Asthma Flashcards
What is asthma?
Asthma is the most common chronic disease in childhood, affecting an estimated seven million children.
Asthma is an inflammatory disorder caused by bronchial hyper-responsiveness or hyper-reactivity. This is a state where bronchospasms (contraction of the muscular coat of the bronchial tubes) are easily triggered causing a narrowing and obstruction of the airways.
Obstructive lung disease
Airway obstruction results in slow exhalation as well as reduced FVC. Thus, the FEV1/FVC ratio is lower in persons with obstructive lung disease (less than 69 percent) than in persons with restrictive disease (88 to 90 percent). Obstructive lung diseases include conditions that make it hard to exhale all the air in the lungs. Asthma and COPD are obstructive lung diseases.
Restrictive lung disease
FVC is reduced but airways are not obstructed, so the person is able to expel air reasonably fast. People with restrictive lung disease have difficulty fully expanding their lungs with air.
β2 adrenergic receptor
A protein found in the smooth muscle of bronchial tubes. A member of the GPCR family, it’s involved in signalling from the exterior cell wall to the interior
what happens when an agonist binds to the β2 adrenergic receptor?
It activates a G protein (heterotrimeric GTP binding protein), which in turns induces a signalling process. The β adrenergic family all work in the same way, but whereas β2 works on smooth muscle, β1 is in the heart and thus therapies have to be inactive or “selective” against β1
B1 receptor
in the heart
B2 receptor
In smooth muscle, Blood vessel and airways
B3 receptor
Fat cells and GI tract
The crystal structure of the β2 adrenergic receptor
It was first solved in 2007 and the X-ray of β2 coupled to its G protein solved in 2011 (Nature).
The picture below shows the 7 helices of the β2 protein with the binding site at the stop. Binding of an agonist causes a change in the conformation of the protein and activate the G protein.
Synthetic beta-2 agonists
they are designed to dial-down the response of the beta2 adrenergic receptor and reduce the bronchospasms. Therapies also have to be ‘selective’ over the beta 1 adrenergic receptor that is located in the heart (think how adrenaline increases your heart rate)
Salbutamol
The “blue inhaler”, was one of the first beta-2 agonists to be developed (first marketed in 1969) and is still widely used today. Note the structural change between adrenaline and salbutamol. These changes to the structure turn it from a non-selective agonist (active against β1, β2 and β3) to a selective β2 agonist (active against β2). Note compounds are not usually completely inactive against closely related proteins. Salbutamol does increased the heart rate, when given at 2-4x the recommended dose.
Drug designers modified existing beta2 agonists, such as Salbutamol in the following way:
Active phenylethanolamine head group to engage receptor. This is the Salbutamol “head group”
Large non polar region to increase logD
Salmeterol
The molecule has a logD of 2, significantly more lipophilic than Salbutamol (logD = -2). This compound was launched as an asthma drug in 1990. It is slow to work but has a much longer duration of action. Thus, Salmeterol is used as an asthma maintenance medication - keeping the airways open for longer.
Salbutamol is typically administered through a MDI:
Metered-dose inhaler. This is where a single dose is administered when the patient presses the inhaler
Salmeterol has to be delivered through a DPI:
Dry powder inhaler.
