Lecture 12 - Antihistamines and Respiratory Pharmacology Flashcards
Define
Respiratory diseases
Any disease process that interferes with gas exchange in the lungs and causes serious changes in the concentration of oxygen and carbon dioxide in the blood
What causes cystic fibrosis?
Mutation in the CFTR gene on chromosome 7. The CFTR gene encodes a chloride channel. Alteration of this channel causes inbalance in salt and liquid homeostasis in epithelia –> mucus buildup
What happens inside the cells with Cystic Fibrosis?
Sodium enters the cells normally but chloride is unable to exit the cell leading to extra water entering the cell
Treatments of Cystic Fibrosis
1) Bronchodilators
2) Mucolytics to thin secretions
3) Antibiotics (against mucin fermenting bacteria)
4) Bronchoscopy with bronchoalveolar lavage to clear mucus plugs from intermediate and small airways
Define
Degranulation
A cellular process of immune cells that release inflammatory mediators or antimicrobial cytotoxic molecules from secretory granules
What are some of the substances immediately released when mast cells degranulate?
Histamine, heparin, serotonin, leukotrienes, platelets, cytokines, and eosinophil-activating factors
Function of Histamine
Histamine interacts with the membrane receptors in certain tissues to produce the symptoms of allergy (itching, redness, hives, stuffy nose)
Pathophysiology of the IgE-mediated hypersensitivity reaction
1) The first time a person comes into contact with an allergen, B cells produce antobodies (ex IgE)
2) IgE binds to Fc receptors on mast cells –> sensitization
3) Repeated exposure to an allergen will cross-link two IgE and trigger mast cell degranulation
How can an allergic reaction be blocked?
- Preventing mast cells from releasing contents
- Blocking the H1 receptors
- Antibodies like Omalizumab that blocks IgE from binding to receptors
Mast Cell Stabilizers
Cromolyn
A prophylactic drug that acts selectively on the mast cells to inhibit IgE-mediated hypersensitivity reaction by preventing the antigen-stimulated release of histamine (also prevents release of leukotrienes and inhibits eosinophil chemotaxis)
When is cromolyn administered?
Before release of histamine
Where is histamine metabolized?
In the liver
Classical Monoamines
Imidazoleamines
Histamine
Classical Monoamines
Catecholamines
Adrenaline (EPI), Dopamine (DA), Noradrenaline (NE)
Classical Monoamines
Indolamines
Serotonin (5-HT), Melatonin (MT)
Histamine Receptors
What type of receptors are Histamine Receptors?
GPCRs
Histamine Receptors
H1 receptors
- Found on skin capillaries, bronchiolar smooth muscle, nerve ending, brain, and intestinal smooth muscle
- Gq/11 –> increased IP3, DAG, and intracellular Ca2+, activated NFkB
Histamine Receptors
H2 receptors
- Found in stomach, heart, blood vessels, mast cells and uterine tissue
- Gs –> increased cAMP
Histamine Receptors
H3 receptors
- Found in CNS and some peripheral nerves
- Gi/0 –> Decreased cAMP
Histamine Receptors
H4 receptors
- Found in hematopoietic cells and gastric mucosa
- Gi/0 –> decreased cAMP, increased intracellular Ca2+
Define
Antihistamines
Prevent interaction between histamines and histamine receptors
- not effective for asthma
Define
Antiallergic agents
Block the release of histamine from mast cells
Physiological response to histamine stimulation
Blood pressure
- Hypotension
- Receptors: H1, H2
Physiological response to histamine stimulation
Heart rate
- Rapid heartbeat
- H2
Physiological response to histamine stimulation
Bronchioles
- Breathing difficulty (constriction)
- H1
Physiological response to histamine stimulation
Intestines
- Constipation/diarrhea
- H1
Physiological response to histamine stimulation
Skin capillaries
- Dilation, edema, redness, flare
- H1
Physiological response to histamine stimulation
Nerves in spinothalamic tract
- Itching in specific fibers
- H1
Physiological response to histamine stimulation
Gastric acid secretion
- Increased, nausea, heartburn
- H2
Effects of histamine on blood vessels
- Temporary decrease in blood pressure
- Hives
- Angiodema
Effects of histamine on extravascular smooth muscle
- Intestinal disturbances, constipation
- bronchoconstriction
Define
Antihistimine H1 antagonists
- Used to relieve the symptoms of allergic reactions after histamine has been released
- Blocks histamine from binding to H1 receptors
- Characterized into first generation and second generation
Antihistamines as inverse agonists
They bind and stabilize the inactive conformation of the H1 receptor which shifts the equilibrium toward the inactive receptor state
Define
First generation antihistmines
Non-selective interaction with peripheral and CNS histamine receptors, has a sedating effect
Examples: Brompheniramine, chlorpheniramine, diphenhydramine, promethazine
Define
Second generation antihistamines
More selective for peripheral H1 receptors, not as sedating, less anticholinergic activity
Ex cetirizine (claritin), fexofenadine, loratadine
Define
Third generation antihistamines
To develop therapeutically active metabolites that are devoid of cardiac toxicity
Ex Fexofenadine, levocetirizine
Routes of administration for antihistamines
- Oral
- Topical
- Nasal spray
- Eye drops
Not very effective for anaphylaxis and asthma
Asthma triggers
- Allergens
- air pollutants
- infections
- exercise
Characteristics of asthma
- Bronchoconstriction
- shortness of breath
- wheezing
- veiwed as an inflammatory disease
Leukotrienes in asthma
The most potent bronchoconstrictor
Zileuton
5-lipoxygenase inhibitor
Montelukast and Zafirlukast
CysLT1 receptor antagonist
Role of the Autonomic Nervous System in Asthma
1) Bronchodilation produces sympathetic stimulation
2) parasympathetic stimulation produces bronchoconstriction and increased mucus secretion
3) SYMPATHOMIMETIC drugs decrease parasympathetic activity (muscarinic antagonists, theophyline)
Asthma Treatments
1) Bronchodilator drugs
2) anti-inflammatory drugs
3) anti-allergic agents
4) Mucokinetics: mucolytics and expectorants
Bronchodilator Drugs
Non-selective Beta-adrenergic drugs (agonists)
Epinephrine and isoproterenol
- stimulate beta-1 and beta-2 adrenergic receptors
- may cause tachycardia and cardiac arrhythmias
Bronchodilator Drugs
Selective beta-2 adrenergic drugs
Albuterol, salmeterol, formoterol (long-lasting)
- Used in chronic asthma and COPD
- prevent mediators from being released by mast cells
Bronchodilator Drugs
Anticholinergics (antagonists)
- Blocks action of acetylcholine
- not as potent as Beta-drugs
- lowers volume of respiratory secretions
- considered first line drugs for COPD
- EX Ipatropium Bromide (Atrovent)
Methylxanthine drugs - Examples
Theophylline, caffeine, theobromine
Methylxanthine drugs - Mechanism of action
- Inhibits phosphodiesterase –> increased cAMP
- Bronchodilating, increased respiratory contractility and mucociliary clearance
Anti-inflammatory drugs
Corticosteroids
- Most potent
- interferes with all stages of the inflammatory and allergic response (antibody production, immune cell activity, release of mediators)
- inhibits the inflammatory response that occurs in the respiratory airways
Anti-inflammatory drugs
Leukotriene inhibitor drugs - Zileuton
- Prevent synthesis of leukotriene
- used in the chronic control of asthma
Anti-inflammatory drugs
Leukotriene receptor antagonist (CysLT1 receptor)
Montelukast and zafirlukast
Antiallergic agents
Cromolyn sodium
- Interferes with the antigen-antibody reaction to release mast cell mediators
- Administered by inhalation, ingestion, or as an eye solution
- Acts prophylactically, does not help an asthma attack that has started
Antiallergic agents
Omalizumab
- Binds to and inactivates IgE
- reduces the severity and frequency of allergic asthma attacks
Mucokinetics
Mucolytics
- Liquefy bronchial mucus
- enable removal of mucus by coughing or suction apparatus
- N-Acetylcysteine (NAC) - breaks down the glycoproteins in bronchial secretions
Mucokinetics
Expectorants
- Facilitates removal of thickened mucus from the lungs and helps liquefy the mucus
- Guaifenesin - used to provide relief of unproductive coughing
- Signals the body to increase the amount or hydration of secretions, lubricates the irritated respiratory tract
How does Mucolytics affect the mucus mesh?
- Treatment with hypertonic saline increases the spacing within the mucus mesh
- Treatment with NAC breaks disulfide bonds within the network of the mesh
What is N-Acetylcysteine (NAC)?
- Mucolytic agent and management of acetominophen poisoning
- derivative of cyysteine with an acetly group attached to the amino group of cysteine
- a pro-drug that is converted into cysteine and absorbed into the blood stream
- replenishes glutathione stores
Overall preferred therapy for Asthma
Mild intermittent Asthma
- Beta-2 bronchodilator
Overall preferred therapy for Asthma
Mild Persistent Asthma
- Corticosteroid
- Cromolyn
- Anti-leukotriene
Overall preferred therapy for Asthma
Moderate Persistent Asthma
- Corticosteroids
- Beta-2 bronchodilator
Overall preferred therapy for Asthma
Severe Persistent Asthma
- Corticosteroid
- Beta adrenergic bronchodilator
- anti-leukotriene
