In this lecture, I'm going to talk about adrenergic agonists. 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 L3,4-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 postganglionic adrenergic neurons or nicotinic receptors on adrenal medulla. Now the adrenergic neuron release norepinephrine while adrenal gland releases approximately 20% norepinephrine and about 80% epinephrine. At the end, norepinephrine and epinephrine bind to receptors on affector 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 are also located on the dilator muscle of the iris and when activated they lead to medriasis, 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 are 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 beta1, beta2, beta3, beta4, beta5, beta6, beta7, beta8, beta9, beta10, beta11, beta12, 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 increased heart rate, increased cardiac contractility and increased 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 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 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 adjacent carbons on benzene ring.
That's the name non-catecholamine. Now these structural differences create three main differences in properties between catecholamines and non-catecholamines. 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 non-catecholamines which lack the catechol hydroxyl groups and because of that They are not a good substrate for COMT and they are metabolized by MAO very slowly. As a result, non-catecholamine 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 agonists in clinical practice is epinephrine. Epinephrine can activate almost all adrenergic receptors, and because of that, it is the 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 increasing 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 increase 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 a 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-1 beta receptors but also eight 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 are 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. Okay 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, oxymetazolem can also be found in eye drops 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, stimulation 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 terbuterline which are used for relief of acute asthma symptoms and we also have long-acting beta-2 agonists such as salmeterol and formeterol which produce prolonged bronchodilation and that's why are used to prevent asthma attacks. Finally, we have beta-3 selective agonists, namely mirabegrone, which stimulates beta-3 receptors on the surface of the trusser muscle, leading to relief of symptoms of overreactive 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 the reuptake or inhibition of their degradation. Best 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 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 increase heart rate. Lastly, I wanted to briefly discuss mixed action adrenergic agonists.
The example of drugs that belong to this group is ephedrine and pseudophedrine, which cause activation of adrenergic receptors by both direct binding as well as release of stored norepinephrine from presynaptic terminals. Ephedrine and pseudophedrine 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. Sudaphedrine, 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 decreased inflammation of nasal passages as well as decreased mucus production. For this reason, surafer is actually very commonly used as a decongestant. And with that, I wanted to thank you for watching.
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