L 05 Treatment of Asthma (B2 agonist, corticostiroids) Flashcards
Where are B2 receptors found?
Lungs
Where are B1 receptors found?
heart
Why do adrenergic receptors need to be selective?
So you don’t stimulate tachycardia(increased heart rate) for someone with hypertension while you are trying to treat their asthma.
Stimulation of B2 receptors in the lungs causes?
Bronchodilation, decreased secretions, increased airway diameter (good target for asthma)
Stimulation of B1 receptors in the heart causes?
Increased heart rate & contractility,
Causes atrial arrhythmias,
Increased cardiac output,
Be suppressed by partially blocking impulses being conducted through the AV node
Stimulation of receptors in the bladder (Beta) and sphincter (Beta 2R )?
Relaxation (if B receptors stimulated)
Beta 2R is stimulated causes Contraction of the sphincter (to prevent urination)
What type of receptor is the adrenoreceptor?
a class of GPCR NOTE: adrenergic receptor (AR) and adrenoreceptor (AR) are the same.
Name the 2 AR types and the subtypes of each?
Types: alpha and beta (x and b)
Subtypes: x1, x2, b1, b2, b3
How are the different adrenoreceptor subtypes relevant therapeutically?
As they all have different: - Structure of the ligand binding site - Signalling pathways - Tissue distribution Therefore we can target one receptor subtype over another.
Define allosteric and orthosteric
Allosteric: binding site outside of where the natural substrate binds
Orthosteric: binding to where the natural substrate binds
Define (full) agonist
A drug that binds and activates a receptor and gives its highest pharmacological response
Define partial agonist
A drug that activates a receptor to less than its highest pharmacological response
Define inverse agonist
A drug that binds to a receptor and produces a pharmacological response that is opposite to that of an agonist.
Define antagonist
A drug that binds to a receptor and blocks its pharmacological response.
How does an agonist cause a signal?
Binds to GPCR, causes shape change. Receptor becomes stabilised in the active conformation.
This change in receptor shape at the intra-membrane face causes a signal
When naming chemical compounds, what does “nor-“ mean?
Minus a methyl group “desmethyl”
What are the endogenous AR agonists? (Class + examples)?
Class: catecholamines
Examples: noradrenaline/adrenaline
Why can’t we use adrenaline to treat asthma?
Need to increase selectivity (otherwise will activate B1)
and increase duration of action. Adrenaline is used as a starting point.
What Changes we do to adrenaline to improve its drug functionality:?
Change catechol group (reduces metabolism)
Extend lipophilic chain (binding site selectivity and duration)
De-amination of amine (reduces metabolism)
Short acting B2-AR agonists (SABAs) are selective for… (+exception)?
Selective for B-AR over x-AR and more selective for B2-AR over B1-AR.
Exception: selectivity is dose related.
Features of SABAs (x4) + example?
- Fast onset
- 4-6 hour duration (longer than the endogenous agonist
- Catechol removed (a common building block of organic synthesis)
- Bulky N group reduces metabolism (MAO) and improves B2 selectivity.
Ex of SABA e.g Salbutamol
Can SABAs be marketed as enantiomers?
Yes, most drugs are racemic mixtures of enantiomers
Features of LABAs + example?
- Long lipophilic chain anchors in membrane = longer duration of action
- More lipophilic than SABAs (higher cLogP)
Example of LABA- e.g salmeterol, formoterol
Do SABAs or LABAs have an ionisable amine @ 7.4? + e.g?
LABAs
They are formulated as a salt to increase lipophilicity and therefore membrane retention.
e.g. formoterol as fumarate dihydrate
How many muscarinic subtypes are there? What are MRs also known as?
There are 5: M1-M5
also known as mAChR
What is the endogenous agonist for a mAChR?
What are its effects?
What will using an antagonistic drug do?
Acetylcholine
ACh acts directly at mAChRs on airway smooth muscle to cause bronchoconstriction (particularly M1,M2,M3).
An antagonist will therefore cause bronchodilation by blocking the endogenous effects of ACh.
What improvements does ipratropium bromide have compared to atropine?
Removed alkyl chain and added an anion to the nitrogen:
- Can form salt
- Permanent positive charge!!!
What does the permanent positive charge do on ipratropium bromide?
Limits diffusion: across the membrane into systemic circulation. Therefore it has increased selectivity for the lung tissue (it cant reach anywhere else)
Also will have poor oral bioavailability but not relevant due to being a lung condition.
Why are LAMAs long acting? Do they have systemic effects?
FOR KINETIC REASONS
- slow off binding rate from the M receptor (esp. M3)
- No systemic effects due to permanent quaternary nitrogen.(same as SAMAs)
Are LAMAs long acting for the same reason as LABAs?
No. LAMAs are long acting due to their kinetic properties.
LABAs are long acting due to their high lipophilicity anchoring them close to the lipophilic membrane.
What type of corticosteroid are anti-inflammatory drugs? Which receptor do they act at?
They are glucocorticoids. Act at glucocorticoid receptor.
What 2 medicine types are often co-formulated for asthma
Corticosteroid (ICS = preventer) and LABAs
What is the core structure of a steroid
17 carbons arranged in 4 fused rings
What are common features of steroids with good activity at the glucocorticoid receptor?
- OH
- Double bond
- Ketone
- Bulky group = tends to favour GR over MR
Name an oral corticosteroids that is administered as a prodrug
Prednisone (converted to prednisolone)
Is it possible to inhale prodrugs? Why/why not?
Inhaled prodrugs are still possible if the conversion to the active drug can occur in the lung/airway
What is the conversion required to turn prednisone into prednisolone?
The ketone at C11 must be converted into an alcohol (for glucocorticoid activity)
Why is prednisone not used via inhalation delivery?
Because the converting enzymes are not found in the lungs, only in the liver.
