in this lecture I'm going to talk about adrenergic agonist so let's get right
into it adrenergic agonists are a large
group of drugs that mimic the actions of norepinephrine and epinephrine which
naturally occur in our bodies norepinephrine is also known as
noradrenaline and epinephrine is also known as adrenaline now collectively the
agents that activate adrenergic receptors are called sympathomimetics
and the agents that block the activation of adrenergic receptors are called
sympatholytics so now to get a better understanding of how these drugs work
let's take a closer look at neurotransmission process in adrenergic
neuron there are five main steps involved in adrenergic neurotransmission
first amino acid tyrosine is transported into the neuron by the sodium dependent
tyrosine transporter once inside the neuron tyrosine gets hydroxylated by the
enzyme tyrosine hydroxylase to L-3,4-dihydroxyphenylalanine also known as
L-dopa or levodopa next L-dopa is converted to dopamine by the enzyme
aromatic amino acid decarboxylase the second step involves transport of
dopamine into the synaptic vesicle where the enzyme dopamine beta hydroxylase
converts dopamine to norepinephrine in the third step arrival of the action
potential triggers opening of calcium channels and thus influx of calcium into
the neuron the increase in calcium causes the synaptic vesicle to fuse with
the membrane and release its contents into the synapse in the fourth step
norepinephrine binds to the postsynaptic receptor on effector organ which
triggers intracellular response norepinephrine also binds to presynaptic
receptor which results in decrease of norepinephrine release through negative
feedback in the fifth and the final step norepinephrine is removed from synaptic
space by diffusing out into the systemic circulation
also by being inactivated by the enzyme catechol o-methyltransferase COMT for
short and most of all norepinephrine gets transported back into the neuron by
sodium chloride dependent norepinephrine transporter NET for short
now once inside the neuron norepinephrine may be either transported
back to the synaptic vesicle for future use which basically means it gets
recycled or it can be broken down to inactive metabolites by the enzyme
monoamine oxidase MAO for short now let's talk about adrenergic receptors
that is receptors which can be activated by norepinephrine epinephrine and
adrenergic drugs as you may recall from my previous video discussing nervous
system sympathetic preganglionic neurons release acetylcholine which then binds
to nicotinic receptors on post ganglionic adrenergic neurons or
nicotinic receptors on adrenal medulla now the adrenergic neuron release
norepinephrine while adrenal gland releases approximately 20%
norepinephrine and about 80 percent epinephrine at the end norepinephrine
and epinephrine bind to receptors on effector organs these receptors are
called alpha and beta now let's talk about these receptors in more detail and
let's start with alpha receptors alpha receptors can be divided into two main groups
that is alpha-1 and alpha-2 these can be further subdivided into alpha-1a alpha-1b
alpha-1c etc but for simplicity let's just focus on alpha-1 and alpha-2
now alpha-1 receptor is a Gq protein-coupled receptor and as a rule
of thumb when activated it causes stimulatory response mediated by
increase in intracellular calcium now alpha-1 receptors are mainly located on
vascular smooth muscle throughout the whole body and when activated they lead
to vasoconstriction they're also located on the dilator muscle of the iris and
when activated they lead to mydriasis which is dilation of pupil they are also
located on urinary sphincters and when activated they lead to contraction and
urinary retention alpha-1 receptors are also located in liver and when
activated there they lead to glycogenolysis which is breakdown of
glycogen to glucose lastly alpha-1 receptors are also found in the kidney
and when activated there lead to inhibition of renin release and as a
reminder renin is an enzyme that is secreted by the kidney and is involved
in the regulation of blood pressure so in summary activation of alpha-1
receptors leads to sympathetic response just think about it when you are in a
fight-or-flight mode it's advantageous to have constricted blood vessels in
case you start bleeding you also want to retain urine when you're fighting or
running away and you definitely need extra glucose now what about alpha-2
receptors well alpha-2 receptors are a Gi
protein-coupled receptors they are primarily located on presynaptic nerve
endings and when activated they cause decrease in production of intracellular
cAMP which in turn leads to inhibition of further release of norepinephrine
additionally alpha-2 receptors can be found on the pancreatic islets and when
activated they lead to decrease in insulin secretion now let's move on to
beta receptors beta receptors can be divided into three groups that is beta-1
beta-2 and beta-3 unlike alpha receptors beta receptors are coupled with Gs
protein now let's start with beta-1 receptors beta-1 receptors are
mainly located on the heart and when activated they lead to increase heart
rate increased cardiac contractility and increase AV node conduction beta-1
receptors are also located on the juxtaglomerular cells in the kidney
and when activated there they lead to increased renin release which results in
increase in blood pressure now let's move on to beta-2 receptors beta-2
receptors are mainly located in the lungs on the bronchial smooth muscle
and when activated they lead to bronchodilation they are also located on
the vascular smooth muscle and the arteries of skeletal muscle and when
activated they lead to relaxation of blood vessel or in other words
vasodilation they are also located on smooth muscle in the GI tract and uterus
and when activated there they lead to smooth muscle relaxation which in GI
results in decreased motility and in the uterus
it can cause inhibition of labor lastly beta-2 receptors can be found in
pancreas and when activated there they lead to increase in insulin secretion
and now before we move on let's not forget about beta-3 receptors beta-3
receptors are mainly located in adipose tissue and when activated they lead to
increase in lipolysis or simply breakdown of stored fat beta-3
receptors can also be found in the urinary bladder and their activation
there is thought to cause relaxation of the bladder and prevention of urination
now let's switch gears and let's talk about actual adrenergic agonists so
adrenergic agonists fall into two major chemical classes that is catecholamines
and noncatecholamines as a refresher catecholamine is an organic compound
that has a catechol which is basically a benzene ring with two hydroxyl side
groups intermediate ethyl chain and terminal amine group on the other hand
noncatecholamine have similar backbone structure but without those two hydroxyl
groups on adjacent carbons on benzene ring thus the name
non catechol amine now these structural differences create three main
differences in properties between catecholamines and noncatecholamines
first oral usability second duration of action third CNS penetration so let's briefly
talk about how they compare in terms of oral usability catecholamines are
completely ineffective as they are quickly metabolized by COMT and MAO
enzymes in the gut liver CNS and even inside the neurons furthermore hydroxyl
groups on the catechol portion make the whole molecule polar which results in
poor penetration into the CNS now on the other hand we have noncatecholamines
which lack the catechol hydroxyl groups and because of that there are not a good
substrate for COMT and they're metabolized by MAO very slowly as a
result notcatecholamine can be given orally they have much longer duration of
action and because they are less polar they also penetrate into the CNS fairly
easy now there are three types of adrenergic agonists number one direct acting
agonists number two indirect acting agonists and number three mixed action
agonists so now let's take a look at some examples starting with direct acting
agonists these agents produce their effects by binding to alpha or beta
receptor and mimicking the actions of epinephrine norepinephrine and dopamine
that naturally occur in our bodies speaking of epinephrine norepinephrine
and dopamine keep in mind that they are non selective meaning they can act on
both alpha and beta receptors there are also catecholamines which means that
their main route of administration is by injection now one of the most commonly
used direct acting agonist in clinical practice is Epinephrine Epinephrine can
activate almost all adrenergic receptors and because of that it is
a treatment of choice for anaphylactic shock activation of alpha-1 receptors by
Epinephrine leads to vasoconstriction which in turn decreases mucosal
edema relieving airway obstruction and increases blood pressure relieving shock
next activation of cardiac beta-1 receptors leads to increase in cardiac
output which is why epinephrine is also used to restore cardiac function in
patients experiencing cardiac arrest caused by asystole lastly activation of
beta-2 receptors in lungs leads to bronchodilation which is why
epinephrine is sometimes used for emergency treatment of respiratory
conditions now what about norepinephrine norepinephrine is actually
very similar to epinephrine however unlike epinephrine at the therapeutic
doses norepinephrine mainly stimulates alpha-1 receptors which leads to
profound vasoconstriction and ultimately increased blood pressure
norepinephrine has almost no beta-2 activity which is why it has more
limited clinical use in comparison to epinephrine the only useful indications
for norepinephrine are cardiac arrest and hypotensive shock now let's talk about
dopamine so dopamine is somewhat special in that it not only stimulates alpha and
beta receptors but also a dopamine receptors and it stimulates them in a
dose-dependent manner at low therapeutic doses dopamine acts on dopamine
receptors only then as dose increases it also activates cardiac beta-1
receptors and finally at even higher doses it
additionally activates alpha-1 receptors and we are not going to discuss dopamine
receptors here as they're the main target for neuropsychiatric drugs which
is a topic for another video however what you should know at this time is that by
activating cardiac beta-1 alpha-1 and dopamine receptors found on vascular
smooth muscle dopamine is very useful in treatment of acute severe heart failure
and hypotensive shock ok so thus far we talked about non-selective agents which
also happen to occur naturally in our bodies but guess what happened when
scientists started tweaking these chemicals
well we actually created selective adrenergic agonists so let's quickly
discuss the most commonly used drugs in this group and let's start with drugs
that are primarily alpha-1 selective best example of these is Oxymetazoline
and Phenylephrine due to alpha-1 receptor stimulation both
of these agents can be found in products used for treatment of nasal congestion
however Oxymetazoline can also be found in eyedrops used for treatment of eye
redness and Phenylephrine due to its ability to raise systolic and diastolic
blood pressure is sometimes used in hospitalized patients to treat
hypotension now let's talk about alpha-2 selective drug and here we have a very
popular medication called Clonidine as you may recall simulation of alpha-2
receptors leads to decrease in sympathetic tone which among other
things results in lowering of blood pressure this is why Clonidine is
commonly used for treatment of hypertension
Clonidine has also other indications such as attention deficit hyperactivity
disorder or ADHD and also withdrawal symptoms from alcohol and opioids now
let's move on to beta-1 selective agonist best example of this one is
Dobutamine and again as you may recall beta-1 receptors are mainly found in
cardiac tissue so Dobutamine increases cardiac rate and cardiac output which is
why it is used to treat acute heart failure next we have beta-2 selective
agonists which stimulate beta-2 receptors predominant in lungs and lead to
bronchodilation these agents are classified by length of action so we
have short-acting beta-2 agonists such as Albuterol and Terbutaline which are used
for relief of acute asthma symptoms and we also have long-acting beta-2 agonists
such as Salmeterol and Formoterol which produce prolonged bronchodilation
and that's why are used to prevent asthma attacks
finally we have beta-3 selective agonist namely Mirabegron which
simulates beta-3 receptors on the surface of detrusor muscle leading
to relief of symptoms of over-reactive bladder so that's it for direct acting
agonists now let's move on to indirect acting adrenergic agonists drugs in this
group do not directly interact with postsynaptic receptors instead they
enhance the effects of epinephrine or norepinephrine by either
inhibition of their reuptake or inhibition of their degradation best example of
these are Cocaine and Amphetamine which work by blocking reuptake of
norepinephrine as well as dopamine particularly in the region of the brain
that controls reward system and this is why they are highly addictive
additionally these drugs stimulate alpha-1 and beta-1 receptors which lead to
sympathetic response such as rise in blood pressure and increased heart rate
lastly I wanted to briefly discuss mixed action adrenergic
agonists the example of drugs that belong to this group is Ephedrine and
Pseudoephedrine which cause activation of adrenergic receptors by both direct
binding as well as release of stored norepinephrine from presynaptic
terminals Ephedrine and Pseudoephedrine have long duration of action because
they are not catecholamines and thus are poor substrates for COMT and MAO
enzymes now primary effects of Ephedrine are vasoconstriction and bronchodilation
however due to its side effects and availability of better drugs Ephedrine
is rarely used in clinical practice Pseudoephedrine
on the other hand also causes vasoconstriction and relaxation of
bronchial smooth muscle however it mainly activates receptors located in
the nasal passages the constriction of blood vessels allow less fluid to leave
and results in decrease inflammation of nasal passages as well as decreased
mucus production for this reason Sudafed is actually very commonly used
as a decongestant and with that I wanted to thank you for watching I hope you
enjoyed this video make sure to subscribe and stay tuned
for more videos