Week 12: Respiratory Pharmacology - Asthma and COPD Flashcards
Describe where the drugs deposit upon entering the body and the clinical significance
- Most swallowed and reabsorbed → entering systemic circulation
- Use of large-volume spacer reduces the amount swallowed and reabsorbed → limits systemic effects
System effects lead to potential side effects
Why are spaces effective when depositing the medication?
- More of the medication gets down into the lungs (vs using the puffer without a spacer)
- Spacers work just as well as a nebuliser and are cheaper and easier to carry around.
- Less of the medicine gets stuck in the mouth and throat → cuts down risks of side effects in the mouth and throat
‣ e.g. thrush, hoarse voice and a sore throat when using steroid puffers
- Cuts down systemic side affects
Describe the mechanism of action of B2-adrenoreceptor agonists
• Bronchodilation: Direct action on the β2 adrenoceptors of smooth muscle
- Mimics the effect of the endogenous agonist (adrenalin)
- β2 agonists results in the activation of the Gs-adenylyl cyclase-increases cAMP- PKA pathway → resulting in phosphorylative events → decrease in MLCK → leading to bronchial smooth muscle relaxation
What are 4 effects of B2-adrenoreceptor agonists
- Prevention of mediator release from mast cells (via β2 receptors)
- Prevention microvascular leakage and oedema after exposure to mediators - i.e. histamine, LTD4, and prostaglandin D2
- Increase in mucus secretion from submucosal glands and ion transport across airway epithelium (may enhance mucociliary clearance)
- Reduction in neurotransmission in human airway cholinergic nerves by an action at presynaptic β2 receptors to inhibit ACh release
What are the two types of B2 agonists and whats the difference between them?
Short-Acting β2 Agonists (SABA)
- Inhaled SABAs are the most widely used and effective bronchodilators in the treatment of asthma
- Convenient, easy to use, rapid in onset, no significant systemic side effects
- SABAs are the bronchodilators of choice in treating acute severe asthma.
Long-Acting Inhaled β2 Agonists (LABA)
- The LABAs salmeterol, formoterol, and arformoterol are a significant advance in asthma (and COPD) therapy
- They have a bronchodilator action of more than 12 hours – 24 hours and also protect against bronchoconstriction for a similar period
- Improve asthma control
What are some potential side effects of B2 agonists
• Muscle tremor
- Direct effect on skeletal muscle β2 receptors
• Tachycardia
- Direct effect on atrial β2 receptors, reflex effect from increased peripheral vasodilation via β2 receptors
- Thus have to be careful giving this to patients with hypertension
• Hypokalemia
- direct β2 increase of skeletal muscle uptake of K+
- Restlessness
- Hypoxemia
- ↑ V̇/Q̇ mismatch due to reversal of hypoxic pulmonary vasoconstriction)
• Metabolic effects
- ↑ FFA, glucose, lactate, pyruvate, insulin
What is a drug that is used to treat asthma and COPD, it is also cheap and used widely in developing countries
Theophylline
What are some theories to the mechanism of action of theophylline
• Inhibition of PDEs
- Nonselective PDE inhibitor → elevation of cellular cAMP and cyclic GMP → smooth muscle relaxation
• Adenosine receptor antagonism
- Adenosine → bronchoconstriction in airways from asthmatic patients by releasing histamine and LTs
- Antagonism of A1 receptors → serious side effects (cardiac arrhythmias and seizures)
• Interleukin 10 release
- IL-10 has a broad spectrum of anti-inflammatory effects
• Effects on gene transcription
- Prevents the translocation of the pro-inflammatory transcription factor NF-κB into the nucleus → reducing the expression of inflammatory genes in asthma and COPD
• Effects on apoptosis
- Promotes apoptosis in eosinophils and neutrophils
• Histone deacetylase activation
- Recruitment of HDAC2 by glucocortical receptors (GRs) switches off inflammatory genes
Theophylline reactivate HDAC → enhancing the anti-inflammatory effects of corticosteroids
What are some potential side effects of theophylline
What are the 4 bronchodilator drugs and 1 drug that is a bronchidilator that we are learning about this week
- Beta-2 adrenoreceptor agonists
- Theophylline
- Muscarinic antagonists
- Leukotriene receptor antagonists
- Glucocorticoids
What is the name of the drug that is a muscarinic antagonists
ipratropium
What is the mechanism of action for ipratropium
- Non-selective (M1/M2/M3) muscarinic ACh receptor antagonist
- M3 receptors mediate ACh effect on bronchial constriction – (Gq → ↑ IP3 → ↑ Ca2+)
- A quaternary ammonium ion analogue of atropine (atropine methyl nitrate)
- Poor absorption → minimises systemic adverse effects = used as an inhaled bronchodilator
What is the mechanism for leukotriene receptor antagonists and which type of asthma do they specifically inhibit
- Binds to LT1 and LT2 receptors for leukotrienes (LTC4, LTD4 and LTE4)
- The ‘lukast’ drugs (montelukast and zafirlukast) antagonise LT1
- Inhibit exercise-induced asthma and decrease both early and late responses to inhaled allergen
- They work to relax the airways in mild asthma
- Less effective than salbutamol (their action is additive - i.e. used in addition to other drugs)
Which drug is mainly used to prevent the progression of chronic asthma into acute severe asthma?
Glucocorticoids
What is the mechanism of action of glucocorticoids?
• Goes into membrane -. bind to receptors → translocates into nucleus → changes transcription of inflammatory cytokines
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What action does glucocorticoids have (there are 6)
- Decrease formation of TH2 cytokines → decreased production of IgE
- Inhibit the induction of COX-2 (responsible for inflammation and pain) → generation of decreased production of vasodilators PGE2 and PGI2
- Inhibit the allergen-induced influx of eosinophils into the lung
- Inhibit the production of cytokines that activate eosinophils (i.e. reduce mediator release)
- Upregulate β2-adrenoceptors
- Decrease permeability
what are the 3 treatments used for severe asthma?
- Oxygen (in high concentration, usually ≥ 60%)
- Salbutamol (inhalation of nebulised)
- Hydrocortisone (intravenous )
Why are glucocorticoids ineffective in treating COPD?
- Inflammatory gene activation results from acetylation of nuclear histones around which DNA is wound
- Acetylation opens up the chromatin structure, allowing gene transcription and synthesis of inflammatory proteins to proceed
- HDAC is a key molecule in suppressing production of proinflammatory cytokines
- Corticosteroids recruit HDAC to activated genes, reversing acetylation and switching off inflammatory gene transcription
- HDAC activity is inhibited by smoking-related oxidative stress, which may explain the lack of effectiveness of glucocorticoids in COPD
What are the effects on the bronchi from ipratropium
• Anticholinergic drugs inhibit vagally mediated airway smooth muscle contraction
- Thus they cause bronchodilation
• Small affect in normal airways but greater in COPD as COPD airways are:
- Structurally narrowed (small radius ) → have higher resistance to airflow
• Explanation: airway resistance is inversely related to the fourth power of the radius
- Just like in blood vessels
what are some new treatment approaches for COPD and what is the best treatment
- Chemokine antagonists → directed against the influx of inflammatory cells into the airways and lung parenchyma
- Targeting inflammatory cytokines such as TNF-α
- PDE IV inhibitors (phosphodiesterease 4 inhibitors)
- Inhibitors of cell signalling
- p38 mitogen-activated protein kinase – nuclear factor κβ
- phosphoinositide-3 kinase-γ
- Antioxidants
- Inhibitors of inducible NO synthase
- Leukotriene B4 antagonists
- There is a search for serine protease and matrix metalloprotease inhibitors to prevent lung destruction and the development of emphysema.
best way to treat COPD is to stop smoking
