The Adrenergic System II

Question 1

What are the clinical uses of the beta1 receptor?

Answer 1

In the heart, this increases heart rate and force of contraction
It is used for acute heart failure, or decreased cardiac output (CO) that can occur after heart surgery

Question 2

What are the clinical uses of the beta2 receptor?

Answer 2

In the lungs this causes bronchodilation and relaxation of the uterus
It is useful for the treatment of asthma and COPD and to prevent premature labor

Question 3

Generally, what are beta agonists (with regards to functional groups)?

Answer 3

Most of the therapeutically used beta agonists are secondary amines
The majority of beta agonists are phenylethylamines (no imidazolines act as beta agonists)

Question 4

Describe the requirements for the structure of the beta adrenergic agonist

Answer 4

It’s a phenethylamine structure
The aromatic ring is required for activity
As the R increases, generally the affinity increases for beta receptors
N has to be charged for receptor binding (ionic interaction with Asp)
H bond is more important for beta2 receptor binding and not required for beta1 receptor binding (beta position)
Meta position OH is more important for activity than para
Most beta agonists have an OH or and equivalent group capable of forming hydrogen bonds
As with NA and A, for both alpha and beta receptor activity, configuration at the beta (position 1) position is R

Question 5

How do N-substitutions of phenethylamine affect alpha receptor activity?

Answer 5

Large R substituents on the N decrease intrinsic activity at alpha1 and alpha2 receptors but affinity increases as R gets very large

Question 6

How do N-substitutions of phenethylamine affect beta receptor activity?

Answer 6

Large R substituents on the N increase affinity for beta1 and beta2 receptors while keeping intrinsic activity the same or increasing it

Question 7

Why are isopropyl and t-butyl N substitutions desired?

Answer 7

They have high affinity for beta receptors, as well as intrinsic activity but they don’t have a lot of affinity for alpha receptors. This makes them much more selective for beta receptors (we don’t necessarily want alpha antagonists cause this is a source of side effects).
Isopropyl is selective for beta receptors over alpha receptors
T-butyl is selective for beta2 receptors vs beta1

Question 8

How can we engineer beta2 selectivity over beta1 in the alpha position (position 2)?

Answer 8

A single methyl group here is selective for alpha2 receptors but a methyl or ethyl group also increases beta2 affinity over beta1.
Because alpha receptor affinity is reduced with an ethyl group but beta2 affinity is retained, an ethyl group is preferred

Question 9

How can we engineer beta2 selectivity over beta1 in the beta position (position 1)?

Answer 9

An OH here is more important for beta2 affinity than beta1

Question 10

How can we engineer beta2 selectivity over beta1 in the R1?

Answer 10

Ring substitution usually consists of two substitutions capable of forming H-bonds (donor or acceptor) anything less tends to reduce beta2 and beta1 affinity
The resorcinol ring structure tends to increases beta2 affinity over beta1

Question 11

How can we engineer beta2 selectivity over beta1 in the R position?

Answer 11

T-butyl increases beta2 affinity
An N ethylphenol group increases both affinity and intrinsic activity at beta2 receptors. Moreover large hydrophobic 7-11 atom long chains also increase affinity and activity at beta2 receptors while prolonging duration (more on this later)

Question 12

Describe the binding site of beta2 receptors

Answer 12

The structure of potent beta2 agonist suggest that there are two binding sites beyond the Asp-COO- on TM3 to which the N ion pairs. The nearest site to the N accommodates a t-butyl group and distal to this is a hydrophobic binding pocket that also seems to require a phenolic OH for optimal binding or a longer hydrophobic chain

Question 13

What does isoproterenol have affinity for?

Answer 13

N-isopropyl produces the highest intrinsic activity for beta1 receptors
It has affinity for beta1 and beta2 receptors and low affinity and activity for alpha 1 or alpha2

Question 14

What do we use isoproterenol for?

Answer 14

It has limited use as a bronchodilator because it has cardiac stimulatory activities conferred by beta1 receptors binding
Isoproterenol decreases vascular resistance by causing vasodilation in muscular blood vessels. Also increases CO (HR and SV) and force of contraction
Sometimes used to treat hear block or shock (heart block is when there are problems with conducting between the SA and AV nodes

Question 15

What does dobutamine have affinity for?

Answer 15

N-isopropyl produces the highest intrinsic activity for beta1 receptors
Dobutamine was originally was thought to be only a selective beta1 receptor agonist, but its action is complicated by an alpha1 antagonist and agonist activity

Question 16

Describe the chirality of doputamine

Answer 16

Dobutamine has a chiral centre and it is administered as a racemic mixture
R-enantiomer is potent beta1 agonist and weak alpha1 antagonist (these effects appose each other)
However the S-enantiomer is a potent alpha1 agonist that is 10x more potent than an alpha1 antagonist activity of the R-enantiomer (we don’t know why it has alpha1 agonist activity)

Question 17

What is dobutamine used for?

Answer 17

Dobutamine is used in acute hear failure, cariogenic shock, septic shock, and for cardaic insufficiency after heart surgery
It modestly increases heart rate but increases contractile force more (such drugs are called inotropic)

Question 18

What is the problem with isoproterenol and dobutamine?

Answer 18

They have short half lives and low bioavailability because they are both rapidly metabolized by COMT and MAO

Question 19

Should isoproterenol be used as a bronchodilator?

Answer 19

Isoproterenol is not appropriate as a bronchodilator for asthma or COPD because of its targets beta2 and beta1 receptors therefore it will have effects on the heart

Question 20

How do we make selective beta2 agonists?

Answer 20

We must utilize what we know about beta2 vs beta1 selectivity and employ strategies to prevent metabolism so the drugs will have longer half lives

Question 21

How do we reduce MAO metabolism?

Answer 21

MAO accepts many substrates (phenylethylamine structures) including some N substituted R groups. This means that many potential beta receptor agonists are substrates for MAO.
An alpha methyl substituent on the alpha position (position 2) can reduce MAO activity but an ethyl substituent eliminates MAO activity
T-butyl substitutions on the N act as a steric block reducing or eliminating the activity of MAO

Question 22

How do we reduct COMT metabolism?

Answer 22

The active site geometry of COMT predicts that the meta position (3’ or 5’) is the preferred site of methylation on the catechol ring based on the coordination complex with magnesium. Thus we only need to protect meta OH groups from metabolism. The 4’ position can remain an OH because because it is not methylated by COMT

Question 23

When making substitution in the meta position to reduce COMT metabolism, what should be considered?

Answer 23

Substitutions in the 3’ or 5’ positions can be made to reduce COMT metabolism but some part of that substitution should be capable for forming H-bonds. If not, the affinity is reduced.

Question 24

Are resorcinol derivatives COMT substrates?

Answer 24

Resorcinol derivatives do not form the right geometry of the magnesium coordination complex and therefore resist COMT methylation

Question 25

How do beta2 agonists treat asthma?

Answer 25

In asthma, beta2-receptor agonists can temporarily but completely reverse the airway obstruction that results from the disease via bronchi dilation. Short acting beta2 agonists are particularly useful for fast bronchodilation in the event of an acute asthma attack. No other drugs will help fast enough
Asthma is primarily a disease of inflammation and as a result beta2 receptor agonists are never the only treatment. Patients should also get inhaled glucocorticoids (most important)

Question 26

For asthma therapy, how are beta2 receptor agonists divided?

Answer 26

Beta2 receptor agonists are divided into two groups.
Short acting beta2 receptor agonist that are only used when needed (i.e., when having difficulty breathing or an asthmatic attack)
Long acting beta2 receptor agonist used when asthma is not controlled
Both are also used in COPD

Question 27

Why do asthmatics need glucocorticoids?

Answer 27

Glucocorticoids are critical to therapy. They must be taken regularly to reduce the frequency and severity of asthmatic attacks

Question 28

What is salbutamol?

Answer 28

Brand name: ventolin
Most common short acting beta 2 agonist
Supplied as MDI or a syrup

Question 29

What is terbutaline?

Answer 29

Brand name: bricanyl
Second most common short acting beta2 agonist
Sold as a dry powder inhaler many people tolerate this better (this is generally used for people who cannot tolerate an MDI)

Question 30

What is orciprenaline?

Answer 30

Beta2 agoinst supplied as a syrup for children who cannot take MDI
Not as beta2 selective as salbutamol.
No idea why they still use this (it has cardiac side effects)

Question 31

What is fenoterol?

Answer 31

Brand name: duovent
It is a combination inhaler with ipratropium
It can be used with asthma but more often use with COPD

Question 32

Name 4 short acting beta2 receptor agonist?

Answer 32

Salbutamol
Terbutaline
Orciprenaline
Fenoterol

Question 33

What is ritodrine?

Answer 33

It is given IV or PO to arrest premature labor

Ritodrine prolongs pregnancy but may actually not have a net benefit. However, it may increase maternal morbidity

Question 34

What are the side effects of beta2 agonists?

Answer 34

Muscle tremors (there are beta2 receptors on the muscles; this is a good sign that the patient is using their rescue inhalers too much)
Increased heart rate or irregular heart rate (palpitations)

Question 35

What should be done if a patient is using their rescue inhaler too much?

Answer 35

Add a long acting beta2 agonist or increase glucocorticoid dose

Question 36

What could be the result of a patient overusing their rescue inhaler too much (besides muscle tremors)?

Answer 36

Desensitization of the bronchial beta2 receptors can easily occur when beta2 agonistic drugs are overused. The agonist-occupied beta2 receptors start to form dysfunctional clusters in the bronchial membranes; the receptors can no longer activate adenylate cyclase. Serious drug tolerance then develops, and much higher doses of the beta2 agonists are then required for adequate bronchodilation

Question 37

What are some long acting beta2 receptor agonists (LABAs)?

Answer 37

Salmeterol
Formetrol (brand name: Oxeze)
Indacaterol (brand name: Onbrez)

Question 38

What is salmeterol?

Answer 38

Brand name: Adair or Serevent
Advair is a combination of a glucocorticoid and salmeterol inhaled BID. This generally provides good control and decreases use of the rescue inhaler

Question 39

Describe the structures of LABAs

Answer 39

All structures have an extended (at least) 7 atom hydrophobic chain, sometimes with an either O or an aromatic group. These substitutions make these structures have higher affinity for beta2 vs beta1 receptors. The added lipophilicity conferred by extended N substitution also plays a role in conferring longer duration

Question 40

How do LABAs interact with beta2 receptors (specifically salmeterol)?

Answer 40

The extended lipophilic chain binds to an alternate site on T4 and this has the effect of tethering salmeterol to the receptor (the exocite model)
Because salmeterol is always tethered to the receptor its local concentration relative to the receptor is high increasing the rate of receptor re-association

Question 41

What is the other LABA mechanism?

Answer 41

The microkinetic model
In this case, the LABA partitions in to the lipid bilayer of the lung membranes because of the highly lipophilic nature of LABAs
The membrane acts as a reservoir for the LABA which is continuously released with a first-order rate constant

Question 42

Is the exocite model and microkinetic model the only LABA mechanism?

Answer 42

There are other models because neither can totally explain the behaviour of LABAs

Question 43

Why is indacterol special?

Answer 43

At physiological pH, salbutamol exists as a positively charged secondary amine. Indacterol exists as a zwitterion which either gives it the properties of lower and higher logP beta2 agonists or it promotes interaction with the lipid membranes and to the beta2 receptor. It has a high logP and long duration (24 hours) but its onset is rapid (5-10 minutes)