Week 12: Respiratory Pharmacology - Asthma and COPD Flashcards

1
Q

Describe where the drugs deposit upon entering the body and the clinical significance

A
  • 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

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2
Q

Why are spaces effective when depositing the medication?

A
  • 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
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3
Q

Describe the mechanism of action of B2-adrenoreceptor agonists

A

• 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
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4
Q

What are 4 effects of B2-adrenoreceptor agonists

A
  • 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
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5
Q

What are the two types of B2 agonists and whats the difference between them?

A

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
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6
Q

What are some potential side effects of B2 agonists

A

• 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
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7
Q

What is a drug that is used to treat asthma and COPD, it is also cheap and used widely in developing countries

A

Theophylline

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8
Q

What are some theories to the mechanism of action of theophylline

A

• 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

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9
Q

What are some potential side effects of theophylline

A
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10
Q

What are the 4 bronchodilator drugs and 1 drug that is a bronchidilator that we are learning about this week

A
  1. Beta-2 adrenoreceptor agonists
  2. Theophylline
  3. Muscarinic antagonists
  4. Leukotriene receptor antagonists
  5. Glucocorticoids
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11
Q

What is the name of the drug that is a muscarinic antagonists

A

ipratropium

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12
Q

What is the mechanism of action for ipratropium

A
  • 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
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13
Q

What is the mechanism for leukotriene receptor antagonists and which type of asthma do they specifically inhibit

A
  • 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)
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14
Q

Which drug is mainly used to prevent the progression of chronic asthma into acute severe asthma?

A

Glucocorticoids

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15
Q

What is the mechanism of action of glucocorticoids?

A

• Goes into membrane -. bind to receptors → translocates into nucleus → changes transcription of inflammatory cytokines
[1]

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16
Q

What action does glucocorticoids have (there are 6)

A
  • 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
17
Q

what are the 3 treatments used for severe asthma?

A
  • Oxygen (in high concentration, usually ≥ 60%)
  • Salbutamol (inhalation of nebulised)
  • Hydrocortisone (intravenous )
18
Q

Why are glucocorticoids ineffective in treating COPD?

A
  • 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
19
Q

What are the effects on the bronchi from ipratropium

A

• 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
20
Q

what are some new treatment approaches for COPD and what is the best treatment

A
  • 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