Beta-2 Adrenoceptor Agonists: Mechanism of Action Flashcards
(36 cards)
What type of receptor is the β₂-adrenoceptor?
It is a G-protein-coupled receptor (GPCR) coupled to a Gs (stimulatory) protein.
What happens when a β₂-agonist (or adrenaline) binds to the β₂-adrenoceptor?
The Gs protein activates adenylyl cyclase, increasing the conversion of ATP to cyclic AMP (cAMP).
What is the effect of increased intracellular cyclic AMP (cAMP) in airway smooth muscle cells?
It activates protein kinase A (PKA).
What does PKA (protein kinase A) do after being activated by cAMP?
It phosphorylates target proteins, leading to a reduction in intracellular calcium levels.
Why is decreasing intracellular calcium important in airway smooth muscle?
Because bronchoconstriction is a calcium-dependent process; high calcium is needed for actin-myosin cross-bridge formation and muscle contraction.
How do β₂-agonists counteract bronchoconstriction?
By lowering intracellular calcium, they inhibit the contractile process → smooth muscle relaxes → airway diameter increases.
Which bronchoconstrictor mediators increase intracellular calcium in airway smooth muscle?
• Acetylcholine
• Histamine
• Leukotrienes
What is the term for the way β₂-agonists oppose the effect of multiple constrictors?
Functional antagonism – they counteract contraction through different receptors and signaling pathways, not by directly blocking the same receptor.
Why is the effect of β₂-agonists in cardiac muscle different from their effect in airway smooth muscle?
In cardiac tissue, β-adrenoceptor activation increases intracellular calcium, enhancing contraction force. The effect is tissue-specific due to different enzymes and proteins involved.
Why is overuse of short-acting beta-2 agonists (SABAs) problematic in asthma?
Overuse can lead to beta-2 adrenoceptor downregulation (↓ receptor number and/or ↓ stimulus-response coupling), reducing bronchodilator effectiveness over time.
What does the rapid onset but short duration of action of SABAs indicate?
SABAs relax airway smooth muscle quickly, but the physiological effect lasts only 2–4 hours—not due to drug half-life but due to diffusion away from the airways.
How are inhaled SABAs removed from the lungs if not metabolized locally like noradrenaline?
They are not reuptaken or metabolized in the airway but instead diffuse into bronchial circulation and are later metabolized by the liver.
What is the clinical significance of SABAs being removed via diffusion rather than metabolism?
Their effects are short-lived; they don’t linger at the site of action, making them suitable only for acute relief—not long-term control.
Why shouldn’t SABAs be used alone as regular treatment in asthma?
They treat symptoms but not the underlying inflammation. Over-reliance without anti-inflammatory therapy (e.g., inhaled corticosteroids) worsens outcomes and increases asthma-related risks.
What is the main clinical use of LABAs in asthma management?
LABAs are used prophylactically to maintain constant airway relaxation and prevent bronchospasm caused by mediators like histamine, leukotrienes, and prostaglandins.
How do LABAs help prevent asthma symptoms?
By maintaining airway smooth muscle relaxation around the clock, they reduce the likelihood of bronchoconstriction in response to irritants or allergens.
Why are LABAs not used for acute symptom relief in asthma?
Their onset is slower and they are intended for long-term maintenance, not rapid relief like SABAs.
What is the most common adverse effect of beta-2 agonists (including LABAs)?
Muscle tremor—due to stimulation of beta-2 receptors in skeletal muscle.
How do beta-2 agonists cause palpitations or tachycardia at high doses?
By causing vasodilation (↓ BP), which triggers a reflex tachycardia, and potentially through non-selective stimulation of beta-1 receptors in the heart.
Why are adverse effects of inhaled LABAs usually uncommon?
Because the inhaled route targets the lungs directly, allowing for lower doses and minimizing systemic absorption.
What are the common adverse effects of beta adrenoceptor agonists?
Tremor, palpitation, tachycardia, headache. Selectivity for the beta-2 adrenoceptor is important to minimise these effects.
What precautions should be taken when using beta adrenoceptor agonists?
- Cardiovascular disorders: risk of worsened outcomes due to increased oxygen demand, tachycardia, hypokalaemia, increased cardiac workload, and arrhythmias.
- Concurrent use of sympathomimetic amines: increases adverse effects.
- Diabetes: beta agonists can exacerbate hyperglycaemia by stimulating hepatic glucose production and inhibiting insulin secretion.
Diabetes:
1. β2-adrenoceptor stimulation in the liver: Activates glycogenolysis (breakdown of glycogen into glucose)
Stimulates gluconeogenesis (formation of new glucose) ➤ This leads to increased glucose output into the bloodstream
2. β2-adrenoceptor effect on pancreatic islets: Inhibits insulin secretion from pancreatic β-cells. Less insulin = less cellular uptake of glucose. May also enhance glucagon secretion (from α-cells), which further promotes hepatic glucose production
3. Peripheral effects: Promotes lipolysis (fat breakdown), increasing free fatty acids. FFAs can impair insulin signaling → insulin resistance
What immune response characterizes allergic asthma?
Th2-mediated inflammation with eosinophils, mast cells, and increased IgE.
Which cytokines are involved in asthma and what are their roles?
- IL-4, IL-13: Stimulate IgE production.
- IL-5: Recruits eosinophils.
- IL-13: Supports mast cell survival.
