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pharmacology unimelb > therapeutic uses of drugs (week 4-8) > Flashcards

therapeutic uses of drugs (week 4-8) Flashcards

1
Q

What is asthma?

A

A heterogenous syndrome (several potential root causes) of chronic airway inflammation that is of high prevalence in Australia

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2
Q

How is asthma classified?

A

Originally classified into two asthmas (allergic and non-allergic) asthma is now classified into overlapping phenotypes based on the allergic response and response to medication (some forms of asthma may or may not respond to steroids)

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3
Q

What causes asthma?

A

There is no 1 cause. It is a combination of host factors (genetics, gender, obesity) and environmental factors (indoor and outdoor allergens, chemical irritants, tobacco smike, air pollution, respiratory infections)

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4
Q

What are the characteristics of TH2-type asthma?

A
  1. Airway obstruction: airway lumen is narrowed
  2. Increased Airway Hyper Responsiveness: smooth muscle is hyper responsive, exaggerated response to less mediators
  3. Chronic eosinophilic airway inflammation: predominant cell type is eosinophils (white blood cell = hyper allergenic response)
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5
Q

What is the process of pathogenesis that leads to asthmatic symptoms in the TH2-type asthma?

A
  1. Allergen detected by antigen
    presenting cell
  2. Antigen presenting cell is detected by
    naive T lymphocyte - initiating
    sensitisation
  3. Naive t lymphocyte differentiates
    into T helper 2 (TH2) type lymphocyte
  4. TH2 releases cytokines - IL-4, IL-13,
    IL-5
  5. A. IL-4 & IL-13 stimulate B
    lymphocytes to secrete IgE
    B. IL-5 recruites eosinophils
    (predominant cell type)
  6. A. Primes mast cells for re-exposure
    to allergen
  7. On subsequent allergen exposure:
    A. allergin binds to IgE on mast cell
    causing degranulation, releasing
    mediators
    B. eosinophils also release number of
    mediators
  8. Get bronchoconstriction, mucous,
    and vascular leaks (oedema) all
    associated with asthmatic response
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6
Q

How does inflammation function in asthma?

A

Inflammation is a normal process but becomes sidetracked in asthma and doesn’t quickly resolve, becoming chronic inflammation - causes the structural changes seen in asthma

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7
Q

What are structural changes in an asthmatic airway?

A

Caused by chronic inflammation and mediators:

  1. Brochoconstriction of airway smooth muscle
  2. Obstruction from angiogenesis - increased blood vessel formation
  3. Oedema (plasma leakage) impacting lumen
  4. Fibrosis of basement membrane (becomes stiff)
  5. Hyperplasia and hypertrophy of airway smooth muscle - muscle increases in size
  6. Excess mucous in airways from goblet cells - mucuous hypersecretion
  7. Hyper-responsiveness of airway smooth muscle - exaggerated constriction
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8
Q

How is airway hyperresponsiveness tested?

A

Forced Expiratory Volume (FEV)

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9
Q

What are the 3 strategies to target asthma?

A
  1. Prevent allergy development (currently impossible - difficult and not all asthma caused by allergy)
  2. Prevent or reverse airway obstruction (promoting muscle dilation/relaxation)
  3. Prevent or reverse airway inflammation (reverse narrowing and obstruction of airways)
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10
Q

What drug targets are used to target prevention or reversal of airway obstruction?

A

Beta adrenoreceptors:

  1. Short acting = relievers
  2. Long acting = preventers
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11
Q

What drug targets are used to target prevention or reversal of airway inflammation?

A

Glucocorticoids (corticosteroids)

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12
Q

Why are asthma drugs delivered via inhalation?

A

Delivered straight to the site of action faster:

  • Can therefore lower the dosage as can worry less about absorption or first pass metabolism
  • Less is circulated throughout the body, therefore less adverse effects
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13
Q

What type of antagonism is being used in relaxation of airway smooth muscle (ASM)?

A

Functional antagonism

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14
Q

What is the process of action of the β2-agonists in promoting smooth muscle relaxation (bronchorelaxation)?

A
  1. β-adrenoreceptors in lungs are G-protein coupled receptors coupled to the stimulatory protein which is stimulated
  2. This stimulatory protein (GS) is coupled to the enzyme adenylate cyclase (AC) that when triggered through agonist binding causes an increase in adenylate cyclical activity
  3. This causes an increase in conversion of ATP into cyclic AMP
  4. Increased cyclic AMP causes increased activity of enzyme, protein kinase A
  5. Protein kinase A decreases cytosolic calcium
  6. Contraction of airway smooth muscle (ASM) is dependent on calcium, lessens this response caused by bronchoconstrictors (all mediators: histamine, acetylcholine etc.)
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15
Q

What is the process of myosin light chain phosphorylation and how it effects bronchconstriction?

A

Myosin light chain when phosphorylated causes vasoconstriction, while dephosphorylated myosin light chain causes relaxation. Protein kinase A pushes for more dephosphorylated myosin light chain, also stimulating myosin light chain phosphatase which further promotes more dephosphorylated myosin light chain

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16
Q

How does a short-acting β2 adrenoceptor agonist work?

A
  • Short-acting β2-adrenoceptor agonists are relievers (SABA)
  • Provide acute symptom relief, prevent exercise-induced asthma
  • Must be inhaled with a corticosteroid
  • Rapid onset = 2-5 minutes
  • Duration of 2-4 hours and are lost via diffusion rather than metabolism
17
Q

Why must short-acting β2 adrenoceptor agonists be used infrequently?

A

Frequent use is associated with poor outcomes (thus why not used alone). Cause downregulation of β2-adrenoceptors (less receptors) meaning SABA bronchodilator response will decline

18
Q

How does a long-acting β2 adrenoceptor agonist work?

A
  • Used for prophylaxis - prevent bronchoconstriction
  • Hold tone of airways in relaxations state - bronchoconstriction has less of an effect
  • Always inhaled with a glucocorticoid
  • Slow or rapod onset depending on drug
  • Long duration of action
19
Q

What are potential adverse effects of β2 adrenoceptor agonists?

A

Tremor, palpatations, tachycardia (high HR - can be in effort to restore blood pressure), headache, non-selective effects on β1 adrenoceptors

20
Q

What asthma drugs prevent or reverse inflammation?

A

Glucocorticoids (corticosteroirds, glucocorticoid steroids) - endogenous drugs that mimic effect of cortisol

21
Q

What is the mechanism of glucocorticoids?

A
  1. Lipid soluble glucocorticoid (needs to be lipid soluble as receptor is in cytoplasm) binds to glucocorticoid receptor
  2. Binding causes the dimerisation of the two receptor agonist complexes (increase anti-inflammatory gene expression, decrease in inflammatory gene expression)
  3. Translocation occurs - moving dimerised receptor agonist complex into nucleus
  4. In nucleus interacts with DNA, effecting protein synthesis
22
Q

What are the two receptor agonist complexes in glucocorticoid anti-inflammatory asthma medication?

A
  1. Increased anti-inflammatory gene expression: increased expression of β2 adrenceptors, annexin-1
  2. Decreased inflammatory gene expression: decrease expression of inflam. enzymes (COX-2, PLA2 (phospholipase A2), decrease cytokines (TNFa), decrease in adhesion molecules (ICAM-1)
23
Q

What are the characteristics of glucocorticoid preventor medications?

A
  • Is a regular daily dreatment that decreases symptoms, flare-ups etc.
  • Since inducing change in gene expression has slow onset - can take weeks-months to have maximum effect
  • Can be inhaled or taken systemically (only taken systemically when flare-up)
24
Q

What are adverse effects of systemically (orally) taken glucocorticoid drugs?

A
  • Mood changes
  • Weight gain
  • Diabetes
  • Oesteoporosis
  • Hypertension
  • Immune suppression
  • Suppression of hypothalamic-pituitary-adrenal axis (reduce slowly or may experience low cortisol)
25
Q

What are the adverse effects of inhaled glucocorticoid drugs?

A

Well tolerated effects:
- hoarseness and weakness of boice (atrophy of vocal cords)
- oral thrush (use mouthwash)

26
Q

What does Leukotriene do in the context of asthma?

A

Synthesised through 5-lipoxygenase, release is triggered by asthma:
- vasodilation (plasma leakage)
- stimulate mucous secretion
- bronchoconstriction
- recruitment of eosinophils

27
Q

How are leukotriene 1 receptors blocked/antagonised?

A

Cysteinyl-leukotriene receptor antagonists =
- less active so can be taken orally
- modest bronchodilation
- used for aspirin-induced asthma (aspirin blocks cox, therefore more leukotrine, uncommon)

28
Q

What are monoclonal antibodies?

A

Biologics that can be used in severe forms of asthma where other drugs don’t work - target specific mediators involved in the process

29
Q

What are the 4 monoclonal antibodies involved in severe asthma treatment?

A
  1. Mepolizumab = binds to IL-5 and stops from binding to oesinophils
  2. Benralizumab = binds to IL-5 RECEPTORS on eosinophils reducing their activation
  3. Dupilumab = binds to subunit of IL-4 and IL-13, preventing their signalling
  4. Omalizumab = binds to IgE, bops it up and prevents priming of mast cells and therefore mast degranulation

pharmacology unimelb (2 decks)

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