treatments for the respiratory system Flashcards
what is asthma characterised by
airway obstruction
in context to asthma, what is airway obstruction caused by (2)
hyper responsive airway smooth muscle - e.g. change in temp of air, PM, can be spontaneous - narrowing, wheezing, shortness of breath
airway inflammation - overproduction of proinflammatory proteins
what can airway hyper responsiveness be triggered by (4)
allergens
cold air
excercise
emotional stress
what does exposure to stimuli result in
release of pro-inflammatory proteins
what are symptoms of asthma (4)
difficulty breathing
shortness of breath
wheezing
coughing
what drugs are used to treat asthma (2)
anti inflammatory drugs
bronchodilators
what drugs can patients with asthma benefit from
corticosteroids (type of glucocorticoid)
ideal as asthma is inflammatory
reduces inflammation
how to minimise off target systemic effects from corticosteroids
inhaled corticosteroids (ICSs)
goes to lungs
examples of inhaled corticosteroids (3)
fluticasone
budesonide
beclomethasone
are inhaled corticosteroids useful for long or short term asthma attack prevention
long term
how are inhaled corticosteroids administered and why
spacer device e.g. AeroChamber
dec. amount of drug deposited from mouth and upper airways
facilitates delivery of ICSs to bronchioles
what occurs when corticosteroids are inhaled
diffuse across cell membrane, bind to glucocortioid receptors in cell cytoplasm
what are glucocorticoid receptors (GRs)
type of nuclear receptor
what are nuclear receptors
sense steroid and thyroid hormones
bind directly to DNA in nucleus and regulate expression genes
are thus classified as transcription factors
what occurs once glucocorticoid receptors (GRs) are activated
in cell cytoplasm form homodimer
translocate into nucleus and produce effect
the glucocorticoid receptors interact with the glucocorticoid response element (GRE) in the promoter region of steroid responsive genes
this switches on (sometimes off) gene transciption
examples of genes activated by inhaled corticosteroids (ICSs) (2)
β2-adrenergic receptors
Anti-inflammatory proteins
2 examples of anti inflammatory proteins
secretory leukoprotease inhibitor
mitogen activated protein kinase phosphatase-1 (MKP-1)
what does mitogen activated protein kinase phosphatase-1 (MKP-1) do
inhibit MAP kinase pathways which thus promotes mucus production to obstruct airways
what occurs when glucocorticoid receptors (GRs) interact with negative glucocorticoid response element (GRE)
may suppress gene transcription
may be important in mediating side effects associated with ICS use
when glucocorticoid receptors (GRs) interact with negative glucocorticoid response element (GRE) gene transcription may be suppressed. this may be important in mediating side effects associated with ICS use. what is an example of this?
corticosteroids inhibit the expression of osteocalcin that is involved in bone synthesis
what is the major action of corticosteroids
to switch off multiple activated inflammatory genes that encode for pro-inflammatory mediators e.g. cytokines
corticosteroids switch off multiple activated inflammatory genes that encode for pro-inflammatory mediators e.g. cytokines. how are these genes switched on in airways?
by proinflammatory transcription factors e.g. nuclear factor-κB (NF-κB)
interact with coactivator molecules like CREB-binding protein (CBP)
what is an example of a proinflammatory transcription factor
nuclear factor-κB (NF-κB)
Corticosteroid-activated glucocorticoid receptors (GR) interact with coactivator molecules such as CREB-binding protein (CBP) and this inhibits the action of ____ with coactivators
NF-κB
Corticosteroid-activated glucocorticoid receptors (GR) interact with coactivator molecules such as ____ and this inhibits the action of NF-κB with coactivators
CREB-binding protein (CBP)
ICSs only inhibit inflammation when____
it is activated through proteins such as NF-κB
what are bronchodilators
treatment of asthma
dilates bronchi and bronchioles to decrease airway resistance in and increase airflow to lungs
relaxes smooth muscle
what are the three main drug classes of bronchodilators
Short-Acting β2-agonists (SABA) aka ‘Reliever inhalers’
Long-Acting β2-agonists (LABA) aka ‘Preventer inhalers’, taken once daily Muscarinic acetylcholine receptor antagonists, also called short - acting muscarinic antagonists (SAMA)
what is an example of a Short-Acting β2-agonist (SABA)
salbutamol
mechanism of action of Short-Acting β2-agonists (SABA)
SABAs bind to β2-adrenergic receptors (β2-AR) in the lower respiratory tract
activates Gas
β2-AR stimulates cyclic adenosine monophosphate (cAMP) production
cAMP activates protein kinase A (PKA)
myosin light chain kinase (MLCK) promotes airway muscle contraction via sliding filament theory - two filaments contract and slide together
cAMP and PKA inhibit MLCK, promotes bronchodilation
cAMP and PKA activate myosin light chain phosphatase (MLCP), promotes smooth muscle relaxation
how much does asthma cost the NHS
1.1 billion annually
what are β2-adrenergic receptors (β2-AR) an example of
GPCRs
what are β2-adrenergic receptors (β2-AR) GPCRs coupled to
Gas/ G alpha stimulatory pathway
activates adenylate cyclase
myosin light chain phosphatase (MLCP)
promotes smooth muscle relaxation
myosin light chain kinase (MLCK)
promotes airway muscle contraction
what is an example of a Long-Acting β2-agonist (LABA)
salmeterol with ICS fluticasone
mechanism of action of Long-Acting β2-agonist (LABA)
LABAs bind to β2-adrenergic receptors (β2-AR) in the lower respiratory tract
activates Gas
β2-AR stimulates cyclic adenosine monophosphate (cAMP) production
cAMP activates protein kinase A (PKA)
myosin light chain kinase (MLCK) promotes airway muscle contraction via sliding filament theory - two filaments contract and slide together
cAMP and PKA inhibit MLCK, promotes bronchodilation
cAMP and PKA activate myosin light chain phosphatase (MLCP), promotes smooth muscle relaxation
same as SABA
how are Long-Acting β2-agonist (LABAs) administered
with inhaled corticosteroids ICSs
as ICS suppresses chronic inflammation, activate genes to increase β2-adrenergic receptor production, reduce airway hyper responsiveness
synergistic drug action
synergistic drug action example
Long-Acting β2-agonist (LABAs) with inhaled corticosteroids ICSs
as ICS suppresses chronic inflammation, activate genes to increase β2-adrenergic receptor production, reduce airway hyper responsiveness
thus, ICS increases drug targets for LABA
and protects against downregulation of β2-receptors after long term administration as ICSs switch on pathways
Long-Acting β2-agonist (LABAs) affect glucocorticoid receptors (GRs) and enhances anti inflammatory effects of ICSs by inc translocation into nucleus
what is a synergistic effect
two drugs used together and result is greater than what you would expect if you add together the effect of each drug independently
what is an additive effect
two drugs used together and result is what you would expect if you add together the effect of each drug independently
β2-adrenergic receptor mutations
can cause inc in downregulation
what are nebulisers
mist of drug to breathe in, easier to enter lung tissue
nebulisation and COVID-19
may cause dispersion of COVID-19 into surrounding environment, potentially putting surrounding people at risk
Viable SARS-CoV-2 is reported in aerosols generated by nebulisers for up to __ hours
3
other than LABAs and SABAs, ___ ___ ___ are also used bronchodilators
muscarinic receptor antagonists
or anticholinergic bronchodilators
muscarinic receptor antagonists or anticholinergic bronchodilators exert their function through
muscarinic acetylcholine receptors (mAChRs)
muscarinic acetylcholine receptors (mAChRs) are
Gq - coupled GPCRs that raise intracellular calcium levels
muscarinic acetylcholine receptors (mAChRs) pathway
Gq activation
some shit abt pip2 idk
inc intracellular calcium inc PKC activation
calcium ions interact with calmodulin forming calcium-calmodulin complex
complex activates MLCK
MLCK phosphorylates myosin, promotes smooth muscle contraction
examples of muscarinic acetylcholine receptor (mAChR) antagonists (2)
ipratropium
tiotropium
muscarinic acetylcholine receptor (mAChR) antagonist mechanism of action
inhibit activation of mAChRs
no inc in intracellular calcium
no MLCK activation
prevent contraction of smooth muscle in airways
chronic obstructive pulmonary disease (COPD) treatment focus
no cure, therapies slow progression
chronic obstructive pulmonary disease (COPD) treatments
ICSs
SABAs
LABAs
mAChR antagonists
smoking prevention
nicotine cessation therapy
what is nicotine
major psychoactive compound in cigarette smoke
binds to nicotine acetylcholine receptors (nAchRs)
what contributes most to nicotine-dependence
rate of metabolism (varies by person)
nmr
how is nicotine metabolised
phase 1 metabolism via cyp2a6 (90%) and cyp2b6 (10%)
into cotenine
via cyp2a6
into 3’ hydroxycotinine
how does nicotine absorption occur
oral cavity mostly
skin
lung
urinary bladder
gastrointestinal tract
respiratory absorption of nicotine is __ to __ %
60 to 80
large value when smoked due to high surface area of alveoli in lungs
absorption of nicotine when ingested
poorly absorbed as gastric fluid is acidic causing ionisation in stomach
well absorbed in small intestine
three types of nicotine cessation therapy
nicotine replacement therapy e.g. nicotine patches
varenicline
bupropion
varenicline
competitive partial agonist for nAChR
competes with nicotine, get lesser effect when exposed to nicotine
bupropion
non competitive antagonist of nAChR
allosteric binding
what is the nicotine metabolite ratio (NMR)
ratio of ‘3 hydroxycotinine to cotinine
indicates cyp2a6 ability in smokers
faster metabolisers of nicotine have a ____ NMR
greater
slower metabolisers of nicotine have a ____ NMR
smaller
faster metabolisers of nicotine are likely to benefit from ___
varenicline
as not metabolised as quick as nicotine in nicotine patches would
slower metabolisers of nicotine are likely to benefit from ___
varenicline or nicotine replacement therapy equally
ICSs switch off activated inflammatory genes through recruitment of _____ _____ _____
histone deacetylase 2
HDAC2
COPD patients are _____ resistant
corticosteroid
thus, admin. with LABAs
asthma patients who smoke are more _____ resistant. why
corticosteroid
as reduction in HDAC2 expression, less target for ICSs to switch off
ICSs activate ______ which decreases inflammatory peptides like ______ and other inflammatory cells like ____ and ____
lipocortin-1
endothelin-1
mast cells and dendritic cells
ICS budenoside
greater first pass metabolism, less likely to produce systemic effects at high doses, inc local effect on airway mucosa
spacer chambers
reduce oropharyngeal deposition and reduces systemic absorption
in COPD, it was found that adding _____ to ICS is more effective than increasing ICS dose alone
salmeterol
ICS local side effects
dysphonia - common
pneumonia - esp in COPD
ICSs systemic side effects
bruising as inhibits dermal fibrolasts that produce collagen, which is needed for resilience and skin structure
spacer device e.g. AeroChamber are attachments for ____ and (general indo)
pressurized metered-dose inhalers (pMDIs)
ensures more med reaches lungs vs depositing in the oropharynx
inc drug efficacy
dec local side effects e.g. oral candidiasis
compare asthma treatments - 4 main points
ICS more effective as switch off inflammatory genes
bronchodilators provide rapid symptom relief (or long term if LABA)
better used synergystically - LABA and ICSs for moderate to severe cases
ICS side effects dec by using spacer device/improved drug delivery - esp found in children dec side effects
Myosin light chain kinase (MLCK) and myosin light chain phosphatase (MLCP) control the activity of
myosin II - which is a motor protein involved in sliding filament mechanism
activated MLCK phosphorylates the regulatory light chain of myosin, inducing a
conformational change in myosin
inc ATPase activity
causing muscle contraction
Myosin light chain Phosphatase (MLCP) dephosphorylates the regulatory light chain of myosin, causing
red in myosin ATPase activity
causing muscle relaxation
sliding filament theory in smooth muscle - 6 steps
calcium influx intracellularly
calcium binds to calmodulin
MLCK activation
phosphorylation by MLCK of myosin light chain enables cross bridge cycling with actin
myosin binds to actin, hydrolises ATP, produce sliding of actin filaments over myosin , causing contraction
when MLCP dephosphorylates myosin, ATPase activity red and muscle relaxation
combination therapy in COPD case study
muscarinic receptor antag/ SAMA
ipratroprium combined with albuterol SABA
sig additive effects
albuterol binds to B2 adrenergic receptors
activates cAMP, inc PKA, MLCK function - bronchodilation
ipratropium blocks M3 muscarinic receptors which normally activated by ACH, thus inhibits PLC IP3 pathway, dec intracellular calcium levels, bronchodilation
separate mechanisms so additive - better symptom relief, improved lung function when used together
what clinicals we gaf - 2
asthma
copd
types of drugs used to treat clinicals - 6
asthma and copd:
anti inflammatory drugs (ICS
bronchodilators (SABA, LABA, Muscarinic acetylcholine receptor antagonists, also called short - acting muscarinic antagonists (SAMA)
copd only:
smoking prevention
nicotine cessation therapy
examples of each drug type - 10
asthma and copd:
ICS: fluticasone, budesonide, beclomethasone (with nebulisers oops covid maybe) (copd dont do well so add laba)
SABA: salbutamol
LABA: salmeterol with ICS fluticasone - synergistic
SAMA: ipratropium, tiotropium
copd only:
nicotine replacement therapy e.g. nicotine patches
varenicline
bupropion
