Pharmacology - ADRENERGIC RECEPTORS & AGONISTS (MADE EASY)

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

Channel: Speed Pharmacology

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Keywords: adrenergic receptors, adrenergic system, sympathomimetic drugs, adrenergic and cholinergic pharmacology, adrenergic drugs nursing, adrenergic drugs, adrenergic agonist, receptors pharmacology, adrenergic agonists, adrenergic pharmacology, adrenergic antagonist, catecholamines, noncatecholamines, agonists, adrenergic vs cholinergic, receptors, norepinephrine, clonidine, phenylephrine, antagonists, epinephrine, pharmacology, autonomic nervous system, sympathetic nervous system, pseudoephedrine

Id: KtmV-yMDYPI

Length: 17min 50sec (1070 seconds)

Published: Tue Sep 20 2016