in this lecture I'm going to talk about adrenergic antagonists so let's get
right into it adrenergic antagonists also called sympatholytics
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 secrete 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 Phentolamine and Phenoxybenzamine can cause
tachycardia and even cardiac arrhythmias now
the main difference between these two drugs is that Phenoxybenzamine is a
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 effect
lasts only about four 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 Alfuzosin and Silodosin and note that this
ending with "-osin" is a pretty good giveaway when it comes to identifying
alpha-1 blocker 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 Silodosin 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 blocker that you may 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 agonist such as Xylazine 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
example of these agents include Propranolol Pindolol or Nadolol
Sotalol and Timolol now practically all 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
heart 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 Timolol when applied topically to the
eye was found to decrease intraocular pressure which is why it is often used
for a 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 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 cardio-selective beta blockers
now this cardio-selectivity makes these agents more suitable in patients with
chronic lung disease however keep in mind that at high enough doses this beta-1
selectivity can be lost and beta-2 receptor blockade may occur example 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 little 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 Carvedilol and Labetalol 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 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 Nebivolol 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 sympathomimetic activity of couple beta
blockers namely Pindolol and Acebutolol 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 sympathomimetic
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