Respiration Week 6

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Questions and Answers

What is a primary action of inhaled glucocorticoids in asthma treatment?

Synthesize additional β2 adrenoceptors

Act as fast-relief bronchodilators

Block leukotriene synthesis

Decrease the formation of Th2 cytokines (correct)

What is the nature of the feedback mechanism that controls corticotrophin release?

Direct stimulation from glucocorticoid production

Negative feedback from circulating glucocorticoid levels (correct)

Positive feedback from increasing corticotrophin levels

Autonomic regulation by the respiratory system

What is a notable characteristic of CLT antagonists compared to glucocorticoids?

They have virtually no side effects (correct)

They are more effective than glucocorticoids

They act solely as relievers without controller effects

They cause more side effects than glucocorticoids

Which is a role of HDAC in the context of glucocorticoid action on inflammation?

It mediates the alteration of gene expression Signup and view all the answers

What is the main mechanism of action for the human monoclonal anti-IgE antibody omalizumab in asthma treatment?

Target and neutralize IgE to prevent allergic reactions Signup and view all the answers

What is the primary role of Th2 cytokines in asthma?

Attract inflammatory cells to mucosal surfaces Signup and view all the answers

What effect do IL-4 and IL-13 have on B cells?

They convert B cells to IgE synthesis Signup and view all the answers

Which step in asthma treatment is recommended for very mild disease?

Inhaled short-acting bronchodilator alone Signup and view all the answers

What is the main purpose of using bronchoconstrictors in asthma management?

To reverse bronchospasm immediately Signup and view all the answers

Which of the following pharmacological treatments acts as a glucocorticoid-sparing agent?

Theophylline Signup and view all the answers

What role do antigen presenting cells play in asthma?

They phagocytose and present environmental allergens. Signup and view all the answers

What is a direct consequence of IL-5 interaction with eosinophils?

Priming eosinophils to produce cysteinyl leukotrienes Signup and view all the answers

Which cytokines are emphasized in the pathogenesis of asthma due to their role in IgE synthesis?

IL-4 and IL-13 Signup and view all the answers

What is the primary mechanism of action of muscarinic receptor antagonists like Ipratropium?

Decrease formation of cyclic guanosine monophosphate (cGMP) Signup and view all the answers

How does the absorption of Ipratropium affect its systemic availability?

Minimal systemic absorption due to its high polarity Signup and view all the answers

What is the dosage frequency for Zafirlukast, a cysteinyl leukotriene receptor antagonist?

Twice daily Signup and view all the answers

Which of the following are effects of cysteinyl leukotriene receptor antagonists?

Inhibit early and late responses to inhaled allergen Signup and view all the answers

Which anticholinergic drug is commonly combined with salbutamol for asthma management?

Ipratropium Signup and view all the answers

What are the primary excretion pathways for Ipratropium?

Renal and feces Signup and view all the answers

What distinguishes Tiotropium from Ipratropium in terms of their clinical use?

Tiotropium is a long-acting antimuscarinic specifically for COPD. Signup and view all the answers

Which of the following statements about the 'lukast' drugs is correct?

They are less effective than salbutamol but show additive effects. Signup and view all the answers

What are the primary causes of symptoms experienced during an asthma attack?

Symptoms are primarily caused by airway inflammation, hyper-responsiveness, and bronchial constriction. Signup and view all the answers

Describe the difference between the early and late phases of an asthma response.

The early phase occurs immediately after exposure to a trigger, while the late phase begins 4 to 8 hours later and can last for up to 24 hours. Signup and view all the answers

How does airway hyper-responsiveness affect asthma patients compared to non-asthmatics?

Asthma patients exhibit heightened sensitivity in their airways, reacting to stimuli that typically have no effect on non-asthmatics. Signup and view all the answers

Why is the reversibility of airway obstruction in asthma significant?

It indicates that asthma is characterized by an inflammatory process that can be effectively managed and reversed, unlike chronic obstructive pulmonary disease (COPD). Signup and view all the answers

What role do inflammatory cells play in the pathology of asthma?

Inflammatory cells, such as Th2 lymphocytes, infiltrate the airways and contribute to the chronic inflammation characteristic of asthma. Signup and view all the answers

What is the primary metabolic pathway for Zafirlukast?

Zafirlukast is primarily metabolized through the hepatic pathways involving CYP2C9 and CYP3A4. Signup and view all the answers

Why are CLT antagonists preferred for treating children with respiratory conditions?

CLT antagonists are preferred for children because they have minimal side effects compared to glucocorticoids. Signup and view all the answers

What role does the hypothalamus play in glucocorticoid release?

The hypothalamus releases corticotrophin releasing factor (CRF), which stimulates corticotrophin secretion from the pituitary gland. Signup and view all the answers

What is the effect of glucocorticoids on β2 adrenoceptors?

Glucocorticoids up-regulate the levels of β2 adrenoceptors, enhancing bronchial responsiveness. Signup and view all the answers

How does zileuton inhibit cysteinyl leukotriene synthesis?

Zileuton inhibits the synthesis of cysteinyl leukotrienes by blocking the 5-lipoxygenase enzyme. Signup and view all the answers

What are the three types of sensory receptors involved in airway resistance regulation?

Slowly adapting stretch receptors, rapidly adapting irritant receptors, and unmyelinated sensory C-fibres. Signup and view all the answers

Describe the significance of airway resistance measurements such as FEV1 and PEFR in respiratory health.

FEV1 and PEFR are important metrics for assessing airway resistance, helping to evaluate the severity of respiratory conditions like asthma and COPD. Signup and view all the answers

How does the respiratory centre in the medulla contribute to the regulation of respiration?

It integrates chemoreceptor signals regarding pO2 and pCO2 levels, modulating the respiratory rate and depth accordingly. Signup and view all the answers

What symptoms are triggered by the activation of irritant receptors during an asthma attack?

Coughing, bronchoconstriction, and mucus secretion are triggered by irritant receptor activation. Signup and view all the answers

Why is it crucial to prevent asthma deaths, considering the statistics provided?

Preventing asthma deaths is critical as two-thirds of these fatalities are preventable, emphasizing the importance of effective management and awareness. Signup and view all the answers

Explain the role of Vagal afferents from the lungs in respiratory control.

Vagal afferents contribute sensory information from the lungs to the central nervous system, influencing the reflexes that control breathing. Signup and view all the answers

What internal stimuli can activate C-fibre receptors in the lower airways?

Inflammatory mediators can activate C-fibre receptors in the lower airways. Signup and view all the answers

Discuss the impact of environmental irritants on respiratory function.

Environmental irritants such as cold air and pollutants can exacerbate respiratory conditions by triggering cough and bronchoconstriction. Signup and view all the answers

What is the most effective intervention to improve the rate of progression of COPD?

Stopping smoking. Signup and view all the answers

Why should COPD patients be immunised against influenza?

To prevent potentially fatal superimposed infections. Signup and view all the answers

What role does α1-antitrypsin play in lung health?

It protects the lungs from damage caused by protease enzymes. Signup and view all the answers

What is a reported effect of long-term oxygen therapy in COPD patients?

It can prolong life. Signup and view all the answers

How does cigarette smoke affect α1-antitrypsin and contribute to emphysema?

It leads to the oxidation of methionine 358 of α1-antitrypsin. Signup and view all the answers

What are the side effects associated with muscarinic receptor antagonists, summarized with the acronym 'ABCD's'?

Anorexia, Blurry vision, Constipation/Confusion, Dry mouth, Sedation. Signup and view all the answers

What is the mechanism through which cysteinyl leukotriene receptor antagonists like montelukast and zafirlukast operate?

They antagonize the high-affinity cysteinyl leukotriene receptor CysLT1 on target cells, such as bronchial smooth muscle. Signup and view all the answers

What is the typical duration of action for Ipratropium after inhalation?

Ipratropium's effects last for about 3 to 6 hours. Signup and view all the answers

Which cellular mediators are responsible for the synthesis of cysteinyl leukotrienes in the respiratory system?

Cysteinyl leukotrienes are synthesized by inflammatory cells, including eosinophils. Signup and view all the answers

What differentiates tiotropium from ipratropium in terms of their clinical use?

Tiotropium is a long-acting antimuscarinic bronchodilator specifically beneficial for COPD patients, while ipratropium is often used for asthma management. Signup and view all the answers

How do cysteinyl leukotriene receptor antagonists compare in effectiveness to salbutamol?

They are less effective than salbutamol, but their action is additive when used together. Signup and view all the answers

What are the primary routes of administration for ipratropium?

Ipratropium is administered via inhalation and intranasal routes. Signup and view all the answers

What time frame is associated with the onset of action for Ipratropium after inhalation?

Ipratropium typically takes 5 to 15 minutes to start acting. Signup and view all the answers

How does Annexin-1 contribute to the anti-inflammatory effects of glucocorticoids?

Annexin-1 inhibits phospholipase A2, reducing free arachidonic acid release and therefore decreasing inflammation. Signup and view all the answers

What are the consequences of prolonged high-dose glucocorticoid use in patients requiring oral steroids?

Prolonged high-dose use can lead to detrimental effects such as systemic side effects and increased risk of complications. Signup and view all the answers

Describe the role of glucocorticoids in the reduction of eosinophils in the airways.

Glucocorticoids induce apoptosis in eosinophils and decrease their production from bone marrow. Signup and view all the answers

What distinguishes Maintenance and Reliever Therapy (MART) in asthma management?

MART combines inhaled corticosteroids (ICS) with a fast-acting long-acting beta-agonist (LABA) in a single inhaler for both maintenance and symptom relief. Signup and view all the answers

How is the onset of action for inhaled corticosteroids like Beclomethasone characterized?

The onset of action is approximately one week. Signup and view all the answers

What is the primary metabolism pathway for Beclomethasone?

Beclomethasone is primarily metabolized in the liver and lungs by the CYP450 system. Signup and view all the answers

What essential roles do glucocorticoids play in transcription regulation regarding inflammatory proteins?

Glucocorticoids increase the transcription of anti-inflammatory proteins and decrease the transcription of pro-inflammatory proteins. Signup and view all the answers

What is Dupilumab and its significance in asthma treatment?

Dupilumab is a monoclonal antibody approved for asthma treatment that targets IL-4 and IL-13 pathways, helping to reduce inflammation. Signup and view all the answers

Study Notes

Respiratory Pharmacology

This review focuses on pulmonary disease, specifically asthma, and its treatment.

Topics Covered

Regulation of respiration
Disorders of respiratory function (asthma, COPD), and inflammation principles
Drugs affecting respiration
- Bronchodilators
  - Long-acting and short-acting agents
- Anti-inflammatory agents

Asthma Severity

5.4 million people in the UK have asthma
In Northern Ireland, 1 in 10 (182,000) individuals are currently receiving treatment. This includes 36,000 children and 146,000 adults.
Every 10 seconds, someone is experiencing a potentially life-threatening asthma attack in the UK
The lives of three families are devastated daily by an asthma-related death, with two-thirds of these deaths preventable
More than 12,000 people died in the UK from asthma in the past 10 years (2014-2024)

Respiration

Respiration is controlled by:
- Respiratory centers in the medulla (chemoreceptors and pO2/PCO2 in arterial blood at carotid bodies)
- The CNS (cortex)
- Vagal afferents (sensory neurons) from the lungs
Breathing can be regulated by voluntary control

Afferent Pathways

Slowly adapting stretch receptors
Rapidly adapting irritant receptors (myelinated vagal fibers)
Unmyelinated sensory C-fibers
Physical or chemical stimuli act on irritant receptors in the upper airways and C-fiber receptors in the lower airways
Stimuli can be from the environment (e.g. cold air, irritants like ammonia, sulfur dioxide, cigarette smoke) or from within the body (inflammatory mediators)

Efferent Pathways

Parasympathetic (cholinergic) innervation predominates (vagus nerve)
- M3 receptors cause bronchoconstriction and mucus secretion
- M2 receptors are auto-receptors
- Parasympathetic neurons maintain tone
Sympathetic (adrenergic) innervation – noradrenaline (NA) releasing sympathetic nerves
- Innervates blood vessels and glands, but not airway smooth muscle
- B2-adrenoceptors are found on airway smooth muscle
- Adrenaline binds to multiple receptors

NANC Mediators

Non-adrenergic non-cholinergic mediators
- Possible inhibitory mediators (NO and VIP)
- Possible stimulatory mediators (substance P, bradykinin)—these increase vascular permeability, mucus secretion, and bronchoconstriction

Respiratory Stimulants and Depressants

Used in emergencies (e.g., post-operative respiratory depression, acute respiratory failure)
Doxapram (stimulates carotid chemoreceptors stimulating the respiratory center)
Many CNS depressants lead to respiratory depression (e.g. benzodiazepines, general anesthetics, opioids, ethanol)

Disorders of Respiration

Bronchoconstriction: Muscles surrounding the bronchial tubes controlled by the autonomic nervous system.
Inflammation: A hallmark of asthma. Bronchial tubes shed their inner lining (epithelial cells) causing swelling and inflammation. This reduces airflow.
Increased Mucus: Excessive amounts secreted in the bronchial tubes.
Airway Hyper-responsiveness: Inflamed airways are overly sensitive to stimuli.

Asthma

Defined as a chronic inflammatory disorder.
Symptoms result from chronic airway inflammation, hyper-responsiveness, constriction, and obstruction
In mild cases, lungs tend to be hyper-reactive even with normal airflow
Natural stimuli (e.g. cold air, exercise, chemical fumes) can trigger responses

Airway Hyperresponsiveness

Characterized by inflammation of the airways, bronchial hyper-reactivity, and reversible airway obstruction.

Disorders of Respiratory Function (Inflammation)

Th2 cytokines: Attract inflammatory cells (especially eosinophils) to mucosal surfaces
IL-5: Primes eosinophils to produce cysteinyl leukotrienes
Cells release granule proteins damaging epithelium leading to hyper-responsiveness.
Promote IgE synthesis and responsiveness (IL-4 and IL-13) to cause IgE production and subsequent binding to mast cells and eosinophils aiding adhesion

Asthma (Inflammation, continued).

Allergen exposure triggers a response; genetic susceptibility, environmental factors (e.g., viruses, cigarette smoke) initiate sensitization.
TH2 cells (including IL-4 and IL-13) drive inflammation
Airway inflammation and hyper-reactivity cause an asthma attack.

IL-4 and IL-13

Airway recruitment of eosinophils, the enhancement of ASM contractility, the production of histamine, CysLTs, and prostaglandins, thus airway remodeling, goblet cell hyperplasia and mucus production.

Mechanism for Acute Asthma Exacerbation

Effectiveness of omalizumab emphasizes IgE's role in asthma pathogenesis

COPD

Refers to chronic bronchitis and emphysema
Main cause is cigarette smoking, which causes a triggering abnormal inflammatory response in the lung.
Emphysema involves loss of lung tissue elasticity causing trapped air in the lungs.
COPD is a significant health problem, being a leading cause (third/fourth) of death in the US (with associated significant cost to health care and productivity)
Airflow limitation is often progressively worse over time; marked presence of increased neutrophils
Key processes in COPD lung damage include oxidative stress (from tobacco smoke), cytokine release due to inflammation, and impaired antiprotease enzyme activity.

COPD Diagnosis and Presenting Features

A chronic cough that progresses throughout the winter
Diagnosis requires lung function tests
Pulmonary hypertension may be seen in later stages
Tracheotomy and artificial ventilation are potentially life-saving but invasive procedures, typically considered late course treatments

COPD Management

Stopping smoking is crucial and the only intervention for improved progression rate of COPD.
Current treatment options include bronchodilators (long acting); anticholinergics are generally superior to β2 agonists, and glucocorticoids are less effective than in asthma.
Theophylline can reduce symptoms but with potential drug interactions.
Oxygen therapy can prolong life but is dangerous if smoking continues
Vaccination for influenza is a key factor for prevention of infections, particularly important for COPD patients.

Pharmacotherapy

Two categories:
- Bronchodilators (relievers): for immediate bronchospasm
- Anti-inflammatory agents (controllers/preventers): manage inflammatory components
Steps for managing asthma: start with inhaled short-acting; then add a routine inhaled glucocorticoid; long-acting bronchodilators may reduce the dose of glucocorticoids; lastly, a daily oral glucocorticoid may be considered when control is poor.

Bronchodilators

Sympathetic B₂-adrenergic receptors activation causes dilation in response to an increase in cyclic AMP
Adrenalin (epinephrine) is very effective; However not used widely due to its non-selective activity.
B₂-selective agonists (e.g., salbutamol, salmeterol) relax bronchial muscle while inhibiting mediator release from mast cells and increasing cilia activation.
Typically administered via inhalation, powder, nebulized solution, or orally.
Two categories of beta agonists: short-acting and long-acting
Short-acting include: salbutamol and terbutaline (duration of action 30 minutes/5 hours)
Long-acting: salmeterol and formoterol (duration of action 12-24 hours)

Xanthines

Naturally occurring drugs such as theophylline, theobromine, and caffeine.
theophylline is frequently used as a therapeutic drug.
Theophylline is absorbed from the GIT but metabolized by liver CYP450 system with an 8-hour elimination half-life. (may be complicated by liver disease and heavy smokers.
It interacts with multiple drugs with a narrow therapeutic index; requires TDM

Muscarinic Receptor Antagonists

Activation of muscarinic receptors (M3) causes bronchoconstriction
Muscarinic antagonists like atropine and ipratropium can reduce bronchoconstriction, but can also have impact on other muscarinic receptors (e.g. M2 autoreceptors) and should be considered if needed and safe for the patient.
Ipratropium is a preferred compound due to its inactivity on the blood-brain barrier.
Ipratropium is frequently used; combined with medication for asthma management, e.g., Combivent.

Cysteinyl Leukotrienes

Potent inflammatory mediators driving bronchoconstriction.
Produced in eosinophils and other inflammatory cells.
Antagonists (e.g., zileuton, montelukast, zafirlukast) inhibit cysteinyl leukotriene receptors, providing a potential therapeutic benefit in asthma.

Anti-Inflammatory Agents

Glucocorticoids are controllers (not bronchodilators)
Endogenously released glucocorticoids are controlled by corticotrophin (released from the pituitary gland).
Also inhibited by CRF (corticotrophin releasing factor) in the hypothalamus.
Inhaled glucocorticoids are major preventive agents for asthma treatment.
Main compounds include beclometasone, budesonide, fluticasone, mometasone, and ciclesonide.
Decrease formation of TH2 cytokines.
Up-regulate beta-2 adrenoceptors
Primary effect is to alter gene expression, decreasing pro-inflammatory genes.
Inhibit phospholipase A2 enzyme release, reducing free arachidonic acid

Other Monoclonal Antibodies

Used in severe asthma cases.
Examples include benralizumab, omalizumab, mepolizumab, and reslizumab.
These target specific inflammatory pathways.

Drug Interactions

Anti-asthma drugs can interact with other medications (e.g., beta-blockers, NSAIDs, ACE inhibitors)
Physicians need to consider potential interactions when prescribing.

Further Work / Reading

Review the principles of pharmacology in detail.
Use references, such as Rang and Dale chapters, British Thoracic Society guidelines, etc.

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Description

Test your knowledge on the mechanisms involved in asthma treatment, particularly focusing on inhaled glucocorticoids and their actions. This quiz covers various aspects including feedback mechanisms, characteristics of CLT antagonists, and the role of HDAC in inflammation control. Dive into the pharmacology of asthma therapy and enhance your understanding of key treatments!