Download Allergic Rhinitis

Advanced Pharmacology-I
(PHR5001)
Lecture 10:
Anti-Allergy Drugs
(Anti-Histamines)
Dr. M G Azam
Asstt. Professor
Dept. of Pharmacy, NSU
1
What is an antihistamine?
• A drug that reduces or eliminates the effects mediated by the
chemical histamine
• Histamine is released by our body during an allergic reaction
and acts on a specific histamine receptor
• True antihistamines are only the agents that produce a
therapeutic effect that is mediated by negative modulation of
histamine receptors (other agents may have antihistaminergic
action but are not true antihistamines)
• The term antihistamine only refers to H1 receptor antagonists)
• Antihistamines compete with histamine for binding sites at the
receptors. Antihistamine cannot remove the histamine if it is
already bound.
Histamine is an amine (β-imidazole-ethylamine) present in all tissues.
Role:- Allergic reaction, Inflammation, Gastric acid secretion & central
2
& peripheral neurotransmission
What are allergies?
• Allergies are caused by a hypersensitivity reaction of the
antibody class IgE
• When an allergen is encountered, it binds to IgE, which
excessively activates the mast cells or basophils, leading them
to release massive amounts of histamines.
• These histamines lead to inflammatory responses ranging
from runny nose to anaphylactic shock
•Histamine is distributed in Mast Cells
in all peripheral tissues of the body and
basophils, which circulate in the blood
•When it is released, histamine causes inflammation by increasing
vasodilation, capillary permeability, causing smooth muscle contraction,
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mucus secretion, and parasympathetic nerve stimulation
•
Symptoms
Allergy is a local or systemic.
Local symptoms are:
• Nose :swelling of the nasal mucosa )Allergic Rhinitis)
• Eyes: redness and itching of the conjunctiva ) Allergic Conjunctivitis)
• Airways : Bronchoconstriction ,Wheezing and Dyspnoea.
-Sometimes outright attacks of asthma
-In severe cases the airway constricts due to swelling known as
anaphylaxis
• Ears: feeling of fullness, possibly pain, and impaired hearing
• Skin: rashes (such as eczema ,hives( urticaria and contact dermatitis .
•
Systemic allergy
- Response is also called anaphylaxis ;multiple systems can be
affected including Digestive System, the Respiratory System, and
the Circulatory System.
- Depending of the rate of severity, it can cause Cutaneous
Reactions, Bronchoconstriction, Edema, Hypotension, Coma, and
even Death.
- The severity of this type of allergic response often requires
treatments with Oxgen, injections of epinephrine & diphenhydramine4.
Related Anatomic Structures
Compromised by Allergic Rhinitis
Rhinitis:
Symptomatic
disorder of the
nose characterized
by itching, nasal
discharge, sneezing
and nasal airway
obstruction
• SEASONAL
–
–
–
–
Pollen
Eye symptoms
Skin allergy test +
Symptoms include:
Runny nose, itching,
sneezing, nasal block
Allergic Rhinitis:
Induction of rhinitis
symptoms after allergen
exposure by an IgEmediated immune
reaction; accompanied by
inflammation of the
nasal mucosa and nasal
airway hyperreactivity.
• PERENNIAL
--Skin allergy test – Symptoms include:
itching, nasal block,
facial pain
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Allergic Rhinitis
First exposure – Phase of sensitization
On re-exposure- Mast cell degranulation
Exposure of genetically predisposed individuals to
allergens (pollen, animal dander, fur)
Activation of T-lymphocytes
Stimulates IgE production by B-lymphocytes
IgE coat mast cells [on re-exposure mast cell
degranulation]
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The nasal allergic response
allergen
IgE
preformed &
newly formed
mediators/cytokines
cytokines
chemokines
allergen
Endothelial
cell activation
mast cell
Leukocyte
infiltration and activation
(lymphocytes, eosinophils,
basophils)
IMMEDIATE (early)
RESPONSE
dendritic cell
IL-4
IL-13
T-lymphocyte
B-lymphocyte
LATE-PHASE
RESPONSES
Nasal
Sneezing
obstruction
Pruritus
Rhinorrhea
Rhinorrhea
Nasal obstruction
Ocular symptoms
Nasal
hyperresponsivene
ss
To allergens To irritants and
to
(priming)
atmospheric
changes
IgE
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Allergin Rhinitis: Inflammatory cells
1. Mast cells
– Contain
• Granules (histamine)
• Other mediators (leukotrienes and PGs)
2. Lymphocytes
– T cells
– Increased mobilisation of inflammatory cells
• Eosinophils, macrophages, neutrophils
3. Eosinophils
– Major basic protein, Eosinophilic Cationic Protein
(epithelial injury, nasal block)
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Allergic Rhinitis: Inflammatory mediators
Released by inflammatory cells (mast cells,
eosinophils, lymphocytes)
1. Leukotrienes
– hypersecretion of mucus
– oedema (Increased vascular permeability)
2. Histamine
– itching, rhinorrhea (Allergic rhinitis)
3. Cytokines
– Interleukins (IL)
– IL-4 (IgE production)
– IL-3 and IL-5 (eosinophil, mast cell
recruitment / activation)
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Allergic Rhinitis: Treatment
• Avoid contact with allergen
• Drug therapy
– Antihistamines / Relievers: Nasal sprays (Superior) /
Oral
– Steroids / Preventers: Nasal (Superior) / Oral / Drops
– Other preparations (Na Cromoglycate or Chromone,
Ipratropium, Decongestants, Montelukast)
Antihistamines
Oral: Most common form of Treatment. (Drowsiness /
Dryness of mouth / Urinary retention / Blurred vision /
appetite +).Cetrizine, Rupatidine
Nasal Spray : Azelastine. Potent H1 blocker with immediate
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effect
Histamine Receptors
Location
Type
Effect
Treatment
Agonist
Antagonist
H1
Smooth
muscle,
Endothelial,
CNS, Heart
G-protein
linked to
intracellular
G9
Increase vascular
permeability at
inflammation
Allergies,
nausea,
sleep
disorders
2-methyl- Diphenhydram
histamine ine, cetrizine,
meclizine,
Buclizine
H2
Gastric
parietal cells,
neutrophiles,
CNS, Heart
G-protein
linked to
intracellular
G5
Increase release
of gastric acid
Stomach
ulcers
4-methyl- Ranitidine,
histamine Cimetidine,
famotidine,
Nizatidine
H3
CNS
(Thalamus,
cortex),
Intestine
G-protein
linked to
intracellular
Gi
May release
histamine
Unknown
(R/N)-αThioperamide,
methyl
Ciproxifan,
histamine Clobenpropit
H4
Immune
system
eg. Spleen &
thymus
Unknown but Unknown
may be Gprotein
coupled
Autoimmune
diseases
N-methyl JNJ-77777120
histamine
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Major effects of Histamine & its antagonism
12
Classes of 1st generation H1 receptor antagonist
antihistamines
1.
2.
3.
4.
5.
Ethylenediamines
Ethanolamines
Alkylamines
Piperazines
Tricyclics
1. Mepyramine
(Pyrilamine)
2. Diphenhydramine
3.a) Chlorphenamine
3b. Tripolidine
4.a) Cyclizine
5. Promethazine
13
Common Structural Features of 1st generation
antihistamines
• 2 aromatic rings, connected to
a central carbon, nitrogen, or
oxygen
• Spacer between central atom
and the amine, usually 2-3
carbons in length. (Can be
linear, ring, branched,
saturated or unsaturated)
• The amine is substituted with
small alkyl groups
• Chirality at X and having the
rings in different planes
increases potency of the drug
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1st Generation Anti-histamiines:
3) Alkylamines(Propylamines):
eg. Pheniramine, Chlorpheniramine,
Triprolidine, Phenindamine
4) Piperazine (Cyclizines) :
eg. Hlorcyclizines,
Hydroxyzine, Meclizine,
Flunarizine, Cinnarizine
5) Phenothiazines:
eg. Promethazine,
Trimeprazine,
Methdilazine
6) Piperidines(tricyclics):
eg. Azatadine,
Cyproheptadiene,
Ketotifen
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2nd generation H1-receptor antagonists
• These are the newer drugs and they are much more
selective for the peripheral H1-receptors involved in
allergies as opposed to the H1-receptors in the CNS
• Therefore, these drugs provide the same relief with many
fewer adverse side effects
• They are however bulkier and less lipophilic than the first
generation drugs, therefore they do not cross the BBB as
readily
• Recent studies have also showed that these drugs also
have anti-inflammatory activity and therefore, would be
helpful in the management of inflammation in allergic
airways disease.
Goal : designing antihistamines with “reduced ability to penetrate the
CNS and decreased affinity for central histamine receptors”
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2nd Generation Anti-histamiines:
A) Ethylene diamines:
eg. Acrivastine
B) Piperazines (Cycliziines):
eg. Cetrizine,
Oxatomide
C) Phenothiazines:
eg. Mequitazine
d) Piperidines(tricyclics):
eg. Loratadine, Terfenadine,
Astemizole, Levocabastine, Ebastine
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2nd generation H1-receptor antagonists
Loratadine
Levocabastine
Olopatadine
Azelastine
Azelastine
•It is a mast cell stablilizer
•Available as a nasal spray or eye
drops for pink eye
•Both of these drugs are used as eye drops
to treat allergic conjunctivitis
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3rd generation H1-receptor antagonists
• These drugs are derived from second generation antihistamines
• They are either the active enantiomer or metabolite of the second
generation drug designed to have increased efficacy and fewer S/E.
E.g. Levocetirizine
•Also it is not metabolized and is likely to be safer than other drugs due
to a lack of possible drug interactions.
•It does not cross the BBB and does not cause significant drowsiness
•It has been shown to reduce asthma attacks by 70% in children
A) Piperazines(cyclizines):
eg. Levo cetrizine
B) Piperidines(tricyclics):
eg. Desloratadine
Fexofenadine
19
3rd generation H1-receptor antagonists
Fexofenadine
Deslortadine
•It was developed as an alternative to
Terfenadine
•It is the active metabolite of
Lortadine (thought to be more
effective)
•Fexofenadine was proven to be more
effective and safe
Fexofenadine
Selective peripheral H1 receptor antagonist activity
No anticholinergic or alpha1 adrenergic blocking effects observed
Undergoes minimal biotransformation in the body
No sedative or other central nervous system effects observed
Does not cross the blood-brain barrier
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Clinical Uses of Antihistamines
•
•
•
•
•
•
•
•
Allergic rhinitis (common cold)
Allergic conjunctivitis (pink eye)
Allergic dermatological conditions
Urticaria (hives), a kind of skin rash
Angioedema (swelling of the skin)
Puritus (atopic dermatitis, insect bites)
Anaphylactic reactions (severe allergies)
Nausea and vomiting (first generation H1antihistamines)
• Sedation (1st generation H1-antihistamines)
21
Adverse side effects
• Associated with the first generation H1-antihistamines and due
to their lack of selectivity for the H1 receptor and anticholinergic activity. Side effects are due to CNS depression:
•
•
•
•
•
•
•
•
•
•
•
Sedation
Dizziness
Tinnitus (ringing in the ear)
Blurred vision
Euphoria
Uncoordination
Anxiety
Insomnia
Tremor
Nausea/vomitting
Dry mouth/dry cough
• Newer second generation H1-antihistamines are more
selective for the peripheral histamine receptors and have far
less side effects (drowsiness, headache, nausea and dry mouth)
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Advanced Pharmacology-I
(PHR5001)
Lecture 11:
Anti-Asthma Drugs
(Bronchodilators)
Dr. M G Azam
Asstt. Professor
Dept. of Pharmacy, NSU
23
COPD
• Chronic Obstructive Pulmonary Disease, also known as
chronic obstructive lung disease (COLD), chronic obstructive airway
disease (COAD), chronic airflow limitation (CAL) and chronic
obstructive respiratory disease (CORD):
– Caused by emphysema (a disease process involving
destruction of the alveoli (air sacs). Protease enzymes that
cause destruction of the alveolar walls are increased by air
pollution, tobacco smoke, and other respiratory irritants) and
chronic bronchitis
– Causes irreversible changes to respiratory system
• Chronic bronchitis symptoms include:
– Productive cough (with sputum production on most days for 3 months
of a year), difficulty breathing, increased respiratory infections,
24
and restriction of physical activity.
Asthma
• Respiratory condition
characterized by:
–
–
–
–
Bronchoconstriction
Shortness of breath
Wheezing
chronic inflammatory
disorder of the airways
• Triggers for asthma
include:
–
–
–
–
–
Allergens
Air pollutants
Cold air
Infections
Exercise
Causing increased contractability of the surrounding smooth muscles.
This leads to narrowing of the airway and the classic symptoms of
wheezing. The narrowing is typically reversible with or without
treatment. Occasionally the airways themselves change (Typical changes
in the airways include an increase in eosinophils no. of mucous glands.
Other cell types involved include: T lymphocytes, macrophages, and
neutrophils)
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Chemical Mediators
• During inflammatory process chemical mediators are released:
– Histamine:
• Causes bronchoconstriction and mucosal edema
– Eosinophilic chemotatic factor of anaphylaxis (ECF-A):
• Attracts eosinophils to site of irritation
• Prolongs& worsens inflammation and the asthmatic process
• Prostaglandins and leukotrienes:
–
–
–
–
Derived from arachadonic acid
Bronchoconstriction
Edema
Mucus production
• Leukotrienes:
– Potent bronchoconstrictors (LT-1)
– Long durations of action
26
27
Asthma
• Categorization of severity of symptoms
– 1. Mild intermittent: Symptoms 2X weekly or less
– 2. Mild persistent: 2X weekly but < 1X daily, Nighttime
symptoms > 2X monthly
– 3. Moderate persistent: Daily symptoms, Nighttime
symptoms > 1X weekly
– Severe persistent: Continual symptoms
• Assists in determining treatment
1. Short-acting inhaled or oral beta 2 agonist
2. Low-dose inhaled corticosteroid or
2-4: Plus 1 for rescue
Inhaled cromolyn or nedocromil or Leukotriene inhibitors
3. Medium-dose inhaled corticosteroid or
Low- to medium-dose inhaled corticosteroid plus long-acting beta 2 agonist or
sustained release theophylline
4. High-dose inhaled corticosteroid and long-acting beta 2 agonist or sustainedrelease theophylline (May add oral corticosteroid)
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Bronchodilators
• Beta-Adrenergic Drugs:
– M/A: stimulate beta-2 receptors in lungs, which causes
relaxation of airway smooth muscle & consequent
bronchodilation
– IND: -Prevention of bronchospasm
• Treatment of bronchospasm—rescue treatment
• Prevention of exercise-induced asthma
• Epinephrine
• Isoproterenol
• Selective beta-2 drugs
–
–
–
–
–
Albuterol -immediate action, 4-6 hour duration
Levalbuterol -immediate action, 4-6 hour
Metaproterenol -immediate action, 4-6 hour
Salmeterol - 10-20 min onset, 12+ duration
Terbutaline -immediate action, 4-6 hour
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30
Bronchodilators
• Methylxanthine Drugs:
– MOA: inhibits phosphodiesterase and blocks adenosine
receptors, leading to increased cyclic AMP
– Physiologic effect: direct relaxation of respiratory tract,
leading to bronchodilation
– IND: chronic bronchitis and COPD
– Side effects: nausea and vomiting, flushing, vasodilation,
and hypotension, may cause excessive cardiac stimulation
•
•
•
•
Caffeine
Theophylline (narrow therapeutic window)
Theobromine
Plant compound found naturally in tea, cocoa and coffee
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(methylxanthine)
Bronchodilators
• Anticholinergic Drugs:
– M/A: block the action of acetylcholine, leading to
bronchodilation
– IND: first-line therapy in the treatment of COPD
– Administered by oral inhalation, as little drug is absorbed
systemically
• Ipratropium Bromide:
– A quaternary derivative of atropine
– IND: asthma and COPD
– Side effects: excessive drying of mouth and upper
respiratory system
• Tiotropium:
– Similar to ipratropium but longer duration of action
32
Antiinflammatory Drugs
• Corticosteroids:
– M/A: interfere with all stages of the
inflammatory and allergic response (inhibits
inflammatory mediators from mast cells)
– Potent antiinflammatory actions
– IND: control of chronic asthma and COPD
• Main route of administration is oral
inhalation, but may be used systemically to
treat initial acute phase of inflammation
– Adverse effects: oral infections, hoarseness,
and vocal cord disturbances
33
Antiinflammatory Drugs
• Leukotriene Inhibitor Drugs:
– Zileuton (Zyflo)
– MOA: prevent synthesis of leukotriene or
block the leukotriene receptor
– IND: control of chronic asthma
– Adverse effects:
• Nausea, diarrhea, rash, headache,
increased liver enzymes, fever, dark urine,
clay-colored stools, or jaundice (signs of liver
toxicity)
Antiallergic Agents
• Cromolyn sodium:
– MOA: interferes with antigen-antibody reaction of mast
cells
– IND: prophylactic control of chronic asthma
– Adverse effects:
• Nasal irritation, Headache, Bad taste, Allergic
reaction
• Omalizumab (Xolair):
– MOA: binds to and inactivates IgE
– IND: reduction of the severity and frequency of asthma
attacks
– Adverse effects:
• Pain and inflammatory reaction at site of injection 35
Mucolytics and Expectorants
• Mucolytics:
– Liquefy bronchial mucus
– Enable mucus to be removed by coughing or
suction apparatus
– Acetylcysteine (added to bronchodilator to
decrease irritation, via nebulizer)
• Expectorants: (Mucinex)
– Facilitate removal of thickened mucus from
the lungs, tx: unproductive cough
– Guaifenesin
Preferred Therapy
Preferred Therapy for Asthma and
COPD
Mild
Intermittent
Mild
Persistent
• Beta-2
• Corticosteroid
bronchodilator • Cromolyn
• Antileukotriene
Moderate
Persistent
Severe
Persistent
• Corticosteroid • Corticosteroid
• Beta-2
• Beta
bronchodilator
adrenergic
bronchodilator
• Antileukotriene
37
Screening Models of Bronchodilators
1.Bronchospasmolytic activity in anesthetized guinea
pigs (Konzett-Rössler method)
2. Bronchial hyper reactivity
3. Effect of arachidonic acid or PAF on respiratory function
in vivo
The test allows to evaluate the sites of action of drugs, which
interfere with the mechanisms of broncho-constriction and
thrombocytopenia; in an in vivo-model guinea pigs are challenged
with the spasmogens and platelet-aggregating substances
38
arachidonic acid or PAF (platelet activating factor).
1. Bronchospasmolytic activity in anesthetized guinea pigs
(Konzett-Rössler method)
PURPOSE AND RATIONALE:
•The method is based on registration of air volume changes of a living
animal in a closed system consisting of the respiration pump.
•Bronchospasm decreases the volume of inspired air and increases
the volume of excess air. Thus, the degree of bronchospasm can be
quantified by recording the volume of excess air.
Procedure:
•The trachea of anaesthetized Guinea-pigs is cannulated by means of a two
way cannula, one arm of which is connected to the respiratory pump and the
other to a Statham P23 Db transducer.
•The animal is artificially respired using a Starling pump with an inspiratory
pressure set at 90–120 mm of water, an adequate tidal volume of 3 ml/100 g
body weight and a frequency of 60 strokes per minute.
•Excess air, not taken up by lungs, is measured and recorded on a polygraph
• The internal jugular vein is cannulated for the administration of spasmogens
and test compounds.
39
• The carotid artery is cannulated for measuring blood pressure
2. Bronchial hyper reactivity
PURPOSE AND RATIONALE:
• Symptoms like asphyctic convulsions resembling bronchial asthma
in patients can be induced by inhalation of histamine or other
bronchospasm inducing agents in guinea pigs.
•The challenging agents are applied as aerosols produced by an
ultra-sound nebulizer
• The first symptoms are increased breathing frequency, forced
inspiration, and finally asphyctic convulsions.
•The occurrence of these symptoms can be delayed by
antagonistic drugs.
• Pre-convulsion time, i.e. time until asphyctic convulsions, can
be measured.
40
PROCEDURE
•Ten male albino guinea pigs weighing 300–400 g per group are
used. The inhalation cages consist of 3 boxes each ventilated
with an air flow of 1.5 l/min.
• The animal is placed into box A to which the test drug or the
standard is applied using an ultra-sound nebulizer.
•Alternatively, the animal is treated orally or subcutaneously with
the test drug or the standard.
•Box B serves as a sluice through which the animal is passed
into box C.
There, the guinea pig is exposed to an aerosol of a 0.1%
solution of histamine hydrochloride provided by an ultra-sound
nebulizer.
Time until appearance of asphyctic convulsions is measured.
Then, the animal is immediately withdrawn
from the the inhalation box. The aerosols are removed
from the back wall of the boxes by applying low pressure. 41
The End
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