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Respiratory Block > 2- pharmacology asthma > Flashcards

2- pharmacology asthma Flashcards

1
Q

where are the cell bodies of preganglionic fibres located?

A

in the brain stem

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2
Q

where are the cell bodies of postganglionic fibres located?

A

embedded in walls of bronchi & bronchioles

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3
Q

what does stimulation of post ganglionic cholinergic fibres cause in airways?

A
  • bronchial smooth muscle contraction mediated by M3 muscarinic acetylcholine receptors on airway smooth muscle cells
  • increased mucus secretion mediated by M3 muscarinic acetylcholine receptors on gland (goblet) cells
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4
Q

what does stimulation of postganglionic non-cholinergic fibres cause?

A

bronchial smooth muscle relaxation mediated by nitric oxide (NO) and vasoactive intestinal peptide (VIP) = possible route for therapy

non cholinergic fibers = fibers that release neurotransmitters other than acetylcholine

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5
Q

is there innervation in bronchial smooth muscle?

A

no but there are post ganglionic fibers that supply submucosal glands & smooth muscle in blood vessel

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6
Q

what innervation causes bronchial smooth muscle relaxation?

A

adrenaline released by adrenal glands that enters circulation and activates beta 2 adrenoceptors

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7
Q

what effect does beta 2 adrenoceptor activation cause?

A
  • bronchial smooth muscle relaxation
  • decreased mucus secretion (beta 2 adrenoceptors on goblet cells)
  • increased mucociliary clearance (beta 2 adrenoceptors on epithelial cells)
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8
Q

what happens due to alpha 1 adrenoceptors acting on vascular smooth muscle cells?

A

vascular smooth muscle contraction

(same process as muscarinic 3 Gq)

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9
Q

describe how the g-protein coupled receptor leads to smooth muscle contraction?

A

hormone or transmitter actives g-protein coupled receptor which triggers Gq which swaps GDP to GTP to become activated.
phospholipase C generates 2nd messenger, IP3. IP3 moves through cell and binds to IP3 receptor (which is also Ca channel) opening Ca+ channels which drives contraction

opening of Ca+ = transitory, opens voltage gated Ca+ channels so drives towards max Ca+ so max contraction

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10
Q

how is contraction initiated by calcium in smooth muscles?

A

Ca2+ binds to calmodulin (protein) and combined Ca2+ & calmodulin activates enzyme called myosin light chain kinase (kinase = phosphorylates downstream target). MLCK phosphorylates myosin cross bridges that bind actin so makes contraction

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11
Q

how is relaxation of smooth muscle caused?

A

myosin phosphatase = dephosphorylates myosin which means it is in an inactive state and unable to bind to actin, leading to muscle relaxation therefore myosin phosphatase indirectly causes muscle relaxation

(phosphatase = dephosphorylation)

beta 2 receptor:
- phosphorylates and inhibits MLCK
- phosphorylates and stimulates myosin phosphatase

PKA (made from beta 2 adrenoceptor Gs pathway), phosphorylates and inhibits myosin light chain kinase, inhibition of MLCK prevents it from phosphorylating myosin, thereby promoting muscle relaxation

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12
Q

what is the counter phase that determines how much contraction occurs?

A

MLC dephosphorylated by myosin phosphatase balanced with MLC phosphorylated by myosin light chain kinase

presence of elevated intracellular Ca2+ the rate of phosphorylation exceeds rate of dephosphorylation and vice versa

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13
Q

what regulates levels of myosin light chain kinase & myosin phosphatase?

A

by extracellular signals like adrenaline on beta 2 adrenoceptor

adrenaline activated it’s G-protein coupled receptor which activates Gs

cAMP activates downstream kinase, protein kinase A which phosphorylates & stimulates myosin phosphatase so inhibits myosin light chain kinase and causes relaxation of bronchial smooth muscle

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14
Q

what is function of PDE?

A

controls half life of cAMP (by degrading)

PDE = phosphodiesterase

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15
Q

why is it important that 2nd messengers like cAMP have a short half life?

A

so not continuous stimulation hence why things like PDE there to degrade cAMP

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16
Q

what are symptoms of intermittent attacks of bronchoconstriction?

A
  • tight chest
  • wheezing (increased airway turbulence & increased airway resistance)
  • difficulty breathing
  • cough
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17
Q

what pathological changes to bronchioles result from chronic asthma?

A

pathological change to bronchioles:

  1. increased mass of smooth muscle (hyperplasia & hypertrophy)
  2. accumulation of interstitial fluid (oedema)
  3. increased secretion of mucus
  4. epithelial damage (exposing sensory nerve endings)
  5. sub-epithelial fibrosis = decreased lung compliance
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18
Q

what is effect of airways narrowing on FEV1 and peak expiratory flow rate?

A

decreasing them

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19
Q

what contributes to sensitivity of airways to bronchoconstrictor influences?

A

epithelial damage, exposing sensory nerve endings (c-fibre, irritant receptors)
= may cause neurogenic inflammation by the release of various peptides – (from sensory nerve endings)

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20
Q

what are 2 components of asthma?

A

hypersensitivity (mild) & hyperreactivity (more severe)

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21
Q

what causes early phase & late phase asthma attack?

A

so early phase = bronchospasm & acute inflammation (type I hypersensitivity)

late phase = bronchospasm & delayed inflammation (type IV hypersensitivity)

→in severe asthma attack this is typical

*mild asthma can just be like early phase

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22
Q

what response dominates in a mild to moderate asthma response?

A

Th2 response = immune response involving IgE (much more severe asthmatic response)

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23
Q

what response dominates in a severe asthma response?

A

Th2 and Th1 response

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24
Q

what is the normal response to allergen (in non-atopic individuals)?

A

Th1 response = you recover quickly & remove allergens from your system using IgG &macrophages

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25
Q

describe the process of an allergic response to an allergen (immunology)

A

you breathe in allergen & antigen presenting cells process & display to CD4+ T cells which stimulate Th0 which can preferentially mature to Th2 or Th1 cells - in this case Th2 cells which release IL-4 to attract B cells and activate them binding to them - then making B cells mature to IgE secreting P cells
The Th2 cells also release IL-4 & lL-13 which cause mast cells express IgE receptors and when they bind to mast cells they degranulate and release histamine

26
Q

what happens once mast cell activated by IgE binding to IgE receptors (that are expressed in response to IL4,13 from Th2)?

A
  • the mast cells release secretory granules containing preformed histamine & production of other agents (leukotrienes - LTC4, LTD4) = causing airway smooth muscle contraction
  • release substances like platelet activating factor & prostaglandins (PGD2) that attract cells causing inflammation like eosinophils so when mast cell activated a whole diversity of potential inflammatory signalling molecules produced
27
Q

what is the allergen that binds to G-protein coupled receptor to initiate the Gq response?

A

the IgE bound mast cell which leads to the whole process of PLC activation and IP3 binding to ER making Ca2+ release into mast cell which activates the mast cell

28
Q

what happens in late phase asthma?

A

chemotaxins released by mast cells in immediate phase allow infiltration of Th2 cells & monocytes which release cytokines = activation of inflammatory cells particularly eosinophils which cause epithelial damage, airway inflammation, airway hyperresponsiveness all leading to bronchospasm (wheezing, coughing, mucus oversecretion)

29
Q

what are examples of relievers that are used to treat asthma?

A
  • short acting beta 2 adrenoceptor agonists (SABA)
  • long acting beta 2 adrenoceptor agonists (LABA)
  • CysLT1 receptor antagonists (cysteine leukotriene receptor antagonist)
30
Q

what are examples of controllers/preventers for treatment of asthma?

A
  • glucocorticoids
  • cromoglicate
  • humanised monoclonal IgE antibodies
31
Q

what is an example of a methylxanthies?

A

theophylline = cross divide between reliever & controllers so relieve early phase of asthma but also tamp down longer inflammatory cascade

32
Q

what are the positives & negatives for aerosol over oral administration?

A

aerosol good as delivers directly to site of action, high compliance (easier), effective in mild to moderate

aerosol bad as penetration not good

oral good for more severe as can give longer, more sustained doses

33
Q

what are the 2 categories for beta adrenoceptor agonists?

A

short acting & long acting

34
Q

what are examples of short acting beta 2 adrenoceptor agonists?

A

salbutamol (also called albuterol, terbutaline)
= 1st line for mild, intermittent asthma
taken as needed, works quickly and relaxation persists for 3-5 hours

35
Q

what is effect of short acting beta 2 adrenoceptor agonists?

A

cause smooth muscle relaxation 7 dilation and also increase mucus clearance & decrease mediator release from mast cells & monocytes

36
Q

what are adverse effects of SABA?

A

only a few by inhalation = tremors

(tachycardia, hypokalaemia etc can occur but unlikely)

37
Q

what is example of long acting beta 2 adrenoceptor agonist?

A

= salmeterol & formoterol
- not recommended for acute relief, useful for nocturnal asthma

  • used in combination with glucocorticoid (not used for monotherapy)
38
Q

what is a contraindication drug for LABA?

A

propranolol is non-selective beta blocker so would drive constriction

39
Q

what is mechanism of action for cysteinyl leukotriene receptor antagonist?

A

act competitively at the CysLT1 receptor.
cysteinyl leukotrienes are (LTC4, LTD4 and LTE4) released from mast cells and infiltrating inflammatory cells cause smooth muscle contraction, mucus secretion and oedema

40
Q

what is an example of cysteinyl leukotriene receptor antagonist?

A

montelukast = saved for more severe asthma as expensive & zafirlukast

41
Q

when are cysteinyl leukotriene receptor antagonist effective?

A
  • effective add on therapy against early AND late bronchospasm
  • effective against antigen-induced & exercise induced bronchospasm
  • administered by oral route
  • not recommended for relief of acute severe asthma
42
Q

are cysteinyl leukotriene receptor antagonist well tolerated?

A

generally yes but headache & GI upset have been reported

43
Q

what are methylxanthines?

A

= theophylline & aminophylline

  • present in coffee, tea & chocolate containing beverages (green tea high)
  • inhibits PDE that usually inactivates cAMP and cGMP which are second messengers that relax smooth muscle

PDE inhibitors so sustain half life cAMP so maintain production of PKA so sustain it’s effect

44
Q

what is problem with methylxanthines?

A

narrow therapeutic window and have numerous drug interaction like CYP450s particularly antibiotics that inhibit CYP450s

45
Q

what are corticosteroids 2 main categories?

A
  1. glucocorticoid that do lots of things, regulating metabolism, have influence in food intake and major suppressors of inflammation
  2. mineralocorticoids = influences blood pressure, salt and fluid balance in body
46
Q

what is function of cortisol and what is it?

A

cortisol is main hormone of glucocorticoids (hydrocortisone)
= decrease inflammatory & immunological response and multiple other various processes (a lot about glucose & liver etc)

47
Q

why do glucocorticoids need to be carefully controllled?

A

because they damp down inflammatory response so you don’t want to overdo

48
Q

what are examples of glucocorticoids?

A

generated from cortisol in body = beclometasone, budesonide, fluticasone

49
Q

what is effect of glucocorticoids?

A
  • no direct bronchodilator action and are ineffective in relieving bronchospasm when given acutely
  • but main treatment for prophylaxis of asthma
  • inhalation delivery preferred to minimise adverse side effects
50
Q

what are mineralocorticoid effect and example?

A

aldosterone = regulate the retention of salt (and hence water) by kidneys
= NOT used for asthma treatment

51
Q

what is the molecular mechanism for glucocorticoids?

A

they’re lipophilic so directly cross cell membrane. within cytoplasm combine with nuclear receptors and assemble into homodimers which bind to glucocorticoid response elements in promoter region of specific genes and transcription of specific genes and switched on or off depending - generally they increase transcription of anti-inflammatory proteins and decrease transcription of genes encoding for inflammatory proteins

52
Q

how is histone acetyl transferases (HAT) involved in glucocorticoid molecular pathway?

A

HAT is involved in acetylation (unwinding of DNA from histones) of histones which is associated with inflammatory genes (glucocorticoids affect transcription of these)

53
Q

what do glucocorticoids recruit to help switch off gene transcription?

A

histone deacetylases (HDACs)

54
Q

what effect does glucocorticoid have on inflammatory pathway (immunology one) in asthma?

A
  • they decrease formation of Th2 cytokines (IL-4, IL-5) and cause apoptosis
  • they prevent allergen induced eosinophil influx into lung & cause apoptosis
  • prevent production of IgE by P cells (after B cells)
  • reduce number of mast cells & decrease IgE receptor expression on the mast cells
55
Q

what effects does glucocorticoid have on each inflammatory cell: eosinophil, T lymphocyte, mast cell, macrophage, dendritic cell?

A
  • decrease cytokines that signal for macrophages & T lymphocytes
  • reduce numbers by apoptosis of eosinophils, mast cells & dendritic cells
56
Q

what effect does glucocorticoid have on structural cells?

A

epithelial cells = decrease cytokine mediators
endothelial cells = decrease leak
airways smooth muscle = alter beta 2 receptor cytokines
mucus gland = decrease mucus secretion

57
Q

what are the most common adverse side effects of glucocorticoids?

A
  • dysphonia (hoarse and weak voice)
  • oropharyngeal candidiasis (thrush)
58
Q

are glucorticoids better long term or short term?

A

Short term, they do not alleviate early stage bronchospasm caused by allergens, or exercise, but long term treatment is effective (particularly in combination with a long-acting β2-adrenoceptor agonist; LABA)

59
Q

what are cromones?

A

“mast cell stabilizers” = suppress histamine release of mast cells but mostly uncertain mechanism
- less commonly used now, takes long time for effect

example = sodium cromoglicate

60
Q

what is an example of monoclonal antibodies directed against IgE drug? and how does it work?

A

omalizumab (expensive & requires IV administration)

  • binds IgE via Fc to prevent attachment to receptors and suppresses mast cells response to allergens
  • reduces expression of Fc receptors on various inflammatory cells

mepolizumab

-directed against IL-5, recently introduced treatment for asthma associated with severe eosinophilia

Respiratory Block (46 decks)

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