Cholinergic Receptors

1. Receptors stimulated by ACh are called Cholinergic receptors, or Cholinoceptors

2. Ach is primary neurotransmitter of the Parasympathetic Nervous System (PNS)
responsible for the body’s “rest and digest” state.
Types:
1. Muscarinic receptors
- In addition to Ach, these receptors recognize Muscarine, an alkaloid found in poisonous
mushrooms
2. Nicotinic receptors
- In addition to Ach, these receptors recognize Nicotine
- In CNS, located in adrenal medulla and autonomic ganglia
- In skeletal muscles, located in NMJ
Actions:
1. Decreases heart rate and blood pressure (vasodilation)
2. Bronchoconstriction
3. Contracts smooth muscles of GIT
4. Contracts smooth muscles of urinary bladder (increase detrusor ms. and increase
urination)
5. Stimulates various secretions (increase saliva, gastric, and intestinal secretions, and
motility)
6. Constricts pupil (Miosis) and increases ciliary muscle contraction for near vision
Synthesis of ACh:
1. Acetylcholine is an ester of choline
2. It is synthesized and stored in the nerve terminal
3. When a cholinergic neuron is stimulated, ACh is released into the synaptic cleft where it
binds to its receptor on the postsynaptic cell, triggering cellular response
4. ACh is rapidly cleared from the synapse by the enzyme AChE, which binds to acetylcholine
and hydrolyzes it into choline and acetate
5. The enzyme molecule quickly recycles itself each time, ready for another round of reaction
Choline + AcetylCoA Choline Acetyl Transferase Acetylcholine (ester)
Acetylcholine (ACh) Acetylcholinesterase (AChE) Choline + Acetate
Hydrolyze

Cholinergic Agonist Cholinergic Antagonist

Cholinergic Agonists:
1. Direct-acting cholinergic agonists
- Mimic acetylcholine
- Bind to acetylcholine receptor and activate signaling
- Are not easily metabolized by acetylcholinesterase and therefore last longer at the synapse
1. Acetylcholine
- It binds to both muscarinic and nicotinic receptors
- Used to produce Miosis in Ophthalmic surgery
- Decreases heart rate and blood pressure (vasodilation)
- Bronchoconstriction
- Stimulates secretions (increases salivary, gastric, and intestinal secretions and motility)
2. Bethanechol
- Binds to muscarinic receptors
- Used in treatment of urinary retention
3. Carbachol
- Binds to both muscarinic and nicotinic receptors
- Produces Miosis during Ophthalmic surgery
- Used to reduce IOP in open angle or narrow angle glaucoma,
particularly in patients tolerant to Pilocarpine
- It can cause the release of Epinephrine by the adrenal medulla through its nicotinic action
4. Pilocarpine
- Binds to muscarinic receptors
- Used to treat xerostomia (most potent stimulator of secretions, saliva, sweat, and tears)
- Reduces IOP in open angle and narrow angle glaucoma
- Uncharged tertiary amine that can penetrate the CNS
MOA:
1. Pilocarpine opens the trabecular meshwork around the Schlemm canal, causing
immediate decrease in IOP because of increased drainage of aqueous humor
2. This action occurs within a few minutes and lasts for 4 to 8 hrs
The Miotic action of Pilocarpine is useful in reversing Mydriasis caused by Atropine

2. Indirect-acting cholinergic agonists

AChE cleaves ACh into Choline & Acetate, thus terminating its action
- Inhibitors of AChE indirectly produce cholinergic action by preventing the degradation of
ACh, which results in the accumulation of ACh in the synaptic space

Reversible cholinesterase inhibitors:

- Reversible AChE inhibitors are classified as short-acting and intermediate-acting
Examples:
1. Drugs used to treat myasthenia gravis
2. Drugs used to reverse the effects of anesthesia
3. Drugs used to boost cholinergic activities in Alzheimer’s brain to compensate for the loss
of functioning neurons
Anticholinesterase agents (Reversible):
1. Edrophonium
- Used for the diagnosis of myasthenia gravis
- Used as an antidote for competitive neuromuscular blockers (NMB’s)
- Short duration of action (10 to 20 min)
2. Physostigmine
- Increases intestinal and bladder motility
- Reverse CNS and cardiac effects of TCA’s
- Uncharged tertiary amine that can penetrate the CNS
- Intermediate duration of action (30 mins to 2 hrs)
- Physostigmine is used in the treatment of overdosage of anticholinergic drugs, such as
Atropine, and reverse the effects of NMB’s
3. Neostigmine
- Prevents post-operative abdominal distention and urinary retention
- Used in treatment of myasthenia gravis
- Used as an antidote for competitive neuromuscular blockers
- Intermediate duration of action (30 mins to 2 hrs)
4. Pyridostigmine
- Management of myasthenia gravis
- Intermediate duration of action (3 to 6 hrs)
5. Tacrine
- Used for Alzheimer’s disease previously
- Tacrine is replaced because of hepatotoxicity
6. Donepezil, Rivastigmine, Galantamine
- Used as first-line treatment for Alzheimer’s disease
- They can delay progression of Alzheimer’s disease but cannot stop its progression
- Can be used with Memantine in moderate to severe disease

Irreversible cholinesterase inhibitors:

- Bind to AChE covalently and in an irreversible manner resulting in permanent inactivation
of the enzyme
- These drugs are very toxic, and are used as insecticides and “nerve gases” such as Sarin
- Botulinum toxin, Botox, is a bacterial toxin
- It blocks ACh release by inhibiting exocytosis
- Botox is used to treat localized muscle spasms
- Black widow spider venom depletes stored ACh from synaptic vesicles
Anticholinesterase agents (Irreversible)
1. Parathione and Melathione are used as insecticides
2. Echothiopate
- Used in treatment of open angle glaucoma
- Has long duration of action (100 hrs)
- Side effect is risk of cataract
Reactivation of Acetylcholinesterase:
Pralidoxime: reverses muscarinic and nicotinic effects of organophosphates, but not CNS
effects because it cannot penetrate CNS
Atropine: reverses only muscarinic effects
Diazepam: reduces persistent convulsions
Cholinergic Antagonists:
- Antimuscarinic agents or Anticholinergic drugs that blocks muscarinic receptors
- Compete with acetylcholine for binding to muscarinic receptor
Actions:
1. Increase heart rate
2. Bronchodilation
3.Constipation
4. Reduce secretions
5. Dilate pupils (Mydriasis)
6. Some are used as sedatives and to counteract cholinesterase inhibitors.

Antimuscarinic agents:
1. Atropine
- Injectable Atropine is used to treat sinus bradycardia
- Antispasmodic, reduces activity of GI tract
- Suppresses respiratory secretions prior to surgery
- Treatment of organophosphate poisoning and overdose of anticholinesterase
1. Acts centrally and peripherally
- General action lasts for 4 hours, but in eye lasts for 4 days
2. Atropine blocks muscarinic activity in eye causing:
- Mydriasis
- Unresponsiveness to light
- Cycloplegia
- Increased IOP
3. Used to treat bradycardia
- At low doses, slightly decreases heart rate
- At high doses, increases heart rate by blocking M2 receptors at SA node
4. Atropine blocks salivary, sweat, and lacrimal glands that leads to increased body
temperature, known as Atropine fever
5. Atropine produces prolonged mydriasis of 7-14 days, so replaced by short-acting anti-
muscarinics (Cyclopentolate and Topicamide)
Adverse effects:
1. Tachycardia
2.Dry mouth
3. Blurred vision
4. Sandy eyes
5. Constipation
6. Urinary retention
Effect on CNS:
1. Restlessness
2. Confusion
3. Hallucinations
4. Delirium, which may progress to depression
5. Collapse of circulatory and respiratory system
6. Death
Physostigmine (cholinesterase inhibitor) can be used to overcome Atropine toxicity
2. Scopolamine
- Prevents motion sickness
- Post-operative nausea and vomiting
- Available as transdermal patch that is effective for three days

Atropine and Scopolamine are the most potent antispasmodic drugs available

3. Aclidinium, Glycopyrrolate, Ipratropium & Tiotropium

- Treatment of COPD
- These all are used in inhalation form
- Ipratropium is SAMA and is used to treat rhinorrhea, as it is short-acting, so requires 4 to 5
daily doses
- Aclidinium, Glycopyrrolate, & Tiotropium are LAMA
- Ipratropium & Tiotropium decrease contractility of smooth muscles in lungs, causing
bronchodilation and reducing mucus production

4. Cyclopentolate & Tropicamide

- In ophthalmology, produce mydriasis and cycloplegia prior to refraction
- Short-acting, 6 to 24 hrs

5. Benztropin & Trihexyphenidyl

- Treatment of Parkinson’s disease
- Management of antipsychotic induced extrapyramidal effects

6. Oxybutynin, Trospium
Darifenacin, Solifenacin
Fesoterodine, Tolterodine
- Treatment of overactive urinary bladder
- Oxybutynin is available as transdermal patch and topical gel formulat
 Neuromuscular Blocking Agents:
Nicotinic Antagonist
1. These drugs block ACh transmission between motor nerve endings and nicotinic receptors
on the skeletal muscles
2. These drugs act as ACh antagonists (non-depolarizing) or as ACh agonists (depolarizing) at
the receptors on the end plate of the NMJ
Uses:
NMB’s are used
1. to facilitate rapid endotracheal intubation
2. to facilitate mechanical ventilation in critically ill patients
3. to provide skeletal muscle relaxation during surgery
4. All NMB’s are injected intravenously or occasionally IM

Non-depolarizing (competitive) blockers: Antagonist

Agents:
1. Atracurium
2. Mivacurium
3. Cisatracurium (duration of action 90 mins)
4. Pancuronium (duration of action 90 mins)
5. Rocuronium (duration of action 40 mins)
6. Vecuronium (duration of action 40 mins)
MOA:
1. At low doses: they compete with ACh at nicotine receptor without stimulating it, thus
preventing depolarization of muscle cell membrane and inhibiting muscle contraction
2. At high doses: they block ion channels of the motor end plate, resulting in further
weakening of ACh transmission
Actions:
1. First, rapidly contracting muscles of face and eye paralyze
2. Then, fingers, limbs, neck, and trunk muscles
3. Next, intercostal muscles
4. Lastly, diaphragm
5. The muscles recover in the reverse manner
Drug interactions:
1. Cholinesterase inhibitors:
Edrophonium, Physostigmine, Neostigmine, and Pyridostigmine can overcome the action of
NMB’s. At high doses, Cholinesterase inhibitors can cause a depolarizing block due to
increased AChE conc. at end plate membrane

2. Halogenated hydrocarbon anesthetics:

Desflurane increases neuromuscular blockade by exerting a stabilizing action at NMJ

3. Aminoglycoside antibiotics:
Gentamycin and Tobramycin inhibit ACh release from Cholinergic neurons by competing
with Calcium ions. They increase the effect of competitive blockers, increasing
neuromuscular blockade
4. Calcium channel blockers increases the effect of competitive blockers, increasing
neuromuscular blockade
Depolarizing agents: (Agonist)
Succinylcholine= Suxamethonium
MOA:
1. Succinylcholine binds to nicotinic receptors and acts like Ach to depolarize the plasma
membrane of muscle fiber
2. Succinylcholine is resistant to degradation by AChE and persists at high conc. in the
synaptic cleft, remaining attached to the receptor for a longer time, and provides sustained
depolarization of the muscle cell
Actions:
1. Succinylcholine initially produces muscle fasciculations, causing muscle soreness, and this
can be prevented by admin. of small dose of nondepolarizing NMB prior to succinylcholine
2. Duration of action of Succinylcholine is extremely short due to rapid hydrolysis by plasma
Cholinesterase
Uses:
1. Rapid endotracheal intubation
2. Electroconvulsive shock treatment
Administration:
1. Succinylcholine is injected intravenously
2. Its brief duration of action results from redistribution and rapid hydrolysis by plasma
Cholinesterase
Adverse effects:
1. Malignant hyperthermia
2. Apnea
- Patient deficient in plasma Cholinesterase can suffer from Apnea due to paralysis of
diaphragm
-Patients with electrolyte imbalance receiving Digoxin or Diuretic (Heart failure patient)
Succinylcholine should be used with caution or not at all
3. Hyperkalemia
- Succinylcholine increases potassium release from intracellular stores
- It is dangerous in burn patients and in patients with massive tissue damage in which
potassium is already lost and in patients with renal failure