69 - Drugs that Remodel the Airways Flashcards
Drugs not effective for asthma or colds
Antihistamines
Asthma definition 1) 2) 3) 4)
1) Chronic inflammatory disorder of the airways
2) Many cells, cellular elements play a role
3) Chronic inflammation is associated with hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, coughing
4) Widespread, variable and often reversible airflow limitation
Inflammation in asthma
1)
2)
3)
1) Inflammation of airway wall
2) Eosinophils present. Release cytotoxins
3) Desquamation
What leads to desquamation in asthmatic inflammation
Eosinophils release toxic products that lead to epithelial cell apoptosis
Cells recruited by activated mast cells
1)
2)
1) Eosinophils
2) Neutrophils
Things affected by mast cells in inflammation 1) 2) 3) 4) 5) 6) 7) 8)
1) Other cells (eosinophils, neutrophils)
2) Epithelial cells (shedding)
3) Subendothelial fibrosis
4) Sensory nerve activation
5) Blood vessels (oedema, plasma leak, vasodilation, angiogenesis)
6) Mucus secretion, hyperplasia
7) Cholinergic reflex
8) Airway smooth muscle
Timeline of mucosal oedema in asthma
1)
2)
3)
1) Normal at 0 minutes
2) Closed at 10 minutes
3) Red, glistening, swollen at 30 minutes. From mucus secretion, oedema, vasodilation
What can lead to fatal asthma?
Mucus plugs (can occlude 50% of lumen)
Classes of drugs for treating asthma
Relievers, controllers, preventers
Things that can lead to airway lumen occlusion
1)
2)
3)
1) Airway smooth muscle contraction
2) Bronchial wall oedema
3) Mucus hypersecretion
Asthmatic processes that relievers, controllers and preventers can stop
Airway smooth muscle contraction
Asthmatic processes that preventers can stop
Bronchial wall oedema, mucus hypersecretion
Shape of airway smooth muscle
Single band around the trachea
Why can the trachea resist collapse?
Horse-shoe shape of cartilage. Resists collapse from smooth muscle contraction
Distribution of smooth muscle in airways
Irregularly distributed in smaller intraperenchymal bronchi, together with cartilage plates, which disappear in later generations.
Effect of preventing deep breathing
Can lead to alveolar contraction.
Deep breathing leads to lower pressure in airways from movement of air. Reducing flow of air leads to increasing air pressure, which smooth muscle contracts against.
Airway smooth muscle layout
Arranged roughly circumferentially around the airways in irregularly-distributed bands
Determinant of airway resistance during expiration
Velocity of contraction
Muscle that shortens faster
Unloaded muscle
What opposes muscle shortening?
Stretch
Contractile mechanism of airway smooth muscle 1) 2) 3) 4) 5)
1) Increase in intracellular Ca2+
2) Ca2+ binds calmodulin
3) Calmodulin activates myosin light chain kinase activity
4) Myosin light chain kinase phosphorylates myosin light chain
5) Actomyosin ATPase activated, which allows crossbridge formation
Arrangement of actin and myosin in smooth muscle
Irregular
Mechanism of Ca2+ release into smooth muscle cells
1) Voltage-operated Ca2+ channel leads to PLC/IP3 activation, which leads to Ca2+ release from intracellular stores. Sarcoplasmic reticulum Ca2+ ATPase (SRCA) pumps pump Ca2+ into SR.
Cystenyl-leukotriene potency relative to histamine
300x more potent than histamine
Timeframe of cystenyl-leukotriene release compared to histamine
Cys-leukotrienes are released over a longer period than histamine
Most important chemical mediator in asthma
Cystenyl-leukotriene (more potent than histamine, released over a longer period)
Bronchodilating factors
1)
2)
3)
1) PGE2
2) Adrenaline
3) PGI2
Bronchoconstricting factors 1) 2) 3) 4)
1) ACh
2) HA
3) LTC4
4) LTD4
Things that can activate myosin light chain phosphatase
Protein kinase A
Things that can prevent myosin light chain phosphatase activity
Rho kinase, protein kinase C
Processes that can lead to airway narrowing in asthma
1)
2)
3)
1) Acute inflammation
2) Chronic inflammation
3) Airway remodelling
Things, other than contraction, that airway smooth muscle can do 1) 2) 3) 4)
1) Proliferation
2) Migration
3) Secretion of cytokines (can secrete some cytokines at a greater rate than immune cells)
4) Secretion of ECM (leads to airway remodelling)
Examples of smooth muscle released factors 1) 2) 3) 4) 5)
1) Growth factors
2) Cytokines (IL-5, GM-CSF)
3) Chemokines (IL-8, eotaxin)
4) Lipid mediators (PGE2)
5) ECM proteins (collagen)
Effect of a bronchodilator on an asthmatic FEV1
Should return to normal, very close to normal quickly
Ways to measure airway hyperresponsiveness
Challenge with histamine, methacholine.
Amount of chemical that leads to a 20% decrease in FEV1 correlates with severity of asthma.
How long does it take to reverse hypersensitivity in an asthmatic?
About 12 months free of allergens
Key features of relievers
Short acting agents. Rapid onset (2-5 minutes). Beta2 selective (beta2 adR agonists)
Side effects of beta2 agonists
Tachycardia, tremor, hyperkalaemia
Examples of short-acting beta-adR agonists
Salbutamol, terbutaline.
Effect of short-acting beta2 adR over time
Desensitisation (common for GPCR agonists).
If used according to prescribed dose, this shouldn’t be a problem
How are beta2-adR agonists administered?
Metered inhalers.
Inhaled into lungs, or ingested, and drug on upper airways washed off with mouthwash
Receptor that leads to release of Ca2+ from SR
IP3 receptor
Effect of beta-2 adR stimulation on smooth muscle 1) 2) 3) 4) 5)
1) GPCR leads to adenyl cyclase activation
2) Increasing cAMP activates PKA
3) PKA stimulates SERCA, inhibits IP3R
4) PKA also activates myosin light chain phosphatase, inhibits myosin light chain kinase.
5) Muscle relaxation
Effect of ACh on smooth muscle 1) 2) 3) 4)
1) Muscarinic ACh receptor stimulated
2) PLC cleaves PIP2 to IP3
3) IP3 binds IP3R on SR, leads to Ca2+ release from SR
4) Muscle contraction
Examples of long-acting beta agonist
Formoterol, salmeterol, indacaterol
Examples of controllers
Long-acting beta2 adR agonists
How are controllers administered?
Prophylactically
Slow onset, long acting beta2 adR agonist
Salmeterol
Rapid onset, long acting beta2 adR agonists
Formoterol, indacaterol
Duration of salmeterol, formoterol
12 hours (administered twice daily)
Duration of indacaterol
24 hours (administered once daily)
Worrying association with long-acting beta2 adR use
Monotherapy associated with increased morbidity and mortality.
Tolerance, if beta2 adR always activated by beta2 adR agonists
Combination that long-acting beta2 adR agonists are always prescribed in
With inhaled glucocorticoids (LABA and GCS coformulated)
Example of a muscarinic antagonist for smooth muscle
Ipatropium bromide (short acting) Tiotropium bromide (long acting)
