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BIOS5140 - allergy, acid and asthma (copy)

Introduction to Pharmacology

Overview of BIOS5140

The University of Kent course BIOS5140 focuses on the pharmacological approaches to treating various conditions such as allergies, acid-related disorders, and asthma. This course emphasizes understanding the mechanisms of action and therapeutic effects of different classes of drugs.

Modes of Cell Signaling

1. Neurotransmission

Neurotransmission involves the release of neurotransmitters from nerve terminals across synapses. These neurotransmitters impact various tissues, including skeletal muscle at the neuromuscular junction and diverse tissues in the autonomic nervous system.

2. Endocrine System

The endocrine system functions by secreting hormones from specialized tissues (like the anterior pituitary) into the bloodstream. These hormones travel long distances to reach their target effector tissues—such as the ovaries—which later respond to the hormonal signals. Effective endocrine signaling requires proper hormone stability and sufficient concentration for physiological actions to occur.

3. Paracrine System

In the paracrine signaling system, local hormones or signaling molecules are released from specific cell types, influencing nearby effector cells. This type of signaling plays a crucial role in many physiological processes and will be particularly relevant in discussions related to asthma.

4. Autocrine System

The autocrine signaling mechanism occurs when cells release transmitters that act back on themselves, influencing their own activity. Although this topic is not extensively covered in the module, understanding autocrine signaling is relevant within the broader field, especially in haematology.

Local Transmitters in Allergies and Asthma

Role of Histamine

  • Histamine is a critical paracrine molecule released by mast cells during allergic reactions. It significantly contributes to local tissue responses by promoting inflammation and modulating immune responses.

  • Other mediators, such as prostanoids and leukotrienes, are also released by mast cells and facilitate local signaling during allergic and asthmatic responses.

Role of Mast Cells

  • Mast cells are strategically located in aerated tissues, including the lungs, skin, and gastrointestinal tract. They play an integral role in allergic responses.

  • Upon allergen exposure, IgE antibodies bind to specific mast cell receptors, triggering degranulation and the release of histamine along with other mediators, which leads to an immune response.

  • Basophils and neutrophils respond similarly in the bloodstream upon allergen exposure, illustrating a coordinated immune reaction.

Histamine Functions

  • Synthesis: Histamine is synthesized from the amino acid histidine.

  • Storage: It is stored bound to heparin and ATP in intracellular granules and released in response to allergen exposure.

  • Metabolism: Histamine is metabolized to N-methyl imidazoleacetic acid, effectively terminating its action.

  • Actions: The physiological effects of histamine vary depending on receptor subtype (H1 and H2), influencing inflammatory responses and gastric acid secretion.

Physiological Effects of Histamine

  • Vasodilation (H1): Histamine causes vasodilation, reducing peripheral resistance and affecting venous return, which can lead to decreased cardiac output.

  • Increased permeability (H1): It enhances the permeability of blood vessels, facilitating white blood cell migration and leading to local swelling and redness.

  • Sensory stimulation (H1): Histamine triggers pain perception associated with allergic reactions, such as itching from insect bites.

  • Gastric acid secretion (H2): Histamine promotes acid secretion in the stomach by acting on H2 receptors, and influences bronchial smooth muscle contractility through H1 receptors.

Histamine and Acid Secretion

Histamine's regulation of gastric acid secretion involves autonomic control and cholinergic transmission, with gastrin also contributing to this process. Mast cell degranulation releases histamine, which activates H2 receptors on parietal cells, promoting acid secretion and digestive processes.

Impact of H2 Antagonists

  • Cimetidine and ranitidine function as H2 receptor antagonists, effectively competing with histamine for binding to H2 receptors, subsequently decreasing gastric acid secretion.

  • These drugs are commonly used to treat conditions like indigestion or chronic acid reflux. If symptoms persist or worsen, proton pump inhibitors such as omeprazole may be considered for treatment.

H1 Antagonists and Their Effects

  • H1 antagonists are used to reduce pro-inflammatory processes such as swelling, irritation, and itchiness in various tissues. They are available as over-the-counter tablets and topical creams.

  • Common side effects include initial sedation, and there is variability in effectiveness among different antihistamines. For example, diphenhydramine is often preferred for sedation, while loratadine is more effective for hay fever.

Bronchial Physiology in Asthma

Understanding the bronchial physiology in asthma involves a few key aspects:

  • Smooth muscle control: Airway smooth muscle contracts and relaxes under autonomic control, significantly impacting airway diameter.

  • Mast cell response: Upon exposure to allergens, mast cells release spasmogens (including histamine) that can provoke bronchospasm.

  • Epithelial lining: The epithelium serves as a barrier to protect underlying structures, but chronic asthma can damage this lining.

Asthma Phases: Early and Late

  • Phase 1 (Early): This rapid response phase involves bronchospasm due to spasmogens such as histamine and leukotrienes triggered by allergen exposure.

  • Phase 2 (Late): This phase features a prolonged inflammatory response characterized by complex signaling that leads to airway hyper-reactivity and exacerbated inflammation. Understanding both phases is critical for effective asthma treatment.

Mechanisms of Bronchial Asthma

Key mechanisms contributing to bronchial asthma include:

  • Contraction of airway smooth muscle

  • Edema (swelling) in the airways

  • Excess mucus production These factors collectively contribute to airway hypersensitivity and dysfunction.

Treatment of Bronchoconstriction

Bronchodilators, such as beta-2 agonists, are essential in treating bronchoconstriction. They act by mimicking the action of noradrenaline to open the airways, alleviating symptoms of respiratory distress.

  • Mechanism: Administered via inhalation, these agents target GPCR signaling pathways, activate adenylyl cyclase, resulting in increased cAMP levels, and subsequently activating PKA leading to bronchodilation through the inactivation of myosin light chain kinase.

Beta-2 Agonists Characteristics

  • Short-Acting Beta Agonists (SABAs): These agents, such as Salbutamol, provide rapid relief by acting within minutes (<5 min) and last for approximately 3-6 hours.

  • Long-Acting Beta Agonists (LABAs): Examples include Salmeterol, with a slower onset (~15 min) but an extended duration of action, typically lasting around 12 hours.

Late Phase Inflammatory Response

The late phase response in asthma is marked by ongoing inflammation and bronchoconstriction, primarily involving the recruitment of leukocytes through chemotaxis. When initial bronchodilator therapy is insufficient, glucocorticoids are often used to manage persistent symptoms effectively.Glucocorticoids are used in the later phase -they regulate growth,metabolism and catabolism,salt retention ,bone density,acid secretion,immune system and reproduction system

Role of Glucocorticoids

Glucocorticoids, both endogenous and synthetic, serve key roles in regulating inflammation and modulating immune responses in asthma. They also influence metabolic processes and salt retention. However, they must be utilized cautiously, as side effects can involve unwanted immunosuppression and fluid imbalances.

Mechanism of Glucocorticoid Action

Glucocorticoids interact with specific glucocorticoid receptors, which govern genomic transcription. They undergo dimerization and nucleus translocation, binding to specific gene response elements that regulate inflammation, leading to altered transcription and protein expression.

Inflammatory Effects of Glucocorticoids

Glucocorticoids inhibit pro-inflammatory mediators effectively, reducing the responses associated with delayed inflammation. When inhaled rather than taken systemically, potential side effects are minimized, improving patient outcomes.

Emerging Therapies

Recent advances in asthma management have included:

  • Combination therapies: Such as Fostair, which pairs Formoterol (a LABA) with Betamethasone (a glucocorticoid).

  • New drug classes: Include cysteinyl leukotriene (CysLT) receptor antagonists and phosphodiesterase-4 inhibitors, which offer alternative therapeutic pathways.

Current Clinical Management Guidelines

Clinical management of asthma is based on the level of symptom control. Treatment strategies typically start with prescribing SABAs, progressing to LABAs and glucocorticoids if the patient's condition demands more intensive management.