in this video I'm going to cover cholinergic antagonists so let's get
right into it cholinergic antagonists can be divided
into three groups first antimuscarinic agents second ganglionic blockers
third neuromuscular blockers so let's start with antimuscarinic agents
also known as anticholinergic drugs these agents block primarily muscarinic
receptors thus causing inhibition of muscarinic functions one of the most
well known medications that belongs to this group is Atropine
Atropine's primary sites of actions are the following eye GI tract heart salivary
sweat and lacrimal glands now antimuscarinic activity of Atropine in the eye
results in relaxation of ciliary muscle which causes dilation of the pupil also
known as mydriasis inability to focus visually also known as cycloplegia
and unresponsiveness to light so ophthalmic preparations of Atropine
are used before an eye exam or eye surgery as well as to treat certain
inflammatory conditions of the eye however because of its long duration of
action other antimuscarinic agents such as Cyclopentolate and Tropicamide
are preferred over Atropine while Cyclopentolate and Tropicamide
can produce mydriasis that lasts for hours Atropine's effects can last for
days another feature of Atropine is that it blocks M3 receptors in GI tract which
results in reduction of GI motility from stomach to colon this translates into
prolonged gastric emptying and lengthen intestinal transit time at higher doses
Atropine can also effectively block M2 receptors on the SA node and AV node
which produces tachycardia heart rate may increase by as much as 30 to 40
beats per minute lastly by blocking muscarinic
receptors on salivary sweat and lacrimal glands
Atropine produces dry mouth dry skin and ultimately causes body temperature to
rise the next very well-known medication in the antimuscarinic group is
Scopolamine so Scopolamine unlike Atropine has a
much greater effect on the CNS as well as longer duration of action for that
reason Scopolamine is one of the most effective medications used for
prevention of motion sickness and post-operative nausea and vomiting it is
available in a patch formulation that provides effects lasting up to
three days another medications in the
antimuscarinic group that I want to talk about are Ipratropium and Tiotropium
Ipratropium and Tiotropium block muscarinic acetylcholine receptors without
specificity for subtypes this results in decreased contractility of smooth muscle
in the lungs which in turn leads to bronchodilation and reduction of mucus
secretion Tiotropium and Ipratropium are administered by inhalation for
maintenance treatment of bronchospasms in patients with COPD Ipratropium
also comes in a nasal spray formulation which is often used for treatment of
rhinorrhea which is runny nose the main difference between Ipratropium and
Tiotropium is their duration of action Tiotropium is a long-acting agent that
is dosed once daily while Ipratropium is a short-acting agent that typically
requires up to four times daily dosing another medications that belong to this
group are used for treatment of overreactive bladder
these include Tolterodine Darifenacin Solifenacin Oxybutynin Trospium
and Fesoterodine these agents have varying selectivity for the M3 receptor
which is the main receptor involved in bladder function however the overall
efficacy among all of these is very similar
last but not least I wanted to briefly mention two muscarinic blockers
Benztropine and Trihexyphenidyl which through their ability to suppress
central cholinergic activity were found to be very beneficial in treatment of
Parkinson-like disorders now before we move on to the next group I wanted to
make sure everyone watching this video remembers their ABCDs which will help
us to remember anticholinergic adverse effects where A stands for agitation
B stands for blurred vision C stands for constipation and confusion
D stands for dry mouth and S stands for stasis of urine and sweating now we can
move on to the second group of cholinergic antagonists which are
ganglionic blockers the main agent in this group is Nicotine which is a main
component of cigarette smoke although Nicotine is a cholinergic agonist
it is also considered a functional antagonist because of its ability to
stimulate and then block cholinergic function so Nicotine acts on the
nicotinic receptors of both parasympathetic and sympathetic
autonomic ganglia effects of Nicotine result from increased release of
neurotransmitters such as dopamine serotonin and norepinephrine just to
name a few Nicotine is a nonselective it
stimulates and later depresses autonomic ganglia
for example Nicotine stimulates CNS which at high enough doses can lead to
convulsions and then it depresses CNS which can lead to respiratory paralysis
also by stimulating adrenal medulla and sympathetic ganglia nicotine increases
blood pressure and heart rate but at higher doses it can cause blood pressure
to fall in GI system nicotine increases the motility which can lead to nausea
and vomiting last but not least use of Nicotine in any form can cause addiction
due to CNS stimulation that produces increased alertness and surge of
well-being overall other than to help people quit smoking Nicotine is not very
useful in clinical practice now let's switch gears and let's
talk about neuromuscular blockers neuromuscular blocking agents simply
block the cholinergic transmission between motor nerve endings and
nicotinic receptors on the skeletal muscle so if we zoom in on this part
where nerve ending meets the skeletal muscle fiber you would see these
nicotinic receptors to which acetylcholine can bind and induce their opening opening
of these channels let's sodium ions to enter the muscle fiber and trigger
muscular action potential the potential travels first along the surface of
sarcolemma which is the excitable membrane that
surrounds those cylindrical structures known as myofibrils then the action
potential travels through T-tubule system which penetrates into the fiber
and then the arrival of action potential causes calcium to be released from the
sarcoplasmic reticulum which finally leads to muscle contraction now let's
see all these steps in action so action potential causes release of
acetylcholine channels open sodium goes in triggers another action potential
calcium gets released and muscle contracts it's that easy
now neuromuscular blocking agents work at this junction here by interacting
with these nicotinic acetylcholine receptors we can divide these agents
into two groups first nondepolarizing agents and second depolarizing agents
for all of you who need a quick review of membrane depolarization I strongly
encourage you to watch my short three-minute video about action
potential so let's talk about nondepolarizing agents first these
agents are competitive antagonists they bind to acetylcholine receptors but they
don't induce ion channel opening what that means is that they prevent
depolarization of the muscle cell membrane and thus effectively inhibit
muscle contraction in clinical practice these agents are used to facilitate
mechanical ventilation and tracheal intubation as well as to increase
muscle relaxation during surgery which allows for lower doses of general
anesthetics generally speaking nondepolarizing
agents are not absorbed from GI and that's why must be injected usually
intravenously time to onset of action is rapid usually less than two minutes once
administered these agents paralyze small fast contracting muscle first that is
eyes face fingers then larger muscles of neck trunk and limbs and lastly
diaphragm on the other hand these muscles recover in the reverse manner
that is diaphragm first then limbs trunk and so on and so forth the choice of an
agent typically depends on the desired onset and duration of the muscle
relaxation and just a side note a clinical duration of these agents is a
time measured from administration to recovery of 25% of baseline muscle
strength now some of the most widely used agents in this group are the
following Cisatracurium which has clinical duration of about 90 minutes
Pancuronium which also has clinical duration of about 90 minutes Rocuronium
with clinical duration of about 40 minutes Vecuronium which also has clinical
duration of about 40 minutes and lastly Atracurium with 40 minute clinical
duration as well now when it comes to side-effects Atracurium causes
histamine release which results in fall in blood pressure flushing and
bronchoconstriction it also has toxic metabolite called laudanosine which
can provoke seizures especially in patients with impaired renal function
this is why Atracurium has been largely replaced by its isomer Cisatracurium
which fortunately is much less likely to produce the same adverse effects because
its metabolism is independent of hepatic or renal function therefore
Cisatracurium is often used in patients with multi-organ failure now Vecuronium
and Rocuronium are metabolized by liver so their action may be prolonged in patients
with hepatic dysfunction but overall there are safe and have minimal side effects
lastly Pancuronium is excreted unchanged
in urine and one of its main side effects is increase in heart rate now
let's move on to depolarizing agents so depolarizing agents act as acetylcholine
receptor agonists they mimic the acetylcholine however they are much more
resistant to degradation by acetylcholinesterase and therefore produce persistent
depolarization now the only depolarizing agent that's still used in clinical practice
is Succinylcholine so Succinylcholine binds to the nicotinic receptor and
unlike the nondepolarizing agents it actually causes the sodium channel to
open which results in membrane depolarization now because
Succinylcholine is resistant to acetylcholinesterase it causes
prolonged depolarization which leads to a transient fasciculations and finally
flaccid paralysis this is referred to as phase-1 block now eventually sodium
channel closes and membrane repolarizes however due to continued stimulation
by Succinylcholine the receptor becomes desensitized to acetylcholine thus
preventing formation of further action potentials this is referred to as
phase-2 block now Succinylcholine has a rapid onset of action and therefore is
commonly used to facilitate rapid sequence endotracheal intubation in
critically ill patients it's also sometimes used to provide adequate
muscle relaxation during electroconvulsive therapy following
intravenous administration Succinylcholine causes complete muscle relaxation
within one minute the effects typically last up to ten minutes due to rapid
redistribution and hydrolysis by plasma pseudocholinesterase and that brings us
to adverse effects in patients deficient in plasma pseudocholinesterase or
patients who have genetic variation of this enzyme
Succinylcholine can lead to prolonged apnea next prolonged
depolarization caused by Succinylcholine leads to continued flow of potassium
into the extracellular fluid which can result in hyperkalemia
now in patients with normal potassium levels this is usually not a big issue
however in those with elevated potassium levels for example due to burns or large
tissue damage Succinylcholine can cause serious EKG changes and even in severe
cases asystole lastly in genetically susceptible
patients Succinylcholine can trigger rare and potentially fatal condition called
malignant hyperthermia symptoms of malignant hyperthermia include severe
muscle contractions and dangerously high body temperature that can reach as high
as 43 degrees Celsius and with that I wanted to thank you for watching and I
hope you enjoyed this video