Pharmacology – CHOLINERGIC DRUGS (MADE EASY)

Pharmacology – CHOLINERGIC DRUGS (MADE EASY)


in this lecture I want to talk about
cholinergic agonist so let’s jump right into it
as you may recall from my previous video cholinergic neurons are primarily found
within parasympathetic system however it’s important to remember that they
also participate in sympathetic innervation of sweat glands and blood
vessels in skeletal muscle now cholinergic neurotransmission can be
broken down into six major steps in the first step choline molecule is
transported into the neuron by energy and sodium dependent transport system
once inside choline reacts with acetyl coenzyme A to
form acetyl choline the enzyme responsible for catalyzing this reaction
is choline acetyl transferase in the second step acetyl choline gets
transported into pre synaptic vesicle where it’s protected from degradation in
the third step the action potential causes the voltage-sensitive calcium
channels to open thus allowing calcium to enter the axon this in turn leads to
the fusion of the vesicle with the membrane and release of the
acetylcholine from the terminal in the fourth step acetylcholine binds to
postsynaptic receptor which leads to cholinergic response acetylcholine also
binds to presynaptic receptors and inhibit the release of more
acetylcholine this serves as a negative feedback loop in the fifth step the
enzyme called acetylcholinesterase terminates acetylcholine function at the
synaptic cleft by breaking it down to acetate and choline and finally in the
sixth step the free choline is taken up again by the presynaptic neuron and the
whole cycle gets repeated now let’s talk about the receptors in more details
there are two types of cholinergic receptors first there are muscarinic
receptors and the second are the nicotinic receptors and as you can
probably tell from their names muscarinic receptors have high affinity
for muscarine and nicotinic receptors have high affinity for
nicotine now there are five distinct subtypes of muscarinic receptors
known as M1 M2 M3 M4 and M5 out of these the first three M1 2 and 3 have been
functionally defined therefore we generally focus just on them as far as
their location besides being found on neurons M1 receptors are located in
gastric glands M2 receptors are located on cardiac cells and M3
receptors are found in numerous places on smooth muscle in the eye
lungs digestive tract as well as exocrine glands such as sweat and
salivary now as you may remember muscarinic receptors are members of the
G protein-coupled receptors you may also recall that there are different types of
G protein so the receptors M1 and M3 are coupled to G protein of type Gq as a
quick reminder stimulation of Gq leads to increase in intracellular levels of
calcium this is important to remember because increasing intracellular calcium
content can trigger processes such as contraction secretions and
neurotransmission on the other hand M2 receptors are coupled to G protein of
type Gi and stimulation of Gi can lead to opening of potassium channels which
in turn causes hyperpolarization and reduction of heart rate now let’s talk
about the second major type of cholinergic receptors which are the
nicotinic receptors nicotinic receptors are ligand-gated ion channels now when
acetylcholine binds to them these receptors will undergo conformational
change that allows sodium ions to flow into the cells there are two types of
nicotinic receptors first those receptors that are found on at the
neuromuscular junction are classified as Nm and they’re responsible for muscle
contraction the second receptors that are found in
the central nervous system and autonomic ganglia are classified as Nn and they’re mainly involved in transmission of cholinergic signals so
now let’s talk about the actual drugs we can divide cholinergic agonists into
three different groups number one direct acting number two indirect acting
reversible and number three indirect acting irreversible so let’s start with
direct acting cholinergic agonists they simply mimic the effects of acetylcholine by binding to either muscarinic or nicotinic receptors the first drug that
belongs to this group is not surprisingly Acetylcholine now the
biggest problem with Acetylcholine is that it produces nonspecific cholinergic
effects and it’s rapidly inactivated by cholinesterases therefore its clinical
use is very limited in general when administered intravenously Acetylcholine
decreases cardiac output and heart rate decreases blood pressure and increases
GI activity Acetylcholine is available in ophthalmic solution which is sometimes used to produce miosis during eye surgery the next drug is Carbachol which is
structurally similar to acetylcholine and thus effectively mimics effects of
acetylcholine and along with that goes its limited therapeutic use however
Carbachol is not very susceptible to acetylcholinesterases therefore it
has fairly long duration of action as far as its therapeutic use Carbachol is
sometimes used only locally to constrict pupil during eye surgery and to decrease
intraocular pressure now another drug in this group that’s also used ophthalmically is Pilocarpine Pilocarpine acts on smooth muscle of the eye to constrict the pupil
and more importantly it increases aqueous outflow which results in rapid drop in
intraocular pressure this is why Pilocarpine is very useful in treating
acute glaucoma attack the last drug that I wanted to mention is Bethanechol unlike
the other drugs in this group Bethanechol selectively stimulates urinary and
gastrointestinal tract therefore it is sometimes given orally
or subcutaneously to treat urinary retention or to treat gastrointestinal
lack of muscular tone now let’s talk about the second group of
cholinergic agonists which are the indirect acting agonists these simply
work by binding to acetylcholinesterase enzyme which as you may
remember catalyzes breakdown of acetylcholine this in turn results in
buildup of acetylcholine in the synaptic cleft and corresponding effects so now let’s
talk about reversible agents first and let’s start with Edrophonium
Edrophonium reversibly binds to acetylcholineesterase it has a very
short duration of action only about 10 to 20 minutes and its use is typically
restricted to diagnosis of myasthenia gravis myasthenia gravis is a neuromuscular
disease which is caused by antibodies that block acetylcholine receptors which
leads to muscle weakness so when Edrophonium is administered to
a patient with myasthenia gravis we observe rapid increase in muscle
strength next we have Physostigmine Physostigmine stimulates both
nicotinic and muscarinic receptors and it’s an intermediate acting agent with
duration of action of about 30 minutes to 2 hours it’s been
historically used in the treatment of overdoses of anticholinergic drugs such
as Atropine next we have Neostigmine Neostigmine is
another intermediate acting agent but unlike Physostigmine
its structure is more polar therefore it does not absorb well from the GI tract
and does not enter the CNS it is typically used for symptoms of myasthenia gravis it can also be used to stimulate bladder and GI tract and to reverse the
effects of anesthesia from neuromuscular blocking agents also I wanted to mention
Pyridostigmine which is another agent that is very similar to Neostigmine
and it produces very similar effects lastly I wanted to mention some agents
that are used to ease the symptoms of Alzheimer’s disease and these are
Donepezil Rivastigmine and Galantamine reduction in the
activity of the cholinergic neurons is a well-known feature of Alzheimer’s
disease therefore use of these agents can enhance cholinergic effects and lead
to somewhat improved cognitive function unfortunately none of these agents can
stop the progression of Alzheimer’s disease now that we covered the
reversible anticholinesterase agents I wanted to briefly mention the
irreversible ones many of these drugs are extremely toxic and were developed
by the military as nerve agents and best example of that is sarin gas because of
that the only agent that you might still encounter in medical practice is Echothiophate Echothiophate forms covalent bonds with acetylcholinesterase leading
to a very strong cholinergic stimulation its therapeutic use is restricted to
treatment of open-angle glaucoma only however it is rarely used at all due to
its side effect profile I would like to end this video by sharing some of the
side effects associated with cholinergic agonists now the adverse effects that can
result from use of these agents are due to overstimulation of cholinergic
receptors and there are as follows diarrhea urination miosis and muscle
weakness bronchorrhea bradycardia emesis lacrimation and salivation
now how can you remember all of these well the great mnemonic is right in
front of you “DUMBBELLS” it’s all you need to know to
remember the common side effects associated with cholinergic agonists
thank you for watching make sure you subscribe and stay tuned to the part 2
where I’ll be discussing cholinergic antagonists

13 comments

  1. This is the best "to the point " cholinergic video!!! You are AMAZING!!!!!! Thanks so much and all the best !!!!

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