β2– agonists
These act on β2 adrenoceptors on bronchial smooth muscle, causing dilation of the smooth muscle whatever the cause.
They are selective because they only target the β2 receptors (not β1) and thus do not act on the myocardium
Mechanism
- They bind to the β2 receptor, which then sets of a second messenger system leading to increased activation of cAMP from ATP, leading to activated protein kinases, which ultimately results in reduced circulating Ca2+ and thus smooth muscle relaxation.
- They also reduce mediator release from mast cells thus reducing overall inflammation, and allowing mucous clearance (mucociliary clearance).
- The dose relationship is log linear – which means that you need a 10x increase in dose to 2x the effect.
- The effect of the drug can be seen within 5 minutes
- They have NO EFFECT on bronchial hyper-reactivity, and their effect on the underlying inflammation is limited
Examples
| Category |
Drugs
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Other names
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Short acting (~3-6 hours)
|
Salbutamol
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Ventolin
|
|
Terbutaline
|
–
|
|
|
Long acting (~8-12 hours)
|
Salmeterol
|
–
|
|
Oxis, foradile, foradil, atock
|
Short acting drugs are used PRN
Long acting drugs tend to be used twice a day in patients with severe disease – they are always used in combination with an inhaled corticosteroid – they should never be used alone.
- Their ‘long-action’ is due to a lipophilic side chain, that will stick to part of the cell membrane next to the receptor once the drug has bound to the receptor, and literally just hold it in place for longer.
Note that – with inhaled drugs, only 15% of the inhaled dose actually makes it to the lungs, the rest is mostly deposited on the back of the throat.
Unwanted effects
- Fine tremor – this may be present if a patient is on a high dose of these for a long period. It is unlikely that inhaler use alone will cause this, and it most common occurs in patients who are taking nebulized forms of the drugs. This results from β2 stimulation
- Tachycardia and arrhythmia can result when high doses are taken. This is a result of β1 and β2 stimulation
- Headache
- Bronchospasm can sometimes occur the first time the drug is taken.
- Oral candidiasis can occur when the drugs are used long term. Some practicioners recommend to rinse the mouth and spit after the inhaler is used to reduce the likelihood of this.
- Acute metabolic responses – these will not persist long-term, but initially can include hypokalaemia, hypomagnesaemia and hyperglycaemia.
- Tolerance can occur if you overuse them. Protein kinase A (one of the proteins activated in the 2nd messenger system) attacks the β2 receptor and uncouples it from its G-protein, meaning that activation of the receptor will not result in activation of the 2nd messenger system.
When you give it in an inhaled from, the inhaled dose is usually 100μg of salbutamol. This, when you tell the patient to take two puffs as required, they have a dose of 200μg. Patients can take these two puffs up to 6-8 times a day – even more in an emergency! When you give nebulised salbutamol, you are often giving a dose of 2.5-5mg – thus 10-20x the dose of ‘2 puffs’ from the inhaler.
- E.g. if you see someone who is having a severe asthma attack, it is not unreasonable to give them 15-20 puffs into their mouth if they cannot take it in themselves. Remember much of the dose (80%?) is deposited on the back of the throat