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Anti allergic drugs

Immunomodulators
Classification of anti allergic drugs
1. Drugs that decrease the release of mediators ( histamine, other ABS) from mast cell.
(Stabilization of mast cells)
- glucocorticoids
- sodium cromoglicate
2. Drugs that inhibit the interaction between histamine and its receptors.
H1 histaminoblockers
- diphenhydramine
- clemastine
3. Drugs that diminish the main allergic symptoms:
( hypotension, bronchospasm)
a) adrenomimetics: epinephrine, norepinephrine
b) bronchodilators: I. Musculotropic: aminophylline
II. Sympaphomimetics: salbutamol
III. M-cholinoblockers: ipratropium
IV. Drugs that decrease tissues affection:
- Non steroidal-antiinflammatory drugs
4. Drugs used in cell-mediated immune reactions:
1. Immunosuppressants:
- glucocorticoids
- 4-aminoquinoline derivatives: chloroquine
hydroxichloroquine
- cytostatics :
methotrexate
azathioprine
cyclosporine
mercaptopurine
2. Drugs that diminish the cytotoxic reactions and tissues alteration
- steroid anti-inflammatory drugs
- non steroid anti- inflammatory drugs
Histamine is a biogenic amine involved in local immune responses as well as regulating
physiological function in the gut and acting as a neurotransmitter. As part of an immune response
to foreign pathogens, histamine is produced by basophils and by mast cells found in nearby
connective tissues. Histamine increases the permeability of the capillaries to white blood cells
and other proteins, in order to allow them to engage foreign invaders in the affected tissues. It is
found in virtually all animal body cells.
Types of immune reactions:
Type I reactions: immediate hypersensitivity
Type II reactions: membrane- reactive immunity
Type III reactions: immune complex disease
Type IV reactions: cell-mediated immune reactions.

Histamine exerts its actions by combining with specific cellular histamine receptors. The
four histamine receptors that have been discovered are designated H1 through H4.
Type

Location

Function

H1
histamine
receptor

Found on smooth muscle,


endothelium, and central
nervous system tissue

Causes vasodilation, bronchoconstriction, bronchial


smooth muscle contraction, separation of endothelial
cells (responsible for hives), and pain and itching due
to insect stings; the primary receptors involved in
allergic rhinitis symptoms and motion sickness.

H2
histamine
receptor

Located on parietal cells

Primarily stimulate gastric acid secretion

H3
histamine
receptor

Decreased neurotransmitter release: histamine,


acetylcholine, norepinephrine, serotonin

H4
histamine
receptor

Found primarily in the


basophils and in the bone
marrow. It is also found on
thymus, small intestine,
spleen, and colon.

Unknown role

H1-antihistamines, inhibit competitively H1 receptors and the corresponding effects i. e.


vasodilation and capillary permeability increase. H1-antihistamines which penetrate into brain
elicit, by inhibiting stimulant effect of histamine, drowsiness. They do not inhibit
antigen/antibodies reactions, nor histamine release, they inhibit H1 effects. In addition to this
antihistamine effect, they can have parallel pharmacological properties, for example
antimuscarinic and adrenolytic effects which must be considered.
Roles in the body
Sleep regulation
Histamine is released as a neurotransmitter. The cell bodies of neurons which release
histamine are found in the posterior hypothalamus, in various tuberomammillary nuclei. From
here, these histaminergic neurons project throughout the brain, to the cortex through the medial
forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines
(H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing
neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally,
H3 receptor antagonists (which stimulate histamine release) increase wakefulness.
It has been shown that histaminergic cells have the most wakefulness-related firing pattern of
any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during
periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM)
sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.
Sexual response
Research has shown that histamine is released as part of the human orgasm from mast cells in the
genitals. If this response is lacking this may be a sign of histapenia (histamine deficiency). In

such cases, a doctor may prescribe diet supplements with folic acid and niacin (which used in
conjunction can increase blood histamine levels and histamine release), or L-histidine.
Schizophrenia
It has been found that about half the patients classified as suffering from schizophrenia have low
histamine levels in the blood. This may be because of antipsychotics that have unwanted effect
on histamine, such as quetiapine. Although, in these cases, as histamine levels were increased,
their health improved.
Disorders
As an integral part of the immune system, histamine may be involved in immune system
disorders and allergies.
Nomenclature
"H substance" or "substance H" are occasionally used in medical literature for histamine or a
hypothetical histamine-like diffusible substance released in allergic reactions of skin and in the
responses of tissue to inflammation.
Antihistamines are inhibitors of histamine receptors. One distinguishes H1 and H2 antagonists.
H1-antihistamines have been used for more than fifty years in treating various allergic
manifestations.

Classification of antihistamines
I. according to the chemical structure
II. according to the generations
1. Ethanolamines:
I generations
a. diphenhydramine
- diphenhydramine
b. clemastine (tavegyl)
- clemastine (tavegil)
2. Ethylendamines:
- chlorophiramine (suprastine)
a. chlorophiramine (suprastine)
- chlorphenamine
3. Alkylamines:
- promethasine
a. chlorphenamine
- antasoline
4. Phenothiasines:
- quiphenamide
a. promethasine
II generation
5. Imidasols:
- astemisole
a. antasoline
- loratadine
6. Hynuclidines:
- terfenadine
quiphenamide (phencarol)
- cetirizine
7. Piperidines:
a. astemisole
b. loratadine
c. terfenadine
8. Piperazines:
a. cetirizine
Antihistamines
It is usual to classify H1-antihistamines into two classes: old ones, called first-generation agents,
which are sedating and recent ones, called second-generation agents which have slight or no
sedating effects because they do not cross the blood-brain barrier. In addition, each compound
can have or not have parallel properties, antimuscarinic effects for example. This distinction
between generations must be taken with caution because a product considered as non sedative or
not antimuscarinic can, in certain circumstances, large doses or particular susceptibility of the
patient ,have these effects. Effect duration deffers but in medium is equal 4-8 hours.
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II generation (12- 24 hours)


Antihistamines as histamine have ethylamino-group. In such way this drugs block H 1
histaminoreceptors (they are competitive antagonist of histamine).
Effects;
bronchodilatation
( in practice it is used for
sedative (I generation)
preventing of air-sick )
anticholinergic peripheral
- anesthetic local
effect (I generation)
effect(diphenhidtramine)
antivomiting effect (central
- inhibition of cell
anticholinergic effect)Igeneration
degranulation (II
generation)
First-generation H1-antihistamines
The first-genaration antihistamines have alpha adrenolytic activity which can decrease the
vasoconstrictive effect of adrenaline and noradrenaline and an antimuscarinic effect with the
corresponding adverse effects. Certain H1 antagonists, such as promethazine, have a local
anesthetic effect. Other H1-antihistamines having an important antimuscarinic activity like
diphenhydramine and clemastine, are used in preventive and curative treatment of motion
sickness, but scopolamine which has no antihistamine effect seems more effective than them in
preventive treatment.
Second-generation H1-antihistamines
The two first H1-antihistamines without sedating effect to be marketed were terfenadine and
astemizole. They were withdrawn from the market because they could induce ventricular
arrhrythmias, prolongation of QT interval which can lead to torsades de pointes. This adverse
effect is linked to their effect on potassium channels leading to slowing of repolarization rate.
H1-antihistamines without sedating effect currently marketed are cetirizine, loratadine,
fexofenadine because they do not cross blood-brain and thus their effects remain peripheral.
They have a longer duration of action and longer plasma half-life than the first generation drugs,
which makes it possible to reduce the number of daily intakes. They do not have, in normal dose,
antimuscarinic effect.
Loratadine acts mainly via one of its metabolites, decarboethoxyloratadine, also called
desloratadine, which is also marketed. In case of overdose, loratadine can cause sedation and
antimuscarinic effects.
Cetirizine, carboxyl derivative of hydroxyzine which is used as a sedative and anxiolytic, in
addition to its H1-antihistamine effect, inhibits release of various cytokines and leukotrienes.
Ceterizine is a racemic; one of its isomers called levocetirizine is also released on the market.
Therapeutic use : (all types of allergy) H1-antihistamines are used for supportive care of
allergic manifestations, cutaneous (urticaria) or mucous membranes (rhinitis, hayfever,
conjunctivitis). They are not effective in asthma. Insufficient alone to treat anaphylactic
shock or edema of the larynx, they could prevent them. The drug to use in severe situations
is adrenaline
Adverse effects
The early H1-antihistamines usually induce drowsiness and their prescription to patients with an
activity requiring a normal vigilance, like control of a vehicle, is contra-indicated. By their
alpha-adrenolytic effect especially when they are given by parenteral route, they could reduce the
vasoconstrictive effect of adrenaline, administered for example in case of anaphylactic shock.
New H1-antihistamines induce only exceptionally drowsiness. This possibility, even rare, must
however be taken into account, particularly at time of a first prescription. It is not advised to
prescribe a sedating a H1-antihistamine to infants because, although this is not documented, it
could increase the risk of sudden death.
New H1-antihistamines, terfenadine and astemizole, which were associated with cardiac
adverse effects, prolongation of QT interval, torsades de pointes by inhibition of potassium
channels, are no longer approved for use. .
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Other adverse effects of H1-antihistamines have been reported, in particular allergic


reactions. All H1-antihistamines, including those which are intended for treatment of motion
sickness, are disadvised during the first three months of pregnancy, more for reasons of principle
than for observations of malformations. Promethazine has been prescribed to pregnant women
without inducing malformations.
Stabilization of mast cells.
Sodium cromoglycate belongs to the family of medications called mast-cell stabilizers. It
is used to prevent or treat the symptoms of seasonal allergic rhinitis such as itching,
sneezing, and runny or stuffy nose. This medication works by preventing the release of natural
chemicals from cells in the body (mast cells) involved in an allergic reaction. This medication
may take up to one week before you begin to notice symptom relief. Moreover, by interfering
with the actions of mediator substances on inflammatory cells, it causes a more general
inhibition of allergic inflammation. It is applied locally to: conjunctiva, nasal mucosa, bronchial
tree (inhalation), intestinal mucosa (absorption almost nil with oral intake). Indications:
prophylaxis of hay fever, allergic asthma, and food allergies.
Ketotifen: the same mechanism of action plus also inhibition of H1histaminoreceptors.
`
Glucocorticoids have significant anti-allergic activity and probably interfere with
different stages of the allergic response. Indications: hay fever, bronchial asthma (preferably
local application of analogues with high presystemic elimination, e.g., beclomethasone,
budesonide); anaphylactic shock (i.v. in high dosage)a probably nongenomic action of
immediate onset.
Mechanism of action
1. reduce macrophage chemotaxis and phagocytosis
2. alter limphocute function
3. produce a lymphopenia, particularly of T lymphocytes by destribution of cell into
lymphoid tissue
4. are not very effective in suppressing of B-cell antibody production
-Sympathomimetics, such as naphazoline, oxymetazoline, and tetrahydrozoline, are
applied topically to the conjunctival and nasal mucosa to produce local vasoconstriction, and
decongestion and to dry up secretions , e.g., in hay fever.
Since they may cause mucosal damage, their use should be short-term.
Epinephrine, given i.v., is the most important drug in the management of anaphylactic
shock: it constricts blood vessels, reduces capillary permeability, and dilates bronchi.
2-Sympathomimetics, such as terbutaline, fenoterol, and albuterol, are employed in
bronchial asthma, mostly by inhalation, and parenterally in emergencies. Even after inhalation,
effective amounts can reach the systemic circulation and cause side effects (e.g., palpitations,
tremulousness, restlessness, hypokalemia). During chronic administration, the sensitivity of
bronchial musculature
is likely to decline.

Theophylline belongs to the methylxanthines. Whereas caffeine (1,3,7trimethylxanthine) predominantly stimulates the CNS and constricts cerebral blood vessels,
theophylline
(1,3-dimethylxanthine)
possesses
additional
marked
bronchodilator,
cardiostimulant, vasorelaxant, and diuretic actions. These effects are attributed to both inhibition
of phosphodiesterase ( c AMP elevation,) and antagonism at adenosine receptors. In bronchial
asthma, theophylline can be given orally for prophylaxis or parenterally to control the attack.
Manifestations of overdosage include tonic-clonic seizures and cardiac arrhythmias as early
signs.
Ipratropium can be inhaled to induce bronchodilation; however, it often lacks sufficient
effectiveness in allergic bronchospasm.

Immunomodulators
A. Biologic origin drugs:
1. drugs from thymus
- thymaline
- T-activine
2. other animal origin drugs
- melopid
3. bacterial origin drugs
pyrogenal
prodigiozane
4. drugs from donators blood
interloc
interferon
5. drugs obtained with genetic engineer method
philgastrine
nolgastrine
reaferon
betaferon
interleukine-2
B. Synthetic drugs
levamisol
imunophan
leucadine
polyoxidoniu
Immunomodulators are natural or synthetic substances that help regulate or normalize the
immune system. Immunomodulators correct immune systems that are out of balance.
Immunomodulators correct weak immune systems and temper immune systems that are
overactive, but they do not boost the immune system the way immune stimulants such as
Echinacea do. Immunomodulators are recommended for people with autoimmune diseases and
they are widely used in chronic illness to restore immune system health in people who have been
on lengthy courses of antibiotics or anti-viral therapies.
The benefits of immunomodulators stem from their ability to stimulate natural and
adaptive defense mechanisms, such as cytokines, which enables the body to help itself.
Natural and Synthetic Immunomodulators
Plant sterols and sterolins are excellent immunomodulators fount in waxy fruits and
vegetables although they are lost when vegetables and fruits are cooked. Several products, such
as Moducare, are patent preparations rich in sterols and sterolins. Other natural
immunomodulators include ginseng root, German chamomile tea, lemon/olive drinks, reishi
mushroom extract and olive leaf extract
Prescription synthetic immunomodulator medications, such as azathioprine, 6mercaptopurine, methotrexate, and mycophenolate mofetil, work by suppressing the immune
system and decreasing inflammation in the digestive tract in people with inflammatory bowel
disease, ulcerative colitis, and Crohn's disease. Tacrolimus can be used in Crohn's disease when
corticosteroids prove ineffective. In children, immunomodulators are less likely to cause growth
failure than corticosteroids.
Topical immunomodulators such as tacrolimus and pimeocrolimus have been found to
offer benefits in patients with eczema, vitiligo and nickel allergy. Topical immunomodulators are
well tolerated even in infants.
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Side effects of prescription immunomodulator medications include nausea, vomiting, diarrhea,


stomach ulcers, rash, malaise and liver inflammation. Natural immunomodulators are less potent
than prescription immunomodulators and also less likely to cause side effects.
Immune Modulators
Both the prevention of transplant rejection and the treatment of autoimmune disorders
call for a suppression of immune responses. However, immune suppression also entails
weakened defenses against infectious pathogens and a long-term increase in the risk of
neoplasms. A specific immune response begins with the binding of antigen by lymphocytes
carrying specific receptors with the appropriate antigen-binding site. B-lymphocytes recognize
antigen surface structures by means of membrane receptors that resemble the antibodies formed
subsequently. T-lymphocytes (and naive B-cells) require the antigen to be presented on the
surface of macrophages or other cells in conjunction with the major histocompatibility complex
(MHC); the latter permits recognition of antigenic structures by means of the T-cell receptor. Thelper cells carry adjacent CD-3 and CD-4 complexes, cytotoxic T-cells a CD-8 complex. The
CD proteins assist in docking to the MHC. In addition to recognition of antigen, activation of
lymphocytes requires stimulation by cytokines. Interleukin-1 is formed by macrophages, and
various interleukins (IL), including IL-2, are made by T-helper cells. As antigen-specific
lymphocytes proliferate, immune defenses are set into motion.
I. Interference with antigen recognition. Muromonab CD3 is a monoclonal antibody
directed against mouse CD-3 that blocks antigen recognition by T-lymphocytes (use in graft
rejection).
II. Inhibition of cytokine production or action. Glucocorticoids modulate the
expression of numerous genes; thus, the production of IL-1 and IL-2 is inhibited, which explains
the suppression of T-cell-dependent immune responses. Glucocorticoids are used in organ
transplantations, autoimmune diseases, and allergic disorders. Systemic use carries the risk of
iatrogenic Cushings syndrome
Cyclosporin A is an antibiotic polypeptide from fungi and consists of 11, in part atypical,
amino acids. Given orally, it is absorbed, albeit incompletely. In lymphocytes, it is bound by
cyclophilin, a cytosolic receptor that inhibits the phosphatase calcineurin. The latter plays a key
role in T-cell signal transduction. It contributes to the induction of cytokine production, including
that of IL-2. The breakthroughs of modern transplantation medicine are largely attributable to the
introduction of cyclosporin A. Prominent among its adverse effects are renal damage,
hypertension, and hyperkalemia. Tacrolimus, a macrolide, derives from a streptomyces species;
pharmacologically it resembles cyclosporin A, but is more potent and efficacious. The
monoclonal antibodies daclizumab
and basiliximab bind to the - chain of the II-2 receptor of T-lymphocytes and thus prevent their
activation, e.g., during transplant rejection.
III. Disruption of cell metabolism with inhibition of proliferation. At dosages below
those needed to treat malignancies, some cytostatics are also employed for immunosuppression,
e.g., azathioprine, methotrexate, and cyclophosphamide. The antiproliferative effect is not
specific for lymphocytes and involves both T- and Bcells. Mycophenolate mofetil has a more
specific effect on lymphocytes than on other cells. It inhibits inosine monophosphate
dehydrogenase, which catalyzes
purine synthesis in lymphocytes. It is used in acute tissue rejection responses.
IV. Anti-T-cell immune serum is obtained from animals immunized with human Tlymphocytes. The antibodies bind to and damage T-cells and can thus be used to attenuate tissue
rejection.
Miyelopid consists of amino acids, its composition is completely deciphered, which
served as prerequisite for developing the new synthetic immunomodulators of the medullary
origin: Seramil, Bivalen. To the high-molecular, chemically pure immunocorrectors , obtained
with the aid of the directed chemical synthesis, relates the immunomodulator Of polioksidoniy.
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Polioksidoniy it possesses the pharmacological action of wide spectrum on the organism:


immunomodulating, that detoxify, antioxidant and membranoprotektornym. The detoxifying
properties Of polioksidoniya are manifested in its ability to reduce in the blood the concentration
of toxic substances, for example the level of lipopolysaccharide of enterobacteria, in patients
with the burn disease. In patients with the the sharp by pankreonekrozomi Of polioksidoniy
significantly is reduced the level of malonic dialdehyde and diene acids. The detoxifying
properties Of polioksidoniya are connected with its high molecular weight and presence on the
surface of the molecule of a large quantity of different active groups. Therefore Polioksidoniy it
intensively adsorbs the circulating in the blood dissoluble toxic substances and microparticles.
The formation of immune response occurs under the control of a number of immunoregulator
molecules.
Immunomodulators are assigned in the complex therapy simultaneously with the
antibiotics, the antifungal, protivoprotozoynymi or antiviral means. ImmunocSupsprings
(immunodepressants) are antibiotics , hormones, cytostatics.