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JL Respiratory > Pharmacology > Flashcards

Pharmacology Flashcards

0
Q

In the parasympathetic division, which nerve carries preganglionic fibres?

A

Vagus nerve

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1
Q

What innervation of the airways is the dominant neuronal control of bronchial smooth muscle tone?

A

Parasympathetic cholinergic innervation

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2
Q

In the parasympathetic division, where are the ganglia embedded?

A

In the walls of bronchi and bronchioles

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3
Q

What do post-ganglionic fibres of the parasympathetic division do?

A

Innervate bronchial smooth muscle and submucosal glands

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4
Q

What 3 things does stimulation of the parasymapthetic division cause?

A
  1. Bronchial smooth muscle contraction mediated by ACh acting upon M3 muscarinic ACh receptors
  2. Increased mucus secretion mediated by ACh acting upon M3-muscarinic ACh receptors
  3. Collectively, increased airway resistance
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5
Q

A distinct subpopulation of postganglionic parasympathetic fibres employ vasoactive intestinal peptide (VIP) and nitric oxide (NO) as transmitters - when stimulated what do these do?

A

Relax bronchial smooth muscle

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6
Q

What division has no, or sparse innervation of bronchial smooth muscle in humans?

A

Sympathetic division

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7
Q

What do postganglionic fibres of the sympathetic division supply?

A

Sub-mucosal glands and smooth muscle of blood vessels

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8
Q

What does stimulation of the sympathetic division do to bronchial smooth muscle?

A

Relaxation (via beta-2-adrenoceptors activated by adrenaline released from the adrenal gland)

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9
Q

In the sympathetic division: pre-ganglionic fibres release ACh - what does this activate?

A

Nicotinic ACh receptors on adrenal chromaffin cells

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10
Q

Sympathetic division: once ACh from pre-ganglionic fibres have been received at nicotinic ACh receptors what is released?

A

Adrenaline (and noradrenaline) into circulation

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11
Q

Sympathetic division: once noradrenaline has been released into the circulation what receptors are activated and what occurs?

A

Activation of beta-2-adrenoceptors on bronchial smooth muscle cells by adrenaline causes relaxation.

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12
Q

What does stimulation of the sympathetic division do to mucus secretion?

A

Decreases mucus secretion mediated by beta-2-adrenoceptors

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13
Q

What does stimulation of the sympathetic division do to mucociliary clearance?

A

Increases it mediated by beta-2-adrenoceptors

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14
Q

What is the name for a recurrent and reversible obstruction to teh airways in response to substances which are not necessarily noxious?

A

Asthma

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15
Q

Give 4 common causes of asthma attacks

A
  1. Allergens (in atopic individuals)
  2. Exercise (cold,dry air)
  3. Respiratory infections (e.g. viral)
  4. Smoke, dust, environmental pollutants
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16
Q

In asthma what 3 things are caused by intermittent attacks of bronchoconstriction?

A
  1. Cough
  2. Wheezing
  3. Difficulty in breathing
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17
Q

What involves pathalogical changes to the bronchioles that result from long standing inflammation?

A

Chronic asthma

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18
Q

Give 4 pathological changes caused by chronic asthma

A
  1. Increased mass of smooth muscle (hyperplasia and hypertrophy)
  2. Accumulation of intersitial fluid (oedema)
  3. Increased secretion of mucus
  4. Epithelial damage (exposing sensory nerve endings)
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19
Q

Airway narrowing by inflammation and bronchoconstriction increase airway resistance, what do they decrease?

A

FEV1 and PEFR

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20
Q

Name 2 sensory nerve endings exposed by epithlial damage

A
  1. C-fibres

2. Irritant receptors

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21
Q

What contributes to increased sensitivity of the airways to bronchoconstriction influences (and may cause neurogenic inflammation) by the release of various peptides?

A

Epithelial damage

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22
Q

What is another term for inhaled bronchoconstrictors?

A

Spasmogens (e.g. histamine or methacholine [muscarinic ACh receptor agonist])

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23
Q

What two phases comprise an asthma attack?

A

Immediate - bronchospasm

Delayed - inflammatory reaction

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24
Q

When an individual is exposed to an allergen what first step occurs?

A

Phagocytosis by antigen presenting dendritic cell

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25
Q

In a non-atopic individual, after phagocytosis by the dendritic cell what type of response occurs?

A

Low-level TH1 response

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26
Q

What type of response is a cell-mediated immune response involving IgG and macrophages?

A

Low-level TH1 response

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27
Q

In an atopic individual, ocne a dendritic cell has phagocytosed the antigen what response occurs?

A

Strong TH2 response

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28
Q

What is a strong TH2 response?

A

Antibody-mediated immune response involving IgE

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29
Q

What are the two phases in the development of allergic asthma?

A

Induction phase

Effector phase

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30
Q

In the induction phase of teh development of allergic asthma - what does the antigen presenting cell present the processed antigen to?

A

CD4 T cell

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31
Q

During the induction phase in the development of asthma - what does the CD4 T cell do to TH0 cells?

A

Causes them to preferentially mature to TH2 cells that produce a cytokine environment

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32
Q

During the induction phase in the development of allergic asthma - what do the T helper 2 cells activate and how?

A

Activate B cells by binding to them and by IL-4 production

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33
Q

During the induction phase of the development of allergic asthma - what happens to the B cells?

A

They mature into IgE secreting plasma cells

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34
Q

During the effector phase in the development of allergic asthma - what do the eosinophils differentiate and activate in response to?

A

IL-5 released from TH2 cells

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35
Q

During the effector phase in the development of allergic asthma - what do mast cells in airway tissue express IgE receptors in response to?

A

IL-4 and IL-13 released from TH2 cells

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36
Q

During the development of allergic asthma - what does the subsequent presentation of antigen cross link with?

A

IgE receptors

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37
Q

During the development of asthma - what does subsequent presentation of antigen stimulate?

A

Calcium entry into mast cells and the release of Ca2+ from intracellular stores

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38
Q

During the development of allergic asthma - what does the increase in intracellular calcium cause the release of?

A
  1. Secretory granules containing preformed histamine and the production and release of other agents (e.g. leukotrienes LTC4 and LTD4) that cause airway smooth muscle contraction.
  2. Substances (e.g. LTB4 and platelet-activating factor PAF and prostaglandins (PGD2) that attract cells causing inflammation (e..g mononuclear cells and eosinophils) into the area
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39
Q

What are chemotaxins and chemokines (LTB4, PAF, PGD2) and spasmogens (histamine, leukotrienes - LTC4, LTD4) released from and what are they released in response to?

A

Activated mast cell in response to increased intracellular calcium ion levels.

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40
Q

During the immediate phase of asthma - what are the first two cells to react?

A

Mast cells and mononuclear cells

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41
Q

During the immediate phase of asthma - what two substances do mast cells release?

A

Spasmogens (cysLTs and histamine)

Chemotaxins and chemokines

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42
Q

In the late phase of asthma - what do chemotaxins and chemokines released from mast cells do?

A

Infiltration of cytokines releasing TH2 cells and monocytes, activation of inflammatory cells, particularly eosinophils

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43
Q

During the late phase of asthma - what two substances do eosinophils release?

A

Mediators cysLTs and others

Eosinophil major basic and catonic proteins

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44
Q

In the late phase of asthma - what do the mediators cysLTs and others cause?

A

Airway inflammation, airway hypersensitivity

Bronchospasm, wheezing and cough

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45
Q

During the late phase of asthma - what do eisoniphil major basic and catonic proteins cause?

A

Epithelial damage which leads to airway hypersensitivity

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46
Q

What two basic classes can drugs used in the treatment of asthma be placed into?

A

Relievers and controllers/preventors

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47
Q

What do relievers act as?

A

Bronchodilators

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48
Q

What do controllers/preventors act as?

A

Inflamamtory agents that reduce airway inflammation

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49
Q

Name 3 types of drugs that act as relievers in asthma

A
  1. Short acting beta-2-adrenoceptor agonists
  2. Long acting beta-2-adrenoceptor agonists
  3. CysLT receptor antagonists
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50
Q

Name 3 groups of drugs that are controllers/preventors

A
  1. Glucocorticoids
  2. Chromoglicate
  3. Humanised monoclonal IgE antibodies
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51
Q

Which group of drugs is both a reliever and a controller/preventor?

A

Methylxanthines

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52
Q

What act as physiological antagonists of all spasmogens?

A

Beta-2-adrenoceptor agonists

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53
Q

When a beta-2-adrenoceptor agonist acts on a beta-2-adrenoceptor on airway smooth muscle, what becomes activated?

A

Gs which then activates denylyl cylase

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54
Q

Once a beta-2-adrenoceptor agonist has acted on a receptor and caused stimulation of Gs and then Adenylyl cylcase, what does adenylyl cyclase then catalyse?

A

The conversion of ATP to cyclic adenosine monophosphate (cAMP)

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55
Q

Once a beta-2-adrenoceptor agonist has acted on a receptor and caused the conversion of ATP to cAMP, what does cAMP then inhibit and stimulate?

A

Inhibits PDE - 5 AMP

Stimulates PKA

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56
Q

Once a beta-2-adrenoceptor agonist has acted on a receptor andc caused the stimulation of PKA (protein kinase A), what becomes phosphorylated and what is the end result?

A

Phosphorylation of MLCK (myosin light chain kinase)

Relaxation of airway smooth muscle

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57
Q

In common with most G protein coupled receptors (GPCR), what does persistent activation of beta-2-adrenoceptors cause?

A

Receptor desensitisation and endocytosis (resulting in loss of function)

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58
Q

During over activation of beta-2-adrenoceptors and desensitisation, what two kinases are involved?

A
  1. Protein kinase A (PKA)

2. G protein receptor kinases (GPRKs) - specifically beta-adrenoceptor kinases

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59
Q

During the desensitisation of beta-2-adrenoceptors, what do protein kinase A and G-protein receptor kinase do to the activated beta-2-adrenoceptor?

A

Phosphorylate it

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60
Q

What can be said about hte phosphorylation of a protein kinase A receptor?

A

Can be phosphorylated with no agonist bound

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61
Q

What can be said about a g-protein receptor kinase receptor in relation to phosphorylation?

A

Receptor is phosphorylated only when agonist is bound

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62
Q

What does a PKA phosphorylated beta-2-adrenoceptor result in?

A

Reduced G-protein coupling

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63
Q

What does a GRK phosphorylated beta-2-adrenoceptor result in?

A

Formation of beta-arrestin receptor complex which leads to loss of G-protein coupling/endocytosis

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64
Q

What acts as a scaffold protein that links the desensitised beta-adrenoceptors to endocytic machinery that internilise the receptor?

A

Beta-arrestin

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65
Q

How are receptors internalised by beta-arrestin?

A

In clathrin-coated pits and vesicles and trafficked to either endosomes for recycling, or lysosomes for degradation.

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66
Q

When does beta-arrestin unbind from the vesicle?

A

Between endocytosis and the endosomal vesicle

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67
Q

In an endosomal vesicle the agonist is still in the receptor on the membrane, when the agonist moves in what occurs to the cell environment?

A

Turns more acidic (acidic vesicle)

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68
Q

Name two short acting beta-2-adrenoceptor agonists

A
  1. Salbutamol

2. Albuterol

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69
Q

What are the first line treatment for mild, intermittent asthma?

A

Beta-2-adrenoceptor agonists - short acting

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70
Q

How long does it take for a short acting beta-2-adrenoceptor agonists to reach maximal effect and how long does relaxation persist for?

A

30 minutes

Persists for 4-6 hours

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71
Q

What increases mucus clearance and decreases mediator release from mast cells and neutrophils?

A

Short acting Beta-2-adrenoceptor agonists

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72
Q

Give two adverse effects due to unwanted systemic absorption of inhaled short acting beta-2-adrenoceptor agonists

A
  1. Fine tremor

2. Occasional tachycardia

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73
Q

Name a long acting beta-2-adrenoceptor agonist?

A

Salmeterol

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74
Q

What type of beta-2-adrenoceptor agonists are useful for nocturnal asthma?

A

Long acting beta-2-adrenoceptor agonists because of their long half life

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75
Q

Can long acting beta-2-adrenoceptor agonists be used as monotherapy?

A

No

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76
Q

What does the use of selective beta-2-adrenoceptor agonists reduce?

A

Potentially harmful stimulation of cardiac beta-1-adrenoceptors

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77
Q

Why are non-selective beta-adrenoceptor antagonists (e.g. propranolol) contraindicated in asthma?

A

Because the risk of bronchospasm

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78
Q

Where do cysLT antagonists act competitively at?

A

The CysLT receptor

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79
Q

Name three CysLTs?

A

LTC4, LTD4, LTE4

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80
Q

Where are cysLTs derived from?

A

Mast cells

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81
Q

When cysLTs infiltrate inflammatory cells what occurs?

A

Smooth muscle contraction, mucus secretion and oedema

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82
Q

During the use of cysLT receptor antagonists, once mast cells have been activated what does phospholipase A2 release?

A

Intracellular arachidonic acid

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83
Q

During cysLT antagonist use, what does arachidonic acid stimulate?

A

Mast cell 5-lipoxygenase by FLAP

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84
Q

What is 5-lipoxygenase blocked by?

A

Zileuton

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85
Q

During cysLT antagonist use, what occurs once mast cell 5-lipoxygenase has been stimulated by FLAP?

A

LTA4 is produced which in turn creates LTB4 and LTC4

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86
Q

During cysLT antagonist drug use, what two substances are transported across the mast cell membrane?

A

LTB4 and LTC4

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87
Q

During cysLT antagonist drug use, what does LTB4 do once it has crossed the mast cell membrane?

A

Infiltration of inflammatory cells released cysLTs

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88
Q

During cysLT receptor mechanisms, once LTC4 has crossed the mast cell membrane, what occurs?

A

It splits into LTD4 and LTE4 which act on the cysLT receptor (which antagonists block)

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89
Q

Once the cysLT receptor has been activated what two responses occur?

A
  1. Bronchoconstriction (early phase)

2. Inflammation (delayed phase)

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90
Q

Name 2 cysLT receptor antagonists?

A

Montelukast and Zafirlukast

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91
Q

What drugs are effective as add on therapy in mild persistent asthma and in combination with other medications in more severe conditions?

A

CysLT receptor antagonists such as Montelukast and Zafirlukast

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92
Q

What two induced bronchospasms are cysLT receptor antagonists such as montelukast and zafirlukast used for?

A

Antigen-induced and exercise induced bronchospasm

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93
Q

How are cysLT receptor antagonists such as Montelukast and Zafirlukast delivered?

A

By the oral route

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94
Q

Name 2 xanthines?

A

Theophylline and aminophylline

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95
Q

What type of bronchodilators are present in coffee, tea and chocolate beverages?

A

Xanthines

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96
Q

What type of bronchodilators have an uncertain molecular mechanism of action - might involve inhibition of isoforms of phosphodieterases (i.e. PDE III and IV) that inactivate cAMP and cGMP (second messengers that relax smooth muscle and perhaps exert an anti-inflammatory effect)

A

Xanthines

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97
Q

What are second line drugs used in combination with beta-2-adrenoceptor agonists and glucocorticoids?

A

Xanthines such as theophylline and aminophylline

98
Q

How are xanthines delivered?

A

Oral route as sustained release preperations

99
Q

Give 4 adverse effects of xanthines at therapeutic concentrations?

A
  1. Nausea
  2. Vomiting
  3. AAbdominal discomfort
  4. Headache
100
Q

Name a drug used in the treatment of asthma that is an anti-inflammatory agent?

A

Corticosteroids

101
Q

The adrenal cortex synthesises two major classes of steroid hormone that are released into the circulation - what are they?

A
  1. Glucocorticoids

2. Mineralcorticoids

102
Q

What part of the adrenal cortex are glucocorticoids produced in?

A

Zona fasiciculata

103
Q

What part of the adrenal cortex are mineral corticoids produced in?

A

Zona glomerulosa

104
Q

What glucocorticoid is the main hormone in man?

105
Q

What hormone decreases inflammatory responses, decreases immunological responses, increases liver glycogen deposition, increases gluconeogenesis, increases glucose output from liver, decreases glucose utilisation, increases protein catabolism, increases bone catabolism and increases gastric acid and pepsin secretion?

A

Hydrocortisone

106
Q

Name a mineralcorticoid?

A

Aldosterone

107
Q

What does aldosterone regulate?

A

The retention of salt and water by the kidneys

108
Q

Are mineralcorticoids wanted in the treatment of inflammatory conditions?

109
Q

Name a synthetic derivative of cortisol

A

Beclametasone

110
Q

What have no direct bronchodilator action and are ineffective in relieving bronchospasm when given acutely?

A

Glucocorticoids

111
Q

What are the mainstay of treatment in the prohpylaxis of asthma and are preferably delivered by the inhalational route to minimise adverse systemic effects?

A

Glucocorticoids

112
Q

What do glucocorticoids signal via?

A

Nuclear receptors (class 1), specifically GRalpha

113
Q

How do glucocorticoids enter cells and what type of molecules are they?

A

Diffusion across plasma membranr

Lipophilic molecules

114
Q

Within the cytoplasm - what do glucocorticoids combine with?

115
Q

Once the glucocorticoid has combined with GRalpha in the cytoplasm - what does this produce?

A

Inhibitory heat shock proteins (e.g. HSP90)

116
Q

Once the glucocorticoid has combined with the GRalpha receptor where does the activated receptor translocate to?

A

The nucleus aided by importins

117
Q

Within the nucleus - what does the activated GRalpha receptor that is combined with a glucocorticoid monomers assemble into?

A

Homodimers

118
Q

Within the nucleus, what do activated GRalpha receptor homodimers bind to?

A

Glucocorticoid response elements (GRE) in the promoter region of specific genes

119
Q

Molecular mechanism of action of glucocorticoids: once the nucleus activated receptor homodimer has binded to GRE what happens to transcription?

A

Transcription of specific genes is either switched on (transactivated) ot switched off (translpressed) to alter mRNA levels and the rate of synthesis of mediator proteins.

120
Q

What are regulated by glucocorticoids acting at glucocorticoid response elements, or by modifying the structure of chromatoin via deacetylation of histones?

121
Q

Generally, what do glucocorticoids do to the transcription of genes encoding anti-inflammatory proteins?

A

Increase transcription

122
Q

What do glucocorticoids do the the transcription of genes encoding inflammatory proteins?

A

Decrease transcription

123
Q

What is expression of inflammatory genes associated with?

A

Acetylation of histones by histone acetyltransferases (HATs)

124
Q

What unwinds DNA from histones allowing transcription?

A

Acetylation

125
Q

What do glucocroticoids recruit to activated genes to switch off gene transcription?

A

Histone deacetylases (HDACs)

126
Q

What is a simple definition of chromatin?

A

DNA plus histones

127
Q

What part of bronchial asthma are glucocorticoids particularly relevant to?

A

Inflammation

128
Q

What prevents allergen-induced influx into lung and cause apoptosis of eosinophils?

A

Glucocortiocids

129
Q

What do glucocorticoids decrease the formation of?

A

TH2 cytokines and cause apoptosis of TH2 cells

130
Q

What do glucocorticoids reduce the number of and decrease?

A 
Number of mast cells 
Decrease Fc (IgE receptor) expression
131
Q

What do glucocorticodis produce the production of?

A

IgE antibodies

132
Q

What effect does glucocorticpdis have on eosinophils?

A

Reduce numbers by apoptosis

133
Q

What effect does glucocorticodis have on T-lymphocytes?

A

Reduce cytokines

134
Q

What effect does glucocorticoid have on mast cells?

A

Reduce numbers

135
Q

What effect does glucocorticoids have on Macrophages?

A

Decrease cytokines

136
Q

What effect do glucocorticoids have on dendritic cells?

A

Reduce numbers

137
Q

What do corticosteroids/glucocorticoids do to epithelial cells?

A

Reduce cytokines and mediators

138
Q

What do corticosteroids do to endothelial cells?

A

Decrease leak

139
Q

What do corticosteroids/glucocorticoids do to airway smooth muscle?

A

Increase beta-2-receptors and decrease cytokines

140
Q

What do glucocorticoids/corticosteroids do to mucus glands?

A

Decrease mucus secretion

141
Q

What combined with glucocorticoids give effective long term treatment of asthma?>

A

Long-acting beta-2-adrenoceptor agonist (LABA)

142
Q

In mild/moderate asthma - how is beclametasone (glucocorticoid) given?

A

Inhalation from a metered dose inhaler

143
Q

Name 2 adverse effects of glucocorticoids (beclametasone), due to deposition of steroid in the oropharynx?

A 
Dysphonia (hoarse and weak voice)
Oropharyngeal candidiasis (thrush)
144
Q

In chronic, severe, or rapidly deteriorating asthma - what may be used in combination with an inhaled corticosteroid to reduce the oral dose required and minimise unwanted systemic effects?

A

Prednisolone

145
Q

What type of drugs are second line drugs and now infrequently used, however can be used prophylactically in the treatment of allergic asthma in children?

146
Q

What drugs are often described as mast cell stablisers?

147
Q

Do cromolins have a direct effect on bronchial smooth muscle?

148
Q

What drugs have an uncertain molecular mechanism of action that incldues a weak anti-inflamamtory effect. A decrease in the sensitivity of irritant receptors associated with sensory C-fibres that trigger exaggerated reflexes and reduction of cytokine release are potential mechanisms?

149
Q

Name a specific cromolin agent?

A

Sodium cromoglicate

150
Q

How is sodium cromoglicate delivered?

A

By inhalation

151
Q

What drug can reduce both phases of an asthma attack, but efficacy may take several weeks to develop - requires frequent dosing?

A

Sodium cromoglicate

152
Q

What are recent approaches to the treatment of asthma that involve anti-inflammatory actions?

A

Monoclonal antibodies directed against IgE

153
Q

Name a monoclonal antibody direcetd against IgE?

A

Omalizumab

154
Q

What drug binds IgE via Fc to prevent attachment to Fc receptors - suppresses mast cell response to allergens?

A

Omalizumab

155
Q

What does omalizumab reduce on various inflammatory cells?

A

The expression of Fc receptors

156
Q

How is omalizumab or other monoclonal antibodies directed against IgE delivered?

A

Intravenously and is expensive

157
Q

What is characterised by airflow reduction that is in some patients partially reversible (with bronchodilators) but which progressively worsens (as assessed by FEV1) and by exacerbation of symptoms including cough and mucus production?

158
Q

What can COPD be clinically divided into\?

A

Emphysema and bronchitis

159
Q

What does smoking/air pollution stimulate?

A

Resident alveolar macrophages

160
Q

In COPD, once resident alveolar macrophages have been stimulated - what is produced?

161
Q

In COPD, once resident alveolar macrophages have stimulated cytokine production - what occurs?

A

Activation of neutrophils, CD8 T cells and increased macrophage numbers

162
Q

In COPD, what do the activation of neutrophils, CD8 T cells and increased macrophage numbers release?

A

Matrix metalloproteinases (e.g. elastase) and free radicals

163
Q

What type of COPD gives inflammation of the bronci and bronchioles, cough, ckear mucoid sputum, indections with purulent sputum and increasing breathlessness?

A

Chronic bronchitis

164
Q

Which type of COPD has distension and damage to alveoli and the destruction of acinial pouching in alveolal sacs?

165
Q

What three types of muscarinic acetylcholine receptors do human airways express?

A

M1, M2 and M3

166
Q

Where is receptor M1, what does it facilitate?

A

Ganglia

Faciliates transmission mediated by ACh acting on Nicotinic receptors (nAChR)

167
Q

Where is receptor M2 and what does it act as?

A

Post ganglionic neurone terminals

Acts as inhibitory autoreceptors reducing the release of ACh

168
Q

Where is receptor M3 located and what does it mediate?

A

Smooth muscle

Mediates contraction to ACh (also present on mucus secreting cells evoking increased secretion)

169
Q

What is a corner stone of the treatment of COPD?

A

Reducing parasympathetic activity with muscarinic receptor antagonists

170
Q

What act as pharmacological antagonists of bronchoconstriction caused by smooth muscle M3 receptor activation in response to ACh released from parasympathetic fibres (and non-neural cells also)?

A

Muscarinic acetylcholine receptor antagonists

171
Q

Molecular mechanism of airway smooth muscle contraction: what is activation by ACh blocked by?

A

Muscarinic receptor antagonists

172
Q

Molecular mechanism of airway smooth muscle contraction: What does M3 muscarinic receptor stimulate?

173
Q

Molecualr mechanism of airway smooth muscle contraction: what does Gq/11 in smooth muscle stimulate?

A

PLC - Phospholipase C

174
Q

Molecular mechanisms of airway smooth muscle contraction: what does phospholipase C PLC do?

A

Converts PIP2 to IP3 (Phosphatidylinositol bisphosphate to inositol triphsophate)

175
Q

Molecular mechanism of airway smooth muscle contraction: what does IP3 stimulate?

A

Ca2+ release from SR (sarcoplasmic reticulum)

176
Q

Molecular mechaism of airway smooth muscle contraction: what does Ca2+ release from sarcoplasmic reticulum finally lead to?

A

Contraction of airway smooth muscle

177
Q

Name 2 short acting muscarinic antagonists (SAMAs)

A
  1. Ipratropium

2. Oxitropium

178
Q

Name 2 long acting muscarinic antagonists (LAMAs)

A
  1. Tiotropium

2. Aclidinium

179
Q

How are all competitive muscarinic receptor antagonists given (SAMAs and LAMAs)?

A

Inhalation

180
Q

What does the quaternary ammonium group c.f. atropine) in muscarinic receptor antagonists do?

A

Reduces absorption and systemic exposure avoiding multiple potential adverse affects

181
Q

What type of amine is found in atropine?

A

Tertiary amine

182
Q

How long does it take for muscarinic ACh receptor antagonists to take action?

A

> 30 minutes (aclinidium may be faster)

183
Q

What do muscarinic ACh receptor antagonists do?

A

Relax bronchospasm caused by irritant stimuli (irritants initiate a vagal reflex that liberates ACh) and also basal block ACh mediated basal tone

184
Q

What do muscarinic ACh receptor antagonists do to mucus secretion?

A

Decrease it

185
Q

What muscarinic ACh receptor antagonist is a non-selective blocker of M1, M2 and M3 receptors?

A

Ipratropium

186
Q

Which msucarinic ACh receptor antagonist blocks M3?

A

Tiotropium

187
Q

How is the functional selectivity of tiotropium over ipratropium achieved?

A

By its longer half-life at the M3 muscarinic receptor

188
Q

Why does tiotropium not block M2?

A

Because the relase of ACh from parasympathetic post-ganglionic neurones is increased

189
Q

What is a prejunctional inhibitory autoreceptor (activatin by ACh inhibits further ACh release, non-selective antagonists increase release) found on hte post-ganglionic neurone?

190
Q

What short acting, and two long acting beta-2-adrenoceptor agonists are used in the treatment of COPD?

A

Salbutamol

Salmeterol and formoterol

191
Q

What is the name of a recently licensed ultra-LABA with a rapid onset of action with once daily dosing?

A

Indacaterol

192
Q

What is superior to either drug alone in increasing FEV1 in moderate COPD?

A

A combination of LABA and LAMA (salmeterol/tiotropium)

193
Q

What is the prominent PDE expressed in neutrophils, T cells and macrophages?

A

Phosphodiesterase-4 (PDE4)

194
Q

What is Rofumilast?

A

A selective PDE4 inhibitor

195
Q

What drug suppresses inflammation and emphysema in animal models of COPD. Approved as oral treatment for severe COPD accompanied by chronic bronchitis but has limiting adverse GI effects?

A

Rofumilast

196
Q

Why might glucocorticoids be unresponsive in COPD patients?

A

Due to oxidative/nitrative stress (associated with chronic inhalation of tobacco smoke) - HDAC2 is reduced in COPD

197
Q

What is a common and often debilitating disease involving acute, or chronic, inflammation of the nasal mucosa?

198
Q

What is rhinorrohea?

A

Runny nose - watery mucus accumulation in nasal cavity

199
Q

What is nasal congestion and obstruction in rhinitis caused by?

A

Swelling of nasal mucosa largely due to dilated blood vessels - particularly cavernous sinusoids

200
Q

What are sneezing, itching, nasal congestion and rhinorrohea all features of?

201
Q

What are the three types of rhinitis?

A
  1. Allergic
  2. Non-allergic
  3. Mixed
202
Q

What are the three types of allergic rhinitis?

A
  1. Seasonal (SAR)
  2. Perennial (PAR)
  3. Episodic
203
Q

During allergic rhinitis - what does inhalation of allergen increase?

A

Specific IgE levels

204
Q

During allergic rhinitis: once inhalation of an allergen has increased specific IgE levels, what does IgE bind to?

A

Receptors on mast cells and basophils

205
Q

During allergic rhinitis - what does re-exposure to allergen cause, in relation to cells?

A

Mast cell and basophil degranulation

206
Q

During allergic rhinitis: what does degranulation of mast cells and basophils cause?

A

Release of mediators including histamine, cysLTs, tryptase, prostaglandins, causing acute itching, sneexing, rhinorrhoea and nasal congestion

207
Q

During allergic rhinitis: what does the delayed response caused by recruitment of lymphocytes and eosinophils to nasal mucosa contribute to?

A

Congestion and obstruction

208
Q

What does non-allergic rhinitis refer to?

A

Any rhinitis, acute or chronic that does not involve IgE - dependent events - caused are diverse

209
Q

What are 5 causes of non-allergic rhinitis?

A
  1. Infection - infectious rhinitis (largely viral)
  2. Hormonal imbalance - hormonla rhinitis (e.g. pregnancy)
  3. Vasomotor disturbances - vasomotor rhinitis (idiopathic)
  4. Nonallergic rhinitis with eosinophilia syndrome (NARES)
  5. Medications - drug induced rhinitis
210
Q

What do both rhinitis and rhinorroea involve?

A

Increased mucosal blood flow, increased blood vessel permeability, or both - these increase he volume of the nasal mucosa and cause difficulty breathing in

211
Q

Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for anti-inflammatory effects?

A

Glucocorticoids

212
Q

Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for mediator receptor blockade?

A

H1 receptor antagonists

cysLT receptor antagonists

213
Q

Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for Nasal blood flow?

A

Vasoconstrictors

214
Q

Targets in the treatment of rhinitis and rhinorrhoea: what is the treatment for antiallergic effects?

A

Sodium chromoglicate

215
Q

Do glucocorticoids reduce vascular permeability?

216
Q

What is the mainstay therapy for seasonal allergic rhinitis and perrennial allergic rhinitis and are of value in NARES and vasomotor rhinitis?

A

Glucocorticoids

217
Q

How are glucocorticoids for rhinitis administered?

A

Topically as a spray to the nasal mucosa (i.e. intranasal administration)

218
Q

Are glucocorticoids for rhinitis effective as monotherapy?

219
Q

What might glucocorticodis be combined with in moderte-to-severe rhinitis?

A

Anti-histamines

220
Q

Give three examples of glucocorticodis used in rhinitis

A
  1. Beclametasone
  2. Fluticasone
  3. Prednisolone (oral)
221
Q

What are anti-histamines?

A

H1 receptor antagonists

222
Q

What is the mechaism for anti-histamines (H1 receptor antagonists)?

A

Competetive antagonists of H1 receptors reduce effects of mast cell derived histamine

223
Q

Give three effects of mast cell derived histamine?

A
  1. Vasodilatation and increased capillary permeability
  2. Activation of sensory nerves
  3. Mucus secretion from submucosal glands
224
Q

What drugs are effective in SAR, PAR and episodic allergic rhinitis but less so for non-allergic rhinitis?

A

Anti-histamines

225
Q

How are anti-histamines for rhinitis administered?

A

Orally, or as an intranasal spray (azelastine)

226
Q

Are anti-histamines effective as monotherapy?

227
Q

Anti-histamines are available as first and second generation agents - which is preferred and why?

A 
Second generation
Reduced sedation (do not cross blood brain barrier) and lack of anti-cholinergic effects
228
Q

Give three examples of second generation anti-histamines

A
  1. Loratidine
  2. Fexofenadine
  3. Cetirizine (also has mild anti-inflammatory action)
229
Q

What are anti-cholinergic drugs?

A

Muscarinic receptor antagonists

230
Q

What is the mechanism for anti-cholinergic drugs (muscarinic receptor antagonists)?

A

ACh released from post-ganglionic parasympathetic fibres activates muscarinic receptors on nasal glands causing a watery secretion that contributes to rhinorrhoea - blocked by muscarinic antagonists

231
Q

What drugs are effective in reducing rhinorrhoea in PAR and SAR but have no influence upon itching, sneezing and congestion?

A

Anti-cholinergic drugs (note the anti-cholnergic activity of first generation H1 blockers may contribute to their ability to suppress rhinorrhoea)

232
Q

How are anti-cholinergic drugs administered?

A

By the nasal route

233
Q

Give one adverse effect of anti-cholinergic drugs

A

May cause dryness of nasal membranes

234
Q

Name the single sole agent used in the anti-cholinergic drug class?

A

Ipratropium

235
Q

Give the mechanism for sodium chomoglicate?

A

Purportedly mast cell stabilsation, but this is uncertain

236
Q

What drug is used for maintanence treatment of allergic rhinitis with an onset of action of 4 to 7 days, but weeks may be required for full effect?

A

Sodium chomoglicate

237
Q

Give the mechanism for Cysteinyl Leukotriene Receptor Antagonists

A

CysLT receptor antagonists reduce the effects of cysLTs upon the nasal mucosa

238
Q

Which drugs are equi-effective with H1 receptor antagonisys in treating PAR and SAR with which their effect may be additive?

A

CysLT receptor antagonists

239
Q

How are cysLT receptor antagonists administered?

A

By the oral route

240
Q

Name the sole agent used in the class of cysLT receptor antagonists?

A

Montelukast

241
Q

Which drugs have a mechanism of action that is direct, or indirect, sympathomimetics to mimic the effect of noradrenaline. Produce vasoconstriction via activation of alpha-1-adrenoceptors to decrease swelling in vascular mucosa?

A

Vasoconstrictors

242
Q

Name a selective alpha-1-adrenoceptor agonisy (given intranasally), which is effective, short term, in reducing congestion in allergic rhinitis?

A

Oxymetazoline

243
Q

Why is nasal administration of oxymetazxoline for more than a few days not recommended?

A

Due to the development of a rebound increase in nasal congestion upon discontinuation (rhinitis medicamentosa). Occurs due to receptor desensitisation and down regulation.

JL Respiratory (27 decks)

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