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Flashcards in Pharmacology Deck (162):
1

what is the dominant neuronal control of bronchial smooth muscle tone?

parasympathetic cholinergic innervation

2

what nerve carries the preganglionic fibres that will eventually supply the bronchial smooth muscle?

vagus nerve

3

where are the parasympathetic ganglia that will go onto supply the bronchial smooth muscle?

embedded in the walls of bronchi and bronchioles

4

post ganglionic parasympathetic fibres innervate what within the airways?

smooth muscle
submucosal glands

5

what 2 things does stimulation of parasympathetic division cause within the airways?
(and what is the combined result?)

1. bronchial smooth muscle contraction
2. increased mucous secretion
(collectively increases airway resistance)

6

what types of receptors are the parasympathetic division acting upon in the airways?

M3 muscarinic ACh receptors

7

how does the sympathetic system achieve its effects on the airways if its has no real innervation of bronchial smooth muscle?

causes release of adrenaline into circulation which acts on B2-adrenoceptors on bronchial smooth muscle

8

what 3 things does the sympathetic division cause within the airways?
(and what is the combined result?)

bronchial smooth muscle relaxation
decreased mucus secretion
increased mucociliary clearance
(collectively reduces airway resistance)

9

what type of receptors is the adrenaline (stimulated by the sympathetic system) acting on in the airways?

B2-adenoceptors

10

what is mucociliary clearance mediated by?

ciliated epithelium layer of the airways which remove particles and bacteria from airways by propelling upwards

11

what is asthma?

a recurrent and reversible obstruction to the airflow (caused by bronchoconstriction due to bronchiole spasms) in response to certain stimuli

12

what are 4 main causes (stimuli) of an asthma attack?

allergens (in atopic individuals)
exercise (cold, dry air)
respiratory infections
smoke, dust, environmental pollutants

13

what is the name for the acute severe type of asthma which is a medical emergency and can be fatal?

status asthmaticus

14

what do intermittent asthma attacks cause?

cough
wheeze
difficulty in breathing

15

what is chronic asthma?

long standing inflammation causing pathological changes to the bronchioles

16

what 4 pathological changes can be caused by chronic asthma?

1. increased mass of smooth muscle (hyperplasia + hypertrophy)
2. accumulation of intestitial fluid
3. increased secretion of mucus
4. epithelial damage

17

why in chronic asthma is there the accumulation of interstitial fluid?

due to increased secretions

18

what is exposed in epithelial damage and what does this result in?

epithelial damage exposes sensory nerve endings and cause them to become more sensitive- hyper-responsiveness

19

what causes a decreased FEV1 and PEFR in asthma?

increased airway resistance
due to inflammation and bronchoconstriction which causes airway narrowing

20

what are the sensory nerve endings that can be exposed if there is epithelial damage in asthma?

C-fibres
a class of irritant receptors

21

what type of substance works on C-fibre endings?
(so will have an increased effect if there is epithelial damage- hyperesponsiveness)

bronchoconstrictors (spasmogens)

22

what 2 phases make up an asthms attack usually?

immediate phase- bronchospasm
delayed phase- inflammatory reaction

23

what is the delayed inflammatory response triggered by?

acute bronchospasm

24

what type of Th cells are part of the antibody-mediate response involving IgE in response to an allergen? (atopic)

Strong Th2 response

25

what type of Th cells are part of the cell-mediated immune response involving IgG and macrophages in response to an allergen? (non-atopic)

low-level Th1 response

26

what do interleukins signal between?

white blood cells

27

what type of environment fo Th2 cells produce?

cytokine environment

28

what is the induction phase in the development of allergic asthma?

antigen presentation
cloncal expansion and maturation

29

what cell type differentiates and activates in response to IL 5 released from Th2 cells?

eosinophils

30

what type of cells express IgE receptors in response to IL 4 and IL 13 released from Th2 cells?

mast cells (in airway tissues)

31

when the specific allergen becomes present and links to the antibodies covering the mast cell, what is stimulated?

calcium entry into mast cells causing the release of calcium from intracellular stores

32

when calcium enters the mast cells and calcium is released from intracellular stores what 2 things occur?

1. release of substances that cause airway smooth muscle contraction (spasmogens)
2. release of substances that attract cells that cause inflammation

33

what substances released from the mast cell are spasmogens?

histamine
leukotriens (LTC4 LTD4)

34

what substances released from the mast cells are chemotaxins/ cytokines?

LTB4, PAF, PGD2
leukotriene, platelet activating factor, prostaglandin

35

what type of leukocytes do chemotaxins/cytokines released from mast cells (in response to an allergen) attract?

Th2 cells
monocytes
eosinophils

36

which group of substances released from a mast cell is responsible for the immediate phase response of an asthma attack?

spasmogens

37

what group of substances released from a mast cell is responsible for the delayed phase response of an asthma attack?

chemotaxins and cytokines

38

what does the inflamamtion caused by the inflammatory cells induced by chemotaxins and cytokines released by mast cells cause in the airways?

airway inflammation
epithelial damage
airway hyper-reactivity
bronchospasm, wheezing, cough

39

what are the 2 types of drugs used in the treatment of asthma?

relievers
controllers/preventors

40

what are the function of relievers?

bronchodilators

41

what are the function of controllers/preventors?

anti-inflammation

42

what is the mechanism of bronchodilators?

B2-adrenoceptor agonists

43

once a B2-adrenoceptor has been stimulated in the airway smooth muscle, what is the result of the chain of pathways?

phosphorylation of MLCK
(myosin light chain kinase)
reduction in intracellular Ca2+

[MLCK cause contraction of smooth muscle, phosphorylation of MLCK inhibits this process and causes relaxation]

44

what happens to the G-coupled protein receptors in the case of persistent activation of B2-adrenoceptors?

receptor desensitisation and endocytosis
(loss of function)

45

what kinases are involved in the desensitisation process of B2-adrenoceptors?

PKA (protein kinase A)
GRK (G protein receptor kinase)- specifically B-adrenoceptor kinases

46

what molecule causes linking of the desensitized B-adrenoceptor to the endocytotic machinery?

B-arrestin

47

what happens to the B-adrenoceptor once inside the cell?

recycles in endosomes or degraded in lysosomes

48

what is salbutamol?

short acting B2-adrenoceptor agonist (SABA)

49

what type of asthma drug are SABAs (eg salbutamol)? (reliever or preventor)

reliever
(bronchodilator)

50

how is a SABA (eg salbutamol) generally administered?
and why?

inhalation
to lessen systemic effects

51

when are SABAs administered oral or IV?

emergency

52

when is the maximal effect of SABAs (eg salbutamol?

within 30 mins

53

by stimulation of the sympathetic system what 3 effects do SABAs (eg salbutamol) have?

dilation of airway smooth muscle
increased mucus clearance
decreased mediator release from mast cells

54

what are the adverse effects of SABAs eg salbutamol? (rare when administered by inhalation)
+ why do they occur?

fine tremor
tachycardia
due to unanted systemic absorption

55

what salmeterol?

long acting B2-adrenoceptor agonist (LABA)

56

why are LABAs (eg salmeterol) not recommened for acute relief of bronchospasm despite technically being relievers (bronchodilators)?

relatively slow to act

57

when are especially LABAs useful?

nocturnal asthma

58

can SABAs be used in monotherapy?

yes

59

can LABAs be used in monotherapy?

no

60

why should you use selective B2-adrenoceptor agonists and not general adrenoceptor agonists for asthma treatment?

to reduce the potentially harmful stimulation of cardiac B1-adrenoceptors

61

why should propanolol not be used in asthmatic patients?

propanolol is a non-selective b-adrenoceptor antagonist so will cause the constriction of airway smooth muscle

62

what type of asthma drugs are cysLT1 receptor antagonists?
(cysteinyl leukotriene receptor antagonists)

relievers
(bronchodilators)

63

how do cysLT1 receptor antagonists work in patients with asthma?

block cysLTs (LTC4, LTD4, LTE4) derived from mast cells and so cause smooth muscle relaxation, decreased mucus secretion and decreased oedema

64

what is montelukast or zafirlukast?

a cysLT1 receptor antagonist

65

what type of asthma drugs are cysLT1 receptor antagonists?
(cysteinyl leukotriene receptor antagonists)

relievers
(bronchodilators)
[but not recommeneded for relief of acute severe asthma]

66

how are cysLT1 receptor antagonists administered?

oral route

67

what are theophylline and aminophylline?

xanthines

68

what type of asthma drugs are xanthines?

relievers AND controllors/preventors

69

how are xanthines prepared and administered?

sustained release preparations by oral route

70

how do xanthines work?

relax bronchial smooth muscle
inhibit mediator release from mast cells
increase mucus clearance

71

what are the adverse effects of xanthines?

nausea
vomiting
abdominal discomfort
headache
(also numerous drug interactions)

72

where are steroid hormones synthesised in the body?

adrenal cortex

73

what 2 types of steroid hormone are synthesised and released on demand from the adrenal cortex?

glucocorticoids
mineralcorticoids

74

what is the main glucocorticoid in the body?

cortisol (hydrocortisone)

75

what are the 2 main functions of glucocorticoids that are important in immune regulation?

decreases inflammatory responses
decreases immunological responses

76

why are exogenous glucocorticoids not recommened for systemic use? (unless its an emergency)

multiple effects on metabolism

77

what is the main mineralcorticoid in the body?

aldosterone

78

what is the main function of mineralcorticoids?

regulate the retention of salt (and therefore water) by the kidney

79

what type of drug is beclometasone?

a corticosteroid

80

what type of asthma drug are corticosteroids?

preventers
(anti-inflammatory NOT bronchodilation)

81

what do glucocorticoids signal via within cells?

nuclear receptors
(specifically GRalpha)

82

how do glucocorticoids enter cells across the plasma membrane?

diffusion

83

within the nucleus what happens to the glucocorticoid-GRa monomer complex?

assemle into homodimers and then bind to glucocorticoid response elements (GRE) in the promotor region of specific genes

84

what is the end result of glucocorticoids entering into a cell?

transcription of specific genes are transactivated or transrepressed to increase expression of anti-inflamatory proteins and decrease expression of inflammatory proteins

85

what is the function of histones?

package the DNA double helix within the nucleus

86

what is chromatin?

DNA plus histones

87

in addition to its function with GRE (glucocorticoids response elements) what can glucorticoids do to chromatin?

deacetylation of histones to modify chromatin structure to become condensed and not able to be transcribed

88

what are the 4 main effects of glucocorticoids that are particularly relevant to inflammation in bronchial asthma?

1. decrease formation of Th2 cytokines and cause apoptosis
2. prevent production of IgE
3. reduce number of mast cells and decrease Fc receptor expression
4. prevent allergen-induced eosinophil influx into lungs and cause apoptosis

89

what are the 4 smaller structural effects of glucocorticoids that are particularly relevant to inflammation in bronchial asthma?

1. decrease production of cytokine mediators from epithelial cells
2. reduces leaking from endothelial cells
3. increase B2-receptor expression in airway and smooth muscle
4. reduced mucus secretion

90

why are corticosteroids useful in the long term not short term?

they do not alleviate early stage bronchospasm but resolve established inflammation

91

when does efficacy of corticosteroids develop?

over several days

92

what are the most common adverse effects of corticosteroid inhalers?
(and why?)

dysphonia (hoarse and weak voice)
oropharyngeal thrush
due to steroid deposit in the oropharynx

93

what is a good way to prevent dysphonia and oropharyngeal thrush when using corticosteroid inhalers?

drinking water after using inhaler

94

what form of oral corticosteroid is used in chronic, severe or rapidly deteriorating asthma?

oral prednisolone

95

how do cromolins work?

mast cell stabiliser: prevents degranulation
weak anti-inflammatory effect
decreased hypersensitivity of sensory C-fibres

96

what is sodium cromoglicate?

cromolin

97

how is sodium cromoglicate administered for asthma treatment?

inhalation

98

what type of drug is sodium cromoglicate?

reliever AND preventer
(ie bronchodilation and anti-inflammatory but not recommended for use for relief during an acute attack)

99

how long does efficacy of sodium cromoglicate take to develop?

several weeks

100

what is omalizumab?

monoclonal antibody against IgE

101

how do monoclonal antibodies work in the treatment of asthma?

Bind IgE via Fc to prevent attachment to FC receptors
-prevents mast cells becoming activated

102

how are monoclonal antibodies administered?

IV

103

what is COPD?

airflow reduction that is in some patients partially reversible (with bronchodilators) but which progressively worsens and gets exacerbations of symptoms including cough and mucus production

104

what can COPD be divided into?

chronic bronchitis
emphysema

105

what are 5 characteristics of chronic bronchitis?

1, inflammation of bronchi and bronchioles
2. cough
3. clear mucoid sputum
4. infections with purulent sputum
4. increasing breathlessness

106

what are the 2 characteristics of emphysema?

1. distension and damage to alveoli
2. destruction of acinal pouching in alveolar sacs

107

where are M1 muscarinic ACh receptors int he airways located?

in galnglia

108

what is the function M1 muscarinic ACh receptors in the airways?

faciliate transmission mediated by ACh acting on nicotinic receptors

109

where are M2 muscarinic ACh receptors in the airways located?

postganglionic neurone terminals

110

what is the function of M2 muscarinic ACh receptors in the airways?

act as inhibitory autoreceptors reducing the release of ACh

111

where are M3 muscarinic ACh receptors in the airways located?

smooth muscle effector
submucosal glands

112

what is the function of M3 muscarinic ACh receptors in the airways?

contraction of airway smooth muscle
increased secretion of submucosal glands

113

what is ipratropium?

short acting muscarinic antagonists (SAMAs)

114

what is tiotropium?

long acting muscarnic antagonists (LAMAs)

115

how are muscarinic antagonists administered?

inhalation

116

atropine is also a muscarinic antagoinist, how is it different to the muscarinic antagonists used in COPD?

contains a tertiary amine instead of a quaternary ammonium like ipratropium and tiotropium

117

why is a quaternary ammonium more useful than a tertiary amine in the treatment of COPD?

reduces absorption and systemic exposure

118

what is the general onset of action for muscarinic antagonists used in the treatment of COPD? (SAMAs and LAMAs)

>30mins onest of action
(delayed)

119

what 3 effects do muscarinic antagonists have in the treatment of COPD do?

1. relaxes bronchospasm caused by irritant stimuli (which initiate a vagal reflex that liberates ACh) 2. blocks ACh-mediated basal tone
3. reduces mucus secretion

120

why do muscarinic ACh receptor antagonists have few adverse effects?

little systemic absorption due to quaternary ammonium group

121

why is tiotropium more effective than ipatropium? (apart from the fact it is longer acting)

tiotropium is selective for M3
ipratropium is non-selective for M1, M2 and M3
(block of M2 is not desirable + actually increases ACh release from parasymp post-ganglionic neurones)

122

what 4 -adrenoceptor agonists are also used in the treatment of COPD?

salbutamol (SABA)
salmeterol, formoterol and indacaterol (LABA)

123

why is indacaterol classed as an ultra-LABA?

rapid onset of action vs normal LABAs

124

what combination of drugs is especially effective in moderate COPD?

LABA/LAMA combo
eg salmeterol/tiotropium

125

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

PDE4

126

what does PDE4 cause?

inflammation

127

what is rofumilast?

a selective PDE4 inhibitor

128

what does rofumilast do?

suppresses inflammation and emphysema

129

how is rofumilast administered?

oral

130

what type of adverse effects does rofumilast have?

GI effects
(due to PO administration)

131

even though glucocorticoids are of benefit in COPD patients who develop frequent and severe exacerbations, why might there be glucocorticoid unresponsiveness in some patients?

due to oxidative/nitrative stress associated with chronic inhalation of tobacco and smoke
HDAC2 is reduced in COPD

132

what is a triple inhaler?

LABA/LAMA/glucocortidoic
(eg formoterol/tiotropium/ciclesonide)
not lisenced for use

133

what is rhinitis?

a common disease involving acute or chronic inflammation of the nasal mucosa

134

what 4 features is rhinitis charactersed by?

1. rhinorrhoea (runny nose)
2. sneezing
3. itching
4. nasal congestion and obstruction

135

why does rhinorrohea occur in rhinitis?

watery mucus accumulation in nasal cavity

136

why does nasal congestion and obstruction occur in rhinitis?

swelling of the nasal mucosa due to dilated blood vessels

137

what are the 3 types of rhinitis?

allergic
non-allergic
mixed

138

what are the 3 types of allergic rhinitis?

seasonal (SAR)
perennial (PAR)
episodic

139

what are some non-allergic causes of rhinitis?

infection
hormonal imbalance (eg preg)
vasomotor disturbances
medications
nonallergic rhinitis with eosiophilia syndrome (NARES)

140

what are the 5 types of rhinitis/rhinorrhoea treatment?

glucocorticoids
H1 receptor antagonists
CysLT1 receptor antagonists
vasoconstrictors
sodium chromoglicate

141

what is the function of glucocorticoids in the treatment of rhinitis/rhinorrhoea?

anti-inflammatory

142

what is the function of H1 receptor antagonists in the treatment of rhinitis/rhinorrhoea?

reduce effects of mast cell derived histamine eg prevent vasodilation, prevent activation of sensory nerves, decrease mucous secretion)

143

what is the function of sodium chromoglicate in the treatment of rhinitis/rhinorrhoea?

anti-allergic

144

what is the mainstay treatment of SAR and PAR?

glucocorticoids

145

in the treatment of rhinitis/rhinorrhoea how are glucocorticoids administered?

topical nasal spray
(OD)

146

what 3 glucocorticoids can be used in the treatment of rhinitis/rhinorrhoea?

beclometasone
fluticasone
prednisolone

147

which types of rhinitis ar H1 receptor antagonists more effective in?

SAR, PAR and episodic AR
(not too good at non-allergic)

148

how are H1 receptor antagonists administered?

orally or topical nasal spray

149

what are loratidine, fexofenadine and cetirizine?

second generation H1 receptor antagonists

150

what is the function of cysLT1 receptor antagonists in the treatment of rhinitis/rhinorrhoea?

reduces the effects of CysLTs upon the nasal mucosa

151

what is the function of vasoconstrictors in the treatment of rhinitis/rhinorrhoea?

decrease nasal blood flow via a1 adrenoceptors

152

what is the function of sodium chromoglicate in the treatment of rhinitis/rhinorrhoea?

mast cell stabilisers- prevent degranulation

153

what is the sole muscarinic receptor antagonist agent used for rhinorrhoea?

ipatropium

154

how is ipatropium administered for rhinorrhoea?

topical nasal spray

155

how is sodium cromoglicate administered for rhinitis/rhinorrhoea?

topical nasal spray

156

what type of rhinitis are CysLT1 receptor antagonists effective at treating?

PAR and SAR

157

how are CysLT1s administered for treatment of rhinitis/rhinorrhoea?

oral

158

what is the sole CysLT1s receptor antagonist used for the treatment of rhinitis/rhinorrhoea?

montelukast

159

what is oxymetazoline?

a selective a1-adrenoceptor (Vasoconstrictor) used for allergic rhinitis

160

how is oxymetazoline administered?

topical nasal spray

161

why does rebound increase in nasal congestion occur after use of oxymetaxoline for a few days?

receptor desensitisation and down regulation

162

what is the name for the rebound increase in nasal congestion which occurs after use of oxymetaxoline for a few days?

rhinitis medicamentosa