Cholinergic drugs are used to modulate the parasympathetic nervous system during anesthesia. The parasympathetic system is responsible for functions such as salivation, gastrointestinal motility, and slowing of the heart rate. Cholinergic drugs can be used to counteract the effects of anesthetics that cause unwanted suppression of the parasympathetic system.
In this blog we’ll discuss cholinergic drugs, actions of the Sympathetic & Parasympathetic system and parasympathomimetic drugs.
Autonomic Nervous System (ANS)
It is the part of the nervous system which controls the involuntary functions.
It consists of the different output from the central nervous system i.e. brain and spinal cord.
ANS is divided into two parts, based on anatomy
Nerve fibres which originate from the thoraco-lumbar portion of spinal cord are called sympathetic nerve fibres.
Nerve fibres which originate from the Cervical or sacral portion of spinal cord are called parasympathetic nerve fibres.
Consists of Thoraco- lumbar outflow
Cranio – sacral outflow
Pre-ganglionic fibres are small and post-ganglionic fibres are long
Pre-ganglionic fibres are long and Post-ganglionic fibres are small
Ganglion is near the spinal cord
Ganglion is away from the spinal cord
All the pre-ganglionic fibres, whether they belong to the sympathetic system or parasympathetic system release the same neurotransmitter i.e. Acetylcholine.
The receptor for this Ach is also the same i.e. NN receptor, present at the post ganglionic fibre.
The post-ganglionic fibre carries the information to the organ.
This fibre releases a neurotransmitter which acts on the receptors present in the organ
The neurotransmitter is different for different fibres
Parasympathetic system: Ach
Since both pre-ganglionic and post-ganglionic fibres of parasympathetic system release Ach, it is also called Cholinergic system
Sympathetic system: Nor-adrenaline
The sympathetic system is also called Adrenergic system
Post ganglionic sympathetic fibres in sweat glands release Acetylcholine
At renal blood vessels, the neurotransmitter secreted is Dopamine
Actions of Sympathetic & Parasympathetic system
Organ / Sympathetic system
i. Heart : +++
(+ve chronotropic +ve dromotropic +ve ionotropic)
(-ve chronotropic-ve dromotropic)
Apart from heart, at all other places the effect is opposite. Sympathetic will inhibit and Parasympathetic will stimulate
ii. Bronchus: Broncho-dilation
iii. GIT: Constipation
iv. Bladder: ↓ Urine outflow
↑ Urine outflow
v. Glands: ↓ Secretions (but sweat ↑)
vi. Eye: Mydriasis (Dilation of pupil)
Miosis (Contraction of pupil)
vii. Sex: Ejaculation
In the case of sexual system, both sympathetic and parasympathetic system complement each other
Previous Year Question
Question: Which of the the following action is expected on stimulation of muscarinic receptors? (AIIMS Jun 2020)
Increased contraction of cardiac muscles
UNDERSTAND WITH EXAMPLE
Point and Shoot: ‘Point’ means erection and ‘P’ for parasympathetic
‘Shoot’ means ejaculation and ‘S’ for sympathetic
It originates from cranio-sacral nerves
III, VII, IX, X are parasympathetic
Rest all are autonomic nerves
No cranial nerve is sympathetic
Sacral Nerves : 2,3,4 are parasympathetic
Also called cholinergic system because both the pre-ganglionic and post-ganglionic fibres secrete Ach.
First step is uptake of choline from outside the neuron
This choline forms Acetylcholine inside the neuron. This Ach is stored inside the vesicle where it remains safe
When the impulse arrives, this Ach is released into the synapse and starts stimulating the post-synaptic receptor.
To stop the action of Ach after stimulation of receptors is complete, the Ach is broken down by enzyme Acetyl cholinesterase
Rate limiting step: Uptake of choline
Regulation of Ach level in the synapse
Inhibit choline uptake
Hemicholinium: It inhibits the uptake of choline in the neuron so parasympathetic action decreases
Inhibit uptake of Acetylocholine
Vesamicol: It inhibits the uptake of Acetylcholine in the vesicles
Inhibit release of Acetylcholine
Botulinum toxin: It inhibits the release of Acetylcholine from the neuron into the synapse
Inhibit Ach breakdown
Physostigmine: It increases the level of Ach by inhibiting its breakdown via Acetylcholine esterase (AchE)
The 1st three drugs have actions opposite to the parasympathetic system
The last drug physostigmine has similar action as the parasympathetic system
The cholinergic receptor are of two types :
M1: Stomach -↑HCL secretion
M2: Heart - Bradycardia
M3: Present almost everywhere
Eye, Bronchus, GIT, Bladder, Glands
All 5 Muscarinic receptors are present in brain
NN: Present at Ganglia (both SNS and PNS)
NM: Present at NMJ. It requires optimal stimulation
Drugs acting on these receptors
Their action is similar to the parasympathetic nervous system
These drugs block the action of parasympathetic system
PARASYMPATHOMIMETIC DRUGS (aka Cholinergic Drugs)
These drugs mimic the actions of parasympathetic system
They are also called cholinergic drugs
These are of two types
Directlyacting: These are the drugs that directly stimulate the Nicotinic and Muscarinic receptors
Indirectlyacting (AchE inhibitors): These drugs inhibit AchE, so Ach cannot be broken down and its level increases
Directly Acting drugs
AchE present in synapse: True AchE
AchE present in plasma: Pseudo AchE or Butryl ChE
If we give Ach clinically, as soon as it reaches the blood, it is broken down by the Pseudo ChE. Thus Ach is very short acting and not suitable to be used clinically
Bethanechol mainly works on the urinary bladder (M3). It is used in treatment of Atonic bladder
Methacholine acts on the myocardium (M2). It is used in Tachyarrhythmia
Pilocarpine acts on the pupil (M3). It is used for treatment of glaucoma
These drugs act on muscarinic receptors. None of these 3 drugs acts on Nicotinic receptors
Carbachol is the only drug in the category which acts on both muscarinic as well as Nicotinic receptors
Cevimeline is a recent directly acting cholinergic drug that acts on M3 receptors. It stimulates the glands and increases secretions, so used in treatment of Sjogren’s syndrome
These drugs are inhibitors of AchE. They may be of 2 types
Reversible AchE #
Irreversible AchE #
These are commonly used clinically
Permanently inhibits AchE, so there is permanent↑ in Ach
So these drugs are not used clinically
These are of 2 types
Lipid soluble: Physostigmine
Water soluble: Neostigmine
1. Lipid soluble drugs
Lipid soluble drugs will cross the membranes and water soluble drugs cannot cross the membranes
So physostigmine can be used in GIT, Eye or CNS conditions and Neostigmine cannot be given as it won’t get absorbed
Physostigmine is lipid soluble because it is a tertiary amine and tertiary amines are lipid soluble
Also, Neostigmine is water soluble because it is a quaternary amine and quaternary amines are water soluble
Physostigmine is used for treatment of glaucoma. It leads to miosis in the eye.
Physostigmine can cross the blood brain barrier, so can be used for treatment of Atropine poisoning. Atropine is a muscarinic blocker, so in atropine poisoning muscarinic receptors are not working
Atropine blocks the receptors both inside the brain and outside the brain because it is lipid soluble. Therefore, Physostigmine is DOC for Atropine poisoning
Basal Nucleus of Meynert
Basal nucleus of Meynert is the area in the brain that contains plenty of Ach and is a major area of cholinergic supply.
This area is involved in memory - it is responsible for acquiring and retaining the memory
So Ach is required for memory
If there is death of neurons in the Basal area of Meynert, there is loss of memory, i.e. Dementia. This death of neurons occurs more in old age people, so this is called Senile Dementia or Alzheimer’s dementia. It commonly occurs after 60 yrs of age
If we give Physostigmine for Alzheimer’s disease, it affects the muscarinic receptors outside the brain too. So it will improve the memory but also lead to various side effects
Tacrine is also a lipid soluble AchE# like Physostigmine. But unlike Physostigmine, Tacrine has >99% entry in the brain, so it will improve memory without causing significant side effects
But problems with Tacrine are – it is short acting and hepatotoxic. Also it needs to be given 4 times a day and Alzheimer’s patients cannot remember to take the drug 4 times a day, so Tacrine is not DOC anymore.
New drugs for Alzheimer’s
Lipid soluble AchE# with >99% entry in brain, similar to Tacrine
But unlike Tacrine, these drugs are long-acting and do not cause liver damage, so these have become the DOC for Alzheimer’s disease
Other drugs used for Alzheimer’s disease
Memantine: Blocks the receptors of Glutamate so it improves memory and can be used for Alzheimer’s disease
Aducanumab: It is a monoclonal antibody against Aβ2 amyloid, which is causing destruction of neurons. So it treats the underlying cause of Alzheimer’s disease
Water soluble drugs
Water soluble AchE# drugs are
These are preferred when we want action outside the brain. These are water soluble so won’t cross the blood brain barrier
There is formation of antibodies against NM receptors, so less stimulation of NM receptors occurs. This leads to muscle weakness
Most commonly involved muscle is Levator Palpabrae Superioris (LPS), leading to Ptosis
NM receptors require optimal stimulation to work normally. If there is over – stimulation of these receptors it leads to cholinergic crisis
This is opposite to myasthenia gravis. The treatment is also opposite in both the conditions
To differentiate between the 2 conditions, we give Edrophonium I.V. It inhibits AchE and leads to ↑ level of Ach. This Ach stimulates the NM receptors. As a result, if the condition improves, the diagnosis is myasthenia gravis. But if the condition worsens, it is diagnosed as Cholinergic crisis
Edrophonium is used because it is very short acting. So if the condition worsens, it will not last beyond 10min. So it is DOC for diagnosis of Myasthenia gravis. This test is known as Edrophonium test or Tensilon test
For treatment of Myasthenia gravis, we need long acting drugs like Neostigmine and Pyridostigmine
Pyridostigmine is slightly longer acting than Neostigmine
Apart from inhibiting AchE, these drugs also directly stimulate the NM receptors.
Neostigmine is given along with Atropine for the treatment of Myasthenia gravis. Atropine blocks the muscarinic side effect caused by neostigmine
Cobra is a neurotoxic snake. Its venom goes to the NMJ and binds to the NM receptors. This leads to muscle weakness
The treatment of choice for any snake bite is Anti-Venom. But it is not available in every hospital, so we can treat the patient symptomatically by giving Neostigmine + Atropine
Reversal of muscle relaxants
Drugs which block the NM receptors like Atracurium, Pancuronium lead to muscle relaxation. These belong to the category of Non-Depolarizing Muscle Relaxants (NDMR)
These drugs are used for surgery. Their action is long lasting, so we need to give a drug to reverse their action after the surgery is over
We use Neostigmine + Atropine for reversal of muscle relaxants. Atropine is added to prevent the muscarinic side effects
Postoperative paralytic ileus
It is a muscarinic use of neostigmine
After any abdominal surgery, we keep the patient NPO (Nil per oral) because the ileum is not working. We come to know that the ileum is working again, after passage of flatus
In some people, flatus is not passed and the ileum does not start working again. This condition is called Paralytic ileus
So we need to stimulate the ileus from outside. We give Ach to stimulate the M3 receptors on the ileum. This is done by giving neostigmine which increases the level of Ach.
We don’t add Atropine with neostigmine in this case because Atropine will block the M3 receptors
Bethanechol can also be used
Post-op. urinary retention
This is similar to post-operative paralytic ileus, so we give Neostigmine to stimulate the muscarinic receptors on the bladder
Atropine is not used here
Bethanechol can also be used for this condition
Ecothiophate is an example
It can be used as eye drops for miosis
These drugs can be divided into 2 types
Endrin is an organo-chlorine, not an organo-phosphate
These drugs are not used clinically
They are used commercially as insecticides, pesticides, etc. by farmers
So they can cause poisoning in farmers because they are highly lipid soluble
They permanently block the AchE and thus increase Ach. This leads to various muscarinic effects like:
To treat these poisonings we give Atropine. It is the DOC because it blocks the muscarinic receptors.
Atropine is given by I.V. route because it is an emergency. The dose is repeated every 5 min because the amount of poison in the body is not known. So we repeat the dose till we see some signs. These signs are called Signs of Atropinization
Signs of Atropinization are
Mydriasis : When the pupil dilates and we see reversal of atropinization
Decrease in secretions
HR >100 :Tachycardia occurs.
MC sign is Mydriasis
Most reliable / specific sign is Decreased Secretions
Atropine can reverse all the symptoms of OP poisoning except muscle weakness. In most cases, muscle weakness is seen after other symptoms have subsided.
Other drugs given for poisoning are : AchE Reactivators (aka Oximes)
AchE Reactivators (Oximes)
Diacetyl monoxime (DAM)
AchE has 2 sites
Ach binds to the Esteratic site and it is broken down very fast. The breakdown is so fast that this site is considered always free
When Organophosphates bind to the esteratic site, they do not break down and do not leave, so when Ach comes it cannot bind and thus not broken down. So Ach level increases.
We need to remove the OP from this site so that AchE is available again
We give Oximes which bind to the Anionic site. Then they form a bond with the OP on the esteratic site. This bond is very strong and breaks the bond between the OP and the esteratic site. So the esteratic site is now free.
In the case of Carbamates
Carbamates are big molecules and occupy both esteratic and anionic sites
So, oximes cannot bind to the anionic site and thus cannot reverse the poisoning caused by carbamates
Oximes are C/I in carbamate poisoning
Pralidoxime has peripheral action only whereas Diacetyl monoxime has dual action- brain as well as periphery
If oximes are given early on in the poisoning, they work efficiently. But if we give them very late, they cannot work properly because the bond between OP and the esteratic site has become too strong to break. This is called the Ageing of Enzymes.
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