Advanced Pharmacology-I(PHR5001)

Lecture 10:

Anti-Allergy Drugs (Anti-Histamines)

Dr. M G AzamAsstt. Professor

Dept. of Pharmacy, NSU1

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 & peripheral neurotransmission

2

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, mucus secretion, and parasympathetic nerve stimulation

3

4

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 & diphenhydramine.

Related Anatomic StructuresCompromised by Allergic Rhinitis

• SEASONAL– Pollen– Eye symptoms – Skin allergy test +– Symptoms include:

Runny nose, itching, sneezing, nasal block

• PERENNIAL--Skin allergy test -– Symptoms include:

itching, nasal block,

facial pain

Allergic Rhinitis:

5

Rhinitis: Symptomatic disorder of the nose characterized by itching, nasal discharge, sneezing and nasal airway obstruction

Induction of rhinitis symptoms after allergen exposure by an IgE-mediated immune reaction; accompanied by inflammation of the nasal mucosa and nasal airway hyperreactivity.

Allergic RhinitisFirst exposure – Phase of sensitization

On re-exposure- Mast cell degranulation

Exposure of genetically predisposed individuals to allergens (pollen, animal dander, fur)(pollen, animal dander, fur)

Activation of T-lymphocytes

Stimulates IgE production by B-lymphocytes

IgE coat mast cells [on re-exposure mast cell degranulation] 6

Endothelialcell activation

Leukocyteinfiltration and

activation(lymphocytes, eosinophils, basophils)

IMMEDIATE (early)RESPONSE

LATE-PHASERESPONSES

preformed &newly formed

mediators/cytokines

mast cell

SneezingPruritusRhinorrheaNasal obstructionOcular symptoms

Nasal obstructionRhinorrhea

Nasal hyperresponsi

venessTo allergens

(priming)To irritants

and toatmospheric

changes

IgEallerg

en

dendritic cell

T-lymphocyte

cytokineschemokines

allergen

B-lymphocyte

IgE

IL-4IL-13

The nasal allergic response

7

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)8

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)9

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)

AntihistaminesOral: Most common form of Treatment. (Drowsiness / Dryness of mouth / Urinary retention / Blurred vision / appetite +).Cetrizine, Rupatidine

Nasal Spray : Azelastine. Potent H1 blocker with immediate effect 10

Histamine ReceptorsLocation Type Effect Treatment Agonist Antagonist

H1Smooth muscle, Endothelial, CNS, Heart

G-protein linked to intracellular G9

Increase vascular permeability at inflammation

Allergies, nausea, sleep disorders

2-methyl-histamine

Diphenhydramine, 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- histamine

Ranitidine,Cimetidine, famotidine,Nizatidine

H3 CNS (Thalamus, cortex), Intestine

G-protein linked to intracellular Gi

May release histamine

Unknown (R/N)-α-methyl histamine

Thioperamide, Ciproxifan, Clobenpropit

H4 Immune system eg. Spleen & thymus

Unknown but may be G-protein coupled

Unknown Auto-immune diseases

N-methyl histamine

JNJ-77777120

11

12

Major effects of Histamine & its antagonism

Classes of 1st generation H1 receptor antagonist antihistamines

1. Ethylenediamines

2. Ethanolamines

3. Alkylamines

4. Piperazines

5. Tricyclics

1. Mepyramine (Pyrilamine)

2. Diphenhydramine

3b. Tripolidine

3.a) Chlorphenamine

4.a) Cyclizine5. 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

14

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

15

CN

Alkyl amines

H

N N

Piperazines(cyclizines)

1st Generation Anti-histamiines:

N

N

S

Phenothiazines

N

Piperidines(tricyclics)

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” 16

A) Ethylene diamines:

eg. Acrivastine

B) Piperazines (Cycliziines):

eg. Cetrizine,

Oxatomide

C) Phenothiazines:

eg. Mequitazine

17

NN

Ethylene diamine

N N

Piperazines(cyclizines)

N

N

S

Phenothiazines

2nd Generation Anti-histamiines:

d) Piperidines(tricyclics):

eg. Loratadine, Terfenadine,

Astemizole, Levocabastine, EbastineN

Piperidines(tricyclics)

Azelastine

Levocabastine

•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

Olopatadine

18

Loratadine

2nd generation H1-receptor antagonists

Azelastine

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

N N

Piperazines(cyclizines)

N

Piperidines(tricyclics)

19

3rd generation H1-receptor antagonists

Deslortadine Fexofenadine

•It is the active metabolite of Lortadine (thought to be more effective)

•It was developed as an alternative to Terfenadine

•Fexofenadine was proven to be more effective and safe

20

Selective peripheral H1 receptor antagonist activity No anticholinergic or alpha1 adrenergic blocking effects observedUndergoes minimal biotransformation in the body No sedative or other central nervous system effects observedDoes not cross the blood-brain barrier

Fexofenadine

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 H1-

antihistamines)• 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 anti-cholinergic 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) 22

Advanced Pharmacology-I(PHR5001)

Lecture 11:

Anti-Asthma Drugs(Bronchodilators)

Dr. M G AzamAsstt. Professor

Dept. of Pharmacy, NSU23

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, and restriction of physical activity.

24

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)

25

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 agonist2. Low-dose inhaled corticosteroid or Inhaled cromolyn or nedocromil or Leukotriene inhibitors3. Medium-dose inhaled corticosteroid or Low- to medium-dose inhaled corticosteroid plus long-acting beta 2

agonist or sustained release theophylline4. High-dose inhaled corticosteroid and long-acting beta 2 agonist or

sustained-release theophylline (May add oral corticosteroid)

2-4: Plus 1 for rescue

28

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

29

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

(methylxanthine) 31

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

37

Screening Models of Bronchodilators

38

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 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.• The carotid artery is cannulated for measuring blood pressure

39

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 withdrawnfrom the the inhalation box. The aerosols are removedfrom the back wall of the boxes by applying low pressure.

41

The End

42