WEEK 2: Pharmacology of airways obstruction Flashcards
What is asthma?
“A chronic inflammatory disorder of the airways in which many cells and cellular elements play a role.
The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly at night or in the early morning.
These episodes are usually associated with widespread but variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment.”
State the 3 types of bronchodilators used for asthma.
Β2 agonists
Muscarinic receptor antagonists
Methylxanthines
Describe the MOA of Β2 agonists.
- Binding to β2 Adrenergic Receptors:
β2 agonists, such as albuterol (short-acting) or salmeterol (long-acting), bind specifically to β2 adrenergic receptors located on the smooth muscle cells of the bronchioles in the lungs. - Activation of Adenylyl Cyclase:
Binding of β2 agonists to the receptors activates an enzyme called adenylyl cyclase. - Conversion of ATP to cAMP:
Adenylyl cyclase catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). - Activation of Protein Kinase A (PKA):
Elevated levels of cAMP activate protein kinase A (PKA), an enzyme that plays a crucial role in cellular signal transduction. - Phosphorylation of Proteins:
PKA phosphorylates various proteins within the smooth muscle cells, leading to relaxation and bronchodilation. - Inhibition of Smooth Muscle Contraction:
The phosphorylation of proteins inhibits the contraction of smooth muscle cells in the bronchioles. - Opening of Potassium Channels:
β2 agonists also open potassium channels, leading to the efflux of potassium ions from the smooth muscle cells. This further contributes to muscle relaxation. - Inhibition of Mediators of Inflammation:
β2 agonists may also have anti-inflammatory effects by inhibiting the release of mediators involved in the inflammatory response.
Give 2 examples of SHORT-ACTING BETA AGONISTS.
How are they given?
When do their maximum effect occur and what is their duration of action?
Albuterol (salbutamol) and terbutaline.
These are given by inhalation;
The maximum effect occurs within 30 min and the duration of action is 4-6 hours
They are usually used on an ‘as needed’ basis to control symptoms.
Give 2 examples of LONG-ACTING BETA AGONISTS
How are they given?
What is their duration of action?
What are they used for?>
Salmeterol and Formoterol
These are given by inhalation, and the duration of action is 8-12 hours.
Given regularly, twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by glucocorticoids.
State adverse effects of B2 agonists.
Fine tremor, tachycardia and hypokalemia
Fine Tremor: Beta-2 agonists can stimulate beta-2 receptors not only in the lungs but also in other parts of the body, including skeletal muscles. Activation of these receptors can lead to muscle tremors, particularly in the hands and fingers, which are often described as “fine tremors.”
Tachycardia: Activation of beta-2 receptors in the heart can lead to an increase in heart rate (tachycardia). While beta-2 receptors primarily cause bronchodilation in the lungs, they also exist in cardiac tissue, and their stimulation can result in a faster heart rate.
Hypokalemia: Beta-2 agonists can cause the shift of potassium ions from the extracellular space into cells, leading to a decrease in serum potassium levels (hypokalemia). This effect is primarily due to the stimulation of beta-2 receptors in skeletal muscle and possibly other tissues.
Dose related
Minimized by use of the inhaled route which selectively delivers the drug to the airways.
State the 3 main MUSCARANIC RECEPTOR ANTAGONISTS.
Atropine
Ipratropium bromide
Tiotropium bromide
State the different types of muscarinic receptors and where they are found.
M1 receptors:
*Location: Salivary glands, Parietal cells
M2 receptors:
*Location: Heart
M3 receptors:
*Location: Mainly found in smooth muscle tissues, such as those in the gastrointestinal tract, bronchi, and urinary bladder.
Also present in glands (e.g., salivary glands) and vascular endothelial cells
Reversible and non-selective M receptor antagonist
Tertiary amine belladonna alkaloid
Highly lipid soluble
Rapidly absorbed absorbed across the respiratory epithelium
Dry mouth. Inhibition of Sweating. Tachycardia. Blurring of vision. Hallucinations
Name the drug.
Atropine
Quaternary derivative of N-isopropyl atropine
It is given by aerosol inhalation.
The maximum effect occurs approximately 30 min after inhalation and persists for 3-5 h.
It is highly polar and is not well absorbed into the circulation, limiting systemic effects.
Adverse effects such as xerostomia: Dry mouth, bitter taste, mydriasis are related to local anticholinergic effects.
***Mydriasis refers to the dilation of the pupil of the eye.
Name the drug.
IPRATROPIUM BROMIDE
Long-acting muscarinic antagonist
After inhalation, onset typically begins within half an hour and lasts for 24 hours
Once daily dosing
It may also be considered in patients with poorly controlled moderate-severe asthma
Maintenance treatment of chronic obstructive pulmonary disease
Name the drug.
TIOTROPIUM BROMIDE
Outline the 3 main METHYL-XANTHINES.
Theophylline
Theobromine
Caffeine
State the adverse effects of methylxanthine.
Stimulation
Insomnia
Tremor
Increase secretion of gastric acid and digestive enzymes
Vasodilation
Tachycardia
Diuresis
State the 4 main anti-inflammatory drugs.
Glucocorticoids
Leukotriene modifiers
Mast cell stabilizers
IgE antibody (Omalizumab)
Describe the MOA of glucocorticoids.
- Inhibition of Phospholipase A2:
Glucocorticoids inhibit the activity of phospholipase A2, an enzyme involved in the production of arachidonic acid.
Arachidonic acid serves as a precursor for the synthesis of pro-inflammatory eicosanoids, such as prostaglandins and leukotrienes.
- Inhibition of Pro-inflammatory Cytokines:
Glucocorticoids suppress the production of pro-inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). This leads to a reduction in the inflammatory response. - Reduction of Inflammatory Cell Infiltration:
Give examples of inhaled Glucocorticosteroids.
Why are they inhaled?
State their adverse reactions.
Beclomethasone , Fluticasone, Mometasone, Ciclesonide
The aim is to achieve maximum anti-inflammatory effect in the lung whilst minimizing systemic absorption
Oropharyngeal candidiasis
Hoarseness
Give examples of systemic steroids.
Why are they typically limited to patients with severe acute or chronic disease that cannot be otherwise controlled?
Such prednisone, may be considered if the inhaled drugs are inadequate.
Used as a Short bust for exacerbations
Long-term treatment of asthma that cannot be controlled with other medications
Systemic corticosteroids have more widespread anti-inflammatory effect than inhaled corticosteroids, but they also have a more substantial adverse effect profile.
For this reason, the use of systemic corticosteroids is typically limited to patients with severe acute or chronic disease that cannot be otherwise controlled.
Describe the MOA of leukotriene modifiers as anti-inflammatory drugs.
Describe their adverse effects.
Inhibition of 5-Lipoxygenase:
Arachidonic acid is metabolized by the enzyme 5-LO to produce leukotrienes, including leukotriene B4 (LTB4) and the cysteinyl leukotrienes (LTC4, LTD4, and LTE4).
Zileuton inhibits 5-LO, thereby reducing the production of leukotrienes.
Less effective than inhaled corticosteroids
Well, tolerated Oral drugs.
Systemic allergic disorders
Aspirin-exacerbated respiratory disease
Describe MOA of mast cell stabilizer.
State their adverse effects.
State examples of mast cells stabilizer.
Block mast cell degranulation, stabilizing the cell and thereby preventing the release of histamine
Weak anti-inflammatory effects and short duration of action.
Localized adverse effects (Sore throat, Cough, Unpleasant taste)
CROMOLYN & NEDOCROMIL
Describe MOA of IgE ANTIBODY: Omalizumab
Omalizumab Binding to IgE:
Omalizumab is a monoclonal antibody that binds specifically to the constant (Fc) region of IgE antibodies circulating in the blood.
By binding to IgE, omalizumab prevents IgE from attaching to its receptors on the surface of mast cells and basophils.
Discuss the STEPWISE MANAGEMENT OF ASTHMA.
Step 1: Intermittent Asthma
Short-Acting Beta-Agonist (SABA):
As-needed use of a short-acting beta-agonist (e.g., albuterol) for quick relief of symptoms.
Step 2: Mild Persistent Asthma
-Low-Dose Inhaled Corticosteroids (ICS):
Regular use of low-dose ICS, which is the preferred long-term control medication for persistent asthma.
-As-Needed SABA:
Continued use of a short-acting beta-agonist as needed for symptom relief.
Step 3: Moderate Persistent Asthma
-Low-Dose ICS + Long-Acting Beta-Agonist (LABA):
Combination therapy with low-dose ICS and a LABA for better asthma control.
-As-Needed SABA:
Short-acting beta-agonist as needed for symptom relief.
Step 4: Severe Persistent Asthma
-Medium-Dose to High-Dose ICS + LABA:
Increased dose of ICS, and possibly a LABA, for individuals with severe persistent asthma.
Consider Adding Other Controllers:
Depending on the severity, other controllers such as leukotriene modifiers, theophylline, or oral corticosteroids may be considered.
-As-Needed SABA:
Short-acting beta-agonist as needed for symptom relief.
Step 5: Very Severe Persistent Asthma
-High-Dose ICS + LABA + Oral Corticosteroids:
High-dose ICS and LABA, along with oral corticosteroids, for those with very severe persistent asthma.
-Consider Biologics:
In some cases, particularly when asthma is not well-controlled with standard therapy, biologic agents targeting specific pathways (e.g., anti-IgE monoclonal antibodies) may be considered.
-As-Needed SABA:
Short-acting beta-agonist as needed for symptom relief.
How are drugs delivered?
Dry-powder inhalers
Nebulizers
Describe how a METERED-DOSE INHALER works.
Shaking the Inhaler
Breathe out all the way.
Breathe in and compressed gas.
Propels a fixed dose of the drug out of the device.
Hold breathes for a count of 10.
Breathe out slowly.
Describe how A DRY POWDER INHALER works.
Inspiration
Turbulent flow within the device
Scatters a dry powder
