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Case 7: Asthma - Coggle Diagram

- - - - Non enveloped double stranded DNA viruses
        
        6 genera: Human adenoviruses are all mastadenoviruses
        
        88 human serotypes in 7 species (A to G)
    - - Can cause the common cold
      - Most common cause of the common cold
        
        Non-enveloped, icosahedral ssRNA virus
        
        3 species, 108 serotypes
        
        Several serotypes circulate simutaneously for several years then displaced, therefore difficult to develop an effective vaccine
    - - Enveloped single stranded RNA viruses
        
        4 Genera (Alpha, beta, gamma, delta)
        
        Particularly virulent strains are SARS, MERS, and COVID-19
    - - Enveloped single stranded RNA viruses
        
        HPIV - Group of viruses that cause resp. illnesses like the common cold, and pneumonia
        
        Most common in children and elderly, but can affect anyone
        
        4 types and 2 subtypes
        
        Most causative agent of bronchiolotis and pneumonia in infants
    - - Enveloped RNA viruses with a segmented genome
      - Causes Influenza A, B, and C
        
        Cases peak in winter months (UK)
  - - - Respiratory syncytial virus (RSV): A common virus in young children.
      - Influenza viruses: Types A and B are common causes of respiratory infections.
      - Parainfluenza viruses: A common cause of respiratory infections.
      - Adenoviruses: A common cause of respiratory infections
      - Rhinoviruses: The most common cause of respiratory illnesses.
      - Coronaviruses: A common cause of respiratory infections.
      - Rates
        
        Viral respiratory infections are the most common in people of all ages and genders
        
        Younger people are more likely to have viral resp. infections
        
        Older people and people with compromised immune systems also at risk
      - Spread
        
        Resp. infections are spread through inhalation of droplets or aerosols, physical contact with infected people, and contaminated surfaces
        
        Children most commonly introduce infection into family
    - - Coryzal symptoms
        
        Bronchitis, pneumonia, high fever
        
        Gastroenteritis
        
        Infants, elderly, and immunosuppresed are at high risk infections
    - - Symptomatic treatment
        
        Over the counter medication
        
        If developed into pneumonia, antiviral are available
    - - Hygiene:
        
        Diligent hand washing
        
        Cover mouth and nose when coughing
        
        Stay home
        
        Disinfect surfaces
        
        Avoid contaminated food and water
      - Vaccination
      - Avoid close contact with infected
      - Others:
        
        Wear mask
        
        Physical distancing
      - Public health measures:
        
        Isolation, quarantine
  - - - Antigenic shift:
        
        Process that creates a new virus subtype when 2 or more different strains of a virus combine in a host cell
        
        Can result in a new flu that infects humans for the first time
      - Antigenic drift:
        
        Process that causes small changes in the genes of influenza virus' surface proteins, making it harder for the immune system to recognize the virus
- - - - Atopy and allergy
        
        Type 1 IgE mediated hypersensitivity
        
        Onset of asthmatic attacks preceded by allergic rhinitis and eczema
        Positive family history of atopy/allergies are common
        
        Hygiene hypothesis
        
        Lack of exposure to micro-organisms leads to an underdeveloped immune system, causing a more sensitive IgE atopic immune responses
      - Non-atopic
        
        No evidence of allergen sensitivity
        
        Induced by other triggers like:
        
        Occupational exposure
        
        Cold air
        
        Dust, fumes, irritants
        
        Drugs like NSAIDs and Betablockers
        
        Resp. tract infection
    - - Sensitization and Immune response phase
        
        Patient is exposed to allergen
        
        Dendritic cells capture them and present them to naive T cells in the lymph nodes
        
        Presentation leads to differentiation of TH2 cells
        
        TH2 cells produce cytokines like IL-4, IL-5, and IL-13
        
        IgE production and Mast cell activation phase
        
        1 more item...
        
        IL-4 - Stimulates B cells to produces IgE antibodies, which sensitizes mast cells
        IL-5 - Recruits eosinophils, which causes airway inflammation and damages
        IL-13 - Promotes mucus production, airways hyperresponsiveness, and fibrosis
        
        Naive T cell - Immature helper T cell
- - - - 5-11 adults out of 1000 get pneumonia
        
        22-42% of these are admitted to hospital
        
        1.2-10% of the admitted with Community Aquired Pneumonia (CAP) are admitted to ICU
        
        More than 50% of deaths related to pneumonia occurs in ppl over the age of 84
      - Pneumonia accounts for 14% of all deaths for children under 5 y/o
        
        Can be caused by viruses, bacteria, or fungi
        
        Can be prevented by immunization, adequate nutrition, and by addressing environmental factors
        
        Can be treated by antibiotics if caused by bacteria
        
        Only 1/3 of children get the antibiotics they need
      - Streptococcus pneumoniae - the most common cause of bacterial pneumonia in children
        
        Haemophilus influenzae type b - The 2nd most common cause of bacterial pneumonia
        
        Respiratory syncytial virus (RSV) - the most common viral cause of pneumonia in children
        
        Pneumocytis jiroveci - one of the most common causes of pneumonia, responsible for at least one quarter for all pneumonia deaths in HIV infected infants
    - - By clinical setting
        
        Community acquired pneumonia (CAP)
        
        Pneumonia acquired by someone outside of a hospital
        
        Strep. pneumoniae - the most common cause of bacterial pneumonia
        
        Haemophillus influenzae
        
        Staph aureus
        
        Atypical pneumonias:
        
        Mycoplasma pneumonia
        
        Legionella spp
        
        Chlamydophila pneumoniae
        
        Transmitted by inhalation of aerosol, droplets, or food, liquids, vomit, or fluids from mouth into the lungs
        
        Steptococcus pneumoniae:
        
        Causes pneumoccoal pneumonia, which is the most common cause of CAP
        
        General symptoms, mucus may be rust coloured
        
        Mycoplasma pneumoniae:
        
        Small, wall-less bacteria which causes atypical pneumonia
        
        Risk factors:
        
        Age >65
        
        Residence in healthcare settings
        
        COPD
        
        Exposure to cigarrete smoke
        
        Alcohol abuse
        
        Antacids
        
        Contact with children
        
        Hospital-acquired pneumonia (HAP)
        
        Health care associated pneumonia
        
        Ventilator associated pneumonia
      - By cause
        
        Infectious:
        
        Bacterial
        
        Viral
        
        Fungal
        
        Chemical:
        
        Inhalation
        
        Aspiration
      - By affected area
        
        Lobar pneumonia
        
        Broncho-pneumonia
    - - CURB65 score
        
        C - Confusion (mental test score <8/10) U - Plasma urea level >7mmol/L
        R- Resp. rate >30/min
        B - Sys BP <90mmHg / Dias <60mmHg 65 - Age >65
        1 pt for each
        
        0-1 outpatient treatment
        2 admit to hospital
        3 ICU
        
        Low severity (0 or 1): Amoxicillin
        Moderate severity (2): Amoxicillin
        Severe (3-5): Co-amoxiclav
        Other combinations for allergy
    - - Culture from good quality sputum of bronchioalveolar lavage
      - Blood culture
      - Tests to identify bacterium
      - Others
        
        Antigens in urine - For S. pneumoniae, and Legionella
        
        Antibodies in blood - For S. aureus
        
        Enzyme linked immunosorbent assay or PCR/detection of IgM antibodies - For M. pneumoniae
- - - - B2 adrenoreceptor agonist:
        
        Stimulates B2 adrenergic receptors, which causes bronchodilation directly
        
        Also inhibits the release of mediators from mast cells
        
        Administered via inhalation of aerosol, nebulised solution, and powder; oral administration, and parenteral
        
        Types:
        
        Adrenaline:
        Non selective A, B1, and B2 effects
        (rarely used)
        
        Selective B2 agonists
        
        Short-acting B2 agonists (SABA):
        
        Use for acute episodes
        
        Inhalation
        
        Relieved within 5-10 mins, max effect within 30 mins
        
        Lasts for about 3-5h
        
        Salbutamol, Terbutaline
        
        Long-acting B2 agonists (LABA):
        
        Used for long-term management
        
        Given regularly twice daily
        
        Slower onset, not appropriate for acute episodes
        
        ~12h duration
        
        Used with corticosteroids
        
        Salmeterol, Formoterol
        
        Adverse effects:
        
        Tachycardia/palpitations
        
        Cardiac dysrhythmia
        
        Tremors
        
        Hypokalaemia
        
        Reduced when administered via inhalation
        
        Uses:
        
        Asthma
        
        COPD
        
        Allergen or exercise induced bronchospasm
        Salbutamol: Moderate to sever hyperkalaemia and uncomplicated premature labour
      - Methylxanthines
        
        MOA:
        
        The activation of B2 adrenergic receptors causes adenyl cyclase to turn ATP into cAMP, which activates protein kinasea A, which triggers bronchodilation.
        
        Phosphodiesterases normally break cAMP into AMP.
        
        So Methylxanthines like Theophylline and Aminophylline inhibit phosphodiesterases, which leads to an increase in cAMP levels.
        
        Uses:
        
        Asthma
        
        COPD
      - Anticholinergics
        
        MOA:
        
        Competitive antagonist at the M3 acetlycholine receptor
        
        Which reduces vasoconstriction, and decreases mucus secretion
        
        Uses:
        
        COPD (main use)
        
        Asthma
        
        When B2 agonists dont work or are contraindicated (IHD, tachyarrhythmias)
        
        Types
        
        Short-acting antimuscarinic agents (SAMA)
        
        Onset of 30-60mins, relieft for 4-6hrs
        
        Given via inhalation, 3-4 tomes a day
        
        Used in COPD. Most used SAMA in asthma
        
        Ipratropium bromide
        
        Long-acting antimuscarinic agents (LAMA)
        
        24hrs duration of action
        
        Given one daily via inhalation
        
        Used in COPD
        
        Tiotropium bromide, Umeclidinium bromide
    - - Corticosteroids
        
        MOA:
        
        Inhibit inflammatory cytokine production & inflitration of lungs
        
        This reduces bronchial hyperreactivity & mucosal oedema, and suppresses inflammatory response
        
        This leads to reduced asthma exacerbations, and airway remodelling, retarding disease progession
        
        They also increase the responsiveness of airway smooth muscle to B2 agonists
        
        Usually takes weeks for full effect, so it is used for preventative treatment
        
        Uses:
        
        Used in Asthma and COPD
        
        Commonly combined with a LABA in an inhaler
        
        Administration:
        
        Inhalation (budesonide, fluticasone, beclomethasone)
        
        Oral (prednisolone)
        
        IV (Hydrocortisone)
      - Leukotriene receptor antagonists
        
        Leukotriene is a major intermediate in inflammatory signaling, making it an important mediator of bronchial asthma
        
        MOA:
        
        Antagonists like Montelukast or zafirlukast:
        
        Block the Cysteinyl LT1 receptor on respiratory mucosa, and infiltrating inflammatory cells
        
        Taken orally, in combination with an inhaled corticosteroid
        
        Less anti-inflammatory than corticosteroids
        
        Well absorbed orally, highly plasma protein bound, biliary excretion
        
        Adverse effects:
        
        May cause abdominal pain and headache
        
        Uses:
        
        Approved for the prevention of asthma (not an acute reliever)
        
        5-Lipoxygenase inhibitor like Zileuton:
        
        Inhibits the action of 5-lipoxygenase, which reduces the amount of leukotriene produced
    - - Omalizumab:
        
        Humanized monoclonal antibody against IgE
        
        Neutralizes free IgE in circulation without activating mast cells and other inflammatory cells
        
        Administered via s.c.
        
        Found to reduce exacerbations and steroid requirement
        
        Adverse effects:
        
        Headache
        
        Flu-like symptoms
        
        Reserved for severe and resistant asthma
- - - - Rates of invasive fungal infections have increased in recent decages because of increasing populations at risk
        
        Immunosuppressed
        
        HIV infections
        
        Patients on immunosuppresive drugs
        
        Patients with chronic debilitating diseases
    - - Can be opportunistic, or endemic mycoses
        
        Opportunistic
        
        Occurs in individuals whose immune systems are compromised
        
        Infections do not follow any particular geographic distributions
        
        Invasive pulmonary aspergillosis and systemic candidiasis are the most prevalent opportunistic fungal infections
        
        Apergillus fungus is the leading cause of infection-related death in stem cell transplant recipients
        
        Endemic
        
        Follows distinct geographic distributions that are determined by soil and climate conditions optima for fungi growth, and can affect healthy individuals
        
        NA and Africa are home to 3 of the major endemic mycoses:
        
        Histoplasmosis
        
        Blastomycosis
        
        Coccidioidomycosis
      - Examples
        
        Candida spp
        
        It is a genus of yeast-like fungi that are part of the normal microbiota of the human skin, mucous membranes, and GI Tract
        Can become pathogenic under certain conditions
        
        C. albicans is the most frequent species isolated from resp. samples
        -Normal oropharyngeal flora and upper resp. tract
        
        Associated with predisposing clinical circumstances
        
        Candida pneumonia is a rare infection of the lungs, with the majority of cases occuring secondary to haematological dissemination
        
        Aspergillus spp
        
        It is a genus of fungi that is widespread in the environment, particularly decaying matter
        Certain species are part of the normal microbiota of the resp. tract
        
        Aspergillus fumigatus is the most frequent species that causes invasive pulmonary apergillosis (IPA)
        
        Resp. infection of a critically ill patient
        
        Conidia (spores) of Aspergillus are easily aerosolized, so transmission by air is nearly universal
        
        Humans continuously inhale Aspergillus conidia but it is eliminated well by the immune system
        
        Blastomycosis
        
        AKA NA blastomycosis, Blastomycetic dematitis, or Gilchrist's disease
        
        Affects humans and other animals, notable dogs and occasionally cats, cause by the organism Bastomyces dermatidis
        
        Clinical symptoms are similar to histoplasmosis
- - - - Multivalent antigents have more than 1 epitope
        
        An antibody has multiple binding sites, and antigens have multiple binding sites also
  - - - Mature in bone marrow
        
        Recognize soluble or membrane bound antigens
        
        When an antigen binds to a B cell receptor, it will proliferate and differentiate into a plasma cell, which secretes antibodies
    - - Mature in thymus
        
        Recognize antigens on body cells present by MHC molecules
        
        Cytotoxic T cells kill virus infected cells
        
        Helper T cells modulate the activity of macrophages or B cells
        
        Regulatory T cells modulate the immune response
  - - - Lymphoid organs:
        
        Primary
        
        Bone marrow
        
        Thymus
        
        Site of lymphocyte generation/maturation
        
        Secondary
        
        Lymph nodes
        
        Spleen
        
        Mucosal lymphoid tissues
        
        Sites of lymphocyte storage and the site of immune response
        
        Spleen
        
        White pulp:
        
        Circular in structure
        
        Made up mainly of lymphocytes
        
        Functions similar to the nodules of lymph nodes
        
        Red pulp:
        
        Surrounds white pulp
        
        Contains mainly red blood cells and macrophages
        
        Main function is to phagocytize old RBCs
      - Lymph:
        ECF Fluid that accumulates in tissues and is carried by a network of lymphatic channels back to the blood stream
        Drains back into the blood stream at the left subclavian vein
- - - - Activated macrophages release:
        
        TNF-a:
        
        Lymphocyte activation
        
        Increases vascular permeability
        
        Activates NK cells
        
        eases access of effector cells
        
        FEVER SHOCK
        
        IL-6:
        
        Lymphocyte activation
        
        FEVER
        
        IL-12:
        
        Activates NK Cells
        
        CXCL-8:
        
        Recruitment of leukocytes
        
        IL-1b:
        
        Stimulates lymphocyte activation
        
        Improves access of effector cells at the site of infection
        
        FEVER
      - Interferon ɤ:
        
        Produced by NK and T cells. Main function is to activate macrophages
        
        Binds to Interferon-gamma receptor (IFNGR)
      - Interleukin 2:
        
        Produced mainly activated T helper cells or Cytotoxic cells.
        
        Main functions are activation, growth and differentiation of T cells, B cells, and NK cells.
        
        Binds to the Interleukin 2 receptors (IL2R) expressed on Lymphocytes
      - Interleukin 4:
        
        Produced by T cells.
        
        Stimulates the differentiation of naive T Helper cells to T helper 2 Cells (TH2), and the differentiation of B cells into plasma cells.
        
        Binds to the IL-4Ra
      - Granulocyte Macrophage Colony Stimulating Factor (GM CSF):
        
        Produced by a range of cells.
        
        Stimulates Haematopoietic stem cells to produces granulocytes and monocytes.
        
        Binds to GM-CSF receptors
      - IL4: can stimulate B cells to switch antibody secretion to the antibody IgE
        
        IL5: stimulates B cell growth and increases antibody secretion
        
        IL9: stimulates T and B cell proliferation and prevents apoptosis (cell death) of lymphocytes
        
        IL13: Central Regulator of IgE synthesis, goblet cell hyperplasia, mucus hypersecretion and airway hyperresponsiveness
  - - - Chemotaxis - Directed movement of cells in response to a chemical gradient
        
        Positive chemotaxis - Movement towards a chemical stimulus (e.g., neutrophils moving towards and infection site)
        Negative chemotaxis - Movement away from a harmful stimulus
  - - - Used in various therapies for conditions such as:
        
        Chronic Hepatitis B and C infection
        
        Cancer (melanoma)
        
        Some leukemia
  - - - Innate immunity
        
        Produced mainly by mononuclear phagocytes in response to infectious agents – TNFα, IL12, Type 1 Interferons (from all cells)
      - Adaptive immunity
        
        Produced mainly by T lymphocytes in response to specific recognition of foreign antigens – IFNγ, IL2, IL4
    - - Produced by bone marrow and stromal cells, leukocytes and other cells and stimulate the growth and differentiation of immature lymphocytes – GM-CSF
- - - - Serous inflammation:
        
        Marked by exudation of cell-poor fluid
        
        E.g., Skin blister
      - Fibrinous inflammation:
        
        More severe injuries, greater degree of vascular permeability
        
        Larger molecules (fibrinogen) pas the vascular barrier
        
        Fibrin is formed and deposited in the extravascular space
      - Suppurative Inflammation & Abscesses:
        
        Characterised by the collection of pus consisting of neutrophils, necrotic cells, and oedema fluid
        
        Cause: Pyogenic bacteria that causes liquefactive necrosis
        
        Abscess - Localised collection of pus buried in a tissue, organ, or confined space
      - Ulcers:
        
        Local defect of the surface of an organ or tissue that is produced bu the sloughing (shedding) of inflamed necrotic tissue
        
        Common locations
        
        Mucosa of mouth, Stomach, Intestines, or genitourinary tract
        
        Skin and subcutaneous tissues of lower extremities in older people
  - - - Recognition of the offending agent/injury
        
        Recruitment of leukocytes
        
        Removal of the offending substance
        
        Regulation of the response
        
        Repair of the damaged tissue
        
        Margination - Leukocytes move from the central part of the blood vessel, and directly engage with the endothelial cells at the peripheral. Made possible by stasis
        
        Rolling - Leukocytes roll along the surface of the endothelial layer mediated by selectin/glycoprotein interactions, which are fragil and easily break
        
        Stable adhesion - Cytokines from the site of injury increase integrin and integrin receptor binding which stops the leukocyte at the site of infection/injury
        
        Transmigration - Leukocytes squeeze through endothelial gap junctions with the help of PECAM
        
        Chemotaxis - Leukocytes follow a chemokine gradient to find and locate pathogens
        
        Major components of Acute inflammation
        
        Vascular
        
        Dilation of the small vessels, causing slow blood flow (stasis)
        
        Increased vascular permeability of the microvasculature, enabling plasma proteins and leukocytes to leave circulation
        
        Cellular
        
        Emigration of leukocytes from microcirculation, causing them to accumulate at the site of injury before being activated to eliminate offending agent
    - - Neutrophils are the first ones to get to the site of injury (6-24hrs), but they are replaced by macrophages (24-48hrs)
        
        Why?
        
        Neutrophils are the most abundant leukocyte and they have the highest level of endogenous expression of glycoproteins and Integrin
  - - - 1. Fever
        
        Pyrogens - Substances that induce fever
        
        Secretion of Cytokines into the bloodstream
        
        Cytokines reach the brain
        
        They bind to receptors on brain endothelial cells
        
        Which activates Prostaglandin E2 Synthesis
        
        1 more item...
        
        Prevents replication of microorganisms
        
        Promotes elimination of microorganisms
      - 2. Acute-phase proteins
        
        C-reactive protein - Induced by By IL-6
        
        Normal levels - Less than 10mg/L
        
        Fibrinogen - BY IL-6
        
        ESR Test
        
        Hepcidin
        
        Mostly synthesised by the liver, and are the markers of inflammation
      - 3. Leukocytosis
        
        Triggered by TNF and IL-1
        
        During inflammation, there are more immature neutrophils in the blood (Left Shift)
        
        Leukocyte count - rises to 15,000 - 20,000 cell/mL
        
        Highest level - 40,000 - 100,000 cells/ml
        
        Neutrophilia - more neutrophils
        
        Common in bacterial infections
        
        Lymphocytosis - more lymphocytes
        
        Common in viral infections
        
        Eosinophilia - More eosinophils
        
        Common in allergies and parasitic infections
    - - metabolic disturbances : insulin resistance and hyperglycaemia.
        
        disseminated intravascular coagulation (DIC): blood clots form throughout the body, blocking small blood vessels.
        
        hypotensive shock, and
- - - - Immediate phase (due to preformed mediators stored in granules):
        
        Smooth muscle spasm
        
        Vasodilation, and leakage
        
        Hives, itching
        
        Increased mucus secretion by nasal, bronchial, and gastric glands
      - Late phase (Due to newly synthesised mediators on cell activation):
        
        Inflammation
        
        Epithelial damage
        
        Bronchospasm
    - - I = Allergic, Anaphylaxis, and Atopy
        II = Antibody
        III = Immune Complex
        IV = Delayed
        
        Type I:
        
        Immediate (symptoms appear within minutes)
        
        IgE Mediated
        
        Common in geneticaly susceptible individuals
        
        Allergen - Any antigen that triggers an allergic reaction
        
        Pathogenesis:
        
        Patient is exposed to allergen for the first time
        
        Dendritic cell picks up allergen
        
        Dendritic cell shows allergen to Helper TH2 cells
        
        Helper TH2 cells release cytokines
        
        Cytokines cause B cells to become plasma cells
        
        Plasma cells release IgE antibodies
        
        IgE antibodies attach to Mast cells
        
        Upon subsequent exposure to allergen, the IgE antibodies bind to the antigen
        
        The antibodies cross link
        
        Cross-linking sends a signal to the nucleus of the mast cell
        
        The mast cell degranulates, releasing mediators such as histamine, leukotrienes, and prostaglandins
        
        Type II:
        
        Caused by antibodies directed against target antigens fixed on the surface of cells or tissue
        
        Antibody mediated: IgG, rarely IgM
        
        Organ specific
        
        3 Mechanisms:
        
        Opsonization and phagocytosis
        
        Activation of the complement system
        
        Interfering with normal cellular functions
        
        Opsonization and Phagocytosis:
        
        IgG binds to antigen (E.g., surface of platelets)
        
        Macrophages phagocytosise the platelet with the help of the Fc receptor
        
        Results in reduced platelet count
        
        Activation of complement system:
        
        The Fc receptors on a neutrophil binds to the antigen on a fixed tissue (E.g., basement membrane of lungs)
        
        C1 complex protein is activated, and it makes complement by products C5a, and C3a
        
        This leads to inflammation and injury of the tissue
        
        Interfering with normal cellular functions
        -
        
        Type III:
        Normal person:
        
        Antigens are free floating inside the cell
        
        B cells differentiate into plasma cells, which release free antibodies that enter the cell
        
        The antibodies bind to the antigen, forming antigen-antibody complexes
        
        Antigen-antibody complexes are temporary, and are removed by phagocytes
        
        Patient with Type III HS:
        
        Type IV:
        
        T-cell mediated
        
        2 Types of reactions
        
        Cytokine-mediated inflammation
  - - - Without it, hypersensitivity reactions occur
        
        Hypersensitivity reactions
        
        Exogenous
        
        Allergy/Allergic reaction
        
        Endogenous
        
        Autoimmune diseases
        
        Definition: Objectively reproducible symptoms initiated by exposure to a defined stimulus at a sode tolerated by normal persons
- - - - Glucocorticoids:
        
        Widespread actions on carbohydrate and protein metabolism
        
        Potent anti-inflammatory and immunosuppressive properties
        
        Example: Cortisol
        
        Commonly used for anti-inflammatory and immunosuppresive properties
        
        Excluding replacement therapy
        
        Metabolic/other actions are unwanted side effects
        
        Synthetic steroids - Exhibits a partial separation of glucocorticoids/mineralocorticoid actions. Not yet been possible completely to separate the anti-inflammatory from the other actions
      - Mineralocorticoids:
        
        Regulation of water & electrolyte balance
        
        Example: Aldosterone
    - - Corticosteroids bind to specific receptors in the cytoplasm:
        
        Mineralocorticoid receptors:
        
        High affinity so occupied most of the time
        
        Only expressed in certain tissues like the kidneys, heart, colon, hippocampus
        
        Corticosteroids can take hrs-days for effects to occur
        
        Mineralocorticoid actions:
        
        Aldosterone act on the MR in the DCT and CD in the kidneys, increasing the reabsorption of Na and water, and increases K and H excretion
        
        Glucocorticoids receptors:
        
        Low affinity so only activated by high levels during morning or by stress
        
        Ubiquitously expressed
        
        Actions of glucocorticoids:
        
        Metabolic actions
        
        Anti-inflammatory actions
        
        Immunosuppressive actions
        
        Other actions
        
        Metabolic actions:
        
        Decreased uptake and utilisation of glucose, increased gluconeogenesis - can cause hyperglycaemia
        
        Reduced catabolism and increased anabolism of proteins
        
        Permissive effect on lipolytic hormones and fat redistribution
        - Provides the body with energy for combat stress
        
        Anti-inflammatory actions:
        
        Inhibit both early and late stages of inflammatory response
    - - Replacement therapy:
        
        In patients with adrenocortical insufficiency caused by either adrenal disease, destruction or removal of gland or pituitary failure
      - Anti-inflammatory effects:
        
        Respiratory: Asthma and COPD
        
        Skin: Eczema, dermatitis
        
        Musculoskeletal: Arthritis, gout, bursitis
        
        GI: IBS
      - Immunosuppressive effect:
        
        Prevents organ rejection in transplant recipients
        
        Autoimmune disorders
        
        Allergic reactions
      - Malignancies:
        
        Leukaemia and Lymphomas, antiemetic adjuvant, to reduce cerebral oedema in tumours
      - Accelerate foetal lung maturation in premature birhts
- - - - Synthesis of histamine occurs in most tissues, with highest amount found in lungs, skin and GI tract
    - - Regulates leukocytes
        
        Helps leukocytes mature and activate, and directs them to sites of inflammation
      - Modulates immune cells
        
        Affects how monocytes, T cells, macrophages, neutrophils, eosinophils, B cells, and dendritic cells function
      - Increases vascular permeability
        
        Allows WBCs to enter the tissue
        
        Causes swelling
      - Stimulates inflammatory mediators
        
        Stimulates the release of inflammatory mediators like IL6, IL8 and prostaglandins
  - - - H1:
        
        Drives cellular migration, vasodilation, bronchoconstriction, and nocieption
        
        Also plays a role in allergic response
        
        Found in many tisses and cells such as the brain, heart, blood vessels, and immune system
      - H2:
        
        Modifies gastric acid secretion, vascular permeability, and airway mucus production
        
        Found mainly in the gastric lining as well as the heart
      - H3:
        
        Plays a role in neuro-inflammatory disease.
        
        Also regulates the release of histamine and other neurotransmitters
        
        Found mainly in the CNS
      - H4:
        
        Involved in allergy and inflammation
        
        Present in bone marrow, and haematopoietic cells, where it plays a role in blood cell formation
        
        Found in immune system, GI Tract, and CNS
    - - H1 antihistamines:
        
        Treats allergic reactions by blocking H1 receptors
        
        Can treat nausea and insomnia
        
        First generation:
        
        Cross blood brain barrier easier than second generation
        
        Can cause drowsiness and impair cognitive and pschomotor function
        
        Example:
        Chlorphenamine, cinnarizine, dipenhydramine, hydroxyzine, promethazine
        
        Second generation:
        
        Cross the blood brain barrier less easiler than first generation
        
        Generally sager and interact with fewer medications
        
        Example:
        Acrivastine, cetrizine, fexofenadine, loratadine
        
        Competitively blocks histamine from binding to H1 receptors on smooth muscles, nerve endings, and endothelial cells
        They are both inverse agonists and competitive blockers
      - H2 antihistamines:
        
        Treats conditions that involve excess stomach acid ike heartburn, acid indigestion, ulcers