Respiration Week 6

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.

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!