Adrenergic Receptors & Agonists Simplified

Today, 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 sympathomimetic s’ and the agents that block the activation of adrenergic receptors are called sympathetics.

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 el34 dihydroxy phenylalanine 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 all methyl transferase comt for short and most of all norepinephrine gets transported back into the neuron by sodium chloride appended norepinephrine transporter and ET 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 enacted metabolized by the enzyme monoamine oxidase (Mao) 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.

Adrenergic Receptors

Now let’s talk about these receptors in more detail and let’s start with alpha receptors after etc can be divided into two main groups that is alpha 1 and alpha 2 these can be further subdivided into alpha 1 a alpha 1 B alpha 1 C 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 madrasahs which is dilation of pupil they are also located on urinary sphincter and when activated they lead to contraction and urinary retention alpha

One receptors IS also located in liver and when activated there they lead to glycogenolysis which is breakdown of glycogen to glucose lastly alpha one 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 one 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.

What about alpha two receptors? well alpha two 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 it turn leads to inhibition of further release of norepinephrine additionally alpha two 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 G as protein now let’s start with beta 1 receptors beta 1 receptors 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 Jacksonville Mariel cells in the kidney and when activated their daily – 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 bronchioles 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.

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 may the three 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 agonist so adrenergic agonists fall into two major chemical classes that is catecholamines and non catecholamines 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 non catecholamine have similar backbone structure but without those two hydroxyl groups on carbons on benzene ring does the name non catechol Amy now these structural differences create three main differences in properties between cat economies and non category meats first or 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 level 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 non catecholamines 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 not catecholamine can be given orally they have much longer duration of action and because they are less poor they also penetrate into the CNS fairly easy now there are three types of other nergic agonist number one direct acting agonist number two in direct acting agonist and number three next action agonist.

Direct acting agonist

so now let’s take a look at some examples starting with direct acting agonist 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 selected 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 added edema relieving airway obstruction and increases blood pressure relieving shock next activation of cardiac beta 1 receptors leads to increasing cardiac output which is why epinephrine is also used to restore cardiac function in patients experiencing cardiac arrest caused by assistly lastly activation of beta 2 receptors in lungs leads to bronchial dilation which is why epinephrine is sometimes used for emergency treatment of respiratory conditions now what about nor epinephrine norepinephrine is actually very similar to epinephrine however unlike epinephrine at the therapeutic doses norepinephrine mainly stimulates alpha 1 receptors which leads to profound basic constriction and ultimately increase blood pressure.

norepinephrine has almost no beta to activity which is why it has more limited clinical use in comparison to epinephrine the only useful indications for an RP nephron are cardiac arrest and hypotensive shock now let’s talk about dopamine so dopamine is somewhat special in that it not only stimulates up on beta receptors but also a dopamine receptors and it stimulates them in a dose-dependent manner upload repeated doses dopamine acts on dopamine receptors only then as those increases it also activates cardiac beta 1 receptors and finally add 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 new psychiatric drugs which is a topic fun order 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 talked about non-selective agents which also happened to occur naturally in our bodies but guess what happened when scientists started tweaking these chemicals well we actually created selectively a greener G agonist so let’s quickly discuss the most commonly used drugs in this group and let’s start with drugs that are primarily alpha one selected this example of these is oxymetazoline and fan letter 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.

Alpha 2 selective drug

Let’s talk about alpha 2 selective drug and here we have a very popular medication called quantity 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 co Nadeem 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 this example of this one is dobutamine and again assuming 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 agonist 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 agonist such as albuterol and terbutaline which are used for relief of acute asthma symptoms and we also have long-acting beta 2 agonist such as cell metal and for metal which produce prolonged bronchodilation and that’s why are used to prevent asthma tax finally we have beta3 selective agonist namely me Radha groan which simulates beta-2 receptors on the surface of the true sore muscle leading to relief of symptoms of over-reactive bladder so that’s it for direct acting agonist.

Indirect acting adrenergic agonist

Now let’s move on to indirect acting adrenergic agonist drugs in this group do not directly interact with postsynaptic receptors instead they enhance the effects of epinephrine on Ornette norepinephrine by either inhibition of the reuptake or inhibition of their degradation this example of these are cocaine and amphetamine which work by blocking reuptake or norepinephrine as well as dopamine particularly in the region of the brain that controls reward system and this is light 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 increase heart rate lastly I wanted to briefly discuss mix action and energic agonist 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 there are not catecholamines and thus are poor substrates for comt and mao enzymes now primary effects of ephedrine are vasoconstriction and bronchodilation however due 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 Suh referred is actually very commonly used as a decongestant and with that I wanted to thank you for reading I hope you enjoyed this article make sure to subscribe and stay for more posts.

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