Download Antiallergic agents

Sumy State University
Lecture on pharmacology
for 3-rd year students of medical institute
Gluschenko N.V.
Allergy
represents
a
sensitivity
to
a
specific substance,
called an allergen,
that is contacted
through the skin,
inhaled into the
lungs or injected.
The prevalence of allergic diseases
and asthma is escalating.
 Approximately 30 to 40 percent of the world’s population
suffers from allergic diseases.
 An estimated 300 million individuals worldwide have
asthma, and this is likely to increase to 400 million by the
year 2025.*
 Allergic rhinitis, a risk factor for asthma, affects 400
million people annually, and food allergies affect 200 to
250 million.
 The number of avoidable deaths from asthma occurring
every year is estimated at 250,000.*
*World Health Organization (WHO)
Types of allergic reactions
(according to Gell and Cumbs):
I type reactions (anaphylactic) are a severe
whole-body allergic reactions that occur within minutes of exposure,
progresses rapidly and can lead to anaphylactic shock and death.
Examples:
-anaphylactic shock;
-bronchial asthma.
 II type reactions (humoral cytotoxic
immune reactions)
Examples:
-transfusion reactions;
-Rh incompatibility
Types of allergic reactions
(according to Gell and Cumbs):
 III type reactions (autosensibilization)
Examples:
-arthus reactions;
-serum sickness.
 IV type reactions
Examples:
-rejection of transplanted tissues;
-contact dermatitis.
Classification of allergic
reactions in clinic:
1. reactions of immediate type
(I, II, III after Cumbs)
2. reactions of delayed type (IV
type after Cumbs)
Allergy - Diagnosis
Skin test
Several
allergens are
introduced to
the skin
The test is
positive if the
skin shows a
reaction
General principles of prevention and treatment
of allergic reactions:
1) Avoiding contact with the allergen.
2) Performing specific desensitization by repeated
introduction of small doses of specific antigen.
3) Performing nonspecific desensitization through
administration of drugs which depress immune
reactions (immune depressants).
4) Using antiallergic drugs which are able to prevent
releasing the mediators of allergic reactions through
stabilization of mast sells’ membranes or to block
receptors with which these mediators interact
in tissues.
5) Symptomatic treatment of allergic reactions
manifestations which have already developed.
Directions of therapy of hypersensitivity
reactions of immediate type
1) Antiallergic drugs :
 а) drugs which stabilize membranes of mast cells and
basophiles and slow down releasing of mediators of
hypersensitivity reactions;
b) antihistamine drugs – block receptors with which
histamine binds in the tissues.
2) Drugs which decrease damage of the tissues:
Glucocorticosteroids.
3) Drugs of symptomatic treatment:
Adrenalin;
 euphyllin.
Antihistamine drugs
R1
CH3
CH2-CH2-N
R1
CH3
Structure of nucleus of Н1 histamine-receptors
antagonists (H1 histamine-blockers)
Allergy - Histamine
Histamine:
 Endogenous bioactive amine: synthesized, stored and released in
 mast cells, which are abundant in the skin, GI, and the respiratory tract;
 basophils in the blood;
 neurons in the CNS and PNS.
Physiological actions:
 Primary stimulant for gastric acid and pepsin secretion.
 (acid secretion is further enhanced by gastrin and vagal stimulation)
 Neurotransmitter (both in the CNS and peripheral sites).
Pathophysiological actions:
 Mediator of immediate hypersensitivity reactions and acute inflammatory
responses.
 Anaphylaxis.
 Duodenal ulcer.
Allergy - Histamine
Receptors:
part of the super family of G-protein coupled receptors
H1-Receptors:
Gq coupled to Phospholipase C.
CNS, smooth muscle cells of airways, GI tract,
cardiovascular system, endothelial cells and lymphocytes
=> Vasodilation, bronchoconstriction, seperation of
endothelial cells, pain and itching, allergic rhinitis, motion
sickness.
H2-Receptors:
Gs coupled to Adenylyl Cyclase.
Parietal cells of stomach; vascular smooth muscle cells =>
mediate histamine induced gastricacid secretion;
vasodilation.
Allergy - Histamine
H3-Receptors:
Gi/o coupled to AC, also to N-type voltage gated
Ca channels and reduce Ca influx.
CNS => Presynaptic, feedback inhibition of
histamine synthesis and release; also controls
release of other neurotransmitters.
H4-Receptors:
coupled to Gi/o in mast cells, can trigger calcium
mobilization.
found primarily in bone marrow and immune cells
=> mast cell chemotaxis.
Allergy - Histamine Effects
Actions of Histamine:
Vascular:
 H1 - vasodilation mediated by NO and PGs (via endothelial cells);
 H2 - vasodilation mediated by cAMP (vascular smooth muscle cells);
 H1 - coronary vasoconstriction;
 H1 - increased permeability of post capillary venules => edema.
Heart:
 H1 - decreased AV conduction;
 H2 - increased chronotropy;
 H2 - increased inotropy.
Lung:
 H1 – bronchoconstriction;
 H1 - increased mucus viscosity;
 H1 - stimulation of vagal sensory nerve endings: cough and bronchospasm.
Gastrointestinal System:
 H2 - acid, fluid and pepsin secretion;
 H1 - increased intestinal motility and secretions.
Cutaneous Nerve Endings:
 H1 - pain and itching.
Symptoms range from mild allergic
symptoms to anaphylactic shock:
 Mild/cutaneous: erythema, urticaria, and/or
itching.
 Moderate: skin reactions, tachycardia,
dysrhythmias, moderate hypotension, mild
respiratory distress.
 Severe/anaphylactic: severe hypotension,
ventricular fibrillations, cardiac arrest,
bronchospasm, respiratory arrest.
Allergy - Drugs Targeting Histamine
 H1 Receptor Antagonists – H1-histamine
blockers. They are antiallergic drugs.
 H2 Receptor Antagonists – H2-histamine
blockers. This drugs decreas secretion of
HCl, use for the treatment of stomach ulcer.
 Mast Cell Stabilizers
Mechanism of action of
“Antihistamines” drugs
block histamine H1-receptors,
reducing or
eliminating the effects of histamine: spasm of the
bronchial tubes, intestines, uterus, lower blood
pressure, increased vascular permeability, itching,
swelling, redness.
block histamine receptors available. Drugs not
displace molecules mediator, are connected to
receptors. This is because the affinity of histamine
for H1 receptors significantly higher.
H1-Antagonists
(“Antihistamines” drugs)
First generation drugs (Sedating):
Ethylenediamines: 1st antihistamines => obsolete
Ethanolamines:
 Diphenhydramine (Dimedrol, Benadryl)
 Doxylamine
 Clemastine
Alkylamines: Chlorpheniramine (Suprasytine)
Piperazines:
Diprasine, Meclizine, Hydroxyzine
Ather drugs:
 Fenkarol
 Diasoline
Pharmacological characterization of
antihistamine drugs of the first generation
 Peripheral anti-muscarinic effects: (also block Mreceptors). Cased by dry mouth, blurred vision,
constipation, urinary retention.
 Antyserotonin activity (increase of appetite and
increase of body weight).

Potentiate CNS depressants (opioids, sedatives,
general anasthetics, alcochol).
 There are an injectable forms of release so used
for the treatment of acute allergic conditions.
Pharmacological characterization of
antihistamine drugs of the first generation


Effect occurs within 15-20 min. after administration.
Penetrate through blood/brain barrier (lipophilicity) and
block H1-receptors of CNS, and as a result, cause
sedation and reduce coordination of attention
(contraindicated in occupations related to
concentration).


Have short duration of action, as prescribed 3-4 times
per day.
Prolonged use develops tachyphylaxis (reduced
therapeutic efficiency). Therefore is necessary to
replace one drug of another drug from this group every
7-10 days.
Indications for use of antihistamine
drugs of the first generation
1.
2.
3.
4.
5.
6.
Anaphylactic reactions.
Antiallergy
(allergic
rhinitis,
allergic
dermatoses, contact dermatitis).
Sedative/sleep aid.
Prevention of motion sickness.
Premedication.
For potention of CNS depressants (opioids
and nonopoid analgesics, sedatives drugs).
Side effects of Н1-histamine receptors blockers
of 1st generation
1) Depression of CNS (disorders of coordination,
increased tiredness, dizziness, diplopia, tremor,
euphoria, nervousness, insomnia).
2) Disturbance of GI functioning : increase of appetite,
nausea, vomiting, pain in epigastria, constipation or
diarrhea.
3) As a result of M-cholinoblocking activity – dryness of
mucous membranes, eye disorders - blurred vision,
impotence,
ischuria,
tachycardia,
headache,
psychosis.
4) In case of repeated administration – tachyphylaxis.
H1-Antagonists drugs of the second
generetion (non-sedating)
1. Terfenadine
(Lamisil)
2. Astemisole
(Hismanal)
3. Loratadine
(Klaritin)
4. Akrivastine
5. Cetirisine (Zirtec)
6. Levakarbastine
7. Azelastine
Pharmacological characterization of
antihistamine drugs of the second
generation
1.
High specificity and affinity to Н1-receptors.
2.
Non penetrable through blood/brain barrier in therapeutic doses
(have not sedative action).
3.
Absence of blockade of other types of receptors ( M-cholino-,
Serotonin-receptors).
4.
That way don’t increase of appetite and body weight, don’t cased
by dry mouth, blurred vision, constipation, urinary retention.
Pharmacological characterization of
antihistamine drugs of the second
generation
1. Have long duration of action (over 24 hours).
Prescribe 1 time per day.
2. Absence
of
tachyphylaxis.
Can
be
administered for a long time (up to 1 year).
3. After withdrawal of the drugs – have
efficiency during the 1 week.
Side effects of Н1-histamine receptors
blockers of the second generation
Drugs are metabolized by CYP- 450 enzymes
(Terfenadine and Astemisole) .
 In patients with liver diseases, in case of higher
daily doses, with administration of drugs that also
are metabolized by CYP- 450 enzymes can cause
ventricular tachycardia.
 Examples of such drugs:
 Macrolides (erythromycin, clarithromycin)
 Antifungal drugs (intraconazole, ketaconazole).
Drugs are contraindicated during pregnancy and
lactation.
Pharmacological characterization of
antihistamine drugs of the third
generation
 Drugs are pharmacologically active metabolites
of
antihistamine
drugs
of
the
second
generation.
 Have been created to eliminate cardio-toxicity
and enhance the effect.
H1-Antagonists drugs of the third
generetion (non-sedating)
 Active metabolite of Terfenadine – is Fexofenadine
(Allegra, Telfast, Fastofen, Tilfur,
Vifas, Telfexo, Allerfexo)
H1-Antagonists drugs of the third
generetion (non-sedating)
 Active metabolite of
Loratadine – is
Dezloratadine
 NeoClarityn,
 Claramax,
 Clarinex, Larinex,
 Aerius, Dazit,
 Azomyr,
 Deselex.
H1-Antagonists drugs of the third
generetion (non-sedating)
Active metabolite of
Cetirizine – is
Levocetirizine
(Xyzal)
Pharmacological characterization of
antihistamine drugs of the third generation
Have 3 mechanisms of action:
1. antihistaminic — blocking of Н1-histamine
receptors;
2. antiallergic — suppression of leukotriene and
proinflammatory cytokine production;
3. anti-inflammatory
effect
—
decrease
in
production of granulocytic macrophage factor.
Action begin in 15–30 minutes after the intake and
lasts more than 24 hours. Prescribe 1 time/day.
Pharmacological characterization of
antihistamine drugs of the third
generation
They are not linked to cytochrome Р450 system, and thus it
does not overload hepatocytes in relation to detoxification
function. Have not cardiotoxic action.
This medicinal drugs are excreted by liver and kidneys in
unchanged state. Owing to such peculiarities, can be taken
concomitantly with other preparations.
 Antibiotics
 Antimycotics
 Antidepressants
 H2-histamine receptor blockers
 Ethanol
Indications for use of H1-Antagonists
drugs of 2- and 3- generetions
allergic rhinitis and pollinosis;
allergic conjunctivitis, pharyngitis;
acute urticaria;
 atopic dermatitis;
 bronchial asthma of allergic etiology;
medicamentous allergy, which is manifested by
skin symptomatic — there may develop
Quincke's edema, Lyell's syndrome, and
Stevens-Johnson syndrome.
Contrindications for use of
H1-antagonists drugs of 2- and 3
generetions
Should not be used in cases of:
Pregnancy.
Lactation.
Hypersensitivity to any components of the
preparation.
The preparation should be used with
caution in:
Sever liver failure.
Young age prior to 2 years.
Mast Cell Stabilizers
 Sodium
Cromoglycate (Intal, Nasalcrom)
 Nedocromil (Tilade)
Mechanism of action
 They
block a calcium channel essential for
mast cell degranulation,
 stabilizing the cell and thereby preventing
the release of histamine and related
mediators.
 One
suspected
pharmacodynamic
mechanism is the blocking of IgE-regulated
calcium channels.
 Without intracellular calcium, the histamine
vesicles cannot fuse to the cell membrane
and degranulate.
Indications for use:
 Treatment
of bronchial asthma ( As inhalers to
prevent asthma attack).
 Allergic rhinitis (as nasal sprays).
 Allergic conjunctivitis (as eye drops).
 Drugs only help prevent them - and they
work best if and only if you use their
regularly, and if you start using it well
before (like 2-4 weeks before) the
beginning of the season for your particular
allergens.
Allergy - Leukotrienes
 Leukotrienes:
 Generated




by
5-
Lipoxygenase:
Converts AA into 5HPETE, which in turn is
converted into
– LTB4: potent mediator
of inflammation
and
– Cysteinyl-LTs (LTC4,
LTD4, LTE4 = SRS-A):
mediate
asthmatic
responses
Physiological actions:
LTB4:
Cys-LTs:
 Mediated by specific LTB4
 Mediated by shared receptor
receptor.
 Adherence, chemotaxis and
activation of macrophages.
 Stimulates cytokine and
chemokine production.
 Present
in inflammatory
exsudates (RA, ulcerative
colititis, psoriasis).
for LTC4, LTD4 and LTE4.
 Contraction of bronchial
muscles (longer lasting than
histamine).
 Peripheral
vasodilation,
coronary vasoconstriction.
 Found in sputum of chronic
bronchitis, asthmatic lung;
lavage of allergic rhinitis.
Classification
1. Leukotriene Esterase Inhibitors:
(5-Lipoxygenase inhibitor)
 Zileuton (Zyflo)
2. Cys-LTs-R antagonists:
Montelukast (Singulair )
Zafirlukast (Accolate)
Zileuton
Mechanism of action:
specific inhibitor of
5-lipoxygenase and thus inhibits
leukotrienes (LTB4, LTC4, LTD4,
and LTE4) formation.
Pharmacological effects:
contribute
to
inflammation,
edema, mucus secretion, and
bronchoconstriction
in
the
airways of asthmatic patients.
Montelukast and Zafirlukast
 Pharmacological
effects:
 Mechanism of action
 blocker Cys-LTs-R and
prevent effects of
cysteinyl -leukotrienes
(LTC4, LTD4, LTE4)
 Decrease airway edema,
smooth
muscle
contraction, and altered
cellular activity associated
with the inflammatory
process.
 In allergic rhinitis,
decrease symptoms
of nasal obstruction.
Cys-LTs-R antagonists:
Indications for use:
 for the prophylaxis and chronic treatment
of moderate and severe bronchial asthma
in adults and children 12 years of age and
older;
 for the relief of symptoms of allergic rhinitis
(seasonal allergic rhinitis in adults and
pediatric patients 12 years of age and
older);
 aspirin-induced asthma.
Side effects
 Erythromycin reduces the absorption of
zafirlukast, potentially reducing the effects of
zafirlukast.
 Hepatotoxicity.
 Indicated in age only 12 and over.
 Contraindicated during pregnancy and breastfeeding.
 Expensive ($ 273 per month for zileuton).
Ant allergic and
anti-inflammatory drugs
Important agents
 Injactable
 Inhalation
 Betamethasone
 Beclamethasone
 Prednisolone
 Flunisalide
 Hydrocortisone
 Budesonide
 Dexamethasone
 Methylprednisolone
 Triamcinolone
Important agents
Oral
Topical
 Betamethasone
 Betamethasone
 Prednisolone
 Flucinolone
 Methylprednisolone
 Clobetasol
 Fludricortisone
 Mometasone
Mechanism of antiallergic action:
 Suppress all types of hypersensitivity and allergic
phenomenon.
 At high dose: Interfere with all steps of
immunological response.
 Causes greater suppression of Cell-mediated
immunity
(graft rejection and delayed
hypersensitivity).
 Transplant rejection:
antigen expression from
grafted
tissues,
delay
revascularization,
sensitisation of T- lymphocytes etc.
Indications for use
 Autoimmune hemolytic anemia.
 Idiopathic thrombocytopenic purpura.
 Organ transplant combine with other
immunosuppressant's.
 In anaphylaxis, angioneurotic aedema, serum
sickness.
 Seasonal allergies, bee sting, drug allergies.
Bronchial asthma
 In severe asthma attack – Hydrocortisone,
Prednisolone,
Methylprednisoline.
 Acute attack – inhalated
Beclamethasone
Flunisalide
Budesonide
Indications for use
 Allergic ocular
diseases.
 Allergic skin diseases
(eczema).
Thank you!!!