فهم مضادات الأدرينالين

In this lecture I'm going to talk about adrenergic antagonists. So let's get right into it. Adrenergic antagonists, also called sympatolitics, bind to adrenergic receptors, but instead of stimulating them, they actually prevent their activation. And just like with adrenergic agonists, we can divide antagonists based on their affinity for alpha or beta receptors. So we can divide adrenergic antagonists into two main groups, that is alpha blockers and beta blockers. So let's start with alpha blockers first. Alpha-1 adrenergic antagonists block the binding of norepinephrine to the smooth muscle receptors, which results in vasodilation and thus lowering of blood pressure. This is why alpha blockers are useful in the treatment of hypertension. Now alpha blockers can be subdivided into two groups, that is non-selective alpha blockers and selective alpha blockers. As you might have guessed, non-selective agents can block both alpha-1 and alpha-2 receptors. Example of these are phentolamine and phenoxybenzamine, which are used in the treatment of hypertension, specifically caused by pheochromocytoma, which is a tumor of the adrenal glands. that secretes norepinephrine and epinephrine. Now we know that through alpha-1 blockade these drugs cause vasodilation, but since they are non-selective they also block alpha-2 receptors, which as you may remember from the previous lecture are mainly located on presynaptic nerve endings. Now norepinephrine acts on alpha-2 receptors to inhibit its own release, so blockade of these receptors results in more norepinephrine release. norepinephrine then can stimulate beta-1 receptors on the heart. This is why non-selective drugs such as phentomine and phenoxybenzamine can cause tachycardia and even cardiac arrhythmias. Now the main difference between these two drugs is that phenoxybenzamine is an irreversible antagonist and the only way the body can overcome its effects is by making new adrenergic receptors which takes about 24 hours or so. On the other hand, Phentolamine is a reversible antagonist and that's why its effects last only about 4 hours or so. Now let's move on to selective alpha blockers and let's discuss alpha-1 blockers first. So these agents selectively and reversibly block alpha-1 receptors located mainly in vascular smooth muscle which reduces peripheral resistance and leads to decrease in blood pressure and they also block receptors in the smooth muscle of the bladder neck and prostate gland which causes smooth muscle there to relax leading to relief of the urinary difficulties associated with benign prostatic hypertrophy BPH for short or simply enlarged prostate. Now examples of alpha-1 selective blockers include prazosin doxazosin, terazosin, tamsulosin, afuzosin and silodosin. And note that this ending with osin is a pretty good giveaway when it comes to identifying alpha-1 blockers. Now the first three of these, that is prazosin, doxazosin and terazosin are effective treatment for hypertension but have lesser effects. on relieving symptoms of enlarged prostate. On the other hand, Tamsulosin, Alfuzosin and Sildosin have little effect on blood pressure but are much more effective for relieving symptoms associated with enlarged prostate. And this is because these agents have increased selectivity for alpha-1 receptors in the prostate, specifically alpha-1a subtype. Now when it comes to side effects orthostatic hypotension is one of the main concerns when initiating alpha-1 blocker, although it's not as severe as that observed with non-selective alpha blockers. Additionally, vasodilation produced by alpha-1 blockers can lead to headaches and nasal congestion. Finally, what about alpha-2 selective blockers? Well, alpha-2 selective blockers have very limited clinical application in humans and they're used mainly in research. One example of alpha-2 blockers that you might encounter is yohimbine, which can be found in some dietary supplements. However, there is not much beneficial evidence supporting its use in humans. On the other hand, yohimbine is used sometimes in veterinary medicine to reverse sedative effects of alpha-2 agonists such as xylosine. Now, let's switch gears and let's move on to beta blockers. So, just like alpha blockers, beta blockers can also be subdivided into selective and non-selective agents. However, unlike alpha blockers, beta blockers can also be grouped in generations. Beta blockers are competitive inhibitors at beta adrenergic receptors and they counter the effects of catecholamines such as epinephrine and norepinephrine which leads to decrease in sympathetic effects mainly on cardiovascular system. This is why beta blockers are useful in the treatment of hypertension, heart failure, heart attacks, angina and cardiac arrhythmias. Additional uses include treatment of glaucoma and migraine prophylaxis. So now let's start by discussing first generation beta blockers, which also happen to be non-selective. That is, they block beta-1 and beta-2 receptors throughout the body. Examples of these agents include propranolol, pendolol, natolol, sotolol, and timolol. Now practically, all of the applications of these agents are based on blockade of beta-1 receptors on the heart, which results in decreased heart rate, delayed conduction through AV node and reduced contractility. So now the final outcome is decreased cardiac output and decreased oxygen demand of hard muscle. Besides being useful in treatment of hypertension, angina and arrhythmia note that propranolol due to its lipophilicity can also penetrate into the CNS and was found to be effective for migraine prophylaxis. On the other hand, thymolol when applied topically to the eye was found to decrease intraocular pressure which is why it is often used for treatment of glaucoma. However all that being said let's not forget about blockade of beta-2 receptors by these non-selective agents and as you may recall beta-2 receptors are predominant in lungs so their blockade can actually lead to bronchoconstriction. For this reason And these non-selective beta blockers are not recommended in patients with COPD or asthma. Now let's move on to the second generation beta blockers, which happen to be selective for beta 1 receptors. And because of that, we also call them cardioselective beta blockers. Now this cardioselectivity makes these agents more suitable in patients with chronic lung disease. However, keep in mind that at high enough doses, This beta1 selectivity can be lost and beta2 receptor blockade may occur. Examples of these agents include Atenolol, Acebutolol, Bisoprolol, Esmolol and Metoprolol. Now let's move on to the third generation beta blockers. And here you need to pay special attention because things can get a lot tricky. So unlike the first generation group that included non-selective agents and unlike the second generation group that included selective agents the third generation group includes both non-selective and selective beta blockers. However what makes the third generation beta blockers different from the other two is that they also act on blood vessels to cause vasodilation. So here we have non-selective agents such as carbetylol and labetylol, which produce peripheral vasodilation by blocking not only beta but also alpha-1 receptors. And on the other hand, we have beta-1 selective agents such as nebivolol, which produce vasodilation by inducing the release of nitric oxide from endothelial cells, and betaxolol, which is thought to be a good agent for the beta-1 receptor. to produce vasodilation by additionally blocking calcium channels. And just as a side note here, betaxolol, due to its ability to decrease intraocular pressure when applied topically to the eye, just like timolol, it is often prescribed for glaucoma. But the bottom line here is that vasodilation produced by the third generation beta blockers make these agents especially effective in treatment of hypertension. Furthermore, Carvedilol and Nabivolol have been also shown to have antioxidant properties which make them beta blockers of choice for heart failure alongside commonly prescribed Bisoprolol and Metoprolol. Lastly, I wanted to briefly discuss intrinsic sympatomimetic activity of couple beta blockers, namely pendelol and acebutylo. Now these two beta blockers are a little special in that they have ability to not only block, but also to weakly stimulate both beta 1 and beta 2 receptors, which leads to diminished effect on cardiac rate and cardiac output. This so-called intrinsic sympatomimetic activity can actually be beneficial in patients who cannot tolerate other beta blockers because of pre-existing bradycardia or heart block. And now before we end you may wonder well what about beta 2 blockers? And the short answer is at this time we don't have clinically useful beta 2 blockers. And with that I wanted to thank you for watching. I hope you enjoyed it and as always Stay tuned for more videos.

So we can divide adrenergic antagonists into two main groups, that is alpha blockers and beta blockers. So let's start with alpha blockers first. Alpha-1 adrenergic antagonists block the binding of norepinephrine to the smooth muscle receptors, which results in vasodilation and thus lowering of blood pressure.

This is why alpha blockers are useful in the treatment of hypertension. Now alpha blockers can be subdivided into two groups, that is non-selective alpha blockers and selective alpha blockers. As you might have guessed, non-selective agents can block both alpha-1 and alpha-2 receptors. Example of these are phentolamine and phenoxybenzamine, which are used in the treatment of hypertension, specifically caused by pheochromocytoma, which is a tumor of the adrenal glands.

that secretes norepinephrine and epinephrine. Now we know that through alpha-1 blockade these drugs cause vasodilation, but since they are non-selective they also block alpha-2 receptors, which as you may remember from the previous lecture are mainly located on presynaptic nerve endings. Now norepinephrine acts on alpha-2 receptors to inhibit its own release, so blockade of these receptors results in more norepinephrine release.

norepinephrine then can stimulate beta-1 receptors on the heart. This is why non-selective drugs such as phentomine and phenoxybenzamine can cause tachycardia and even cardiac arrhythmias. Now the main difference between these two drugs is that phenoxybenzamine is an irreversible antagonist and the only way the body can overcome its effects is by making new adrenergic receptors which takes about 24 hours or so.

On the other hand, Phentolamine is a reversible antagonist and that's why its effects last only about 4 hours or so. Now let's move on to selective alpha blockers and let's discuss alpha-1 blockers first. So these agents selectively and reversibly block alpha-1 receptors located mainly in vascular smooth muscle which reduces peripheral resistance and leads to decrease in blood pressure and they also block receptors in the smooth muscle of the bladder neck and prostate gland which causes smooth muscle there to relax leading to relief of the urinary difficulties associated with benign prostatic hypertrophy BPH for short or simply enlarged prostate. Now examples of alpha-1 selective blockers include prazosin doxazosin, terazosin, tamsulosin, afuzosin and silodosin. And note that this ending with osin is a pretty good giveaway when it comes to identifying alpha-1 blockers.

Now the first three of these, that is prazosin, doxazosin and terazosin are effective treatment for hypertension but have lesser effects. on relieving symptoms of enlarged prostate. On the other hand, Tamsulosin, Alfuzosin and Sildosin have little effect on blood pressure but are much more effective for relieving symptoms associated with enlarged prostate.

And this is because these agents have increased selectivity for alpha-1 receptors in the prostate, specifically alpha-1a subtype. Now when it comes to side effects orthostatic hypotension is one of the main concerns when initiating alpha-1 blocker, although it's not as severe as that observed with non-selective alpha blockers. Additionally, vasodilation produced by alpha-1 blockers can lead to headaches and nasal congestion.

Finally, what about alpha-2 selective blockers? Well, alpha-2 selective blockers have very limited clinical application in humans and they're used mainly in research. One example of alpha-2 blockers that you might encounter is yohimbine, which can be found in some dietary supplements. However, there is not much beneficial evidence supporting its use in humans.

On the other hand, yohimbine is used sometimes in veterinary medicine to reverse sedative effects of alpha-2 agonists such as xylosine. Now, let's switch gears and let's move on to beta blockers. So, just like alpha blockers, beta blockers can also be subdivided into selective and non-selective agents. However, unlike alpha blockers, beta blockers can also be grouped in generations.

Beta blockers are competitive inhibitors at beta adrenergic receptors and they counter the effects of catecholamines such as epinephrine and norepinephrine which leads to decrease in sympathetic effects mainly on cardiovascular system. This is why beta blockers are useful in the treatment of hypertension, heart failure, heart attacks, angina and cardiac arrhythmias. Additional uses include treatment of glaucoma and migraine prophylaxis. So now let's start by discussing first generation beta blockers, which also happen to be non-selective.

That is, they block beta-1 and beta-2 receptors throughout the body. Examples of these agents include propranolol, pendolol, natolol, sotolol, and timolol. Now practically, all of the applications of these agents are based on blockade of beta-1 receptors on the heart, which results in decreased heart rate, delayed conduction through AV node and reduced contractility. So now the final outcome is decreased cardiac output and decreased oxygen demand of hard muscle. Besides being useful in treatment of hypertension, angina and arrhythmia note that propranolol due to its lipophilicity can also penetrate into the CNS and was found to be effective for migraine prophylaxis.

On the other hand, thymolol when applied topically to the eye was found to decrease intraocular pressure which is why it is often used for treatment of glaucoma. However all that being said let's not forget about blockade of beta-2 receptors by these non-selective agents and as you may recall beta-2 receptors are predominant in lungs so their blockade can actually lead to bronchoconstriction. For this reason And these non-selective beta blockers are not recommended in patients with COPD or asthma.

Now let's move on to the second generation beta blockers, which happen to be selective for beta 1 receptors. And because of that, we also call them cardioselective beta blockers. Now this cardioselectivity makes these agents more suitable in patients with chronic lung disease. However, keep in mind that at high enough doses, This beta1 selectivity can be lost and beta2 receptor blockade may occur.

Examples of these agents include Atenolol, Acebutolol, Bisoprolol, Esmolol and Metoprolol. Now let's move on to the third generation beta blockers. And here you need to pay special attention because things can get a lot tricky.

So unlike the first generation group that included non-selective agents and unlike the second generation group that included selective agents the third generation group includes both non-selective and selective beta blockers. However what makes the third generation beta blockers different from the other two is that they also act on blood vessels to cause vasodilation. So here we have non-selective agents such as carbetylol and labetylol, which produce peripheral vasodilation by blocking not only beta but also alpha-1 receptors. And on the other hand, we have beta-1 selective agents such as nebivolol, which produce vasodilation by inducing the release of nitric oxide from endothelial cells, and betaxolol, which is thought to be a good agent for the beta-1 receptor. to produce vasodilation by additionally blocking calcium channels.

And just as a side note here, betaxolol, due to its ability to decrease intraocular pressure when applied topically to the eye, just like timolol, it is often prescribed for glaucoma. But the bottom line here is that vasodilation produced by the third generation beta blockers make these agents especially effective in treatment of hypertension. Furthermore, Carvedilol and Nabivolol have been also shown to have antioxidant properties which make them beta blockers of choice for heart failure alongside commonly prescribed Bisoprolol and Metoprolol.

Lastly, I wanted to briefly discuss intrinsic sympatomimetic activity of couple beta blockers, namely pendelol and acebutylo. Now these two beta blockers are a little special in that they have ability to not only block, but also to weakly stimulate both beta 1 and beta 2 receptors, which leads to diminished effect on cardiac rate and cardiac output. This so-called intrinsic sympatomimetic activity can actually be beneficial in patients who cannot tolerate other beta blockers because of pre-existing bradycardia or heart block. And now before we end you may wonder well what about beta 2 blockers? And the short answer is at this time we don't have clinically useful beta 2 blockers.

And with that I wanted to thank you for watching. I hope you enjoyed it and as always Stay tuned for more videos.

Transcript for:فهم مضادات الأدرينالين

Transcript for:
فهم مضادات الأدرينالين