Pharmacology Flashcards
(127 cards)
1
Q
Where are cell bodies of the parasympathetic preganglionic fibres located?
A
brainstem
2
Q
Where are cell bodies of parasympathetic postganglionic fibres located?
A
Walls of the bronchi and bronchioles
3
Q
What nerves carries preganglionic fibres to the bronchial and bronchi walls?
A
Vagus nerve (CN X)
4
Q
Stimulation of postganglionic cholinergic fibres cause what?
A
Bronchial smooth muscle contraction (ASM airway smooth muscle cells)
Mucus secretion from goblet cells
5
Q
Which neurotransmitter is used in stimulation of postganglionic cholinergic fibres?
A
ACh (acetylocholine)
6
Q
What are the receptors which the ACh binds to on the smooth muscle cells and goblet cells?
A
M3 muscarinic ACh receptors
7
Q
what does Stimulation of postganglionic noncholinergic fibres cause?
A
Relaxation of smooth muscle cells (ASM)
8
Q
What neurotransmitters are involved in the noncholinergic pathway?
A
Nitric oxide (NO)
Vasoactive intestinal peptide (VIP)
9
Q
There is sympathetic innervation of bronchial smooth muscle in humans true or false?
A
false
10
Q
How does the sympathetic system act on bronchial smooth muscle cells?
A
Nicotinic acetylcholine receptor (nAChR) which are located on the adrenal grand, chromaffin cells when stimulated release adrenaline into circulation which act on smooth muscles
11
Q
Which receptors does the adrenaline act on in both goblet and smooth muscle cells?
A
beta2 adrenoceptors
12
Q
What does sympathetic stimulation cause on the airways?
A
- ASM cells relaxation
- decreased mucus secretion on goblet cells
- increased mucociliary clearance on epithelial cells
- vascular smooth muscle contraction- alpha 1 adrenoceptors
13
Q
How does the release of Ca2+ cause contraction of smooth muscles?
A
- Ca2+ activates calmodulin to Ca2+ calmodulin
- Inactive MLCK is activated by Ca2+ calmodulin to form active MLCK
- Active MLCK and phosphate group (formed from hydrolysis of ATP) Cause inactive myosin cross bridge to phopshyrlated cross bridge (binds to actin)
14
Q
What enzyme is responsible for phosphorylation of Myosin light chain (MLC) (contraction)?
A
Myosin light chain kinase (MLCK)
15
Q
What enzyme is responsible for dephosphorylation of myosin Light chain (relaxation)?
A
Myosin phosphatase
16
Q
What is asthma?
A
recurrent and episodic condition of the obstruction to the airways in response to substances or stimuli
17
Q
What are the main causes of asthma?
A
- Allergens
- Exercise (cold,dry air)
- Resouratiry infections
- smoke, dust and environmental pollutants
18
Q
What effects does chronic asthma have on the airways?
A
- increased mass of smooth muscle (hyperplasia + hypertrophy)
- accumulation of intestitial fluid (oedema)
- increased secretion of mucus
- epithelial damage (exposes sensory nerve endings)
- Sub-epithelial fibrosis
19
Q
What is acute severe asthma called?
A
status asthmaticus
20
Q
What effect does air narrowing have on airway resistance?
ii. what does this cause
A
Increases it
ii. FEV1 and PEFR values decrease
21
Q
Epithelial damage from chronic asthma exposes what type of sensory nerve endings?
A
C fibres- irritant receptors
22
Q
What does epithelial damage lead to in the airways?
A
Hypersensitivity (X axis)
Hyper-reactivity (Y axis)
23
Q
What is inhaled with provocation tests which real hyper-responsiveness?
A
Broncho constrictors (spasmogens)
e.g. histamine (activates ASM H1 receptors)
Methacholine (activates ASM M3 receptors)
24
Q
What does an asthma attack consist of ?
A
- immediate phase- Bronchospasm Type 1 hypersensitivity reaction
- Delayed phase ( inflammatory reaction) Type IV hypersensitivity reaction
25
what type of Th cells are part of the antibody-mediate response involving IgE in response to an allergen? (atopic)
TH2 cell- strong response
| T helper cell
26
What type of Th cells are part of cell-mediated immune response involving IgG and macrophages (nonatopic)?
TH1 cell- low level response
| T helper Cell
27
What cell matures in TH2?
ii. what environment needs to be present for to occur?
TH0
ii. cytokine environment
28
How do TH2 cells activate B lymphocytes?
1. directly binds to B cells
| 2. releases Interleukins which bind to B cells (IL 4)
29
What do B lymphocytes mature to?
IgE secreting plasma cells
30
Interleukin 5 (IL 5) which are released from TH2 cells cause what?
Activation of eosinophils
31
Mast cells express what in response to to IL 4 and IL 13 from TH 2 cells?
IgE receptors
32
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
33
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 chemotaxins and chemokines that attract cells that cause inflammation (eosinophils)
34
What are the spasmogens released from mast cells?
Histamine
Leukotrienes ( LTC4,LTD4)
both also released by eosinophils.
35
What chemotaxins and chemokines are released?
LTB4
Platelet -activating factor (PAF)
Prostaglandins (PGD2)
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
How do relievers treat asthma?
act as bronchodilators
39
How do controllers treat asthma?
Act as anti-inflammatory agents
40
Give examples of relievers?
Short acting beta 2 adrenoceptor agonists (SABAs)
Long acting Beta 2 adrenoceptor agonists (LABAs)
CysLT1 receptor antagonists-block cysLTs (LTC4, LTD4, LTE4) derived from mast cells and so cause smooth muscle relaxation, decreased mucus secretion and decreased oedema
Methylxanthines
41
Give examples of controllers?
Glucorticoids
Cromoglicate
Humanised monoclonal IgE antibodies
methylxanthines
42
Describe the differences between aerosol and oral therapy for asthma?
Pharmacokinetics:
Aerosol- slow absorption from lung surface and rapid systemic clearance
Oral- Good absorption and slow
systemic clearance
Dose: Aerosol: Low
Oral: High
systemic concentration of drugs:
aerosol - Low
Oral- high
Incidence of adverse effects:
Aerosol- Low
Oral- high
distribution of drug:
aerosol- reduced in severe airway disease oral- unaffected by any airway disease
Compliance:
aerosol: good with bronchodilators not good with anti-inflammatory.
Oral: Good with both
Ease of administration:
aerosol- difficult for small children and infirm people.
Oral: Easy
Effectiveness:
aerosol- only effective in mild to moderate diseases.
Oral: very effective
43
When are SABAs used?
first line treatment for mild/intermittent asthma
44
How are SABAs administered?
inhalation via metered dose/dry powder device
can be administered:
Oral(children)
IV (emergency)
45
How long does it take SABAs to act on bronchial smooth muscle?
Very rapid ( maximal effect within 30 mins) feel effect in 5 mins
lasts for 3-5 hours
46
What is the main effect of SABAs?
ii. what are the adverse effects?
Increase mucus clearance and decrease mediator release from mast cells
ii. Very few- fine tremor most common. Can have tachycardia, cardiac dysrhythmia and hypokalaemia
47
What is the main type of SABA?
salbutamol
48
When are LABAs used?
Useful for noctural asthma (lasts for 8 hours)
49
Should you use LABAs for acute relief of bronchospasm??
NO- slow to act especially salmeterol
50
Can LABAs be used as a monotherapy for asthma?
ii. if not then what should it be co-administered with?
No- can worsen asthma increase risk of death
ii. Always a glucocorticoid
51
Give examples of LABAs.
Salmeterol
Formoterol
52
What should you use to reduce potentially harmful stimulation of Cardiac B1 adrenocopetors?
Selective Beta 2 adrenoceptor agonists
53
What happens if you use non selective beta adrenoceptor agonists?
increase risk of bronchospasm
54
When are CysLT1 receptor antagonists used?
Add on therapy (inhaled corticosteroids
used for early and late bronchospasm in mild persistent asthma
Effective against antigen and exercised induced bronchospasm
55
What are the effects of cysLts?
ii. what are the adverse effects?
relax bronchial smooth muscle
ii. well tolerated can have headaches and GI upset
56
How do you administer CysLts?
ii. when shouldn't you administer them?
Orally
Acute severe asthma
57
Give examples of CysLt1 receptor antagonist.
montelukast
zafirlukast
58
Give examples of Methylxanthines
Theophylline
Aminophylline
59
What effects do methylxanthines have?
Inhibit mediator release from mast cells
increase mucus clearance
increase diaphragmatic contractility
reduce fatigue- increases lung ventilation
60
When are methylxanthines used?
ii. what are they co-administered with?
second line therapy
ii. B2 adrenoceptor agonist
and
glucorticoids
61
How are methylxanthines administered?
orally
62
What are the adverse effects of methylxanthines?
Supratherapeutic concentrations: Dysrhythmia, seizures and hypotension
therapeutic concentrations: Nausea, vomiting, abdominal discomfort and headache
63
What are the two main steroid hormones synthesised by the adrenal cortex?
1. Glucorticoids (zona fasiciculata)
| 2. Mineralocorticoids (zona glomerulosa)
64
What are the effects of glucocorticoids?
Decreases inflammatory and immunological responses
increases Liver glycogen deposition, gluconeogenesis and glucose output from liver
Increases protein and bone catabolism
65
what is the main glucocorticoid in the body?
cortisol
66
What is the main mineralocorticoid which regulates salt retention via the kidney?
aldosterone
67
Which type of steroid hormone is not wanted to treat inflammatory conditions?
mineralocorticoid
68
When are glucocorticoids ineffective against bronchospasm?
ii. when is it mainly used?
When given acutely- no direct bronchodilator effect
ii. treatment in prophylaxis of asthma
69
How are glucocorticoids administered?
inhalation- minimises adverse systemic effects
70
What do glucorticoids bind to?
ii. specifically which receptor?
Nuclear receptors (class 1)
ii. GR alpha- bind to glucorticoid response elements
71
What are the two main effects of clinically administered glucocorticoids in asthma treatment?
1. prevent inflammation
| 2. resolve established inflammation
72
How should glucocorticoids be administered?
Long term treatment- especially in combination with LABA
mild moderate asthma- inhalation from a metered dose inhaler
chronic/severe asthma- oral prednisolone with an inhaled steroid to reduce the oral dose required
73
What are the main glucocorticoids used in an inhaler?
Beclometasone
budesonide
fluticasone
74
What are the adverse effects of glucocorticoids in asthma?
Dysphonia
thrush
both caused by deposition of steroid in oropharynx
75
When are cromones administered?
second line drug used prhophylactically in allergic asthma
used infrequently- used to be used a lot for children due to lack of adverse effects
76
What is an example of a cromone?
sodium cromoglicate
77
Give an example of a monoclonal antibody directed against IgE
omalizumab
given IV
78
Give an example of a monoclonal antibody directed against IL 5?
Mepolizumab
very expensive- started being used against asthma associated with severe eosinophilia
79
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
80
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
81
What are the two subtypes of COPD?
1. chronic bronchitis
| 2. emphysema
82
What are the symptoms of chronic bronchitis?
1. Inflammation of bronchi and bronchioles
2. cough
3. Clear mucoid sputum
4. Infections with purulent sputum
5. Increasing breathlessness
83
What are the symptoms of emphysema?
Distention and damage to alveoli
Destruction of acinal pouching in alveolal sacs
loss of elastic recoil
84
What is the build up which leads to COPD?
1. smoking (air pollution)
2. Stimulation of resident alveolar macrophages
3. Cytokine production
4. Activation of neutrophils, CD8+, Increased macrophage numbers
5. release of free radicals
85
What is the main characteristic of COPD?
increased resistance to airflow during expiration
86
Muscaranic receptor antagonists act against bronchoconstriction caused by which smooth muscle receptor?
M3 receptor
87
Where are M1 muscarinic receptors found?
ii. what is their role?
Ganglia
Facilitate fast neurotransmission mediated by ACh acting on nictonic receptors
88
Where are M2 muscarinic receptors found?
ii. what is their role
Postganglionic neurone terminals
act as inhibitory autoreceptors reducing release of ACh
89
Where are M3 muscarinic receptors found?
ii. what is their role?
post junctional muscarinic end plate receptors found on smooth muscle effector submucosal glands
contraction of airway smooth muscle
increased secretion of submucosal glands
90
What are the two types of competitive Muscarinic receptor antagonists used to treat COPD?
ii. how are they administered?
1. SAMA
2. LAMA
ii. Inhalation
91
Give an example of SAMA?
Ipratropium (non selective)
92
Given examples of LAMA
Tiotropium (selective M3)
Glycopyrronium (selective M3)
aclidinum (selective M3)
93
contraction of airway smooth muscle
| increased secretion of submucosal glands
reduces absorption and systemic exposure
94
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
95
Why are selective M3 blockers superior to ipratropium?
Block of M3 and M1 is good
Block of M2 is not as release of ACh from post-ganglionic neuronse is increased by autoreceptor antagonism
96
Which LABAs should not be used in acute bronchospasm?
Indacterol
olodaterol
97
What is the best way to treating COPD?
Combination of B2 agonist and muscarinic antagonist
(Muscarinic antagonist- prevent contraction of airways)
(Beta 2 agonists cause relaxation of airways)
98
When are LABA and LAMAs combinations at the most effective?
Deposited in the same location in the airways
99
What is administered in combination inhalers for COPD?
Glucocorticoids and Beta agonist or muscarinic antagonist
100
What is Rofumilast?
a selective PDE4 inhibitor - suppresses inflammation and emphysema in animals
oral treatment for severe COPD with chronic bronchitis
101
What is rhinitis
common disease involving acute or chronic, inflammation of the nasal mucosa
102
What are the main symptoms of rhinitis?
rhinorrohea- runny nose
sneezing
itching
nasal congestion and obstruction ( swelling o nasal mucosa largely due to dilated blood vessels- mainly cavernous sinusoids
103
What types of rhinitis are there?
1. allergic- involved IgE dependent events
2. non-allergic- not involve IgE dependent events
3. mixed
104
What are the subtypes of allergic rhinitis?
1. seasonal
2. perennial
3. episodic
105
what is a triple inhaler? (for COPD)
LABA/LAMA/glucocortidcoid
(eg formoterol/tiotropium/ciclesonide)
not lisenced for use
106
What are the causes of Non allergic rhinitis?
1. infection
2. hormonal imbalance
3. Vasomotor disturbances
4. Non allergeic rhinitis with eosinophilila syndrome (NARES)
5. Drug induced (aspirin)
107
What does occupational rhinitis involve?
allergic and non allergic components
108
What do both rhinitis and rhinorrhoea involve?
Increased mucosal blood flow
increased blood vessel permeability
or both
this causes increases volume of nasal mucosa- difficulty breathing
109
What is the mechanism of Glucocorticoids for rhinitis treatment?
reduces vascular permeability
recruitment and activity of inflammatory cells
110
What type of rhinitis are Glucocorticoids mainly used to treat?
seasonal allergic rhinitis
perennial allergic rhinitis
can be also used for NARES and vasomotor rhinitis
111
How are Glucocorticoids administered for rhinitis?
Topically as a spray - effective as a monotherapy takes several weeks to reduce all symptoms
can be given orally in short term
112
What can Glucocorticoids be combined with to treat severe-moderate rhinitis
Anti-histamines
113
What is the mechanism for anti-histamine (H1 receptor antagonists) for treatment of rhinitis?
Competitive antagonist- reduces effect of histamine from mast cells
114
What are the effects of histamine?
1. vasodilatation and increased capillary permeability
2. Activation of sensory nerves
3. mucus secretion from submucosal glands
115
What type of rhinitis do anti-histamines treat?
Mainly allergic
116
How are Antihistamines adminsitered?
ii. when are they administered?
orally or intranasal spray
effective as monotherapy
ii. first or second - primarily second due to reduced sedation
117
Give examples of second generation anti-histamines
Loratidine
fexofenadine
118
What is the mechanism for anti-cholinergic drugs for treating rhinitis?
Blocks ACh released from post-ganglionic parasympathetic fibres activates M receptors on nasal glands causing a watery secretion that contributes to rhinnorhoea
119
What type of rhinitis do anti-cholinergic drugs treat?
Reduces rhinorrhoea in PAR and SAR - has no effect on other symptoms though
120
How are anti-cholinergics administered?
intranasally
121
Give an example of an anticholinergic drug.
ipratropium
122
When do you use sodium cromoglicate?
maintenance treatment of allergic rhinitis
via nasal administration- less effective than nasal corticosteroids
123
When should you use CysLt1 for rhinitis?
PAR and SAR
124
Give an example of CysLT1
Montelukast
125
What is the mechanism of vasoconstrictors?
Directly/indirectly mimic noradrenaline- cause vasoconstriction via activation of alpha 1 adrenoceptor
126
What is oxymetazoline?
selective alpha 1 adrenoceptor agonist- intranasally administered- only short term too long and nasal congestion can occur
127
what does Chronic agonist induced stimulation of airway beta-2 receptors results in?
Beta-2 receptor up regulation and enhanced receptor coupling to G protein -adenylyl cyclase
