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PH2113 Disease & Drugs 1 > U2 Asthma > Flashcards

U2 Asthma Flashcards

1
Q

What are obstructive respiratory diseases?

What are some examples?

A

diseases affecting the movement of air in and out of the lungs

Asthma and COPD

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2
Q

What are restrictive respiratory diseases?

What are some examples?

A

diseases affecting total lung capacity

e.g. lung cancer and pulmonary fibrosis

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3
Q

What is asthma caused by?

A

lung inflammation

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4
Q

Why can obstructive lung diseases such as asthma develop restrictive features in severe disease?

A

due to damage to lung architecture caused by prolonged lung inflammation

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5
Q

What is the main characteristic of asthma?

A

episodic periods of breathing difficulties

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6
Q

What is the asthma causing inflammation due to in those who have the condition?

A

generally type 1 hypersensitivity

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7
Q

What is an asthma attack?

A

manifestation of bronchoconstriction which is caused by inflammation in generating smooth muscle contraction

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8
Q

What is bronchoconstriction?

What does it cause?

A

Narrowing of the airways (reduced airway diameter)

causes increase in restriction to airflow

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9
Q

What two factors, caused by inflammation during type 1 hypersensitivity reactions, cause bronchoconstriction and consequently reduced airflow?

A
  1. smooth muscle contraction
  2. increased mucous production

both result in decreased airway diameter

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10
Q

what is resistance to airflow proportional to?

A

1/airway radius ^4

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11
Q

What are airflow needs determined by?

A

metabolic rate

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12
Q

How does the brain increase airflow in response to exercise?

A
  • increased rate and depth of breaths
  • release of adrenaline
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13
Q

How does the release of adrenaline cause bronchodilation?

A

adrenaline activates beta2 adrenoreceptors on airway smooth muscle

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14
Q

what is the formula to calculate airflow?

A

pressure gradient / resistance (determined by airway diameter)

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15
Q

what influences the pressure gradient between the chest cavity and the atmosphere?

A

diaphragm, internal and external intercostal muscles

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16
Q

How is airflow measured clinically?

A

spirometry

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17
Q

what is meant by ‘peak flow’ ?

A

maximum rate of exhalation

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18
Q

What is FEV1?

A

volume of air that can be forcibly exhaled in 1 sec

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19
Q

What is the process of resting inhalation?

(consider air pressure and pressure in thoracic cavity)

A

atmospheric pressure > pressure in chest

diaphragm moves down and out and external intercostal muscles contract

air moves in, lungs expand, chest volume increases

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20
Q

What body parts are involved in resting respiration?

A

diaphragm and external intercostal muscles

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21
Q

What is the process of resting exhalation?

(consider air pressure and pressure in thoracic cavity)

A

pressure in chest > atmospheric pressure

diaphragm moves in and up (relaxes), external intercostal muscles relax

elastic recoil repels air, air moves out

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22
Q

How is the process of exhalation when exercising different from exhalation when at rest?

A

(diaphragm and external intercostal muscles relax)
- internal intercostal muscles contract
- abdominal muscles contract
air is forced out

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23
Q

In order for asthma patients to get the same airflow as is normal (to compensate for increased resistance), what must change?

A

the pressure gradient between the atmosphere and the thorax has to increase

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24
Q

External intercostal muscles are located where?

What is their role?

A

On the outside of the ribs

Pull ribcage up and out

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25
Q

Internal intercostal muscles are located where?

What is their role?

A

inside the ribcage

pull the ribcage down and in

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26
Q

The increase in demand of the intercostal muscles to generate a greater pressure differential to overcome increased airflow resistance in asthma patients has what effect on the person?

A

breathing difficulties - they have to work harder to generate the airflow required by the body

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27
Q

What three sorts of inhalers can be used to treat asthma?

A
  1. relievers
  2. preventers
  3. combi-inhalers
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28
Q

What colour are reliever inhalers?

How do reliever inhalers work?

What is an example of a reliever?

A

blue

  • cause bronchodilation - relieve acute asthma symptoms
  • no anti-inflam action - no affect on disease progression

Salbutamol - long acting beta agonist

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29
Q

What colour are preventer inhalers?

How do preventer inhalers work?

What is an example of a preventer?

A

brown

  • anti-inflam action; limit disease progression
  • no affect on airway diameter therefore no acute relief of symptoms

mostly corticosteroids e.g. beclametasone, fluticasone

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30
Q

What do combi-inhalers contain?

How do combi-inhalers work?

What is an example of a combi-inhaler?

A

both preventer (steroid) and reliever (long acting beta agonist

provide long term bronchodilation and prophylaxis by limiting pulmonary inflam

Symbicort

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31
Q

What is the advantage to using an inhaler?

What type of delivery is this?

A
  • delivered to target site without need to be transported around body in blood
  • reduces risk of side effects

topical

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32
Q

Why might systemic symptoms due to inhaled steroids become apparent?

A

Due to high doses and increased absorption

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33
Q

What kind of inhaler would be needed to relieve the symptoms of an asthma attack?

Within how long will relief become noticeable?

How long can the relief last?

A

reliever

within minutes

from an hour to twelve depending on drug

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34
Q

Why shouldn’t long-acting beta agonists be taken without a steroid?

ie. why is it recommended to have both a reliever and a preventer or one combi-inhaler?

What could be the consequence of this?

A

long-acting beta agonists can mask the progression of asthma
- patient unaware of progression

serious asthma attack once bronchodilation cover insufficient

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35
Q

What does SABA stand for?

A

short acting beta agonist e.g. salbutamol

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36
Q

What does ICS stand for?

A

inhaled corticosteroids

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37
Q

What two treatment-related factors are thought to be contributory to asthma related deaths?

A
  1. underuse of ICS
  2. overuse of SABA

SABA monotherapy is now outdated

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38
Q

What does LABA stand for?

What is an example of this?

A

long acting beta agonist
(will be fast acting)

formoterol

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39
Q

What is the preferred treatment options for those with a new asthma diagnosis?

A

ICS plus LABA - formoterol

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40
Q

The first step in the treatment ladder for asthma will be what from November 2024?

A

ICS/Formoterol prn

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41
Q

How has the use of formoterol influenced daily dosage needs for ICS?

A

decreased

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42
Q

How do ICS reduce the severity and frequency of asthma attacks?

A
  • limits pulmonary inflam
  • reduces airway remodelling and disease progression
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43
Q

What are the most common active ingredients in combi-inhalers?

A

budesomide with formoterol

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44
Q

Why is it important to prescribe combi-inhalers by brand?

A

to ensure patients get same inhaler device from pharmacy, not all brands have same APIs

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45
Q

How many people in the UK have asthma?

A

5.4 million

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46
Q

How many households are affected by asthma?

A

1/5

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47
Q

How many people a day die from asthma?

A

3

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48
Q

What percent of asthma-related hospital admissions are estimated to be avoidable?

A

75%

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49
Q

What percent of asthma deaths are preventable?

A

up to 46%

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50
Q

For what three reasons are asthma statistics so bad?

A
  1. poor patient compliance
  2. incorrect inhaler use
  3. steroid resistance
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51
Q

How extensive is steroid resistance among asthma patients?

What can steroid resistance look like?

A

not very, only in small proportion of patients

ranges from reduced response to no response at all

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52
Q

WHO estimates that patient compliance for long-term treatments such as ICS for asthma is as low as what?

A

50%

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53
Q

Why is patient compliance with ICS use so poor?

A
  • wary of steroid-associated side effects
    e.g. those associated with abuse of anabolic steroids in sports (not the same)
    or serious effects of systemic use of CS
  • comparing to relief felt from relievers; believe preventer not helpful (passive drug effect)
  • do not believe in the risks associated with asthma
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54
Q

How can poor patient compliance be combated?

A

education about disease and the way in which ICS needed to manage it

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55
Q

In what two circumstances could a patient see the serious effects of systemic use of corticosteroids?

A
  1. high dose ICS
  2. short-term use of oral corticosteroids to combat acute exacerbations
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56
Q

What is the possible consequence of incorrect inhaler technique?

A

subtherapeutic dose, even if patient fully adherent

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57
Q

How do metered dose inhalers as preventers work?

A

deliver medicine in a puff under pressure

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58
Q

How do dry powder preventer inhalers work?

A

force of the patient’s inspiration is required to pull the drug away from its carrier

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59
Q

What is the simplest way of classifying asthma phenotypes?

A

Extrinsic / allergen-induced

Intrinsic / non-allergy induced

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60
Q

What are some common triggers for allergen induced asthma?

A
  • pollen
  • house dust mites
  • mould
  • ragweed
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61
Q

What are some common triggers for non-allergen induced asthma?

A
  • viral infection
  • cold, dry air
  • pollution
  • aspirin
  • cigarette smoke
  • exercise
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62
Q

Why is there a considerable overlap in the triggers between extrinsic and intrinsic asthma?

A

Hyperresponsiveness

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63
Q

What is the definition of a phenotype?

A

One or more symptoms caused by an interaction between genetics and the environment

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64
Q

What is the definition of an endotype?

A

A subclass of a disease based on differences in functional response or pathological mechanism

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65
Q

What is early phase bronchoconstriction during an asthma attack?
How long does it take to resolve?

What causes it?

A

Rapid bronchoconstriction manifested as difficulty breathing
- resolves after about 30 mins

Caused by exposure to an allergen that the asthmatic is sensitive to

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66
Q

What are the characteristics of a delayed phase bronchoconstriction in an asthma attack?

A
  • no re-exposure to allergen; continuation of previous allergen-induced inflam
  • often 6-8 hours after early phase
  • lasts longer than early phase
  • often occur at night
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67
Q

What is thought to be the cause of delayed phase bronchoconstriction?

A

Inflammatory mediators released by mast cells during early phase

  • causes chemotaxis of other inflam cells to lungs
    Including EOSINOPHILS
  • temporally associated with delayed phase bronchoconstriction
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68
Q

What is PEFR? What are its units?

What can it be used to indicate?

A

Peak Expiratory Flow Rate (litre/min)

Volume of air forcefully expelled from the lungs in one quick exhalation

Can indicate ventilation adequacy and airflow obstruction

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69
Q

What is the average value for PEFR?
( ie when not having an asthma attack)

A

400 litres/min

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70
Q

How does the value for PEFR change for patients during

  1. Early phase bronchoconstriction
  2. Delayed phase //
A
  1. Dramatic decrease until <25% of normal rate, short term then dramatic increase back to normal
  2. Fairly dramatic decrease until around 25% (+) of normal rate, prolonged attack with PEFR increasing slowly over a few hours back to normal
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71
Q

What is FEV1?

What can it be used for?

A

Forced Expiratory Volume in 1 sec

Can be used to categorise the severity of obstructive lung diseases

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72
Q

Hyperresponsiveness is a key characteristic of asthma. What does it mean?

A

Responses by asthmatic patients to environmental stimuli are exaggerated (to level of attack)

  • more severe
  • occur in response to smaller amounts of stimuli
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73
Q

Allergic asthma is nearly always linked with..?

There is quite a strong link between asthma and …?

A

Other allergies e.g. hay fever

Childhood eczema

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74
Q

What is the first half of the process of sensitisation?

A
  1. Dendritic cells in lung recognise foreign allergen
  2. Dendritic cells present allergen to undifferentiated T cells (Th0) @ lymph nodes
  3. T helper cells differentiate into Th2
  4. Th2 activate B cells to generate IgE that binds the specific allergen
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75
Q

What part of the sensitisation process differs between asthmatic and non-asthmatic patients?

A

When B cells have generated specific IgE, in non-asthmatics
- regulatory process preventing inappropriate inflam processes being mounted against benign proteins

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76
Q

What is the second half of the process of sensitisation?

A
  1. IgEs bind to surface of mast cells via receptors
  2. Allergen binds to IgE upon re-exposure ; cross-linking of receptors
  3. Degranulation, activation triggered
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77
Q

What kinds of receptors does the Fc region of IgE bind to on the surface of mast cells?

A

High affinity Fc epsilon RI

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78
Q

Apart from mast cells, what other cells do IgE bind to?
Via what receptors?

A

Eosinophils via low affinity Fc epsilon RII

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79
Q

What is the primary event in triggering an allergic asthma attack?

A

Activation and Degranulation of mast cells by allergen-induced cross-linking IgE receptors on the surface of mast cells

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80
Q

What triggers the arachidonic acid cascade?

What is the result of this?

(See cascade in U2 L2 slide 7)

A

Mast cell activation - activates membrane-bound phospholipase A2

Results in production of other inflam mediators

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81
Q

What is the role of leukotrienes and prostaglandins as inflam mediators?

A
  • promote and drive inflam response or
  • terminate or limit it
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82
Q

What leukotriene receptor is important in bronchoconstriction and recruitment of eosinophils?

A

CysLT1 receptor

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83
Q

What is one example of a drug target for asthma?

A

CysLT1 leukotriene receptor

(Used clinically in asthma treatment)

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84
Q

How can glucocorticoids stop the activation of the arachidonic acid cascade?

A

By preventing the activation of membrane-bound phospholipase A2

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85
Q

What inflammatory responses is histamine responsible for? (Not exclusively)

A
  • vasodilation
  • increased vascular permeability
  • leukocyte recruitment
  • increased mucous production by goblet cells
  • bronchoconstriction
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86
Q

What inflammatory responses do leukotrienes play a part in? E.g. LTC4, LTB4

A
  • vasodilation
  • increased vascular permeability
  • leukocyte recruitment
  • increased mucous production by goblet cells
  • bronchoconstriction
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87
Q

What inflammatory responses is IL-8 responsible for? (Not exclusively)

A
  • increased vascular permeability
  • leukocyte recruitment
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88
Q

What inflam mediators are directly responsible for bronchoconstriction?

A

Histamine

PGD2

LTC4

Tryptase

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89
Q

How are eosinophils drawn into the lungs during delayed bronchoconstriction?

A

From circulation via expression of proteins on surface of pulmonary blood vessel endothelium

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90
Q

How do eosinophils contribute to delayed (late phase) bronchoconstriction?

What other athsmatic characteristic is this thought to contribute towards?

A

Eosinophils release inflam mediators which can damage the epithelial layer - reduces integrity of protective barrier

Hyper-responsiveness

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91
Q

What are the consequences of reduced epithelial layer integrity in the lungs?

(Indirectly caused by eosinophils)

A
  • Oedema from pulmonary vessels due to increased leakiness therefore
  • increased bronchiole wall thickness reducing airway diameter and therefore
  • delayed bronchoconstriction
92
Q

What is the role of both sympathetic and parasympathetic nerves in delayed bronchoconstriction?

A

Both activated - increase in inflam mediator and acetylcholine release from sensory nerve fibres therefore

  • increased smooth muscle contraction
  • increased mucous secretion
93
Q

What receptors, activated by the parasympathetic system, contribute towards bronchoconstriction?

A

ACh, M3

94
Q

How do eosinophils (as well as other inflam cells) contribute towards hypersensitivity?

A
  • release of cytotoxic mediators
  • causes damage to epithelium
  • causes hyper-reactivity
95
Q

How do eosinophils contribute towards increased severity and frequency of asthma attacks?

A
  • release of remodelling mediators
  • causes fibrosis, hypertrophy of bronchial wall
  • increased freq and severity of attacks
96
Q

What are the main effects of inflammatory-driven changes to the structure of the lungs and airways?

A
  • airway wall is thicker, reduced diameter, increased flow resistance
  • lungs less stretchy therefore reduced capacity & reduced elastic rebound when exhaling
97
Q

How does chronic inflammation affect the process of mucus production as well as the mucus produced?

A
  1. increased # of goblet cells
  2. more viscous, less mobile mucous - increased airway occlusion
98
Q

What is pulmonary angiogenesis?

What causes it?

A

creation of new blood vessels in the lungs

chronic inflammation

99
Q

What are the consequences of pulmonary angiogenesis?

A
  • increased oedema in airway wall
  • increased SA for eosinophils to access lungs
100
Q

How does chronic inflammation affect smooth muscle cells?

What is the effect of this?

A

hypertrophy (increase in cell size) and hyperplasia (increase in cell number)

reduced airway diameter, increased strength of bronchoconstrictor responses

101
Q

What repair process that functions alongside inflammation has a negative effect on lung capacity?

Why?

A

activation of fibroblasts - increase in fibrosis

counter-productive as lungs need to be stretchy;
lungs will have
- reduced capacity to expand
- impaired elastic rebound

102
Q

What is the overall consequence of changes in lung structure?

What is the main goal of therapy for asthmatics?

A

progressive worsening of asthma symptoms in response to repeated attacks

to break the cycle of inflammation to prevent (at least limit) airway remodelling

103
Q

How can inflammation of the lungs and airways become chronic?

A

repeated cycles of allergen exposure that do now allow sufficient time for resolution of the inflammatory response

104
Q

What is the most common reliever medication used in asthma treatment?

Into what groups are they divided?

A

beta2-adrenoreceptor agonists

Divided into short and long-acting AKA SABA and LABA

Most common SABA is Salbutamol

105
Q

Why must LABAs never be prescribed without an ICS?

A

LABAs mask the symptoms of asthma; allows condition to worsen without being detected therefore increasing rates of morbidity/mortality

106
Q

What are Xanthines?

Are they used for asthma treatment?

A

Class of drug that includes caffeine

Not caffeine but other two members of this drug class are

107
Q

Why does the parasympathetic system have more of an effect on airway muscle tone?

A

Has direct innervation of bronchial smooth muscle via vagus nerve (unlike sympathetic)

(Sympathetic efferent nerves may control vasomotor tone only)

108
Q

What is the effect of the activation of Muscarinic M3 receptors on smooth muscle tone in the airways?

A
  • bronchoconstriction
  • increased mucous production
  • vasodilation of bronchial vessels
109
Q

Where are beta-2 adrenoreceptors located?

What is the effect of their activation?

A

Expressed abundantly on airway smooth muscle

Stimulation e.g. by adrenaline (mediator) causes bronchodilation

110
Q

What is the effect of M3 receptor antagonists?

A

Bronchodilation ie. Same as beta 2 adrenoreceptor agonists

111
Q

In what sorts of variants are muscarinic antagonists available?

When would muscarinic antagonists be used clinically? Why?

A

Short and long-acting ie SAMA, LAMA

Used more in COPD treatment because
Lungs of COPD patients have increased cholinergic tone than those of asthma patients (ACh acts on muscarinic receptors) therefore more effective

112
Q

What is the effect of activation of the CysLT1 receptor on airway smooth muscle?

What bocks this receptor?

How do leukotrienes usually act on this receptor?

A

Bronchoconstriction

Leukotriene receptor antagonists

High affinity agonists - contribute to inflammation-induced bronchoconstriction

113
Q

What can be used as drug targets for asthma?

A
  1. Beta2 adrenoreceptors - agonists
  2. Muscarinic M3 receptors - antagonists
  3. CysLT1 leukotriene receptors - antagonists
114
Q

Are there any histamine receptors that can be used as drug targets in asthma treatment?

A

No;
H1 - antagonists have no effect on bronchoconstriction
H4 - antagonists did not make it past clinical trials (no beneficial effects)

115
Q

What is the general mechanism by which relievers generate bronchodilation?

A

Reduce cytosolic levels of calcium in airway smooth muscle cells
- calcium needed for contraction via actin myosin network filaments

116
Q

Xanthines are known to be able to block adenosine receptors. What is the effect of this in
- asthmatic patients
- non-asthmatics

A

Antagonism of adenosine receptors causes

Asthmatics - bronchodilation
Non-asthmatics - bronchoconstriction

117
Q

How does activation of Beta2 adrenoreceptors lead to the activation of protein kinase A, PKA?

A
  1. agonist activates B2 adrenoreceptor on plasma membrane
  2. Activates G protein, Gs
  3. activates membrane-bound enzyme adenyl cyclase
  4. generation of cAMP from ATP
  5. cAMP activates PKA
118
Q

What enzyme regulates levels of intracellular cAMP?

A

phosphodiesterase (PDE)

119
Q

What is one mechanism for which xanthines e.g. theophylline generate bronchodilation?

A

block PDE, increasing levels of cAMP in the cell

120
Q

What is the approximate duration of action for SABAs e.g. Salbutamol?

A

4-6 hours

121
Q

Why does the hydrophilic nature of Salbutamol contribute towards it being short-acting?

A
  1. limited tissue retention - does not form depot in airway tissues therefore not in close proximity to receptor for extended period
  2. rapid clearance - relatively quick elimination from body
122
Q

What is the approximate duration of action for LABAs e.g. Salmeterol?

A

12 hours

123
Q

Why does the lipophilic nature of LABAs allow them to be relatively long acting?

A

they can get into the plasma membrane as a depot and leech out slowly

124
Q

LABAs must not be prescribed without what?

Why?

A

Corticosteroids e.g. ICS

because long-lasting bronchodilating action can mask worsening asthma symptoms

125
Q

Why are side effects of beta2-adrenoreceptor agonists limited?

A

topical administration to the lung

126
Q

What side effects may occur due to overuse or oral dosing of beta2-adrenoreceptor agonists?

A
  • shakiness
  • tachycardia
  • headaches
  • muscle cramps
127
Q

For how long will cAMP continue to be generated from ATP by the enzyme adenyl cyclase?

A

for as long as the beta2 adrenoreceptor is occupied

128
Q

Through what two mechanisms does the activation of protein kinase A, PKA, reduce free cytosolic calcium levels?

A
  1. phosphorylation of K+ channels
  2. reduction of phosphoinositol hydrolysis
129
Q

What is the effect of having reduced levels of free cytosolic calcium?

A

reduced muscle contraction

130
Q

How does the phosphorylation of K+ channels by PKA lead to a reduction in free cytosolic Ca2+?

A
  • phosphorylated K+ channels lead to increase in K+ efflux
  • membrane becomes hyperpolarised (-)
  • hyperpolarisation inhibits voltage sensitive Ca2+ channels
  • reduced Ca2+ influx into cytosol
131
Q

How does the reduction of phosphoinositol hydrolysis by PKA lead to a reduction in free cytosolic Ca2+?

A
  • reduced phosphoinositol hydrolysis means reduced generation if inositol triphosphate, IP3
  • reduced release of Ca2+ from stores into cytosol
132
Q

What is the role of inositol triphosphate, IP3 in muscle cells?

A

cause the release of Ca2+ from stores into the cytosol

133
Q

What is the role of myosin light chain kinase (MLCK) ?

A

to phosphorylate part of the myosin filament, allowing for binding to actin and formation of cross bridge therefore muscle contraction

134
Q

How does the inhibition of MLCK reduce the size of muscle contraction?

A
  • reduced phosphorylation of myosin filament
  • reduced # of cross-bridge formation
  • reduced size of muscle contraction
135
Q

How does increasing the activity of the Na/K pump cause hyperpolarisation?

A

2 Na out for every 3 K in

  • increased conc gradient of K+ compared to extracellular
  • increased polarisation (-) of smooth muscle membrane
  • eventual increased efflux of K+
  • resting membrane potential becomes more negative than before
136
Q

What is the effect of phosphodiesterase inhibition?

A
  • higher cellular levels of cAMP
  • increased activation of PKA
  • increased inhibition of smooth muscle contraction
137
Q

Phosphodiesterase inhibitors are not yet used to treat asthma. What are they used for?

How do they work?

A

erectile dysfunction e.g. Viagra

inhibits phosphodiesterase, driving muscle relaxation

138
Q

What is the API in viagra?

A

sildenafil

139
Q

Why is there some selectivity of action for PDE inhibitors?

A

there are many isoforms of PDE

140
Q

As well as action at B2 adrenoreceptors, beta 2 agonists have another positive effect for asthmatic patients - what is it?

How does it work?

A

increase mucous clearance from the lung

increasing the rate at which epithelial cilia beat

141
Q

What are the two types of xanthine that can be used clinically to treat asthma?

Which is more soluble?

A

Theophylline and aminophylline

aminophylline

142
Q

why are xanthines inherenly difficult to dissolve?

A

hydrophobic nature

143
Q

Why is the clinical use of theophylline limited?

A
  1. therapeutic index is low
  2. is a substrate for CyP450 therefore subject to many interactions
144
Q

What is meant by therapeutic index?

A

difference between an effective dose and a toxic dose

145
Q

What is the effect of smoking on cytochrome P450?

What does this mean for smokers being treated with theophylline?

A

it is upregulated

smokers require a higher dose than non-smokers

146
Q

What is the role of Cytochrome P450 enzymes?

A

metabolise about 90% drugs

147
Q

What is the possible consequence of a known smoker being treated with theophylline giving up smoking?

A

theophylline overdose as CYP450 levels would return back to normal levels - therefore less drug metabolism

148
Q

What are the possible adverse effects of theophylline?

A
  • GI symptoms e.g. nausea, stomach pain
  • neuronal effects e.g. sleeplessness, restlessness
  • cardiovascular effects e.g. tachycardia and cardiac dysrhythmias
149
Q

What is the clinical use of aminophylline as asthma treatment?

A

in asthma emergencies where it is delivered as a slow IV infusion

150
Q

PDE inhibition is thought to be unimportant in therapeutic brochodilation but what ares the other areas in which it may be important?

A
  • limiting inflammation
  • reducing corticosteroid resistance
151
Q

What is a plausible MOA for xanthines in asthmatic treatment?

A

adenosine receptor activation leads to bronchoconstriction

xanthines are adenosine receptor antagonists

152
Q

What are SAMAs and LAMAs?

A

short-acting muscarinic antagonists and long-acting muscarinic antagonists

153
Q

What is an example of a SAMA?

Approx how long is their duration of action?

A

Ipratropium

3-5 hours

154
Q

What is an example of a LAMA?

Approx how long is its duration of action?

A

Tiotropium

24 hours +

155
Q

Why can SAMAs and LAMAs be delivered via inhalation?

A
  • not selective for different subtypes of muscarinic receptor
  • chemical comp limits absorption into pulmonary circulation; reduced chance of adverse effects
156
Q

What are the more common adverse effects of muscarinic antagonists associated with?

What are some examples?

A

systemic blockade of muscarinic receptors e.g.

  • headaches
  • cough
  • dry mouth
157
Q

What is the general MOA of SAMAs and LAMAs in bringing about any sort of bronchodilation?

A

block M3 receptor subtype on bronchial smooth muscle, preventing ACh from binding and causing bronchoconstriction

158
Q

What neurotransmitter usually acts on M3 receptors to cause bronchoconstriction?

A

ACh from parasymp nerves

159
Q

Why are SAMAs and LAMAs more commonly used in the treatment of COPD than asthma?

A

The more parasympathetic tone there is, the more effective the SAMA/LAMA will be

COPD patients tend to have more parasympathetic tone than asthmatic patients
- SAMA and LAMA more effective for COPD

160
Q

Why is the effect of greater bronchodilation limited when increasing doses of muscarinic antagonists?

A
  • inhaled MAs have access to M2 receptors because no selectivity for muscarinic receptor subtypes
  • increasing MA dose increases antagonism of M2 receptor
  • increased release of ACh therefore increased competition with MA for M3 binding
161
Q

What is the role of the presynaptic M2 receptor?

A

limits release of ACh into synapse
ie. reduces release at moderate, high frequency of stimulation

(ACh binds to M3 causing bronchoconstriction)

162
Q

For what reasons is asthma control an important clinical goal?

A
  1. improves quality of life
  2. reduces risk of early death
  3. reduces costs associated with morbidity
163
Q

What are the main goals of preventer medication?

A
  1. limit pulmonary inflam
  2. reduce remodelling
  3. reduce disease progression
  4. reduce severity and freq of attacks
164
Q

Why is it important for asthma patients to receive a flu jab each year?

A

can control asthma exacerbations where even mild asthmatics can be hospitalised due to resp infection

165
Q

Unless patients are on high doses of ICS, what is the worst symptom patients are likely to experience?

What is this due to?

How can it be avoided?

A

sore throat due to opportunistic Candida

localised immune suppression

rinsing out the mouth after taking the ICS

166
Q

Where is the receptor for glucocorticoids located?

How do glucocorticoids reach such receptors?

A

intracellular

they are hydrophobic so can diffuse into cell via lipid bilayer of cell membrane

167
Q

What happens to glucocorticoids following intracellular receptor binding?

A
  1. receptor becomes activated
  2. receptors dimerise
  3. receptors translocate to nucleus
  4. dimerised receptors bind to glucocorticoid response elements in DNA and influence gene transcription related to inflam
168
Q

Through what two mechanisms is transcription influenced by dimerised glucocorticoid receptors?

A
  1. increase transcription rates of anti-inflam gene products e.g. IL-10 by binding to glucocorticoid-response elements in the promoter region of steroid-sensitive genes
  2. reduce transcription of pro-inflam gene products e.g. cyclo-oxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) via interaction with negative glucocorticoid-response elements
169
Q

Why do ICS take several days to become effective?

A
  • takes time to transcribe, translate and make anti-inflam proteins
  • pro-inflam prpteins must be removed and not replaced before apparent effect
170
Q

What is one feature that can indicate whether a patient is getting benefit from ICS?

Why is this?

A

reduction in night-time asthma attacks

correct use of ICS should reduce/abolish late phase bronchoconstriction (usual cause)

171
Q

How does the effective use of ICS reduce the severity and freq of attacks?

A
  • significant decrease in # of inflam cells in lungs
  • inflam response needs to reach threshold to generate bronchoconstriction sufficiently for patient to notice
172
Q

What effects can ICS have on structural cells?

What are the consequences of these for the patient?

A

(nb epithelial layer actively contributes towards inflam and imms sys)

  1. reduced release of humoral mediators of inflam from epithelial cells
  2. reduced permeability of pulmonary endothelium; reduced oedema in bronchiole walls
  3. increased expression of beta2-adrrenoreceptors on smooth muscle cells - more responsive to relievers
  4. reduced mucous secretion from goblet cells
173
Q

What two factors affect the effectiveness of glucocorticoid action?

A
  1. receptor binding affinity
  2. lipophilicity
174
Q

How does lipophilicity affect glucocorticoid action?

A

high lipophilicity means a corticosteroid is better able to access the intracellular receptor meaning less drug is required

174
Q

How does receptor binding affinity affect glucocorticoid action?

A

the higher the affinity, the smaller the amount of drug is needed to activate the receptor

175
Q

Beclomethasone is a prototypical CS, fluticasone propionate is a new generation CS - why is a much lower dose of FP needed compared to Beclomethasone?

A

FP has
- much higher receptor affinity
- similar lipophilicity

176
Q

How is moderate dose Beclomethasone equivalent to high dose FP?

A

in terms of ICS molecules;
moderate dose BP - 800
max dose FP - 1000

equivalent because FP more potent

177
Q

What factors, other than receptor affinity and lipophilicity, influence dose received from an inhaler?

A

inhaler technique

178
Q

in terms of beclomestasone, how can poor inhaler technique be counteracted?

A

Extrafine beclometasone; more potent

smaller particles have improved lung deposition, can reach deeper into lung, less likely to be deposited in the mouth

less reliant on good inhaler technique to receive therapeutic dose

179
Q

Who are steroid cards given to?

A

those who are likely to have sufficient systemic exposure to CS such that they and other HC workers need to be aware of it

generally those on:
- long-term, high dose ICS
- moderate doses plus drugs that inhibit CYP450 e.g. HIV protease inhibitors
- oral CS treatment lasting more than 3 wks

180
Q

Why are steroid cards given?

A

There is a risk of rebound ie. asthma exacerbations if CS dosing is stopped suddenly

181
Q

How are corticosteroids recommended to be stopped?

A

should be tapered off gradually as part of step-down system

182
Q

What does the wording of a steroid warning card indicate?

A
  • patient on sufficient steroid dosage
  • hypothalamic-pituitary-adrenal axis may be affected
183
Q

What are LTRAs?

A

leukotriene receptor antagonists (preventers)

184
Q

What receptor do LTRAs block?

A

cysteinyl leukotriene receptor 1

185
Q

What is the role of the Cysteinyl leukotriene receptor 1 in asthma?

A
  1. mediates bronchial smooth muscle contraction in response to D4 and C4
  2. implicated in inflam-induced increased vascular permeability that leads to oedemea and eosinophil chemotaxis

both of these contribute to delayed-phase bronchoconstriction

186
Q

How effective are LTRAs in comparison to ICS in terms of asthma treatment?

A
  • effective at reducing some elements of inflam response
  • do not effect freq and severity of attacks as well as ICS
187
Q

Why might LTRAs be less effective than ICS at reducing attack severity and freq?

A

they have a relatively limited spectrum of anti-inflam activity compared to broad spec effects mediated by ICS

188
Q

LTRAs are particularly helpful in what sorts of patients?

A

those with atopic tendency ie. allergy driven asthma ;

in particular those with allergic rhinitis

189
Q

What are two examples of LTRAs?

A
  • Montelukast
  • Zafirkulast
190
Q

What are the most common side effects associated with LTRAs?

A
  • headaches
  • upper-resp infection
  • abdominal pain
191
Q

In children treated with LTRAs as an alternative to ICS, what is the most common adverse effect?

A

hyperactivity

192
Q

How long are patients trialled on LTRAs before stopping if ineffective?

A

3 months

193
Q

What sorts of neuropsychiatric reactions can patients taking LTRAs experience?

A
  • sleep disturbances
  • agitation
  • aggressive behaviour
  • depression
194
Q

Why is it important to counsel patients and their carers taking LTRAs on possible neuropsychiatric effects?

A
  • such rxns not well known among HC professionals, patients, caregivers
  • can speak to a doctor early on, potentially discontinue use
195
Q

When are chromones used clinically in the treatment of asthma?

Why are they used?

A

mostly as alternative to CS in children

recent review identified that the rate of growth in children using CS is reduced

196
Q

What are the two chromones?

A

cromoglycate and nedocromil

197
Q

What is the mechanism of action for how chromones mediate their anti-inflam effect?

A

inhibition of mast cell activation;

reduced release of inflam mediators

198
Q

What could be the reason for chromones being less effective than CS?

A

chromones have no effect on the pulmonary epithelium which also has a role in triggering inflammatory responses, CS do

199
Q

Why might antibodies be used to treat asthma?

A

For severe cases which are thought to be CS resistant

200
Q

What is omalizumab?

What is its’ mechanism of action?

A

antibody treatment for severe asthma

targets IgE to prevent binding to Fc receptors on mast cells
therefore preventing cross-linking and reducing degranulation

201
Q

Why is IL-5 thought to be a good target for antibody treatments of asthma?

Why is this significant?

A

associated with eosinophil recruitment, activation

reduction of eosinophil recruitment is important therapeutic goal to limit airway remodelling and disease progression

202
Q

What are the problems associated with antibody treatments?

A
  1. high costs
  2. must be given via injection
  3. can trigger immune responses e.g. anaphylaxis
203
Q

What is an example of an antibody treatment that targets IL-5?

A

Mepolizumab

204
Q

When might patients with mild asthma experience severe symptoms?

A

respiratory infection e.g. flu

205
Q

What causes severe asthma symptoms when experiencing a respiratory infection?

A

additive effect of different inflam response as well as that from asthma causes severe symptoms

206
Q

Why do asthma patients experiencing respiratory infections often require an oral course of steroids to resolve inflammation?

A

patients are less sensitive to CS treatment

207
Q

What characterises inflammation caused by respiratory viral or bacterial infections?

A

recruitment of neutrophils to the lungs ;

also association between neutrophils and steroid-resistant asthma

208
Q

Which interleukins are considered anti-inflammatory?

A

IL-1, IL-10, IL-12

209
Q

What are four local side effects of high dose ICS?

A
  1. pneumonia (COPD)
  2. dysphonia (hoarseness)
  3. oropharyngeal Candidia
  4. cough
210
Q

What are some systemic side effects thought to be caused by high dose ICS?

A
  1. adrenal suppression
  2. growth suppression
  3. bruising
  4. osteoporosis
  5. cataracts
211
Q

What causes the local side effects of ICS?

A

deposition of ICS in oropharynx

212
Q

How does the occurrence of dysphonia differ depending on device used?

A

as common as 50% prevalence in patients using MDI

thought to be reduced in those using dry powder inhalers

213
Q

What is thought to be the cause of dysphonia?

is it reversible?

A

myopathy of laryngeal muscles

when treatment is withdrawn

214
Q

How can the risk of oropharyngeal Candida be reduced?

A

use of large volume spacer devices that reduce the dose of ICS that deposits on the oropharynx

215
Q

Why are systemic effects of ICS more common in those using MDI?

A
  • 80-90% of dose deposits in oropharynx, is swallowed
  • dose absorbed from GI tract, enters systemic circulation
216
Q

How can systemic effects be reduced in those using dry powder inhalers?

A

mouth washing and disposing fluid

217
Q

What should patients using a daily dose of more than 800 micrograms of ICS be doing to reduce systemic absorption?

A
  1. using a spacer
  2. mouth washing
218
Q

How do CS cause hypothalamic-pituitary-adrenal axis suppression?

A

by reducing corticotrophin (ACTH) production which reduces cortisol secretion by the adrenal gland

219
Q

How do CS lead to a reduction in bone mass?

A
  1. direct effects on bone formation and resorption
  2. indirectly by suppression of HPA and pituitary-gonadal axis
  3. effects on intestinal and renal Ca2+ (re)absorption
220
Q

How do oral and topical corticosteroids effect connective tissue?

A
  1. thinning of skin
  2. easy bruising
  3. telangiectasia - widened venules cause thread-like skin patterns
221
Q

Why do corticosteroids effect connective tissue?

A

probabaly due to loss of extracellular ground substance within the dermis, due to inhibitory effect on dermal fibroblasts

222
Q

How might asthma effect growth in young patients?

How is this counterbalanced?

A
  • delayed onset of puberty
  • decceleration of growth velocity; more pronounced with severe disease

asthmatic children appear to grow for longer

223
Q

Are corticosteroids safe to use when pregnant?

A

no evidence for adverse effects of ICS on pregnancy, delivery or foetus

224
Q
A

PH2113 Disease & Drugs 1 (5 decks)

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