L 05 Treatment of Asthma (B2 agonist, corticostiroids)

Question 1

Where are B2 receptors found?

Answer 1

Lungs

Question 2

Where are B1 receptors found?

Answer 2

heart

Question 3

Why do adrenergic receptors need to be selective?

Answer 3

So you don’t stimulate tachycardia(increased heart rate) for someone with hypertension while you are trying to treat their asthma.

Question 4

Stimulation of B2 receptors in the lungs causes?

Answer 4

Bronchodilation, decreased secretions, increased airway diameter (good target for asthma)

Question 5

Stimulation of B1 receptors in the heart causes?

Answer 5

Increased heart rate & contractility,
Causes atrial arrhythmias,
Increased cardiac output,
Be suppressed by partially blocking impulses being conducted through the AV node

Question 6

Stimulation of receptors in the bladder (Beta) and sphincter (Beta 2R )?

Answer 6

Relaxation (if B receptors stimulated)

Beta 2R is stimulated causes Contraction of the sphincter (to prevent urination)

Question 7

What type of receptor is the adrenoreceptor?

Answer 7

a class of GPCR
NOTE: adrenergic receptor (AR) and adrenoreceptor (AR) are the same.

Question 8

Name the 2 AR types and the subtypes of each?

Answer 8

Types: alpha and beta (x and b)
Subtypes: x1, x2, b1, b2, b3

Question 9

How are the different adrenoreceptor subtypes relevant therapeutically?

Answer 9

As they all have different:
- Structure of the ligand binding site
- Signalling pathways
- Tissue distribution
Therefore we can target one receptor subtype over another.

Question 10

Define allosteric and orthosteric

Answer 10

Allosteric: binding site outside of where the natural substrate binds
Orthosteric: binding to where the natural substrate binds

Question 11

Define (full) agonist

Answer 11

A drug that binds and activates a receptor and gives its highest pharmacological response

Question 12

Define partial agonist

Answer 12

A drug that activates a receptor to less than its highest pharmacological response

Question 13

Define inverse agonist

Answer 13

A drug that binds to a receptor and produces a pharmacological response that is opposite to that of an agonist.

Question 14

Define antagonist

Answer 14

A drug that binds to a receptor and blocks its pharmacological response.

Question 15

How does an agonist cause a signal?

Answer 15

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

Question 16

When naming chemical compounds, what does “nor-“ mean?

Answer 16

Minus a methyl group “desmethyl”

Question 17

What are the endogenous AR agonists? (Class + examples)?

Answer 17

Class: catecholamines
Examples: noradrenaline/adrenaline

Question 18

Why can’t we use adrenaline to treat asthma?

Answer 18

Need to increase selectivity (otherwise will activate B1)

and increase duration of action. Adrenaline is used as a starting point.

Question 19

What Changes we do to adrenaline to improve its drug functionality:?

Answer 19

Change catechol group (reduces metabolism)

Extend lipophilic chain (binding site selectivity and duration)

De-amination of amine (reduces metabolism)

Question 20

Short acting B2-AR agonists (SABAs) are selective for… (+exception)?

Answer 20

Selective for B-AR over x-AR and more selective for B2-AR over B1-AR.
Exception: selectivity is dose related.

Question 21

Features of SABAs (x4) + example?

Answer 21

• 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

Question 22

Can SABAs be marketed as enantiomers?

Answer 22

Yes, most drugs are racemic mixtures of enantiomers

Question 23

Features of LABAs + example?

Answer 23

• Long lipophilic chain anchors in membrane = longer duration of action
• More lipophilic than SABAs (higher cLogP)

Example of LABA- e.g salmeterol, formoterol

Question 24

Do SABAs or LABAs have an ionisable amine @ 7.4? + e.g?

Answer 24

LABAs
They are formulated as a salt to increase lipophilicity and therefore membrane retention.
e.g. formoterol as fumarate dihydrate

Question 25

How many muscarinic subtypes are there? What are MRs also known as?

Answer 25

There are 5: M1-M5

also known as mAChR

Question 26

What is the endogenous agonist for a mAChR?
What are its effects?
What will using an antagonistic drug do?

Answer 26

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.

Question 27

What improvements does ipratropium bromide have compared to atropine?

Answer 27

Removed alkyl chain and added an anion to the nitrogen:

• Can form salt
• Permanent positive charge!!!

Question 28

What does the permanent positive charge do on ipratropium bromide?

Answer 28

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.

Question 29

Why are LAMAs long acting? Do they have systemic effects?

Answer 29

FOR KINETIC REASONS

• slow off binding rate from the M receptor (esp. M3)
• No systemic effects due to permanent quaternary nitrogen.(same as SAMAs)

Question 30

Are LAMAs long acting for the same reason as LABAs?

Answer 30

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.

Question 31

What type of corticosteroid are anti-inflammatory drugs? Which receptor do they act at?

Answer 31

They are glucocorticoids. Act at glucocorticoid receptor.

Question 32

What 2 medicine types are often co-formulated for asthma

Answer 32

Corticosteroid (ICS = preventer) and LABAs

Question 33

What is the core structure of a steroid

Answer 33

17 carbons arranged in 4 fused rings

Question 34

What are common features of steroids with good activity at the glucocorticoid receptor?

Answer 34

• OH
• Double bond
• Ketone
• Bulky group = tends to favour GR over MR

Question 35

Name an oral corticosteroids that is administered as a prodrug

Answer 35

Prednisone (converted to prednisolone)

Question 36

Is it possible to inhale prodrugs? Why/why not?

Answer 36

Inhaled prodrugs are still possible if the conversion to the active drug can occur in the lung/airway

Question 37

What is the conversion required to turn prednisone into prednisolone?

Answer 37

The ketone at C11 must be converted into an alcohol (for glucocorticoid activity)

Question 38

Why is prednisone not used via inhalation delivery?

Answer 38

Because the converting enzymes are not found in the lungs, only in the liver.