Pharmacology – ADRENERGIC RECEPTORS & AGONISTS (MADE EASY)
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Pharmacology – ADRENERGIC RECEPTORS & AGONISTS (MADE EASY)

September 11, 2019


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
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