Lecture 10 (The Adrenergic System 2) Flashcards
What is B1 receptor agonist used for clinically?
increase HR and force of contraction
*used for acute heart failure or decreased CO that may occur after surgery
What is B2 receptor agonist used for clinically?
- bronchodilation of lungs
- relaxation of uterus
- useful for treatment of asthma and COPD
- used to prevent premature labor
Most of therapeutically used B agonists are ?
secondary amines
Majority of B agonists are ?
phenylethylamines
Do any imidazolines act as B agonists?
no
*this is another indication that the imidazolines are only alpha agonists
imidazolines are always _____ agonists
alpha
As R on the B adrenergic agonist increases. what happens?
generally affinity increases for B receptors
Why does the N need to be charged?
for receptor binding
What is the H bond on the OH on B more important for?
more important for B2 receptor binding
not needed for B1 receptor binding
Large R substituents on the N do what for alpha receptors?
- decrease intrinsic activity at alpha 1 and alpha 2 receptors
- but affinity increases as R gets very large
Large R substituents on the N do what for beta receptors?
-increases affinity for B1 and B2 receptors while keeping intrinsic activity the same or increasing it
isopropyl selective for?
B1 and B2 > alpha
t-butyl selective for?
B2 > B1
A methyl group on (alpha or 2) does what?
selective for alpha 2
but a methyl or ethyl group also increases B2 affinity over B1
An OH on (B or 1) is important for ?
it is more important for B2 affinity than B1
What does R1 ring substituents do?
usually consists of 2 substitutions capable of forming H-bonds (donor or acceptor)
*anything less tends to reduce B2 and B1 affinity
What does an N-ethylphenol group do?
increases both affinity and intrinsic activity at B2 receptors.
What do large hydrophobic 7-11 atom long chains do?
also increases affinity and activity at B2 receptors while prolonging duration
Describe the two B2 receptor binding sites
1) the nearest site to the N accommodates a t-butyl group
and distal to this
2) is a hydrophobic binding pocket that also seems to require a phenolic OH for optimal binding or a longer hydrophobic chain
N-isopropyl does what?
-produces the highest intrinsic activity for B1 receptors
- has affinity for B1 and B2 receptors
- low affinity and activity for alpha 1 or alpha 2
What is isoproterenol used for?
has limited use as a bronchodilator because it has cardiac stimulatory activities conferred by B1 receptors binding
How does isoproterenol decrease vascular resistance?
- causes vasodilation in muscular blood vessels
- increases CO (HR and SV) and force of contraction.
Absence of OH on a b1-receptor agonist does what?
makes it more selective for B1 than B2
What group produces the highest intrinsic activity for B1 receptors?
N-isopropyl
What was dobutamine originally thought to be?
only a selective B1 receptor agonist
What is dobutamine actually?
it is a selective B1 receptor agonist but it is complicated by alpha 1 antagonist and agonist activity
Dobutamine has a chiral centre and it is administered as a _____ mixture
racemic
Describe the R-enantiomer of dobutamine
it is a potent B1 agonist and a weak alpha 1 antagonist
**these effects appose each other
Describe the S-enantiomer of dobutamine
it is a potent alpha 1 agonist that is 10X more potent than the alpha 1 antagonist activity of the R-enantiomer
What is dobutamine used for?
acute heart failure
carcinogenic shock
septic shock
cardiac insufficiency after heart surgery
Dobutamine is ______
ionotropic
What is an inotropic drug?
increases contractile force
does dobutamine increase HR a lot?
not really
it modestly increases heart rate but increases contractile force more
Distance of carbons for B1 agonist
3
Distance of carbons for B2 agonist
2
Isoproterenol and dobutamine have ____ half life and ____ bioavailability
short half life and low bioavailability
What are isoproterenol and dobutamine rapidly metabolized by?
COMT
MAO
Why is isoproterenol not appropriate as a bronchodilator for asthma or COPD?
Because it targets B1 and B2 receptors therefore it will have unwanted effects on the heart
How can dobutamine be given so it’s short half life and low bioavailability are not an issue?
by continuous infusion (IV)
*this is most commonly used in hospital setting
MAO accepts many substrates including some ?
N substituted R groups
Because MAO accepts many substrates including some N substituted R groups, what does this mean?
this means that many potential B receptor agonists are substrates for MAO
What do t-butyl substitutions on the N act as? (On R1)
steric block reducing or eliminating the activity of MAO
On R2 - an alpha methyl substituent can _____ MAO activity
reduce
On R2 - an ethyl substituent _____ MAO activity
eliminates
Substitutions in the 3’ or 5’ positions can be made to ______ COMT metabolism but some part of that substitution should be capable for forming H-bonds. If not the affinity is reduced.
reduce
Why can the 4’ position remain to have an OH ?
because it is not methylated by COMT
Why are resorcinol derivatives another COMT block?
resorcinol derivatives do not form the right geometry for the Mg2+ coordination complex and therefore resist COMT methylation
What are B2 receptor agonists used in treating?
asthma and chronic obstructive pulmonary disease (COPD)
How do B2 receptor agonists work in asthma?
they can temporarily but completely bronchodilator the airway which will temporarily reverse obstruction that results in the disease
What are short-acting B2 agonists good for?
acute asthma attacks
Asthma is primarily a disease of _______ and as a result B2 receptor agonists are never the only treatment
inflammation
What other treatment should asthmatics have?
they should also have an inhaled glucocoorticoid
What 2 groups of B2-receptor agonists are there?
1) short acting B2 receptor agonists - used only when needed during an attack
2) long acting B2 receptor agonists - used when asthma not controlled
Are both types of B2-receptor agonists used in COPD?
yes
What else is critical to asthma therapy?
glucocorticoids
How are glucocorticoids taken?
must be taken regularly to reduce the frequency and severity of asthmatic attacks
Everyone with asthma should have what 2 things?
1) short acting B2 receptor agonist
2) glucocorticoid
What is the most common short acting B2 agonist? It is supplied as an MDI and a syrup. It also has a propellant.
salbutamol (ventolin)
What is the second most common short acting B2 agonist? It is sold as a dry powder inhaler and many people tolerate this better.
Terbutaline (Bricanyl)
_______ is supplied as a syrup for children who cannot use an MDI. Not as B2 selective as salbutamol
Orciprenaline
_____ is a combination inhaler with ipratropium and can be used with asthma but more often used with COPD
Fenoterol (Duovent)
Salbutamol, Terbutaline, Orciprenaline, and Fenoterol are all ???
short acting B2 receptor agonists
______ is given IV or PO to arrest premature labor
Ritodrine
Ritodrine has ?? (3)
No meta OH
No COMT metabolism
Has oral bioavailability
Ritodrine does prolong pregnancy, but what else can it do?
increase maternal morbidity
A high enough dose of any adrenergic agonist could do what?
bind to all receptors producing side effects
There are B2 receptors on the muscles that cause ____
tremor
If muscle tremors are occurring in an asthmatic what does that mean? And how can you fix it?
probably means that are using their rescue inhaler too much
in this case, add a long acting B2 agonist or increase glucocorticoid dose
Along with muscle tremors, what is another side effect?
increased HR or irregular heart rate (palpitations)
What can happen if B2 agonistic drugs are overused?
Desensitization of the bronchial B2 receptors can easily occur
Explain what happens when you overuse B2 agonistic drugs
the agonist-occupied B2 receptors start to form dysfunctional clusters in the bronchial membranes - the receptors can no longer activate adenylate cyclase
Drug tolerance develops and then what happens?
a much higher dose of B2 agonists are then required for adequate bronchodilation
List 3 LABAs (long acting B2-receptor agonists)
1) Salmeterol (Advair or Servant)
2) Formetrol (Oxeze)
3) Indacaterol (Onbrez)
Salmeterol is inhaled ___
BID
What contributes to LABA’s long acting effects?
the added lipophilicity conferred by extended N substitution also plays a role in conferring longer duration.
What contributes to LABA’s higher affinity for B2 vs. B1 receptors
they have extended >7 heavy atom hydrophobic chain sometime with an ether O and an aromatic group
*exception = indacaterol = only 7
What is a heavy atom?
anything bigger than H+
see slide 27 for sure
okay girl
Why is Salmeterol’s local concentration relative to the receptor high?
because salmeterol is always tethered to the receptor it’s local concentration relative to the receptor is high increases the rate of receptor re-association
The O on salmeterol acts as a ???
hinge
*slide 28
Microkinetic model
- 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
Duration and onset of: Salbutamol
Duration:
3-6 hours
Onset: 5 mins (rapid)
Duration and onset of:
Formoterol
Duration:
12 hours
Onset: 15 mins (slow)
Duration and onset of:
Salmeterol
Duration:
12 hours
Onset: 20 mins (slowest)
Duration and onset of:
Indacaterol
Duration:
24 hours
Onset:
5-10 mins (rapid)
increasing logP = ____ duration and onset
exception = indacaterol
longer
Why must we never use Salmeterol or Formoterol for an asthmatic attack?
the onset is too slow
Why is indacaterol an exception?
At physiological pH (7.4) indacterol exists as a zwitterion. Which either gives it the properties of lower and higher logP B2 agonists OR it promotes interaction with the lipid membranes and to the B2 receptor
