la acetilatorii leni dect la cei
rapizi.
Aceast anomalie de biotransformare are urmtoarele consecine farmacologice:
- dozele eficiente medii sunt ineficace la persoane din categoria acetilatorilor
rapizi;
- la acetilatorii leni, izoniazida i alte medicamente din aceast categorie produc reacii adverse
puternice.
n continuare se vor prezenta cteva din reaciile adverse prezente la indivizii acetilatori leni, dup
administrarea unor medicamente, ca de exemplu:
- la izoniazid n urma asocierii cu rifampicina poate s apar hepatita iatrogen,
neuropatii periferice, sindrom de lupus eritematos etc.;
- la fenelazin, reacii hepatice i la nivelul S.N.C.;
c. Tulburri de oxidare
i acest gen de tulburri idiosincrazice sunt rezultat al polimorfismului unor
sisteme enzimatice dependente de citocromul P450.
Aceast enzimopatie tip cu oxidare lent este ntlnit la europeni n procent de
9 10 %.
Dintre tulburrile enzimatice cu repercusiuni asupra oxidrii amintim cele
determinate de:
c.1. Existena de forme polimorfe ale hidroxilazelor
Datorit existenei diferitelor forme polimorfe ale acestei enzime, persoanele la
care exist aceast anomalie pot fi mprite n trei grupe din punct de vedere al vitezei
proceselor oxidative determinate pe anumite substane medicamentoase, ca de
exemplu debrisoquin, i anume:
- metabolizatori leni;
- metabolizatori intermediari;
- metabolizatori rapizi etc.
Enzima implicat n metabolismul substanelor amintite este 4-hidroxilaza.
Exist medicamente asemntoare debrisoquinului din punct de vedere al
polimorfismului enzimelor de care sunt metabolizate, ca de
exemplu:
- -adrenolitice (metoprolol, timolol);
- antidepresive triciclice (amitriptilina etc.);
- sparteina etc.
Exist medicamente cu polimorfism diferit de debrisoquin n ce privete
enzimele oxidative implicate n metabolizare, ca de exemplu: fenitoina, warfarina,
tolbutamida etc.
c.2. Polimorfismul alchilazelor
Exist subieci la care metabolizarea unor medicamente ca paracetamolul
devine anormal, conducnd la o cretere exagerat a methemoglobinei.

1.7.1.2. Manifestri idiosincrazice de tip farmacodinamic
Reaciile adverse de acest tip au manifestri farmacotoxicologice care pot fi de
dou feluri:
- reacii adverse diferite de cele specifice ale medicamentului respectiv;
- reacii adverse diferite din punct de vedere cantitativ, manifestate prin frecven
i intensitate crescut chiar la administrarea unei doze mici dintr-un anume
medicament etc.
n continuare se vor prezenta principalele enzimopatii care implic manifestri
de ordin farmacodinamic.
a) Reacii adverse de tip idiosincrazic rezultate prin deficit de glucozo-6-fosfat
dehidrogenaz (G-6-PD)
Sunt cunoscute aproximativ 80 de variaii polimorfe ale acestei enzime.
Incidena indivizilor avnd aceast enzimopatie este mai ales n zona n care este
rspndit malaria, apariia acestei deficiene poate fi o modalitate de aprare
mpotriva parazitului. n deficien enzimatic, cantitatea de glutation redus este
mic, rolul enzimei este meninerea concentraiei normale n hematii. n deficiena de
glutation redus este defavorizat dezvoltarea protozoarului, dar totodat se reduce i
rezistena eritrocitului la substanele oxidante care vor produce hemoliza accentuat,
cum ar fi:
- antimalarice, sulfamide antibacteriene, tolbutamid, nitrofurantoin etc.
Acest deficit enzimatic este ntlnit la aproximativ 3 % din
populaia globului.
Hemoliza rezultat n deficit enzimatic poate fi redus sau de proporii,
rezultnd anemie grav, uneori chiar cu consecine letale.
Manifestarile clinice a deficienelor ar fi urmtoarele:
- anemie acut hemolitic;
- anemie cronic;
- icter fiziologic provocat la nou-nscut etc.
b) Reacii adverse de tip idiosincrazic manifestate prin deficit de uridin-difosfat-
glucuroniltransferaz (UDP-glucuroniltransferaza)
Deficiena acestei enzime afecteaz att biotransformarea prin
glucuronoconjugare a unor componente endogene ca bilirubina, avnd consecine
creterea concentraiei plasmatice i apoi icter, ct i a unor substane
medicamentoase. Glucuronoconjugarea este o biotransformare a stadiului II de
metabolizare a metaboliilor rezultai n urma metaboliz-rilor din stadiul I.
Substanele medicamentoase care sufer glucuronoconjugare sunt: sulfamide,
barbiturice, morfinomimetice, analgezice-antipiretiece, hormoni steroizi etc.
c) Acatalazia
Eritrocitele conin catalazo-enzime care catalizeaz reacii de transformare a
apei oxigenate (H2O2) n ap.
Din punct de vedere al procentului n care se gsete enzima la diferite
persoane, exist:
- indivizi acatalazici;
- indivizi hipocatalazici;
- indivizi normali etc.
La persoanele care manifest acest deficit enzimatic, n urma contactului dintre
apa oxigenat i snge nu rezult efervescen. Rspndirea acestei afeciuni este
mic, fiind ntlnit n unele ri ca: Elveia, Japonia etc.
d) Reacii adverse de tip idiosincrazic produse prin deficit de NADH-
methemoglobin-reductaz
n lipsa acestei enzime nu are loc reducerea methemoglobinei la hemoglobin,
consecinele fiind creterea methemoglobiei la valori cu 20 50 de ori mai mult dect
la indivizii normali. Frecvena enzimopatiei este mic, i anume la aproximativ 1 % din
persoane.
Substanele medicamentoase puternic oxidante sunt methemoglobinizate, iar
prin deficit enzimatic, chiar la doze uzuale terapeutice pot rezulta methemoglobinemii
severe, care au ca rezultat scderea capacitii de oxigenare a esuturilor, deoarece
methemoglobina nu transport oxigenul, iar ca simptome caracteristice sunt:
dispneea, cianoza etc.
Dintre methemoglobinizante amintim: derivai de anilin din categoria
analgezice-antipiretice (paracetamol, fenacetin), sulfamide, antimalarice etc.
e) Reacii adverse de tip idiosincrazic produse prin deficit de inducie de -ALA
sintetaza hepatic
Excesul enzimei este determinat genetic i este responsabil de
apariia porfiriilor hepatice acute.
Aceste suferine sunt rezultat al dereglrii metabolismului porfirinic, iar ca
manifestri pot fi (ca rezultat al acumulrii acestora n ficat): diferite tulburri gastro-
intestinale dureroase sau diferite tulburri neurologice (nevrite periferice), tulburri
psihice, fotodermatoze cutanate etc.
Substanele medicamentoase care produc inducia acestei enzime pot da la
doze uzuale terapeutice crize de porfirie. Exemple de astfel de medicamente inductoare
enzimatice sunt:
- alcool etilic;
- hipnotice barbiturice, glutetimida etc.;
- sulfamide, antidiabetice (tolbutamid);
- benzodiazepine (clordiazepoxid);
- anticonvulsivante (fenitoina);
- analgezice-antipiretice (aminofenazona);
- contraceptive orale;
- antimicotice (griseofulvina) etc.
f) Hemoglobinopatii
Hemoglobina normal este format din 4 lanuri peptidice:
- 2 lanuri
- 2 lanuri
Exist hemoglobinopatii n care apar hemoglobine anormale cu toate
implicaiile fiziologice i fiziopatologice care deriv din aceast stare patologic, ca de
exemplu:
- hemoglobina Zrich are n lanurile o molecul de histidin nlocuit cu o
molecul de arginin. Administrarea de medicamen-te din clasa sulfamidelor la
aceste persoane poate conduce la anumite suferine ca: anemie prin hemoliz,
hiperbilirubinemie cu icter.
- hemoglobina H care are 4 lanuri beta. Persoanele care au acest tip de
hemoglobin sunt sensibile la substane oxidante, manifestrile fiind
aproximativ identice cu cele ntlnite la administrarea sulfamidelor la persoane
cu hemoglobin Zrich.
g) Reacii adverse de tip idiosincrazic ca rezultat al deficienei genetice de
fenilalanil-4-hidroxilaz.
Deficitul enzimei menionate conduce la fenilcetonurie n urma metabolizrii
fenilalaninei la acid fenilpiruvic i fenilacetic, nu n tirozin. Datorit acestei deficiene
de metabolizare, la bolnavii care au aceast suferin tirozina devine aminoacid
esenial, fiind necesar introducerea acestuia n organism prin aport exogen. La
rndul su, tirozina este transformat de ctre enzimele corespunztoare n
catecolamine n dopa i apoi n dopamin, adrenalin etc. Rolul catecolaminelor n
organism este foarte important, deoarece sunt neurotransmitori etc. Problema
rezultat n urma acestei deficiene este c att fenilalanina, ct i metaboliii rezultai
n urma oxidrii sunt toxici pentru S.N.C.
De aceea, cnd exist acest deficit, pot rezulta deficiene mintale la copii,
manifestate prin retardare. Problema poate fi rezolvat prin regim dietetic lipsit de
fenilalanin.
La bolnavii cu acest deficit enzimatic are loc o sensibilizare a receptorilor
adrenergici (prin externalizare), ceea ce d efecte hipertensive grave la administrarea
unor doze terapeutice de catecolamine. Fenomenul este datorat deficienei unei
cantiti adecvate de mediatori.
h) Rezistena la medicament pe fondul unei condiionri genetice
Rezistena la aciunea diferitelor medicamente este o reacie advers pe fond
genetic, care se manifest printr-un rspuns farmacodinamic nul sau mult diminuat
la administrarea medicamentelor n doze uzuale terapeutice.
Ca exemple de afeciuni care se ncadreaz n aceast grup amintim:
- rahitismul rezistent la vitamina D, boal care presupune administrarea de doze
superioare celor terapeutice uzuale;
- rezistena la anticoagulantele cumarinice, care de asemenea se caracterizeaz
prin absena efectului anticoagulant la administrarea dozelor uzuale
terapeutice etc.
i) Glaucomul cortizonic
La unii bolnavi, prin administrarea de corticosteroizi, n sacul conjunctival
poate rezulta o cretere intens a presiunii intraoculare, conducnd chiar la apariia
glaucomului. Mecanismul de producere a bolii nu este bine cunoscut.


j) Hipertermia malign
Aceast suferin poate aprea n cursul anesteziei generale, avnd ca
manifestri: hiperpirexie, rigiditate muscular etc., avnd drept cauz modificarea
capacitii de legare a ionilor de calciu de ctre musculatura striat.

1.7.2. Intolerana dobndit

1.7.2.1. Generaliti
Reaciile adverse care sunt ncadrate n aceast grup sunt numite n
exprimarea curent alergii i apar ca rezultat al unei hipersensibiliti produse de
anumite substane medicamentoase, avnd un caracter temporar sau permanent.
Producerea reaciilor alergice presupune un mecanism imunologic care const
n:
- contactul organismului cu un medicament alergizant, n urma cruia rezult
anticorpi (imunoglobuline), sau produce o sensibilizare a limfocitelor;
- i un contact ulterior al organismului cu aceeai substan, contact care poate
duce la declanarea reaciei alergice.
Substanele care determin formarea anticorpilor sunt:
- antigeni complei: macromolecule proteice, polizaharide etc.;
- i antigeni incomplei (haptene), care pot forma antigeni complei dup legarea
de proteine etc.
n continuare se vor prezenta cteva substane din a II-a categorie (haptene)
care sunt implicate n generarea de reacii de tip alergic, i anume: peniciline
(ampicilina), cefalosporine, sulfamide, procaina, acid acetilsalicilic, barbiturice,
dextrani etc.
Exist situaii n care se poate produce hipersensibilizarea ncruciat (co-
sensibilizare), ca de exemplu paracetamolul, care poate induce hipersensibilizare fa
de sulfamide antibacteriene, procain etc.
Apariia reaciilor alergice poate depinde de anumii factori care favorizeaz
acest tip de reacii adverse, ca de exemplu:
- factori dependeni de medicament (potenial alergic intrinsec al medicamentului
i frecvena contactului cu organismul;
- factori dependeni de organism, n care putem aminti: reactivitatea individual
(mai intens la femei), calea de administrare cu inciden crescut la
preparatele administrate topic pe piele i mucoase etc.
Reaciile alergice au cteva particulariti distincte i anume:
- absena relaiei gradate doz/efect (doze foarte mici pot produce alergii grave);
- organismul sensibilizat prezint un coninut ridicat de anticorpi, ca de
exemplu: imunoglobulina E (IgE), anticorpi ce pot fi pui n eviden prin teste
cutanate sau reacii serologice etc.
1.7.2.2. Tipuri de reacii alergice [9]
Reaciile alergice se mpart, n funcie de mecanismul imunologic implicat, n
patru categorii, i anume:
a) Reacii alergice de tip I (tip anafilactic)
Aceste reacii fac parte din categoria alergiilor de tip imediat i au la baz
cuplarea antigenului cu IgE, de pe suprafaa granulocitelor bazofile, mastocitelor,
declannd eliberarea unor mediatori ai inflamaiei, ca de exemplu: histamina,
prostaglandina, serotonina etc. Aceti mediatori eliberai vor aciona pe receptorii
specifici situai la nivelul diferitelor organe, rezultnd:
- alergii minore ca: rinite alergice, prurit, urticarie, edem Quinque etc.
- sau alergii majore ca astmul bronic sau ocul anafilactic etc.
Medicamentele care pot determina reacii alergice de tip I sunt: penicilinele,
dextroza, anestezice locale, acid acetilsalicilic etc.
b) Reacii alergice de tip II
Acest tip de reacii alergice de tip imediat apar n urma formrii de anticorpi
IgG sau IgH care acioneaz mpotriva unor componente tisulare, efectul principal
fiind citotoxic.
Manifestri clinice rezultate n urma reaciilor alergice de tip II sunt:
- anemia hemolitic imun (produs de penicilin, rifampicin, sulfamide,
fenacetin etc.);
- trombocitopenie imun, produs de: sulfamide, rifampicin, tiazide diuretice
etc.;
- granulocitopenie (produs de peniciline, sulfamide, aminofenazo- n,
hipoglicemiante, fenilbutazon etc.).
Tot n aceast categorie pot fi ncadrate i hepatita cronic imun produs de:
metildopa, fenilbutazon sau lupusul eritematos produs de antimalarice etc.
c) Reacii alergice de tip III [9]
Sunt tot reacii alergice de tip imediat, rezultate n urma formrii unor
complexe circulante ntre antigeni i anticorpii IgG i IgH, complexe care se fixeaz n
vasele mici, producnd inflamaii ale acestora.
Manifestrile clinice ale acestor procese sunt:
- boala serului, care poate fi produs de peniciline (forma retard), sulfamide etc.;
- eozinofilie pulmonar, care poate fi produs de: sulfamide, furazolidon etc.;
- glomerulonefrit cronic poate fi produs de srurile de aur;
d) Reacii alergice de tip IV [9]
Sunt alergii ntrziate datorate sensibilizrii limfocitelor T, care elibereaz
limfokina, substan generatoare de infiltrate monocelulare.
Manifestrile clinice a acestui tip de reacii alergice sunt:
- dermatite de contact, care pot fi produse de aminoglicozide ca: gentamicina,
neomicina etc.;
- eritem polimorf, care poate fi produs de: sulfamide, peniciline, barbiturice,
izoniazid, acid acetilsalicilic etc.
e) Reacii alergice autoimune [9]
Din aceast categorie avem urmtoarele tipuri de manifestri de
tip alergic:
- hepatite autoimune pot fi produse de sulfamide, izoniazid, fenotiazine etc.;
- miastenii autoimune pot fi produse de D-penicilamina;
- anemie hemolitic autoimun poate fi produs de -metildopa etc.
f) oc alergic medicamentos [9]
Este mai frecvent la persoane cu polimedicaie sau avnd diferite suferine, ca:
nevroze, tulburri endocrine etc.
ocul alergic medicamentos este cea mai grav reacie alergic, cu o frecven
de manifestare n continu cretere.
ocul alergic poate fi de mai multe feluri, dar are n general un debut rapid, o
simptomatologie alarmant, evoluie rapid i un sfrit care poate fi exitus (moarte)
sau restabilire prin intervenie de urgen asupra pacientului.
1.7.2.3. Modaliti profilactice de investigare i tratament a manifestrilor de
tip alergic
Pentru a preveni manifestrile alergice iatrogene, se propun cteva msuri de
ordin profilactic, i anume:
- utilizarea cu mult discernmnt a medicamentelor cu potenial alergizant
ridicat;
- evitarea utilizrii topice, cutanate sau pe mucoase a medicamentelor foarte
alergizante, ca de exemplu: peniciline, sulfamide etc.
Ca metode de investigare a manifestrilor de tip alergic, exist
urmtoarele modaliti:
- anamneza atent a bolnavilor;
- teste in vitro (test de hemaglutinare pasiv etc.);
- teste cutanate (intradermoreacie etc.)
Ca mod de tratament al manifestrilor de tip alergic se indic:
- oprirea urgent a administrrii medicamentului;
- utilizarea de medicamente antialergice (antihistaminice H1, adrenalin sau
corticosteroizi administrate i.v. lent).

1.8. Reacii adverse produse de medicamente
imunosupresive

1.8.1. Generaliti

Reaciile adverse de acest tip constau n deprimarea capacitii de aprarea a
organismului mpotriva diferitelor particule cu rol antigenic. n terapie se utilizeaz
medicamente cu rol de modulare a sistemului imunitar.
Mecanismele implicate n producerea reaciilor adverse imunosupresive pot fi
diferite, i anume:
- mecanism farmacodinamic secundar;
- mecanism toxic;
- mecanism imunoalergic.


1.8.2. Tipuri de reacii adverse produse de imunosupresive [9]

n continuare vor fi amintite dou tipuri de reacii adverse datorate imunodepresiei, i anume:
- agranulocitoza, cu manifestri clinice acute, cu o evoluie rapid spre exitus;
- i deficiena imunitar latent, o form cronic latent care poate conduce la:
infecii foarte grave sau tumori maligne.
1.8.2.1. Agranulocitoza
Agranulocitoza poate fi declanat de numeroase medicamente, ca de exemplu:
- analgezice-antipiretice (pirazolona, anilide etc.);
- antiinflamatoare nesteroidiene;
- sulfamide, antibiotice i chimioterapice (peniciline, cefalosporine,
cloramfenicol);
- anestezice generale;
- antiepileptice (carbamazepin, fenitoin etc.);
- neuroleptice fenotiazinice;
- antiaritmice (propranolol);
- antihistaminice H1 i H2;
- antitiroidiene;
- antidepresive triciclice;
- antihipertensive (alfa-metildopa etc.).
Viteza de instalare a bolii este dependent de mecanismele implicate n
producerea ei, mecanismul imuno-alergic avnd evoluie foarte rapid.
n continuare se va prezenta perioada de timp pn la debutul bolii,
produs de diferite medicamente, n funcie de mecanismul de producere implicat, i
anume:
- fenotiazinele pot produce agranulocitoz prin mecanism toxic, viteza de
instalare fiind 3-12 sptmni;
- metamizolul poate provoca, prin mecanism imunologic la pacient nesensibilizat,
boala n 7-10 zile;
- metamizolul poate declana boala prin mecanism imunologic la persoan
sensibilizat n 6-10 ore;
Pentru tratamentul agranulocitozei se impun urmtoarele msuri:
- oprirea imediat a tratamentului;
- spitalizare n camer steril;
- tratament de urgen cu antibiotice n doze mari;
- transfuzie de granulocite;
- transplant medular, n cazul n care aplazia este ireversibil.
1.8.2.2. Deficiena imunitar latent
Aceast suferin poate avea cauze diverse, i anume:
- infestri virale (HIV);
- substane toxice;
- diferite stri careniale;
- medicamente.
n continuare se vor prezenta cteva medicamente care produc deficien
imunitar latent prin diferite mecanisme, i anume:
a. Medicamente ca sulfamidele, fenotiazinele, antitiroidienele, cloramfenicolul,
pot produce aceast boal prin aciune hipoplazic-medular pe seria alb sau
general.
b. Medicamente ca: alcool, anestezice generale, neuroleptice feno-tiazinice,
tranchilizante benzodiazepinice, antibiotice (tetraciclina, rifam-picina, eritromicina,
cotrimoxazol, digoxina pot produce aceast deficien- imunitar prin deprimarea
imunitii celulare.
c. Medicamente ca: anestezice generale, neuroleptice fenotiazinice,
antiepileptice (fenitoina), nicotina n exces, streptomicina, pot produce deficien
imunitar latent prin deprimarea imunitii umorale (scderea sintezei de anticorpi).
d. Antiinflamatoarele nesteroidiene, glucocorticoizii i citostaticele, pot induce
aceast suferin prin inhibarea sintezei proteice, n limfocite etc.

1.8.3. Modaliti de profilaxie a reaciilor adverse de tip imunodepresiv [9]

Reaciile adverse imunosupresive sunt foarte grave, datorit evoluiei care se
poate derula precum s-a artat:
- rapid, iminen de moarte rapid, n cazul ocului toxiinfecios;
- sau lent, cnd pot rezulta tumori maligne sau alte suferine grave.
innd cont de cele afirmate, se impun, n primul rnd, msuri profilactice, ca
de exemplu:
- o bun cunoatere a medicamentelor cu potenial farmacotoxicolo-gic
imunodepresiv;
- limitarea utilizrii medicamentelor care pot produce acest tip de reacii adverse;
- utilizarea cu mult pruden a antibioterapiei profilactice n chirurgie;
- limitarea pe ct posibil a antibioterapiei n perioada copilriei, perioad n care
se dezvolt sistemul imunitar;
- utilizrea antibioticelor sau sulfamidelor numai dup efectuarea antibiogramei;
- asocierea medicamentelor cu potenial imunodepresiv cu imunostimulante la
bolnavii cu risc.

1.9. Tolerana (tahifilaxia)

Acest tip de manifestare const ntr-o sensibilitate sczut a organismului la
aciunea diferitelor medicamente.
Tolerana poate fi de dou tipuri:
- nnscut (congenital);
- sau dobndit.

1.9.1. Tolerana nnscut

Poate fi de mai multe feluri, i anume:
- tolerana de specie, ca de exemplu: iepurele, tolereaz atropina datorit faptului c posed
atropinesteraza, o enzim care metabolizeaz acest alcaloid;
- sau tolerana de grup cnd anumite populaii prezint un anumit deficit
enzimatic cu repercusiuni asupra metabolizrii diferitelor medicamente.




1.9.2. Tolerana dobndit

Acest tip de manifestare const n scderea efectului medicamentului n urma
administrrii repetate, fiind nevoie de creterea dozei pentru obinerea acelorai
efecte.
Tolerana dobndit este de dou feluri, i anume:
- acut (tahifilaxie);
- cronic (obinuin).
1.9.2.1. Tolerana acut
Tolerana acut const n scderea treptat a efectului produs de medicamente
prin administrri repetate, la intervale scurte de timp. Acest tip de toleran are
urmtoarele caracteristici:
- fenomenul este reversibil, dup ntreruperea tratamentului;
- tolerana se instaleaz rapid;
- efectul se diminueaz treptat, pn la dispariie;
- durata efectului este scurt, dup ntreruperea tratamentului.
Tahifilaxia are urmtorul mecanism de producere:
- epuizarea sau saturarea unor receptori;
- desensibilizarea receptorilor prin internalizare (down regulation).
Exemple de medicamente care pot da tahifilaxie sunt:
- efedrina, 2-adrenomimetice, nitrii organici coronarodilatatori etc.
1.9.2.2. Tolerana cronic (obinuina)
Tolerana cronic const n scderea efectului substanelor medicamentoase
dup administrarea repetat, fiind necesar creterea dozei pentru obinerea aceluiai
efect. Datorit obinuinei, organismul poate s suporte la un anumit moment chiar
doze toxice fr probleme. Un tip de obinuin este mitridatismul, nume care vine de
la Mitridates, regele Pontului, care a experimentat o astfel de toleran cronic
dobndit.
Tolerana cronic are urmtoarele caracteristici:
- se instaleaz lent;
- este necesar creterea treptat a dozelor;
- fenomenul este reversibil dup o perioad de timp mai ndelungat.
i n cazul acestui tip de toleran, mecanismul farmacodinamic este
desensibilizarea receptorilor prin down regulation.
Acest tip de toleran poate fi dat de substane medicamentoase, ca: hipnotice
barbiturice, agoniti opioizi etc.

1.10. Farmacodependena (dependena medicamentoas)

1.10.1. Generaliti

Farmacodependea poate fi definit ca starea psihic sau/i fizic care se
instaleaz n organism ca urmare a consumului abuziv, nejustificat, dintr-o substan
medicamentoas, ducnd, n funcie de diferii factori, la instalarea unei nevoi de a
consuma substana respectiv n mod continuu sau periodic.
Farmacodependena apare cnd n contextul existenei persoanei apar anumite
circumstane favorizante, dintre care amintim:
- mediul socio-cultural al persoanei;
- particularitile psiho-somatice individuale;
- utilizarea de substane care produc farmacodependen.

1.10.2. Faze ale farmacodependenei

n funcie de perioada de timp i de ali factori prezentai anterior, se poate
instala farmacodependena, care are mai multe stadii, pe care le vom prezenta n
ordinea apariiei dup administrarea de substane care dau farmacodependen, i
anume:
a) Dependena psihic
Acest tip de farmacodependen const n dorina individului, dezvoltat pe un
fond psihic alterat, de a procura substana incriminat, utiliznd orice modalitate
posibil cu scopul de a nltura disconfortul psihic i de a crea senzaia de bine, n
pofida faptului c indivizii respectivi cunosc bine consecinele acestui fapt n plan
personal, familial i social, ct i prevederile legale care limiteaz utilizarea acestor
substane cu scop protector asupra entitilor amintite anterior.
b) Tolerana a fost studiat anterior i reprezint starea adaptativ a
organismului, manifestat prin scderea efectului substanei respective la
administrarea repetat a unor doze similare, pentru obinerea acelorai efecte fiind
necesar creterea dozei. Scderea efectului este rezultatul diminurii reactivitii
neuronilor la anumite doze din substana administrat.
c) Dependena fizic
Este starea patologic care este evideniat n momentul ntreruperii
administrrii unei substane care creeaz dependen, sau la o reducere semnificativ
a dozelor. Dependena fizic este evideniat prin apariia sindromului de abstinen
sau sevraj. Mecanismul instalrii acestui tip de dependen const n
hipersensibilizarea unui sistem care este dependent funcional de sistemul asupra
cruia acioneaz drogul, ca de exemplu:
- la administrarea opioidelor sunt sensibilizai receptorii adrenergici, prin reglare
ascendent (up regulation), deoarece neurotransmisia adrenergic este
modulat de neurotransmisia prin opioide endogene care inhib eliberarea de
catecolamine,
- sau, n cazul barbituricelor, sunt sensibilizai receptorii glutamatergici a cror
modulare este realizat de sistemul GABA prin inhibarea eliberrii acidului
glutamic, n urma stimulrii ndelungate a neurotransmisiei inhibitoare.
n cazul dependenei fizice, sindromul de abstinen este caracterizat att prin
tulburri psihice, ct i somatice.
d) Toxicomania (psihotoxicitatea) este tipul de intoxicaie cronic, caracterizat
prin cele trei tipuri de dependen definite anterior, i anume: fizic, tolerana,
psihic, conducnd la tulburri majore de comportament de ordin psihic i vegetativ,
astfel nct tratamentul acestei suferine este dificil, presupunnd condiii speciale
pentru readucere la starea normal.
Exist diferite tipuri de toxicomanie, acestea fiind clasificate dup mai multe
criterii:
d1) Dup numrul substanelor administrate:
- monotoxicomanii, cnd s-a administrat o singur substan;
- politoxicomanii, cnd toxicomania apare ca urmare a administrrii ndelungate
a mai multor substane euforizante.
d2) n funcie de substana administrat:
- toxicomanii minore, cele provocate de: barbiturice, hipnotice, tranchilizante,
alcool etc.
- toxicomanii majore, cele provocate de stupefiante.

1.10.3. Substane care pot provoca farmacodependen

n continuare vom aminti categorii de substane care pot crea acest sindrom, i
anume:
- depresive S.N.C. (alcool, hipnotice, sedative, tranchilizante);
- opioide, stimulante ale S.N.C. (amfetamina, cocaina etc.);
- halucinogene (heroina, LSD);
- canabis;
- solveni organici volatili (acetona, tetraclorura de carbon, toluen etc.).

1.10.4. Norme legislative privind farmacodependena

Datorit consecinelor negative ale toxicomaniei pe plan mondial, s-au luat
msuri prin organizaii care reglementeaz regimul acestor substane, i anume:
- Convenia unic asupra stupefiantelor, elaborat de O.N.U.;
- Convenia unic asupra substanelor psihotrope, elaborat de O.N.U.
La nivelul Organizaiei Naiunilor Unite funcioneaz urmtoarele comisii care
reglementeaz circulaia substanelor incriminate n toxicomanii:
- Comisia pentru stupefiante;
- O.I.C.S. (Organismul Internaional de Control al Stupefiantelor);
La nivel european exist:
- Centrul European de monitorizare pentru medicamente i adicie la
medicamente, cu sediul la Lisabona (1994);
- Centrul European de informare asupra medicamentelor i adiciei la
medicamente.
n Romnia, circulaia stupefiantelor este reglementat de prevederile Legii nr.
73/1969, cu alte completri ulterioare.




1.11. Intoxicaiile medicamentoase

1.11.1. Generaliti

Intoxicaiile medicamentoase sunt stri patologice rezultate prin administrarea
n mod accidental sau voit a unor substane toxice.
Intoxicaiile pot fi, n funcie de modul n care apar, mprite n: intoxicaii
acute (crime, sinucideri, intoxicaii accidentale) sau cronice (toxicomanii, dopaj
medicamentos etc.).
Intoxicaiile acute pot fi clasificate, n funcie de doza administrat i evoluia
clinic a strii pacientului, n:
a.Intoxicaii supraacute, n cazul n care sunt ingerate doze superioare celor
letale. Evoluia acestui tip de intoxicaie este rapid (minute, ore) spre exitus, dac nu
se intervine foarte urgent.
b.Intoxicaii acute propriu-zise, cnd pacientul a ingerat doze de substan
superioare dozelor terapeutice (doze toxice), evoluia bolnavului depinznd foarte mult
de primul ajutor acordat.
c.Intoxicaii subacute, rezult n urma acumulrii n organism a unor substane
medicamentoase datorit supradozrii, att prin administrare, ct i datorit unor
probleme la nivelul organelor epuratoare.

1.11.2. Simptomatologia n intoxicaii acute medicamentoase [24]

n caz de intoxicaii acute, sunt monitorizai urmtorii parametri care preced o
bun interpretare a rezultatelor investigaiilor pentru a ajunge la concluzii
corespunztoare, i anume:
a) Statusul S.N.C.
Acest parametru este influenat n mod diferit de anumite clase, i anume:
- stimulantele S.N.C. produc efecte ale stimulrii, ca: agitaie, tremor, euforie,
cefalee, delir, convulsii etc.
- blocantele S.N.C produc: astenie, somnolen, miastenie, colaps, com etc.;
- stimulare iniial urmat de inhibiie produs de: anticolinesterazice, atropin,
antidepresive triciclice etc.
b) Tensiunea arterial i pulsul
Diferitele categorii de medicamente pot influena tesiunea arterial
i ritmul cardiac n diferite moduri, ca de exemplu:
b1) Hipertensiune arterial i tahicardie (anticolinergice, cocaina, derivai de
amfetamin);
b2) Hipotensiune arterial i tahicardie (neuroleptice fenotiazinice, antidepresive
triciclice, teofilina, antihipertensive cu efect periferic;
b3) Hipotensiune cu bradicardie (-blocante, blocante ale canalelor de calciu, agoniti
ai receptorilor 2 presinaptici etc.).
c) Frecvena respiratorie
Exist urmtoarele modificri ale frecvenei respiratorii, i anume:
- tahipnee, care este produs de medicamente care produc acidoz metabolic
(salicilai etc.);
- dispnee, uneori chiar cu scurte perioade apneice, produs de opioide etc.
d) Temperatura corpului.
Acest parametru este influenat de multe medicamente care acioneaz asupra
S.N.C., ca de exemplu:
- doze toxice de amfetamin, atropin, hormoni tiroidieni pot provoca febr;
- majoritatea deprimantelor S.N.C., ca de exemplu: barbiturice, opioide, alcool
provoac hipotermie etc.
e) Diametrul pupilei
Acest parametru poate da indicii asupra tipului de intoxicaie n urmtoarele
moduri, i anume:
- mioz (micorarea diametrului pupilei) este produs de medicamente ca:
opioide, anticolinesterazice, parasimpatomimeti-ce etc.;
- midriaza, produs de parasimpatolitice, amfetamin etc.
f) Tranzitul digestiv poate fi modificat n urmtoarele moduri:
- tranzit accelerat n intoxicaii cu colinomimetice, propulsive etc;
- sau tranzit diminuat n intoxicaii cu parasimpatolitice, opioide etc
g) Aspectul epiteliilor (piele i mucoase)
Aspectul epiteliilor poate da uneori indicii asupra etiologiei intoxicaiei, ca de
exemplu:
- cianoza poate sugera o methemoglobinemie;
- icterul poate sugera o hepatit acut;
- uscciunea gurii, tegumente uscate, pot sugera o intoxicaie cu
parasimpatolitice etc.;
- hipersecreia glandelor sudoripare sau a altor glande exocrine, poate sugera o
intoxicaie cu anticolinesterazice sau parasimpatomimetice.

1.11.3. Modalitile de intervenie a personalului medical n intoxicaii acute cu diferite
substane

Conduita de urgen presupune urmtorii pai:
a) Msuri pentru asigurarea meninerii funciilor vitale, ca de exemplu:
- respiraie artificial;
- ventilaie mecanic;
- masaj cardiac extern;
- administrarea de substane simpatomimetice etc., pentru meninerea funciilor
respiratorii;
- oxigenoterapie, dac este cazul.
b) Msuri de mpiedicare a absorbiei toxicului n mediul intern al organismului, ca
de exemplu:
- splturi gastrice;
- provocare de vom;
- administrare de purgative etc.
c) Msuri prin care este grbit eliminarea toxicului:
- modificarea pH-ului n mod corespunztor, nct s se realizeze disocierea
electrolitic a substanei i s fie mpiedicat absorbia tubular din urina
primar etc.
d) Hemodializa, dac este cazul;
e) Administrarea unui antidot general sau specific.
Pn la obinerea rezultatelor de laborator n urma investigaiei pe anumite
lichide biologice etc., se poate administra un antidot general, cum ar fi crbune
absorbant etc.
Dup descoperirea toxicului, se va recurge la un antidot specific.


1.12. Dopajul medicamentos

Dopajul medicamentos const n utilizarea de substane medicamentoase pentru
a mri randamentul n activiti sportive sau intelectuale. Exist convenii
internaionale care combat dopajul pe considerente de ordin etic, i anume:
- Comitetul Internaional Olimpic (C.I.O.) din aprilie 1989;
- Convenia pentru dopaj din cadrul Consiliului Europei din Strasbourg. n
Romnia, convenia mpotriva dopajului este ratificat prin Legea numrul 171
din 1998.
In continuare se vor prezenta n mod succint grupele de medicamente utilizate i
cteva substane din fiecare grup care utilizate produc dopaj i anume:
a. Stimulante S.N.C.: amfetamina, efedrina, cocaina, amfepramona, stricnina,
metilfenidat etc.
b. Analgezice morfinomimetice: codein, morfin, dextropropoxifen, petidin,
dionin, heroin etc..
c. Steroizi anabolizani: metiltestosteron, nandrolon, testosteron etc.
d. -blocante: atenolol, metoprolol, oxprenolol, propanolol etc.
e. diuretice: furosemid, spironolacton, clortalidon hidroclortiazid,
acetazolamid etc.

1.13. Reacii adverse rezultate la ntreruperea
farmacoterapiei

6.12.1. Generaliti

Cnd se ntrerupe brusc administrarea unui medicament dup o administrare
ndelungat, pot rezulta reacii adverse, uneori cu manifestri clinice grave, dezvoltate
pe fondul adaptrii fiziologice a pacienilor respectivi la agresiunea medicamentoas.
La ntreruperea brusc a unui tratament medicamentos pot aprea urmtoarele
tipuri de reacii adverse:
- reacii adverse rezultate prin ntreruperea unui tratament cu antagoniti
farmacologici;
- reacii adverse rezultate prin ntreruperea unui tratament cu agoniti
farmacologici;
- i reacii adverse rezultate pe fondul unei insuficiene funcionale.
1.13.1.1. Reacii adverse rezultate prin ntreruperea tratamentului
cu antagoniti farmacologici[9]
Acest tip de reacii se dezvolt pe fondul receptorilor antagonizai de anumite
substane medicamentoase, sensibilizare produs n urma unui proces de
externalizare a receptorilor respectivi.
Ca exemple de reacii adverse rezultate printr-un astfel de meca-nism amintim:
- reacii adverse rezultate la ntreruperea tratamentului cu antihistaminice H2
(ranitidin, cimetidin etc.), care pot conduce la agravarea ulcerului gastro-
intestinal pn la perforare;
- reacii adverse rezultate la ntreruperea tratamentului cu -adrenolitice
(propranolol), care pot conduce la hipertensiune arterial sau angin pectoral;
- reacii adverse rezultate la ntreruperea tratamentului cu anticolinesterazice
centrale (atropin, trihexilfenidil etc.), care pot conduce la tulburri
extrapiramidale etc.
Mecanismul implicat n producerea reaciilor adverse de acest tip este creterea
numrului de receptori disponibili prin externalizarea lor la suprafaa membranei n
urma blocrii acestor tipuri de receptori timp ndelungat i fixarea agonistului
fiziologic pe un numr masiv de recep-tori n momentul ntreruperii medicaiei
blocante, rezultnd astfel efecte exagerate. Mecanismul producerii este prin
sensibilizarea receptorilor.
1.13.1.2. Reacii adverse rezultate prin ntreruperea tratamentului cu agoniti
farmacologici[9]
Acest tip de sindrom apare ca rezultat al ntreruperii administrrii (n urma
unui tratament de lung durat) cu substane medicamentoase din categoria agoniti
ai receptorilor farmacologici aparinnd unui sistem modulator sau inhibitor al unei
alte neurotransmisii.
Ca exemple de agoniti din aceast categorie amintim:
- medicamente morfinomimetice care sunt agoniti ai receptorilor opioizi i k, i
care moduleaz neurotransmisia adrenergic;
- medicamente barbiturice sau benzodiazepinice care sunt agoniti ai
neurotransmisiei GABA, neurotransmisie modulatoare pentru neurotransmisia
glutamatergic sau adrenergic.
La ntreruperea administrrii acestui tip de agoniti apare sindromul de
abstinen, de retragere, manifestat prin suprastimularea neurotransmisiilor
modulate de ctre medicamente.
Mecanismul implicat n acest sindrom este urmtorul:
medicamentele de tip agonist (morfin etc.) stimuleaz receptorii din sistemul
modulator sau inhibitor, n cazul morfinei sistemul opioid sau sistemul GABA. n
urma stimulrii receptorilor modulatori n sistemele amintite, este deprimat
eliberarea mediatorului la nivelul heterosinapsei n sistemul modulat adrenergic sau
glutamatergic. Compensator, n sistemul modulator are loc externalizarea receptorilor
cu o cretere a cmpului receptorilor prin mecanism hetero up-regulation. n
momentul ntreruperii medicaiei agoniste, pe sistemul modulator are loc o exacerbare
a funcionrii sistemului modulator, avnd consecinele clinice ale agonizrii acestuia
de ctre neurotransmitorul endogen.
1.13.1.3. Reacii adverse rezultate pe fondul unei insuficiene funcionale [9]
Acest tip de reacii adverse pot aprea pe fondul unor insuficiene funcionale
ale unei glande endocrine, rezultate n urma administrrii de hormoni pe cale
exogen. Funcionarea glandelor endocrine, ca de exemplu corticosuprarenalele, este
coordonat de concentraia sanguin a produsului final de lan metabolic (hormoni
corticosteroizi) prin retrocontrol (feed-back) pozitiv sau negativ, n urma aciunii
acestora la nivelul chemoreceptorilor din hipotalamus i hipofiz.
Pe baza concentraiei sanguine de hormon circulant, hipotalamu-
sul secret neurohormonul hipotalamic (CRF), hipofiza hormonul (ACTH), care au rol
de control a funcionrii endocrine a corticosuprarenalei.
n urma administrrii de corticosteroizi timp ndelungat, se reduce secreia de
corticosteroizi ai glandei corticosuprarenale, mecanismul fiind dirijat prin feed-back
negativ de lanul hipotalamo-hipofizar. La ntreruperea brusc a administrrii
corticosteroizilor, apare fenomenul de insuficien, fenomen manifestat pn la
repunerea n funcie a glandei periferice la un alt nivel, desigur dirijat prin acelai
mecanism, de ctre centrii nervoi care controleaz funcionarea glandei. Pentru
perioada de timp necesar pentru adaptarea glandei endocrine la noile condiii, apare
fenomenul de insuficien funcional, caracterizat prin reacii adverse caracteristice
carenei hormonale.
Medicamente care declaneaz tulburri la oprirea brusc a administrrii lor
Din aceast categorie putem aminti: medicamente antiepileptice (barbiturice,
benzodiazepine), antiparkinsoniene, antihipertensive (cloni-dina), antiastmatice (2
adrenomimetice), antianginoase (2 adrenolitice), antiulceroase prin mecanism
antihistaminice H2, anticolinergice centrale, corticosteroizi, opioide etc.
Medicamentele din aceast clas nu se ntrerup niciodat brusc, ci ntreruperea
tratamentului are loc dup reducerea treptat a dozelor administrate.
Medicamente care pot provoca tulburri la oprirea brusc
Din acest grup putem aminti:
- medicamente neuroleptice;
- tranchilizante (benzodiazepine);
- hipnotice (glutetimid);
- simpatomimetice vasoconstrictoare periferice (decongestionante nazale);
- sedative (bromuri) etc.
i la acest grup de medicamente este bine ca dozele s se reduc treptat.
Medicamente care se presupune c ar determina tulburri la oprirea brusc
Din acest grup amintim: anorexigene, anticoagulante orale.
i la ntreruperea tratamentului cu medicamentele menionate este important s fie luate
toate msurile pentru a ndeprta posibilele reacii adverse de acest tip.

CAPITOLUL II
FARMACOEPIDEMIOLOGIA

2.1. Generaliti

Procesul epidemiologic medicamentos este un fenomen real, motiv pentru care
medicamentul, ca focar epidemiologic trebuie luat n studiu, astfel aprnd o nou
ramur a farmacologiei, cu denumirea de farmacoepidemiologie, aceasta fiind o tiin
de grani ntre farmacie i epidemiologie.
Farmacoepidemiologia, ca ramur cu caracter aplicativ a farmacologiei, este
bazat pe farmacotoxicologie i studiaz contraindicaiile i precauiile n practica
farmacoterapic, respectiv farmacografic.
Farmacoepidemiologia are urmtoarele categorii de obiective, i anume:
a. Obiective cu caracter general, ca de exemplu:
- studiul declanrii, manifestrii i sistrii bolilor produse de medicamente;
- instituirea unor msuri corespunztoare att din punct de vedere profilactic, ct
i curativ, legate de procesul epidemiologic medicamentos.
b.Obiective particulare
Dintre obiectivele particulare ale acestei ramuri amintim:
- studiul tipurilor de reacii adverse raportate la diferite condiii, n contextul n
care au aprut, ca de exemplu: categorie de vrst, zon geografic, grupa
farmacologic etc.;
- studiul modului n care crete procentul reaciilor adverse i al intoxicaiilor n
corelaie cu consumul de medicamente;
- studiul, respectiv instituirea unor msuri prin care s fie defavorizat procesul
epidemiologic medicamentos;
- respectarea contraindicaiilor i precauiilor, respectiv instituirea celor mai
drastice msuri de ordin farmacoterapic i farmacografic;
- elaborarea unor legi generale privind procesul epidemiologic medicamentos.
2.2. Prezentarea din punct de vedere statistic a rezultatelor
unor studii privind prevalena i incidena reaciilor adverse
[9]

n urma studiilor derulate n acest scop, s-a ajuns la urmtoarele concluzii:
- ntre 3 7 % din numrul total de bolnavi spitalizai au ajuns n aceast stare
critic datorit unui proces epidemiologic medicamentos;
- ntre 5 35 % dintre bolnavii internai n spital acuz diferite tipuri de reacii
adverse;
- procentul de reacii adverse crete proporional, cu numrul de medicamente
administrate concomitent;
- exist diferene mari ntre medicamente privind efectele farmaco-toxicologice;
- din numrul total de reacii adverse nregistrate, exist medicamente utilizate
doar n procent de 1 % (din totalul medicamentelor utilizate), dar procentul
reaciilor adverse produse de acestea se ridic la 30 % din total;
- din totalul medicamentelor care produc reacii adverse, locul de leader este
ocupat de ampicilin, dup care un loc important l ocup contraceptivele orale;
- prin administrarea unui singur medicament s-a nregistrat un numr de 16 %
reacii adverse;
- prin administrarea de 10 medicamente concomitent, procentul a crescut la 100
%;
- s-a constatat c un procent de numai 1 % din medicamente au fost implicate n
aproximativ 40 % din cazurile letale declarate;
- cauzele cele mai frecvente de decese datorate reaciilor adverse produse de
medicamente sunt urmtoarele: hemoragii i ulceraii digestive (corticosteroizi,
AINS etc.), hemoragii cu alte localizri (anticoagulante), anemie aplastic
(cloramfenicol), oc anafilactic (peniciline), infecii (imunosupresive), leziuni
hepatice (izoniazid) etc.


2.3. Elemente (Aspecte) de studiu ale procesului
epidemiologic

2.3.1. Definiie

Procesul epidemiologic medicamentos este reprezentat de totalitatea
tulburrilor produse n organism, cu implicaii economico-sociale, rezultate n urma
manifestrii reaciilor farmacotoxicologice ale unei substane medicamentoase.

2.3.2. Etapele procesului epidemiologic

Procesul epidemiologic are urmtoarele etape:
a) Debut
Aceast etap are loc de obicei la introducerea medicamentului n terapie;
b) Evoluie, care poate fi ascendent sau descendent i este dependent de
cantitatea de substan medicamentoas ingerat, ct i de anumii factori care
pot fi determinani sau favorizani;
c) Stingerea focarului epidemiologic
Aceast faz are loc n momentul scoaterii medicamentului respectiv din
terapie.
n continuare vom prezenta cteva substane care au declanat procesul
epidemiologic n anumite zone geografice, ct i modul n care s-a soluionat procesul
respectiv, ca de exemplu:
c1 Talidomida, tranchilizant care a produs malformaii n anumite zone din Europa
de vest, procesul epidemiologic constnd n inhibarea proceselor de cretere ale
braului i antebraului, afectarea producndu-se n timpul vieii uterine, rezultnd
copii cu bra i antebra foarte scurt. Stingerea focarului a avut loc prin scoaterea
medicamentului din terapie.
c2 Acidul acetilsalicilic, medicament analgezic-antipiretic, d reacii adverse digestive
(sindrom ulceros etc.). Dup descoperirea efectului antiagregant plachetar la
administrarea n doze mici, dar prin folosirea continu procesul epidemiologic
medicamentos nregistreaz o cretere.
c3 Aminofenazona, analgezic antipiretic de tip pirazolon are diferite reacii
adverse, ca de exemplu:
- modificri de tip alergic;
- leucopenie;
- favorizarea cancerului gastric prin eliberarea de nitrozamine etc.
n urma acestor observaii, la recomandarea Centrului de Farmacovigilen al
O.M.S., acest medicament s-a scos din terapie n multe ri, iar n alte ri se
elibereaz doar pe baz de prescripie medical. Ca urmare a acestor msuri, procesul
epidemiologic indus de aminofenazon nregistreaz o pant descendent.

2.3.3. Forme de manifestare a procesului epidemiologic medicamentos

Manifestarea acestui proces poate avea loc n diferite moduri, i anume:
- sporadic, procesul se manifest rar;
- endemic, manifestarea procesului epidemiologic este legat de o anumit zon, de
o anumit populaie, se manifest permanent, dar frecvena de apariie este mic;
- epidemic, procesul epidemiologic se manifest limitat ca timp sau regiune
geografic, dar frecvena de apariie a bolii este mare;
- pandemic, un tip de epidemie care afecteaz un teritoriu geografic sau
populaional mare, uneori extinzndu-se la nivelul globului pmntesc.

2.3.4. Factori care declaneaz procesul epidemiologic medicamentos

Factorii incriminai n declanarea procesului epidemiologic medi-camentos
sunt mprii n dou grupe, i anume:
a) Factori determinani
Dintre factorii determinani amintim:
- izvorul epidemiogen, care este dependent de structura chimic a substanei
medicamentoase care declaneaz reacia advers;
- i particularitile biologice ale populaiei sensibile, unde se pot aminti;
reactivitatea individual, structura genotipului, diferite stri patologice etc.
b) Factori care favorizeaz apariia procesului epidemiologic medicamen-tos
Dintre aceti factori amintim:
- consumul exagerat de medicamente, manifestat att prin dozele administrate, ct
i prin frecvena administrrii;
- diferite asocieri medicamentoase urmate de interaciuni;
- alimentaie;
- zona climateric;
- factori socio-culturali (nivel de trai, stres, nivelul educaiei sanitare etc.) etc.

2.4. Formele activitii farmacoepidemiologice

Formele activitii farmacoepidemiologice pot fi de dou tipuri:
- activiti de prevenire a procesului (profilaxia);
- i activiti de combatere a procesului epidemiologic medicamentos.

2.4.1. Activitatea profilactic

Acest tip de activitate const n:
- cunoaterea amnunit a reaciilor adverse, contraindicaiilor i precauiilor care
sunt necesare a fi tiute nc nainte de introducerea n terapie a medicamentului;
- fixarea cadrului legislativ de eliberare, depozitare i circulaie a medicamentelor
cu potenial farmacotoxicologic;
- o educaie sanitar adecvat etc.
Referitor la momentul apariiei reaciilor adverse ale unor medicamente, exist
urmtoarele dou tipuri, i anume:
- reacii adverse cunoscute nainte de autorizare pe piaa mondial;
- reacii adverse depistate dup introducerea n terapie.
2.4.1.1. Reacii adverse depistate nainte de autorizare
Reaciile adverse de acest tip pot fi mprite n dou grupe:
- reacii adverse previzibile dependente de doz, durata administrrii etc.;
- i reacii adverse imprevizibile, independente de doz, i anume: reaciile de tip
alergic i idiosincrazice.
Dintre exemplele de reacii adverse de acest tip amintim:
- anemia aplastic, rezultat n urma tratamentului cu cloramfenicol; - anemia
hemolitic rezultat n urma administrrii de antimalarice la bolnavi avnd
deficient enzima glucoz 6 fosfatdehidrogenaza G-6 PD.
Msurile profilactice care se impun n cazul reaciilor adverse cunoscute sunt:
- prescrierea de doze minime eficace;
- monitorizarea concentraiei plasmatice la medicamentele metabo-lizate de
sisteme enzimatice care prezint polimorfism, ca de exemplu n cazurile:
izoniazidei, sulfamidelor, hipoglicemiantelor, propranol-olului etc.;
- anamneza amnunit a bolnavilor, pentru depistarea unor eventuale
sensibilizri anterioare.
2.4.1.2. Profilaxia reaciilor adverse necunoscute
Cunoaterea ntregului profil farmacotoxicologic al medicamentu-lui nainte de
utilizarea n terapie nu este posibil, deoarece:
- sunt reacii adverse care nu se pot evidenia n cadrul cercetrii pe animale de
laborator, ca de exemplu: ameeal, greuri, insomnie, depresie etc.;
- exist reacii adverse cu inciden nou;
- exist deosebire privind efectele terapeutice la om fa de animale (ex. cazul
talidomidei ) etc.
Din punct de vedere statistic, s-a observat c:
- aproximativ 50 % dintre reaciile adverse observate sunt evideniate numai n
urma administrrii la om;
- exist reacii adverse cu inciden rar i care sunt evideniate la 1/10 000
1/50 000 din indivizii tratai cu o anumit substan medicamentoas, care sunt
depistate n urma activitii de farmacovigilen;
Deoarece situaia se prezint astfel, este necesar s fie luate urm-toarele
msuri:
- monitorizarea atent a medicamentelor nou introduse n terapie;
- utilizarea cu mult pruden a medicamentelor nou introduse;
- neutilizarea medicamentelor nou introduse pentru tratamentul gravidelor i
copiilor pn la vrsta de 15 ani.
2.4.2. Activiti de combatere a procesului epidemiologic medicamentos [9]

Acest tip de activitate presupune:
- depistarea ct mai rapid posibil a reaciilor adverse i intoxicaiilor
medicamentoase;
- diagnosticarea corect a reaciilor adverse i intoxicaiilor produse de diferite
medicamente.
Activitatea de combatere a procesului farmacoepidemiologic este organizat n
cadrul sistemului de farmacovigilen, care presupune nregistrarea i raportarea
tuturor reaciilor adverse sau a intoxicaiilor iatrogene observate.
Reaciile adverse rezultate n urma administrrii medicamentelor pot fi de mai
multe feluri din punct de vedere al gravitii, i anume:
- uoare, care nu presupun administrarea de medicamente antidot sau alte msuri
terapeutice;
- moderate, care impun modificarea tratamentului i pot prelungi timpul pn la
vindecare;
- severe, care necesit ntreruperea tratamentului, pe lng alte msuri terapeutice
care se impun;
- letale, care determin moartea bolnavului.
n funcie de categoriile de reacii adverse se impune un tratament ct mai
adecvat, i anume:
- n cazul reaciilor adverse independente de doz trebuie neaprat sistat
tratamentul i totodat evitarea unei expuneri n viitor;
- n cazul reaciilor adverse dependente de doz, se reduce cantitatea administrat
pn la limitele minime posibile, astfel nct s se obin un efect farmacoterapic.

2.5. Sistemul de farmacovigilen

Acest sistem este organizat la nivel mondial i naional n urmtorul mod:
- exist un sediu central n cadrul O.M.S. (Organizaia Mondial a Sntii care
funcioneaz din 1968;
- exist reele naionale de Farmacovigilen n cadrul diferitelor ri, care trimit
informaii O.M.S. privind reaciile adverse depistate n urma administrrii unor
medicamente.
Rolul sediului central din cadrul O.M.S. este de a prelucra informaiile primite
de la reelele naionale i a ntocmi anumite rapoarte, care sunt trimise reelelor
naionale, care la rndul lor iau hotrri privitor la anumite probleme de ordin
farmacoepidemiologic.
n Romnia sistemul de farmacovigilen este organizat n baza unui ordin al
Ministerului Sntii i cuprinde urmtoarele entiti:
- Comisia Medicamentului, care funcioneaz n cadrul Ministerului Sntii;
- Centre n teritoriu la nivelul Universitilor de Medicin i Farmacie;
- Nuclee de Farmacovigilen la nivelul clinicilor universitare i spitalelor judeene.
Factorii umani implicai n activitatea de farmacovigilen sunt: medici,
farmaciti, ct i personalul tehnic auxiliar.
Activitatea sistemului de farmacovigilen const n depistarea, examinarea,
nregistrarea reaciilor adverse produse de medicamente.
Obiectivele activitii de farmacovigilen sunt:
- observarea ct mai rapid i complet a reaciilor adverse produse de
medicamente;
- cunoaterea msurilor profilactice i modalitilor curative specifice pentru
fiecare tip de reacie advers etc.
Metodele de investigare n farmacovigilen (FV) sunt:
- farmacovigilen prin metoda spontan, care const n raportri individuale
realizate de medici, farmaciti sau alte persoane;
- farmacovigilen prin metoda intensiv, care const n studii bine organizate de
ctre echipe de specialiti asupra unui numr mare de persoane, ca de exemplu:
toi bolnavii internai ntr-un spital, ntr-o anumit perioad de timp.
Farmacovigilena la scara unei populaii, care const n nregistrarea reaciilor
adverse observate n urma unui consum cunoscut de medicamente, n cadrul
populaiei respective.





















BIBLIOGRAFIE


1. Alexandrescu Lygia Elemente de semiologie i farmacologie, Editura Fundaiei
Romnia de Mine, 2007 ;
2. Alecu M., Alecu Silvia, Reacii alergice la medicamente, Ed. Medical, 2002;
3. Benga Gh., Biologie celular i molecular, Editura Didactic i pedagogic
Bucureti,1976;
4. Boji M., Sndulescu R., Roman L., Oprean R. - Analiza i controlul
medicamentelor Vol.1, Editura Intelcredo Deva, 2002
5. Boji M., Sndulescu R., Roman L., Oprean R. - Analiza i controlul medicamentelor
Vol.2, Editura Intelcredo Deva, 2003
6. Cinca Rodica, Popovici Marinela i colab., Curs de Farmacologie, Editura Mirton,
Timioara, 2006
7. Cotru M., Stan T., Popa Lidia, Preda I., Kincsesz-Ajtay Maria, Toxicologie, Ed.
Didactic i Pedagogic, Bucureti, 1991;
8. Cristea Aurelia-Nicoleta,Teodorescu Simona, Paraschiv-Bucur Laura, Petril-
Ciobanu Alexandra, Darie Viorica - Cercetri farmacologice experimentale privind
aciunea diluiilor homeopate de Chamomilla la nivelul sistemului nervos central -
Farmacia, Bucureti, 1994, 62 (1-2), p. 12-15.
9. Cristea Aurelia Nicoleta, - Farmacologie general, Editura Didactic i Pedagogic,
Bucureti, 1998
10. Cristea Aurelia Nicoleta, - Farmacologie, Note de curs, Editura Medical,
Bucureti, 1999
11. Cristea Aurelia Nicoleta, Tratat de farmacologie, Ediia 1, Editura Medical,
Bucureti, 2005
12. Cristea I., Terapia durerii, Editura Medical, Bucureti,1996;
13. Cucuiet Sorina - Farmacologie, 2007 ISBN 978-973-7665-43-0 UMF - TG.
MURES
14. Cuparencu B., Pleca Luminia Actualiti n farmacologie i fiziopatologie,
Editura Dacia, Cluj-Napoca, 1995;
15. Cuparencu B., Timar M., The farmacological receptors, 2
nd
edition, Gloria
Publishing House, Cluj-Napoca, 1998;
16. Danciu Felicia, Kory M., Lupuiu Georgeta, Structur chimic, Editura Dacia, Cluj-
Napoca,1983;
17. Diaconu E. i Nechifor M., Antibiotice betalactamice, Ed. Poligrafic, Cluj, 1988
18. Diaconu E., Nechifor, M., Antibiotice betalactamice, Editura Tehnic, Bucureti,
1985
19. Dinu,V., Popa-Cristea E. Truia,E., Popescu, A., Biochimie medical, Ed. Medicala
Bucureti, 1996;
20. Dobrescu. D., Farmacodinamie, Editura Didactic i Pedagogic, Bucureti,1977;
21. Dobrescu, D., Farmacoterapie, Ed. Medical, Bucureti, 1983
22. Dobrescu, D., Farmacoterapie practic, vol.I i II , Ed. Medical, Bucureti, 1989
23. Dobrescu, D., Gerontofarmacologie, Editura Mondan, Bucureti 1995;
24. Dogaru T. Maria, Vari C.E., Compendiu de farmacologie general, Editura
University Press, 2003;
25. Dogaru T. Maria Feszt G., Vari C.E., Mruteri M., Farmacologie Experimental,
U.M.F. Tg-Mure, 1998;
26. Fulga, I., Farmacologie, Editura Medical, Bucureti, 2004
27.Fontaine Janine, Travaux pratiques de pharmacologie, Universite Libre de Bruxeles,
Institute de Pharmacie, Edition 1995-1996;
28. Gligor Virginia, Tudor Rodica, Popovici Marinela, Curs de farma-cologie, vol. I.
Lito UMF 1993.
29. Gligor Virginia, Curs de farmacologie, vol. II Lito UMF 1994 ;
30. Hulic I., Fiziologie uman, Editura medical,Bucureti,1996
31. Haieganu Elena, Dumitrescu Elena, Stecoza Camelia, Moruciag L., Chimie
terapeutic, vol.I., Editura Medical, Bucureti, 2006 ;
32. Ionescu C., Biotransformarea medicamentelor, Editura Medical Universitar Iuliu
Haieganu Cluj Napoca, 2002;
33. Ionescu-Varo, M., Biologie celular, Editura Didactic i Pedagogic Bucureti,
1976;
34. Katzung G.B., Basic & Clinical Pharmacology, eight ed., 2000, 754-803
35. Klaasen C.D.,(edited by), Casaret and Doull s Tosicology-The Basic Science of
Poisons, 6
th
Editions, McGraw Hill, 2001;


36. Landry, Y., Gies J.P., Pharmocologie molculaire-Mcanismes daction des
mdiateurs et des mdicaments. Edition Arnette, Paris, 1993;
37. Leucua, S., Introducere n biofarmacie, Editura Dacia, Cluj-Napoca,1975;
38. Leucua, S., Pop, R.D., Farmacocinetic, Editura Dacia, Cluj-Napoca,1981;
39. Leucua, S., Farmacocinetica n terapia medicamentoas, Editura Medical,
Bucureti, 1989;
40. Leucua, S., Medicamente Vectorizate, Editura Medical, Bucureti, 1996;
41. Leucua,S., Tehnologie farmaceutic industrial, Ed. Dacia, 2001;
42. Leucua Sorin, Biofarmacie si farmacocinetica, Ed. Dacia 2002
43. Loghin Felicia, Toxicologie general, Editura Medical Universitar Iuliu
Haieganu Cluj-Napoca, 2002;
44. Katzung G.B., Basic & Clinical Pharmacology, VII
th
edition, Appleton & Lange,
Stamford Press, Connecticut,USA, 1998;
45. Manolescu, E., Farmacologie, Editura Didactic i Pedagogic, Bucureti, 1984;
46. Maximilian,C., Ioan D.M., Genetica medical, Editura Medical, Bucureti,1986;
47. Mitrea Vasilescu Niculina.Lupuleasa D., Andrie, A., Milica Enoiu, Biotehnologii
utilizate n prepararea medicamentelor, vol. I. Editura Medical,2001;
48. Mooc, I., Structura moleculelor i activitatea biologic, Editura Facla, Timioara,
1984;
49.Mungiu ,O.C., Algeziologie general, Editura Polirom, Iai, 1999;
50.Mungiu ,O.C., Paveliu, M., Paveliu Fraga, Biochimie - O abordare farmacologic,
Editura Polirom, Iai, 1999;
51. Mungiu, C. O.,(red.), Elemente de farmacologie fundamental, Editura U.M.F.
Gr.T.Popa, Iai, 1995;
52. Murean Ana, Medicaia n boli cardiovasculare, Ed. Medical Universitar Iuliu
Haieganu, Cluj-Napoca, 2005;
53. Mycek H., Farmacologie ilustrat, Editura Callisto, 2000.
54. Popa, I., Toxicologie, Ed. Medicala Bucuresti, 1978;
55. Popescu, L.M., Mixich, F., Biologie celular, Edit.Univ. Carol Davila Bucureti,
1996
56. Popovici Iuliana, Lupuliasa D., Tehnologie farmaceutic, Ed. Polirom, Iai, 2001;
57. Popovici, L., Hulic, I., Patologia Sistemului Nervos Vegetativ, Editura Medical,
Bucureti, 1982;
58. Popovici Marinela, Ghid de studiu n Farmacologie, Editura Mirton, Timioara,
2006;
59. Popovici Marinela, Dumitracu,V., D. Ana, Ioana Ana, Cheverean Adelina,
uta,N., ipo Simona, Lengyel Dana, Malia Ioana, Barac Beatrice, Ghid practic de
farmacologie, Ediia a III-a, Editura Mirton, Timioara, 2004;
60. Raicu, P., Genetica general i uman, Editura Humanitas, Bucureti, 1997 ;
61. Rang, H. P., Dale, M.M., Pharmacology, 2
nd
edition.Churchill Livingstone,1991 ;
62. Restian,A., Medicina cibernetic, Editura Dacia,Cluj-Napoca,1983 ;
63. Rosetti-Coloiu Matilda, Oeleanu, D., Biocatalizatorii n practica medical i
farmaceutic,Editura Medical Bucureti,1980 ;
64. Rusu, V., Baran, T., Brteanu ????,D.D.,Biomembrane i patologie. Editura
Medical Bucureti,vol.I 1988,vol.II 1991 ;
65. Simionovici, M., Crstea, Al., Vladescu,V., Cercetarea Farmacologica si
Prospectarea Medicamentelor, Ed. Medicala Bucuresti, 1983;
66. Schorderet, M., Pharmacologie- Des concepts fondamentaux aus applications
therapeutiques, Edition Frision Roche,Paris, Slatkine Geneve, 1992;
67. Rcz Istvn, Gygyszerformulls, Medicina Knyvkiad, Budapest, 1984;
68. San-Marina, I., Danciu, I., Nedelcu, Al., Anatomia i Fiziologia Omului, Editura
Didactic i Pedagogic, Bucureti, 1979;
69. Saragea ,M., Tratat de fiziopatologie, Editura Academiei, Bucureti, vol. I,1985,vol.
II,1987, vol.III 1994;
70. Stnescu,V., Savapol E., Incompatibiliti medicamentoase, Editura Medical,
Bucureti,1980;
71. Stroescu,V., Constantinescu Cociovei I., Fulga I., Ciubotaru, R., Indreptar pentru
prescrierea medicamentelor, Editura All, Bucureti, 1997;
72.Stroescu, V.: Bazele farmacologice ale practicii medicale. Ed. Medicala, Bucuresti,
1998.
73. Stroescu, V., Bazele Farmacologice ale practicii medicale, Ed.Medical, Bucureti,
1999, Ediia a 6-a
74. Stroescu, V., Bazele Farmacologice ale practicii medicale, ed.a VII-a, Ed.Medical,
Bucureti, 2001
75. Surdulescu, St.: Farmacologie generala. Curs si lucrri practice pentru Medicina
Generala, Stomatologie si Farmacie, vol. I, II, Ed. Ex Ponto, Constanta, 1997.
76. Simionovici,M., Carstea, Al., Vladescu, C., Cercetarea Farmacologica si
Prospectarea Medicamentelor, Ed. Medicala Bucuresti, 1983;
77. Simiti,I.,(red.), Elemente de farmacie clinic, Editura Dacia,Cluj-Napoca,1984;
78. Teodorescu-Exarcu, I.,(red), Fiziologia i fiziopatologia sistemului endocrine,
Editura Medical, Bucureti, 1989;
79. Vizi E. Sz., Human farmakologia, Medicina Konyvkiado, Budapest, 2000;
80. Voicu, V. A., Toxicologie clinic, Editura Albatros, Bucureti, 1997;
81. Voicu, V. A., Mircioiu, C., Mecanismele farmacologice la interfee membranare,
Editura Academiei Romne, Bucureti, 1994;
82. Wagner, J. G., Biopharmaceutics and Relevant Pharmacokinetics, Drug Intelligence
Publications, Hamilton, 1971;
83. Zgrean, L., Elemente de neurobiology, Editura Universitar Carol
Davila,Bucureti, 1996;
84. xxxx Agenda Medical 2006-2007, Ed. Med., Buc., 2006
85. xxxx Agenda Medical 2005-Ediia de buzunar, Ed. Med., Buc., 2005
86. xxxx British Pharmacopoeia, Commission Office: London, 2004
87. xxxx European Pharmacopoeia, 4
th
, Council of Europe, Strasbourg, 2001
88. xxxx European Pharmacopoeia, 5
th
, Council of Europe, Strasbourg, 2004
89. xxxx European Pharmacopoeia, 6
th
, Council of Europe, Strasbourg, 2007
90. xxxx Farmacopeea Romn, Ediia a IX-a,Editura Medical Bucureti 1976
91. xxxx Farmacopeea Romn, Ediia a X-a, Editura Medical Bucureti 1993
92. xxxx Memomed, Ed. Minesan, Bucureti, 2006;
93. xxxx Memomed, Ed. Minesan, Bucureti, 2007;
94. xxxx Nomenclatorul medicamentelor de uz uman 2007;
95. xxxx Revista terapeutic, farmacologie i toxicology clinic, nr. 3, vol. 7 2003
96. xxxx The United States Pharmacopoeea XXIII, (1995), Rockville
97. xxxx The United States Pharmacopoeea 30-NF 25(2006), Rockville
98. xxxx Legea nr. 95/2006 privind reforma n domeniul Sntii, titlul XVII:
Medicamentul, Monitorul Oficial partea I nr. 372/2006
99. xxxx Legea nr. 339/2005 privind regimul juridic al plantelor, substanelor i
preparatelor stupefiante i psihotrope Monitorul Oficial partea I nr. 1095/2005
100. xxxx Hotrrea Guvernului Romniei nr. 1915/2006 pentru aprobarea normelor
metodologice de aplicare a prevederilor Legii nr. 339/2005 privind regimul juridic al
plantelor, substanelor i preparatelor stupefiante i psihotrope, Monitorul Oficial partea
I nr. 18/2007.


















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