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(pharm) pharmacology of asthma Flashcards

1
Q

what five drugs are commonly prescribed to treat asthma?

A

salbutamol

fluticasone

mometasone

budesonide

montelukast

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2
Q

explain the primary mechanism of action of salbutamol

A

agonist of β2 receptors on airway smooth muscle cells

= reduce Ca2+ influx into smooth muscle cells

= less actin-myosin cross-bridge formation

= prevents smooth muscle contraction (reduced frequency and strength)

= BRONCHODILATION

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3
Q

what is the drug target for salbutamol?

A

beta-2 adrenergic receptors (on airway smooth muscle cells)

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4
Q

what are the main side effects of salbutamol?

A

palpitations/agitation

tachycardia

arrythmias

hypokalaemia (at higher doses)

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5
Q

what side effect of salbutamol can be risked at higher doses?

A

hypokalaemia

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6
Q

what can salbutamol be classified as?

A

short-acting beta agonist (SABA)

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7
Q

what is the half-life of salbutamol?

A

approx 2.5 to 5 hours

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8
Q

what is the selectivity of salbutamol like?

A

not specific to beta-2, can have beta-1 cardiac effects too

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9
Q

why can salbutamol cause tachycardia and arrhythmias?

A

direct activation of cardiac β2 adrenergic receptors

= increased sympathetic activation of the heart increases heart rate and arrhythmias

(off-target effects of salbutamol)

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10
Q

why can salbutamol cause tremors?

A

increased stimulation of sympathetic receptors in the skeletal muscles

(off-target effects of salbutamol)

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11
Q

how does salbutamol cause hypokalaemia?

A

via an effect on sodium-potassium ATPase

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12
Q

what can exacerbate the hypokalaemic effect of excess salbutamol administration?

A

coadministration with corticosteroids

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13
Q

explain the primary mechanism of action of fluticasone

A

directly decreases inflammatory cells (e.g eosinophils, mast cells, basophils, macrophages, neutrophils, dendritic cells)

and it decreases the cytokines + leukotrienes + histamine they produce

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14
Q

what is the drug target for fluticasone?

A

glucocorticoid receptors

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15
Q

what are the local side effects of fluticasone?

A

sore throat

hoarse voice

opportunistic oral infections

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16
Q

what are the systemic side effects of fluticasone?

A

growth retardation in children

hyperglycaemia

decreased bone mineral density

immunosuppression

effects on mood

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17
Q

what has a greater affinity to the glucocorticoid receptor: cortisol or fluticasone?

(what is the effect of this?)

A

fluticasone

adrenal suppression

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18
Q

what is the oral bioavailability of fluticasone?

A

less than 1%

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19
Q

how is the impaired oral bioavailability of fluticasone overcome?

A

systemic delivery via the inhaled route (predominantly via the pulmonary vasculature)

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20
Q

how is fluticasone delivered to the systemic circulation?

A

via the inhaled route (i.e. pulmonary vasculature)

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21
Q

why do inhaled corticosteroids cause adrenal suppression?

A

inhaled corticosteroids are a form of exogenous glucocorticoids that in turn suppress the endogenous production of glucocorticoids in the adrenal cortex

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22
Q

what is fluticasone an example of?

A

inhaled corticosteroid

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23
Q

why is the inhaled route better for fluticasone?

A

oral bioavailability is less than 1% AND inhaled route offers direct topical absorption of drug

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24
Q

why is the oral biolavailability of fluticasone less than 1%?

A

increased digestion and breakdown of fluticasone within the GI tract

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25
which drugs have an identical mechanism of action to fluticasone?
mometasone, budesonide
26
explain the primary mechanism of action of mometasone
directly decreases inflammatory cells (e.g eosinophils, mast cells, basophils, macrophages, neutrophils, dendritic cells) + decrease the cytokines /leukotrienes/histamine they produce
27
what is the drug target for mometasone?
glucocorticoid receptor
28
what are the local side effects of mometasone?
sore throat hoarse voice opportunistic oral infection
29
what are the systemic side effects of mometasone?
growth retardation in children hyperglycaemia decreased bone mineral density immunosuppression effects on mood
30
what has a greater affinity to the glucocorticoid receptor: cortisol or mometasone? (what is the effect of this?)
mometasone | adrenal suppression
31
what is the oral bioavailability of mometasone?
less than 1%
32
how is the impaired oral bioavailability of mometasone overcome?
systemic delivery via the inhaled route (predominantly via the pulmonary vasculature)
33
how is mometasone delivered to the systemic circulation?
via the inhaled route (i.e. pulmonary vasculature)
34
why is the inhaled route better for mometasone?
oral bioavailability is less than 1% AND inhaled route offers direct topical absorption of drug
35
why is the oral bioavailability of mometasone less than 1%?
increased digestion and breakdown of mometasone within the GI tract
36
explain the primary mechanism of action of budesonide
directly decreases inflammatory cells (e.g eosinophils, mast cells, basophils, macrophages, neutrophils, dendritic cells) + decrease the cytokines /leukotrienes/histamine they produce
37
what is the drug target for budesonide?
glucocorticoid receptor
38
what are the local side effects of budesonide?
sore throat hoarse voice opportunistic oral infection
39
what are the systemic side effects of budesonide?
growth retardation in children hyperglycaemia decreased bone mineral density immunosuppression effects on mood
40
what has a greater affinity to the glucocorticoid receptor: cortisol or budesonide? (what is the effect of this?)
budesonide | adrenal suppression
41
what is the oral bioavailability of budesonide?
less than 10%
42
how does the oral bioavailability of budesonide compare to that of fluticasone and mometasone and what is the impact of this?
oral bioavailability of budesonide is 10% while that of fluticasone and mometasone is only 1% = SO inhaled budesonide will result in some effective absorption via the GI tract
43
how does budesonide compare to fluticasone and mometasone in terms of potency and what does this mean?
budesonide is LESS potent than fluticasone and mometasone | i.e. budesonide requires higher drug concentrations to evoke the same physiological response
44
explain the mechanism of action of montelukast
antagonist of CysLT1 leukotriene receptor on eosinophils, mast cells and airway smooth muscle cells decreases eosinophil migration + inflammation induced oedema AND reduces bronchoconstriction (relaxes ASM)
45
what is the drug target for montelukast?
CysLT1 leukotriene receptor
46
what are the mild side effects of montelukast?
diarrhoea fever headaches nausea/vomiting
47
what are the more serious side effects of montelukast?
mood changes anaphylaxis
48
what is exercise-induced bronchoconstriction?
(i.e. EIB, exercise-induced bronchospasm, exercise-induced asthma) when airways narrow as a result of exercise, making it hard to breathe
49
how can exercise-induced asthma be treated?
administer montelukast as least two hours before initiating exercise
50
how can montelukast be used to treat exercise-induced bronchoconstriction?
administer montelukast as least two hours before initiating exercise
51
what are the two main possible causes of asthma?
- atopic (i.e. allergens) - precipitated by an infection (also, smoke/fumes, medicines like anti-inflammatories)
52
what are the TWO main therapeutic objectives for patients with asthma?
1) short-term relief | 2) long-term prevention
53
how is short-term relief provided for patient with asthma?
!! during the acute asthma attack !! = relieve symptoms of breathlessness and expiratory wheeze
54
how is long-term prevention provided for patient with asthma?
1) dampen/prevent the late phase of the asthma attack 2) reduce the risk of further asthma attacks 3) attempt to improve lung function
55
what two parts does an asthma attack normally comprise of?
1) acute, immediate phase (mainly bronchospasm) | 2) delayed phase (inflammatory reaction)
56
what does the immediate phase of an asthma attack include?
mainly bronchospasm
57
what does the delayed phase of an asthma attack include?
inflammation
58
following exposure to the allergen, when does the acute phase occur as opposed to the delayed phase?
acute phase = within the hour delayed phase = after 6+ hours
59
what must you remember about managing asthma in under 5s?
very difficult to diagnose objectively | + need to carefully and frequently monitor symptoms
60
explain how bronchodilation is stimulated by a beta-2 agonist
beta-2 agonist acts to activate the beta-2 adrenoreceptor on ASM cells (on which adrenaline normally acts) once activated, Ca2+ entry into the ASMCs is reduced with less Ca2+, less ASMC muscle contraction can occur = overall, bronchodilation occurs
61
explain how bronchoconstriction is normally stimulated
post-ganglionic parasympathetic fibres release ACh ACh acts on the M2 & M3 muscarinic receptors on ASMCs = both collectively stimulate bronchoconstriction
62
which airway smooth muscle cell receptors are activated to stimulate bronchodilation?
beta-2 adrenoreceptors | stimulated by adrenaline
63
which airway smooth muscle cell receptors are activated to stimulate bronchoconstriction?
M2 & M3 muscarinic receptors | stimulated by acetylcholine released by post-ganglionic parasympathetic neurones
64
what are the two possible routes of salbutamol administration?
1) local administration directly into the nose = inhalation of aerosol 2) systemic administration of immediate-release medicines = oral intake of medicines
65
why is the inhalation route preferred over the oral route in terms of salbutamol administration?
inhalation route = direct administration into the nasal path 1) rapid onset of action of drug 2) lower doses need to be administered (less accommodation needs to be made for drug losses as there will be less loss) 3) better efficacy to safety ratio
66
in emergency situations, why is the nebuliser the best method of delivering salbutamol?
- minimal patient cooperation required - suitable for all ages - many drug solutions/combinations - concentration and dose can be modified
67
when salbutamol is inhaled, only 20% is penetrates deep enough into the lungs to achieve its therapeutic effect and influence lung function where does the remaining 80% of the inhaled salbutamol go?
lost via a number of routes 1) exhalation (only 20% is deposited in the lungs) 2) absorption from lungs into systemic circulation 3) mucociliary clearance 4) oral swallowed portion (absorption into GI tract, metabolised in liver, absorbed into the bloodstream) 5) absorbed across the mucous membranes of the oral cavity + pharynx
68
why is lung deposition essential for salbutamol?
the drug needs to remain in the lung in order to have its desired, therapeutic effect
69
what is mucociliary clearance?
primary innate defence mechanism of the lung = comprises of the protective mucous layer + airway surface liquid layer + cilia
70
what happens when salbutamol is swallowed?
absorbed into the GI tract, metabolised by the lungs, absorbed into the systemic circulation
71
which mucous membranes is salbutamol commonly absorbed across?
those of the 1) oral cavity 2) pharynx
72
what are the components that make up mucociliary clearance?
1) protective mucous layer 2) airway surface liquid layer 3) cilia
73
why is a spacer clinically useful (especially in children)?
huge discrepancy between expected and actual dose = spacer will help deliver the MORE drug DEEPER into the lungs so reduced scope for loss of drug (i.e. exhalation, swallowing etc)
74
what is the mechanism of action of fluticasone propionate in terms of reducing eosinophilic inflammation?
fluticasone = inhaled corticosteroid - reduces the number of mast cells, monocytes, macrophages, dendritic cells AND eosinophils along w the cytokines they produce (e.g. IL-4, IL-5, IL-13) - w less IL-5, there is less eosinophilic growth and activation
75
how do viral infections lead to lead to asthma exacerbations? (describe the vicious cycle)
- viral infections can release mediators that will specifically activate eosinophils - eosinophils can lead to epithelial damage due to release of granular contents = in turn, weak epithelium can increase susceptibility to viral infections
76
like salbutamol, a significant proportion of inhaled fluticasone is actually swallowed despite this, the oral bioavailability (i.e. the proportion of drug that reaches the plasma VIA the gastrointestinal tract) is less than 1%. Why is this the case?
due to the impact of first-pass inactivation
77
what is first-pass inactivation?
when a drug gets metabolised at a specific location in the body that results in a reduced concentration of the active drug upon 1) reaching its site of action OR 2) reaching the systemic circulation
78
define oral bioavailability
the proportion of the drug that reaches the plasma via the GI tract
79
what is the mechanism of action of montelukast?
- antagonist of the CysLT1 leukotriene receptor found on the surface of mast cells, eosinophils and ASMCs - results in decreased inflammation-induced oedema, decreased esoinophil migration and decreased bronchoconstriction
80
what is NSAID-induced asthma?
when the symptoms of asthma are caused by NSAID use (inhibits COX enzyme, augments leukotriene synthesis, increased activation of CysLT1 receptor, subsequent asthma symptoms)
81
explain how NSAID-induced asthma occurs
NSAIDs inhibit cyclooxygenase = reduce prostaglandin synthesis = thereby, also augments leukotriene synthesis (from parent arachadonic acid) = w more leukotrienes C4, D4 and E4, there is more activation of the CysLT1 receptor = increased bronchoconstriction, inflammation-induced oedema and eosinophil migration = NSAID-induced asthma
82
explain the mechanism of action of montelukast
montelukast is a CysLT1 antagonist = blocks the CysLT1 receptor so leukotrienes cannot bind to it and activate it = decreased 1) eosinophilic migration (eosinophilic CysLT1) 2) inflammation-induced oedema (mast cell CysLT1) 3) bronchoconstriction (ASMC CysLT1)
83
explain why montelukast is particularly useful for NSAID-induced asthma
montelukast antagonises the CysLT1 receptor = by blocking it, activation of it by leukotrienes is prevented (essential especially when in NSAID-induced asthma, there is an augmented level of leukotrienes) = subsequently, less bronchoconstriction + inflammation-induced oedema and eosinophilic migration
84
why are NSAIDs counter-indicated for asthmatics?
intake of NSAIDs will inhibit the COX enzyme and therefore prostaglandin synthesis = increased subsequent leukotriene synthesis (only other alternative pathway from arachadonic acid) = increased CysLT1 activation = increased bronchoconstriction, increased eosinophilic migration, increased-inflammation oedema soooo asthmatics should avoid NSAID use in the first place
85
why is there normally an augmented level of leukotrienes in NSAID-induced asthma?
when NSAIDs are taken, inhibition of COX enzyme (and therefore the prostaglandin synthesis pathway) = subsequent augmentation of (the only alternative) leukotriene synthesis pathway = increased leukotriene B4, C4, D4, E4 synthesis = increased activation of CysLT1 receptor = symptoms of asthma

brs (phase 1b) (71 decks)

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