Lecture 5 Flashcards
Obstruction of airway flow in asthma is due to 3 things
airway inflammation
bronchial hyperresponsiveness
smooth muscle constriction
Asthma is
chronic long term inflammatory condition affecting the upper airways in the lungs
asthma is characterized by
reversible bronchoconstriction and SOB
COPD is
a chronic progressive respiratory disease
COPD causes
irreversible restricted airflow and breathing problems
restricted airflow is due to
destruction of parts of the lung including alveoli.
mucus blocking the airways
inflammation and swelling of the airway lining.
is COPD curable?
Not curable, but can be managed by medications.
benefits of inhaled drug deposition
- effective use of smaller dose
- lower incidence of unwanted systemic effects
- rapid onset of action
- controlled delivery
Name two common short acting beta agonists
salbutamol and terbutaline
name two common LABA
sameterol, formoterol
MOA of B2 agonists
- B2 agonists bind and stabilize the receptor in the activated stage.
- activates adenylate cyclase, increases generation of cAMP from ATP
- cAMP inhibits Ca, hyperpolarizes smooth muscle cells = bronchodilation
- cAMP also activates protein kinase A, incrasing protein phosphorylation, regulates smooth muscle tone, = bronchodilation
what happens with frequent use of B2 agonists
- enhance inflammatory pathways, downregulation of B2receptors and tolerance to bronchodilator effects
- receptors desensitize rapidly, so B2 agonists do not reduce airway inflammation.
SABA onset of action
5 minutes
SABA peak effect (max bronchodilation)
15-30 minutes
how long do SABA bronchodilation effect last until
2-6 hours
How are SABAs administered
Inhalation, salbutamol sometimes given with IV infusion.
When should SABAs be used and why
intermittently or as needed
LABA duration of action
up to 12 hours, more lipophilic than SABAs and bind to the lipid of the smooth muscle cell membrane.
Which LABA has slower onset compared to others
salmeterol
low efficacy agonist LABA
salmeterol (60% partial agonist activity)
high efficacy agonists LABA
formoterol and Indacaterol - full agonist activity
should LABAs be used alone in asthma
NO! should be used as an add on to ICS to control persistent symptoms in adults. It reduces the risk of exacerbations compared to ICS alone
should LABAs be used alone in COPD
Can be used alone or in combo with CIS or LAMA
what do LABAs do alone in COPD
improve symptoms and exercise tolerance by reducing both air trapping and exacerbations.
ADRs of B2 agonists
muscle tremors, restlessness, headache, arrythmias and tachycardia. Hypokalemia in high doses
LABAS AND SABAS should be used with
Inhaled Corticosteroids for anti-inflammatory therapy
2 steps of Glucocorticoid receptors
- bind GS and GR undergoes confirmational change, ebcomes activates and dissociates from multi-protein complexes
- GR transolcates into the nucleus and regulates gene expression.
Which enzyme moves a gene to the active stage
histone acetyltransferases
which enzyme silences the genes
histone deacetylases
what genes do GCS turn on/off
Switch ON anti-inflammatory gene expression
Switch OFF inflammatory gene expression
Do CS have any benefit in the initial stages
NO, not in an acute attack bc they are NOT bronchodilators just anti-inflammatory agents.
what do CS enable in asthma
less frequent use of bronchodilators
List 4 common systemic corticosteroids
prednisone, prednisolone, methylprednisolone, hydrocortisone
Name 6 inhaled corticosteroids
Beclomethasone, budenoside ciclesonide, fluticasone, mometasone, triamcinolone
When should ICS be used for asthma
drug of choice for regular controller therapy, should be used regularly
side effects local of ICS
hoarseness (dysphonia) caused by drug deposition on vocal cords
throat irritation
coughing
thrush
ICS prolonged use SE
increased pneumonia risk
cataracs
HPA axis supression
osteoporosis
growth restriction
skin thinning/bruising
benefits of LABA ICS therapy
adding a laba to an ICS is more effective than doubling ICS dose which also limits risk of side effects.
what does the M3 receptor in the airways do
bronchoconstriction, increased bronchial secretions
name a SAMA
ipratropium
name a LAMA
Tiotroprium
SAMA onset of action, peak, duration of action
15 mins, peak at 1-2 hours, duration of action 5-6 hours
Ipratropium SE
metallic/bitter taste when inhaled
LAMA MOA
functionally selective for M3 receptors due to faster disassociation from M2
Onset, peak, duration of action
30 mins, 3-4 hours, 24 hours
what is the dosing of a LAMA
once daily dosing
SE LAMA
dry mouth, tachycardia, urinary retentoin
why is tiotropium better than ipratropium?
more specific, longer duration of efficacy
are antimuscarinics more or less effective as bronchodilators than b2 agonists
less
role of antimuscarinics in COPD
release of ACh causes vagally-mediated bronchospasm, major reversible component of COPD
LABA + LAMA combo therapy
additive bronchodilator effect, not synergistic
PDE’s roles
hydrolyze cAMP and cGMP, hence they deactivate their cAMP/cGMP mediated effects
which PDE is important for anti-inflammatory stuff
PDE 4
methylxanthines are ?
PDE inhibitors
Methylxanthines act to relax airways by
inhibit PDEs
Antagonize Adenosine receptors
activation of histone deacetylases
how do methylxanthines work on adenosine recepors
adenosine causes bronchocontriction and inflammation. Methylxanthines inhibit the receptors thus causing bronchodilation and anti-inflammatory effects
name two methylxanthines
theophylline and aminophylline
PDE4 inhibitor
roflumilast
Indication of Roflumilast
Patients with COPD with chronic bronchitis , with frequent exacerbations
can roflumilast be used alone
NO! only has anti-inflammatory effects, doenst work for relief of acute symptoms.
what is Roflumilast CI in
patients taking theophylline because it reduces roflumilast clearance
Leukotrienes are a family of ______
inflammatory lipid mediators
leukotrienes cause
narrowing and swelling of the airways in the lungs
name two leukotriene receptor antagonists
Montelukast and Zafirlukast
