Lecture 13- Treatment of Asthma Flashcards
Goals of Asthma treatment
- Control chronic symptoms
- Maintain normal activity levels and exercise
- Maintain near-normal pulmonary function
- prevent exacerbation of asthma
- Minimise ED/hospital visits
- Avoid adverse medication effects
Types of Asthma treatment
1) Relievers: short term, rapid onset, for acute attack. Relaxes smooth muscle in airway
2) Preventer: No relief, just long-term control. Take daily
3) Others
Bronchodilators/reliever types
1) Inhaled beta-adrenergic agonist
2) Anticholinergic agents
3) Xanthine drugs
Inhaled beta-adrenergic agonist
Used 3000 years ago from plants.
- > Relieves bronchiconstriction by relaxing SM
- > Protects from cold/exercise constrictor stimuli
- > Increases mucociliary clearance due to increased ciliary beat frequency
- > may reduce inflammation due to inhibition of mediator release from inflamm cells
How does B-adrenergic agonist relax SM
B2 agonist diffuses then bonds with a transmembrane receptor, which activates Gs protein, which activates AC (adenylate cyclase) which enhances ATP and converts it to cAMP. Then as cAMP increases, PKA activity/concentration increases also. This has lots of consequences
-Ca2+ & K+ channel activated, lots of K+ outside the cell.
- Inc. Na/K ATPASE
- Decr. PI hydrolysis
- Inc. Na/Ca exchange
-Decr. MLCK
This ALL cause SM relaxation and inhibits mediator release.
Theophylline
SImilar function to B-adrenergic agonist.
Because it inhibits transformation from cAMP to AMP, therefore retaining the cAMP concentration.
Is the B-agonist selective or non-selective
non-selective. Lots of receptors at other areas,
LUNGS: Mainly B2 eg) SM, epithelium, submucosal, club cell etc
When the B2 is activated, it causes SM relaxation, reduces edema and inhibits mediator release
OTHER: in places like Heart(inc HR), arterioles, skeletal muscle(tremor) ((think of hospital)))
..and fat cells (lipolysis- weight control?)
Therefore receptors in other tissues are activated = ADVERSE EFFECTS
Route of Administration
- Inhalation: Very high concentration, fast onset and less systematic (adverse) effects
- Oral: inc adverse effects. BUT helpful if patient can’t breath or is clogged with spetum.
- Direct endotracheal instillation
Types of inhalers
- Metered dose inhalers (aerosol spray): we can deliver 15-20% of drug to the lung. DOn’t need to force to inhale in, just a little training.
- Dry powder device: 25-30% drug to lung, no training required. Not suitable for kids if they can’t breathe or if particles are too large.
Issues with inhalers
- Small airways & tidal volume
- Rapid respiration
- nose breathing
- aversion to masks
- cognitive ability
- Fussiness & crying
Spacer largely improves this by increasing the % of medicine reaching the lungs. Reduces systematic/adverse effects from swallowing meds
Nebulizers
Machine that generates hot warm steam mixed with meds. Comforts airways
easier for patient to cough sputum
allows for mixing of meds
What do we use to decide which B-agonist to use? Commonly used drugs are?
Onset of Action : rapid or slow
Duration of Action: short-acting or long-acting
As an acute attack can occur within 5-10 mins, and we need quick relief, we need a “ rapid-onset long-action drug”
—–> ‘formoterol’
Short-Acting B2-adrenoreceptor Agonists
Rapid onset but short-duration
max effect: with 30min
duration: 4-6hrs
Effective in preventing cold/exercise/allergin triggered asthma
also used for acute severe asthma- use ‘as needed’
Done inhaled or orally
ADVERSE EFFECTS:
- Tremor (due to B2 receptor in skeletal muscle)
- Tolerance/tachyphlaxis (down-reg of B2 receptors) don’t confuse with sputum clogging
- Hypokalemia
- Tachycardia
Long-Acting B2-adrenoreceptor Agonists
Long duration: ~24hr
Use on regular basis
Prevent bronchospasm in patients requiring bronchodilator therapy
Inhaled corticosteroid (ICS) and LABA used as combined therapy»_space; thought to be better asthma control… but turned out to make asthma episodes MORE SEVERE when they did occur.
FDA LABA view
LABAs shouldn’t be used as 1st line to treat asthma.
Only used if other meds don’t control asthma
Don’t relieve sudden wheezing (use bronchodilator)
mmm
horses, tennis players and cyclists banned from using salbutamol in sports
Acetylcholine can cause…..
Acetylcholine cane be synthesized in …
Acetylcholine can cause bronchoconstriction and mucus secretion in airways
Acetylcholine can be synthesized in PS nerves by ‘choline acetyltransferase’ and stored in secretory vesicles.
ACh increases submucosal gland secretion, SM contraction and mediator release from inflamm cells. Anticholinergics are used to inhibit this.
Anticholinergic Agents
Non-selective, block ALL receptors
1) Ipratropium Bromide
- slow-onset (60-90mins), shorter duration (6-8hrs)
- Use on regular basis
- Low side effect, less tachyphylaxis
- Problems: reduced mucociliary clearance
2) Tiotropium Bromide (best)
-long-lasting muscarinic antagonist >24hrs
-Equal affinity for M1-3 receptors (but dissociates rapidly from M2)
-10x potent than ipratropium bromide
-Problems with dry mouth in 10-15%
Side effects: dry mouth, constipation, blurred vision
Theophylline cons
arrhythmia
CNS stimulation
Gastric acid stimulation
diuresis
Theophylline pros
RESPIRATORY
- Bronchodilation
- improve gas exchange
- respiratory stimulation
- increase diaphragm muscle strength and reduce diaphragm fatigue
- increase mucociliary clearance
- improve exercise ability, health status
NON-RESP
- improve cardio-vascular performance
- decrease pulmonary artery pressure
- diuresis
Side effects of theophylline
narrow therapeutic range
easy toxicity
nausea, vomiting etc
Glucocorticoids
class of steroid hormone with anti-inflammatory effects
-One pro-drug that becomes a drug “ON SITE”, reduces systemic effects
- Regulate carbs, protein and lipid metabolism
- Maintain fluid & electrolyte balance
- Preserve normal function of the cardiovascular, immune kidney, skeletal muscles/systems
- preserve organisms homeostasis
How do GCS work?
- GCs diffuse through the membrane, and bond with GR receptor
- then travels into nucleus, where it does
1) gene activation >genetranscription > inc anti-inflam mediator release
2) Gene Repression > decr inflamm gene trnascription
GCs effect
- Supress inflammatory cells (eosinophils, basophils, monocytes, dendritic cells) and reduces their numbers
- Inhibit the synthesis, release and expression of CKs, inflamm peptides, chemokines, growth factors, adhesion molecules
REDUCES INFLAMMATORY RESPONSE
-up-regulation of Beta-adrenergic receptors on airway smooth muscle cells
Oral GCs
Prednisone: inactive pro-drug and is metabolised in liver
Dexamethasone: 25x potent then previous
GCs in chronic asthma treatment
- Inhaled GCs can decrease asthma symptoms, # of bronchodilator uses and frequency of acute asthma symptoms; and can improve lung function and bronchial hyper-responsivness
- Can be seen 2-4weeks in
Common issue of GCs
patients/parents allergic to word ‘steroid’
80% left in mouth and swallowed, so if used long-term it can promote buffalo hump, moon face etc.
This is because you increase glucogenesis >diabtetes or obesity
Osteoporosis
Inc BP
CNS > depressions
Coughing, thrush etc is a common adverse effect of GCs. How can these be prevented?
Rinse mouth, use spacer
Outgrowing asthma
- Only 6% kids ‘outgrew’ their asthma (had non for 1yr)
- 39% had improvement but still symptoms
- Effects of ICS on % outgrowing asthma still unclear
Leukotriene Receptor Agonist
inibit LTC4 and LTD4
Prevents:
-aspirin & exercise induced asthma
-decrease both early & late responses to inhaled allergin
Relaxes airway in mild asthma
-BD effec = 1/3 of salbutamol
can give headache, GI distrurbance
Mast Cell Stabilizer
- For acute response to stabilise SM
eg) cromolyn sodium, nedocromil sodium
Cromolyn Sodium
Prevents both exercise/allergin
Pros:
-non-steroidal
-less systematic effect
Cons:
-takes long time (4-6weeks) to see result
Final note
Although we have lots of drugs to treat asthma, the cause of asthma is still not clear
Xanthine drugs
-non-selective inhibition of phosphodiesterase: causes bronchodilation
-activates histone deacetylases related to anti-inflamm effects
»‘theophylline’
