Pharmacology Flashcards
(139 cards)
1
Q
what does stimulation of post-ganglionic cholinergic fibres cause? (2)
(Parasympathetic)
A
1) bronchial smooth muscle contraction
2) increased mucus secretion
2
Q
what is bronchial smooth muscle contraction mediated by?
Para
A
- M3 muscarinic ACh receptors on airway smooth muscle cells
3
Q
what is mucus secretion mediated by?
para
A
- M3 muscarinic ACh receptors on gland (goblet) cells
4
Q
what does stimulation of post-ganglionic non-cholinergic fibres cause?
(parasympathetic)
A
1) bronchial smooth muscle relaxation
5
Q
what is bronchial smooth muscle relaxation mediated by?
A
- nitric oxide & vasoactive intestinal peptide (VIP)
6
Q
since there is no innervation of bronchial smooth muscle in the SYMPATHETIC division, what mechanism is used to alleviate asthma symptoms?
A
- post-ganglionic fibres supply sub-mucosal glands and smooth muscle of blood vessels
7
Q
In the sympathetic division, what brings about bronchial smooth muscle relaxation via B2-adrenoceptors on ASM cells?
A
- activation by release of adrenaline from adrenal gland
8
Q
In the sympathetic division, what is the result of stimulated B2-adrenoreceptors? (3)
A
1) Bronchial smooth muscle relaxation
2) Decreased mucous secretion (on gland (goblet) cells)
3) Increased mucociliary clearance (on epithelial cells)
9
Q
In the sympathetic division, what is the result of stimulated Alpha-1 adrenoceptors?
A
- vascular smooth muscle contraction
10
Q
describe how contraction of Airway smooth muscle occurs due to transmitters (proteins or hormones)?
A
1) activation of G-protein coupled receptor via a transmitter (hormone or protein)
(transmitter is cholinergic transmitter = parasympathetic)
(G-protein is specific = GQ/11)
(activated GQ/11 activated phospholipase C = PLC)
(PLC generates this intracellular signals IP3)
2) generates an intracellular signal IP3
3) IP3 carries signal to an IP3 receptor
4) mediates calcium release
11
Q
describe how contraction in airway smooth muscle when initiated by calcium.
A
1) Ca binds to calmodulin (calcum compound)
2) this compound then activates a kinase = Myosin light chain kinase (MLCK)
3) active MLCK phosphorylates a myosin cross bridge
(by hydrolysing an ATP, yielding an inorganic phosphate which is transferred to the inactivemyosin cross bridge)
4) the cross bridge glides across actin, causing contraction
12
Q
since contraction of ASM results from phosphorylation of myosin light chain cross bridge due to presence of Ca, how does RELAXATION of ASM occur?
A
= DEPHOSPHORLYATION of MLC by myosin phosphatase
13
Q
what happens to the rates of de/phosphorylation in the presence of elevated intracellular calcium
A
phosphorylation exceeds dephos…
14
Q
what does relaxation require in terms of intracellular Ca2+ concentration to basal level and how is it achieved?
A
1) requires return of Ca2+ concentration to a basal level
2) achieved by active transport
15
Q
what is the activity of myosin light chain kinase and myosin phosphatase dependent on?
A
= extracellular signals
- e.g. adrenaline activating B2-adrenoceptors
16
Q
what 5 pathological changes occur to the bronchioles in chronic asthma as a result of long standing inflammation.
A
1) increased mass of smooth muscle
- hyperplasia & hypertrophy
2) accumulation of interstitial fluid
- oedema
3) increased secretion of mucus
4) epithelial damage
- exposing sensory nerve endings
5) sub-epithelial fibrosis
17
Q
what effect does airway narrowing by inflammation & broncho-constriction have on FEV1 & PEFR?
A
- airway resistance causing deceased FEV1 & PEFR
18
Q
what are the 2 components in bronchial hyper-responsiveness in asthma?
A
1) hypersensitivity
2) hypereactivity
19
Q
what 2 factors cause hypersensitivity & hyperactivity in bronchial hyper-responsiveness in asthma.
A
1) epithelial damage
2) exposing sensory nerve endings
= contributing to increased sensitivity of the airways to broncho-constrictor influences
20
Q
what type of hypersensitivity correlates to the early phase of an asthma attack?
- bronchospasm & acute inflammation
A
type I hypersensitivity
21
Q
what type of hypersensitivity correlates to the late phase of an asthma attack?
- bronchospasm & delayed inflammation
A
type IV hypersensitivity
22
Q
in non-atopic individuals, in response to an allergen & phagocytosis by antigen presenting cells, describe the response.
A
- low level TH1 response
- cell mediated immune repose involved IgG & macrophages
23
Q
in atopic individuals, in response to an allergen & phagocytosis by antigen presenting cells, describe the response.
A
- strong TH2 response
- antibody mediated immune response
- involving IgE
24
Q
in the development of asthma, what does the initial presentation of an antigen innate?
A
- an ADAPTIVE immune response
25
describe the induction phase of the adaptive immune response that leads to allergic asthma.
1) antigen presentation
2) CD4+ T cells colonise into THO cells
3) THO cells differentiate into TH1 or TH2 cells
4) TH2 cells activate B cells with the help of IL-4
5) activated B cells mature plasma cells which secrete IgE
26
what do eosinophils differentiate & activate in response to?
in response to IL5, released from TH2 cells
27
what do the mast cells in airway tissue express IgE receptors in response to?
in response to IL4 and IL13, released from TH2 cells
28
after the TH2 lymphocyte activation, what does the cross link IgE receptors stimulate?
stimulate;
- calcium entry into mast cells
- release of Ca2+ from intracellular stores
29
what does entry and release of Ca2+ evoke?
| 2
1) release of secretary granules containing performed histamine & production & release of other agents
- e.g. leukotrienes, LTC4 & LTD4) causing ASM contraction
2) release of substances that attract cells that cause inflammation into the area
30
what are the 2 phases of an asthma attack?
1) immediate
| 2) late phase
31
what are the products of mast cell and mononuclear cells that result in broncho-spasms & early inflammation in the IMMEDIATE PHASE ASTHMA ATTACK.
1) spasmogens
2) CysLTs
3) histamine
32
what is produced by mast cells and mono nuclear cells in the immediate phase that evokes the late/delayed phase
1) cytokines
| 2) chemotaxis
33
what inflammatory cells in particular is activated in the LATE PHASE ASTHMA ATTACK
eosinophils
34
What 4 pathological things happen in the late phase of an asthma attack?
1) epithelial damage
2) airway inflammation
3) airway hyper responsiveness
4) bronchospasm, wheezing, mucus over-secretion & cough
35
what are the 2 categories of drugs used to treat asthma?
1) relievers
| 2) controllers
36
- what do delivers do?
| - give 3 examples of relievers
= bronchodilators
1) short acting B2 adrenoceptors agonists (SABAs)
2) long acting B2 adrenoceptors agonists
(LABAs)
3) CysLT1 receptor antagonists
37
- what do controllers do?
| - give 3 examples of controllers?
= inflammatory agents that reduce airway inflammation
1) glucocorticoids
2) cromoglicate
3) humanised monoclonal IgE antibodies
38
explain how B2 adrenoceptor agonists treat asthma as bronchodilators.
- act as physiological antagonists of all spasmogens
(substances that induce spasms)
- causes ASM reaction via formation of protein kinase A
- this phosphorylates MLCK & myosin phosphatase
- reduces intracellular Ca conc & activates potassium channels
39
what should be used to treat an acute asthma attack?
= relievers
| = B2 adrenoceptor agonists
40
give 2 examples of a SABA
1) salbutamol
| 2) terbutaline
41
what are SABAs used to treat?
mild intermittent asthma
42
how are SABAs usually administered?
via inhalation
43
describe SABAs acting time?
- they act rapidly to relax bronchial smooth muscle
- maximum effect within 30minutes
- relaxation persists fo 3-5hours
44
what are the few adverse effects of SABAs when administered by the inhalation route?
- unwanted systemic absorption
- few adverse effects;
e. g. finne tremors, tachycardia, cardiac dysrhythmia
45
give 2 examples of LABAs
1) salmeterol
| 2) formoterol
46
what are LABAs not recommended for and what are they useful for?
NOT RECOMMENDED FOR;
- acute relief bronchospasm
USEFUL FOR;
- nocturnal asthma (last 8 hours)
47
describe how LABAs should be used?
- NOT as mono therapy
| - but as an add-on therapy, always co-administered with a glucocorticoid
48
give 2 examples of CysLT1 receptor antagonists.
1) montelukast
| 2) zafirlukast
49
what are CysLTs derived from and what do they cause?
- derived from mast cells & infiltrating inflammatory cells
- they cause smooth muscle contraction, mucus secretion & oedema
50
how do CysLT1s receptor antagonists work?
- act competitively at the CysLT1 receptor
| - therefore, relaxing bronchial smooth muscle
51
how are CysLT1 receptor antagonists administered?
ORALLY
52
should CysLT1 receptor antagonists be used as a mono therapy or as an add-on therapy.
- are effective as add on therapy against early & late bronchospasm in mild persistent asthma & in combination with other medication, including inhaled corticosteroids
53
what are 2 possible side effects of CysLT1 receptor antagonists?
1) headache
2) GI upset
- but are generally well tolerated
54
what are CysLT1 receptor antagonists not recommended for?
not recommended for acute severe asthma
55
give 2 examples of Xanthinens.
1) theophylline
| 2) aminophylline
56
How do xanthines work?
- combine bronchodilator (at high dose) & anti-inflammatory actions
- inhibit mediator release from mast cells
- increase mucus clearance
57
how should xanthines be administered?
orally
58
at what concentration do xanthines exert adverse effects involving CNS, CVS, GI tract & kidney?
give examples of these adverse effects.
at Supra-therapeutic concentrations they exert adverse effects
Examples;
- seizures
- hypotension
- dysrhythmia
59
what adverse effects are caused at therapeutic concentrations of xanthins?
- nausea
- vomiting
- abdominal discomfort
- headache
60
why are xanthines problematic?
because of numerous drug interactions, involving CYP450s as an example.
61
describe the therapeutic window of xanthines?
narrow therapeutic window.
62
what are the 2 classes of corticosteroids used?
1) glucocorticoids
| 2) mineralocorticoids
63
what is the main hormone in glucocorticoids?
| what do glucocorticoids do?
= cortisol (hydrocortisone)
- regulates numerous essential processes e.g. inflammatory & immunological
64
what sort of steroids may contain both glucocorticoid & mineralocorticoid action?
endogenous steroids
65
give 3 examples of synthetic derivatives of cortisol.
1) beclometasone
2) budesonide
3) fluticasone
66
why are synthetic derivatives of cortisol used in the treatment of asthma more so than cortisol itself?
because synthetic derivatives have little or no mineralocorticoid activity
67
do glucocorticoids have bronchodilator activity?
no
| - they are ineffective in receiving broncho-spasms
68
what type of asthma are glucocorticoids the mainstay treatment?
prophylaxis of asthma
| used to PREVENT THE DISEASE
69
why is the inhalation route the preferred option for delivering glucocorticoids?
what are the most common side effects? - think about how they are delivered.
to minimise systemic effects
- hoarse voice
- thrush
70
how do glucocorticoids signal?
via nuclear receptors, specifically GRalpha
71
how do glucocorticoids enter cells?
- they are lyophilic molecules so enter by diffusion
| lipophilic = dissolve in lipids or fat
72
what happens when glucocorticoids are within the cytoplasm?
- glucocorticoids combine with GRalpha
- this causes dissociation of heat shock proteins (HSP)
- the activated receptor translocates (moves from one place to another) to the nucleus aided by importins
73
what happens when glucocorticoids are within the nucleus?
- activated receptor monomers assemble into homodimers & bind to GLUCOCORTICOID RESPONSE ELEMENTS (GRE) in the promoter region of specific genes
74
when the transcription of specific genes is either switched on or off, what happens?
- alters mRNA levels & the rate of synthesis of mediate proteins
75
what do glucocorticoids do to the coding genes of inflammatory proteins in terms of transcription?
- they INCREASE TRANSCRIPTION of genes encoding anti-inflammatory proteins
- they decrease transcription of genes encoding inflammatory proteins
76
what are the 4 effects of glucocorticoids that are relevant to brachial inflammation in asthma?
1) prevent IgE production
2) decrease number of mast cells
3) prevent allergens
4) decrease formation of TH2 cytokines
77
name the 5 inflammatory cells that glucocorticoids decrease the number of.
1) eosinophils
2) T lymphocytes
3) mast cells
4) macrophages
5) dendritic cells
78
what effect does glucocorticoids have on airway smooth muscle cells?
- increase B2 receptors
79
what effect does glucocorticoids have on mucus glands?
- decrease mucus secretion
80
what effect does glucocorticoids have on endothelial cells?
- decreased leakiness
81
what effect does glucocorticoids have on epithelial cells?
- cytokine mediators decrease
82
since glucocorticoid suppress the inflammatory component in asthma, what does that resolve inn?
- precent inflammation
| - resolves existing inflammation
83
should glucocorticoids be give as a mono-therapy or as an add-on in LONG TERM TREATMENT?
In long term treatment they should be used in COMBINATION WITH LABAs
84
what type of drug is cromoglicate?
a SECOND LINE DRUG
85
when should cromoglicate be used?
used prophylactically in treatment of allergic asthma (particularly children)
86
what is cromoglicate often described as?
a MAST CELL STABILISER.
| - agent that surpasses histamine release from mast cells
87
does cromoglicate affect bronchial smooth muscle?
no - it has no effect on brachial smooth muscle
88
how is sodium cromoglicate most commonly administered and why?
inhalation
| - due to little systemic absorption
89
what stages of an asthma attack does sodium cromoglicate target and how long will it take to develop?
- it can target both phases of an asthma attack
| - but efficacy may take several weeks to develop to block late phase reaction
90
in what age category is sodium cromoligcate more effective in treating?
children & young adults rathe than older patients.
91
give an example of a monoclonal antibody directed against IgE.
= omalizumab
92
how dos omalizumab work?
- binds to IgE via Fc
- does to to prevent attachment of Fc receptors
- this suppresses mast cell response to allergens
93
how is omalizumab administered?
via IV
94
give an example of a drug that is a monoclonal antibody directed against IL-5.
= mepolizumab
95
muscarinic receptor antagonists are an important treatment of COPD, how do they work?
= reduce the parasympathetic neuro-effector transmission
96
what do muscarinic receptor antagonists act as?
they act as antagonists of broncho-constriction
97
how is broncho-constriction by smooth muscle initiated?
= M3 receptor activation in response to each release from post-ganglionic parasympathetic fibres
98
what do M1 muscarinic receptors do?
facilitate fast neurotransmission mediated by ACh acting on nicotinic receptors
99
what do M2 muscarinic receptors do?
= act as inhibitory auto-receptors reducing release of ACh
| post ganglionic neurone terminals
100
what do M3 muscarinic receptors do?
mediate ASM CONTRACTIONN to ACh
101
which muscarinic receptor is the most useful to target in order to treat COPD?
M3 msucarinic receptor
102
give 5 examples of competitive muscarinic receptor antagonists.
1) ipratropium (SAMA)
2) tiotropium (LAMA)
3) glycopyronium (LAMA)
4) aclidinium (LAMA)
5) Umeclidinium (LAMA)
103
how are muscarinic receptor antagonists administered?
via inhalation
104
what part of the muscarinic receptor antagonists reduces absorption & systemic exposure, thus avoiding potential adverse effects.
= QUATERNARY AMMONIUM group
105
relative to a SAMA, describe the onset of bronchodilator action of muscarinic receptor antagonists.
- they have a delayed onset of bronchodilator action relative to a SAMA
106
what 2 things do muscarinic receptor antagonists reduce?
1) reduce broncho-spasms
| 2) decrease mucus secretions
107
what do muscarinic receptor antagonists block?
they block ACh-mediated basal
108
why are M3 selective blockers superior to ipratropium?
- the functionally selectively of M3 blockers
| - wherereas, ipratropium blocks all
109
what do and don't B-adrenoceptors do?
DO - bronchodilate
| DON'T - act on underlying inflammation
110
give 2 drugs that act as ultra LABAs.
1) indacaterol
| 2) olodaterol
111
what combination of drugs is best an increasing FEV1.
combination of;
1) B2 agonists
2) muscarinic antagonist
112
when are LABA/LAMA combinations most effective ?
when both drugs are deposited in the same location in thee airway
113
what do muscarinic receptors do when in combo with a LABA?
- block activation by ACh preventing contraction
114
what do B2 agonists do when in combination with a LAMA?
cause relocation by brining to B2 adreenoceptorr
115
what can be administered with LABA/LAMA combos to treat COPD?
- glucocorticoids
116
an example of a selective Phosphodiesterase 4 (PDE4) that suppresses inflammation & emphysema inn COPD.
roflumilast
117
drawbacks of roflumilast?
- adverse GI effects
118
benefits of administering glucocorticoids in combination with LABAs in COPD.
Benefit;
| - in patients who develop frequent & severe exacerbations when given with a LABA
119
why are glucocorticoids unresponsive in patients with COPD?
- due to oxidative/nitrative stress
| - HDAC2 is reduced also
120
3 examples of drugs used in triple inhalers as one daily treatment for COPD.
1) fluticasone
2) umeclidinium
3) vilantereol
121
3 types of rhinitis
1) allergic
2) non-allergic
3) mixed
122
what the classifications of allergic rhinitis?
1) seasonal
2) perennial
3) episodic
123
what is the condition that allergic rhinitis is strongly linked to?
asthma
124
what are the similarities between asthma & allergic rhinitis.
1) inhalation of allergens increase specific IgE levels
2) IgE binds to receptors on mast cells & basophils
3) re-exposure to allergen causes mast cell & basophil
de-granulation
4) release of mediators, e.g. histamine, cysLTs, tryptase, prostaglandins cause the symptoms
125
what does non-allergic rhinitis NOT involve?
IgE dependant events
126
what 5 things can cause non-allergic rhinitis?
1) infection
2) hormonal imbalance
3) vasomotor disturbances
4) non-allergic rhinitis with eosinophils syndrome
5) medication
127
what may occupation rhinitis involve?
both allergic & non-allergic rhinitis
128
what do both rhinitis & rhinorrhoea both involve?
1) increased mucosal blood flow
2) increased blood vessel permeability
= both increase the volume of nasal mucosa causing difficulty breathing in
129
what is used as anti-inflammatory treatment in rhinitis & rhinnorrhoea?
glucocorticoids
130
give 3 examples of glucocorticoids?
- beclametasone
- fluticasone
- prednisolone
131
what is the mechanism of glucocorticoids?
- reduces vasucular permeability
- recruitment & activity of inflammatory cells
- release of cytokines & mediators
132
give 3 examples of antihistamines (H1 receptor antagonists).
1) cetirizine
2) loratadine
3) fexofenadine
133
what is the mechanism for anti-histamines
competitive antagonists that reduces the effects of mast cell derived histamine
134
what are the 3 effects of mast cell derived histamine?
1) vasodilation & increased capillary permeability
2) activation of sensory nerves
3) mucus secretion from sub-mucosal glands
135
what is the mechanism for anti-cholinergic drugs?
muscarinic receptor antagonists
136
how do muscarinic receptors antagonists work?
- ACh released from post-ganglionic parasympathetic fibres activates msucarinnci receptors on nasal glands causing a watery secretion contnributing to rhinorrhoea
137
what is the mechanism of CysLT1 receptor antagonists.
= reduces the effects of CysLTs upon the nasal mucosa
138
what is the mechanism of a vasoconstrictor?
mimics the effect of noradrenaline.
| - produces vasoconstriction via activation of alpha 1 - andreoceptor to decrease swelling in vascular mucosa.
139
what is the mechanism for sodium cromoglicate?
mast cell stabilisation
