S2: Airway Pharmacology Flashcards
What is the difference between physiology and pathophysiology?
Physiology is how tissue/organ functions in health
Pathophysiology is how tissue/organ functions in disease
What can drugs do in respiratory disease?
They can treat/reduce the severity of symptoms
- Reverse airway smooth muscle contraction
- Reduce mucus secretion
- Reduce allergic inflammation of the airways
- Reduce sensitivity to irritiating stimuli (cough)
Treating symptoms can be the difference between life and death
What can’t drugs do in respiratory disease?
They can’t heal, cure or resolve underlying cause of the pathology
- Resolve cause of inflammation
- Reverse airway/lung remodelling
- Repair damage to tissues
Describe the aspects of an diseased airway e.g. during asthma that can be treated with drugs
During an asthma attack, inflammatory mediators induce pathological changes to the airway.
- Contraction of smooth muscle
- Excess mucus secretion
- Oedema/swelling
- Irritation of sensory neurones (cough)
These changes in diseased airway combine to decrease the size of airway lumen, increase airway resistance and limit airflow (obstructing the airways and hence generating symptoms).
Name three types of bronchodilators
- Beta-2 adrenergic receptor agonists
- Long acting muscarinic receptor antagonists
- Phosphodiesterase Inhibitors
What are the 3 types of B2-agonists and give examples
Short acting (SABA) - e.g. salbutamol
Long acting (LABA) e.g. salmeterol
Ultra-long acting (ultra-LABA) e.g. Indacaterol
Name a Long-acting muscarinic receptor antagonists
Tiotropium
Name a phosphodiesterase inhibitor
Theophylline
How do bronchodilators act?
Bronchodilators act by relaxing airway smooth muscle cells
This increases luminal area, decreases resistance therefore increasing air flow
Explain the mechanism of airway smooth muscle contraction (ASMC)
Inflammatory mediators induce ASMC
- Contractile mediators e.g. cysLTs, ACh, PGs
- These bind to GPCRs e.g. M3
- Gq pathway activates intracellular signalling pathways (PIP2 –> DAG + IP3)
- SR releases Ca2+ causing increased calcium mobilisation and sensitivity
- Muscle contraction occurs
Explain the mechanism of B2- agonists as bronchodilators
- Beta 2 agonist e.g. salbutamol
- They bind to the GPCR : b2 adrenoreceptor
- Gs pathway activated
- Positively associated by adenyl cyclase which converts ATP to cAMP
- cAMP activated Protein Kinase A
- PKA inhibits MLCK
- Decrease Ca2+ mobilisation and sensitivity which leads to muscle relaxation
Explain the mechanism of Phosphodiesterase (PDE) inhibitors as bronchodilators
Phosphodiesterase inhibitors relax ASMCs by inhibiting cAMP metabolism and increasing its levels
- PDE inhibitors inhibits the enzyme PDE
- This prevents the breakdown of cAMP to AMP
- Increase levels of cAMP increases PKA
- PKA inhibits MLCK
- Relaxation
Explain the mechanism of Muscarinic receptor antagonists in bronchodilation
- Muscarinic receptor antagonists relax ASMCs by inhibiting the contractile effects of ACh at the M3 receptor
- The M3 receptor in ASM is contractile
- If inhibited contraction can’t occur as ACh cannot bind
However only inhibits ACh mediated contraction
Why is muscarinic receptor agonists less effective than B2 agonists?
It is less effective than B2 agonist as it isn’t inhibiting contraction, just acetyl choline mediated contractions. There are other stimuli that cause smooth muscle contraction that muscarinic receptor agonists do not affect.
What is the pharmalogical treatment for mucus secretion?
LAMAs (long acting muscarininc receptors) reduce mucus secretion by inhibiting M3-mediated mucus gland activation
Explain the mechanism of LAMAs in treating mucus secretion
Irritation of respiratory structures (epithelium) activate sensory neurones that innervates these structures. It sends a signal to the CNS that has a reflex arc that causes cough (motor neurones –>contraction –> cough).
Also, there is activation of cholinergic (PNS) fibres that innervate mucus glands releasing Ach that bind to M3 receptors stimulating mucus glands to produce more mucus.
LAMAs act by blocking Ach at M3 receptors (Muscarinic receptor antagonist)
What 2 things are long acting muscarinic antagonists (LAMA) used for?
- Bronchodilation
- Mucus hypersecretion
What aspects of airway inflammation of potential aspects of pharmalogical treatment?
Decrease these processes:
- Inflammatory mediator- receptor binding
- Ab crosslinking and degranulation
- Antibody production
- Proliferation
- Tissue infiltration from bloodstream (adhesion molecule expression)
- Chemotaxis
- Cytokine receptor binding
- Cytokine production (IL-4, IL-5, IL-13)
Increase this:
- Apoptosis of mast cells e.g. no degranulation
List drug classes used for airway infammation
- Glucocorticoids (asthma)
- Leukotriene inhibitors (asthma) - Leukotriene receptor antagonists block the receptor by which LT mediators produce inflammatory effects on immune cells + tissue
- Biologics (asthma) - Drugs = mAb that block/inhibit a specific pro- protein (e.g. IgE or IL-4, IL-5, IL-13, etc.) involved in the inflammatory pathway.
- Mast cell stabilisers (allergies, asthma) - Prevents degranulation of mast cells and/or sensory nerve activation
- PDE4 inhibitors (COPD) - Inhibits cAMP metabolism. Intracellular signalling effects then lead to changes in protein expression and neutrophil responses (among other cells)
Name a glucocorticoid
Fluticasone
Name a Leukotriene inhibitor
Montelukast
Name a biologics
Omalizumab
Name a Mast cell stabiliser
Sodium cromoglicate
Name a PDE4 inhibitor
Roflumilast
What are corticosteroids used for?
Corticosteroids are used as preventer medication to reduce airway inflammation
Name some inhaled corticosteriods and oral/systemic steriods
Inhaled corticosteroids
- Fluticasone
- Budesonide
- Beclometasone
Oral/systemic steroids
- Prednisone
- Dexamethasone
List the inflammatory and structural cells that corticosteriods affect to reduce inflammation
INFLAMMATORY CELLS ~
- Eosinophils (decreased numebers - apoptosis)
- T lymphocytes ( decreased cytokines)
- Mast cells ( decreased numbers)
- Macrophage (decreased cytokines)
- Dendritic cells (decreased numbers)
STRUCTURAL CELLS ~
- Epithelial cells (decreased cytokines/proinflammatory mediators)
- Endothelial cells (decreased leak)
- Airway smooth muscle (Increased b2-receptors, increased relaxation)
- Mucus glands (decreased mucus secretion)
Explain the mechanism of corticosteroids in reducing inflammation
- Corticosteroid (CS) diffuses through membrane (non polar) and binds to intracellular glucocorticoid receptor (GR)
- Drug receptor complex translocates to the nucleus
- Complex binds to DNA affecting transcription
- Altered transcription of gene is translated into protein
Corticosteroids increase or decrease expression depending on specific gene/protein (e.g. increases anti-inflammatory genes, decreases pro-inflammatory genes)
What are the side effects associated with long term/high dose corticosteroids?
- Growth retardation
- Skin ulcers
- Depression
- Candidiasis
- Hypercortisolism
- Osteoporosis
Describe the mechanism of opiods as a treatment for coughing
Opioids inhibit the activity of neurons within the CNS to produce an anti-tussive effect
Name an opiod
Codeine
What is the mechanism of a cough?
Irritants and inflammatory mediators activate sensory neurones in the epithelium lining the airway lumen.
Sensory nerves transmit info the CNS
CNS passes on impulse to motor neurones which causes respiratory muscle contraction causing a cough
What can treat a cough?
- Cough mixtures such a glycerine and honey line the throat with a physical barrier preventing irritants from activating the sensory nerve
- Opiods inhibit transmission of impulse within CNS
What 2 factors need to be considered when deciding on drugs to treat patients?
DRUG EFFICACY
- Increase quality of life (decrease symptoms, disease severity and disease resolution)
- Increase life expectancy
ADVERSE EFFECTS
- Decrease quality of life increases the risk of developing other diseases
- Economic costs
Why are drugs used in asthma typically administered by metered dose inhalers?
- Maximises therapeutic effect : adverse effect ratio by administering the drug directly to the desired tissue (i.e. the airways). Less drug then reaches the systemic circulation where it will be distributed to other tissues that are the cause of side effects.
- It is also much quicker in the event of rescue/reliever doses.
What are the receptors that b2 agonists e.g. salbutamol act on in other tissues and what effects do they cause?
- At higher concentrations, salbutamol activates b1 receptors at higher concentrations
In the heart, there are more b1 receptors than b2 in SAN and myocardium. This causes tachycardia and palpatations.
In skeletal muscle, there are more b2 receptors than b1. This causes tremor and muscle growth.
How do you decide on a therapeutic strategy (what drugs to use, when, and in what order?)
- Ensure acute risks are managed (All patients presenting with significant bronchospasm given SABA reliever medication)
- Drugs with greater general efficacy used first (SABA before LAMA)
- Drugs with ↓ risk of adverse effects used first (SABA→ SABA + ICS → +PDEi)
- Drugs with broad mechanisms of action used first (ICS (inhaled corticosteriods) before omalizumab)
- Cheaper drugs before more expensive drugs (ICS before omalizumab)
- One or fewer drugs before multiple drugs (SABA → SABA + ICS, SABA + ICS + X)
- Combine drugs if it decreases risk of adverse effects (only use LABA in combination with ICS)
Why is asthma pharmacology is administered in a stepwise manner?
- Move down drug ladder to maintain minimal controlling step if symptoms improve
- Move up to improve control as needed
Why is COPD therapy is administered in a progressive (one direction) stepwise manner?
- Move up as symptoms and dysonoea worsens
- COPD is an irreversible, progressive disorder so more treatment is needed as time goes on
Difference in the way ashtma and COPD therapy is administered
Asthma pharmacology is administered in a stepwise manner while COPD therapy is administered in a progressive (one direction) stepwise manner
COPD is an irreversible, progressive disorder so more treatment is needed as time goes on while asthma symptoms can improve or worsen
