1. School of Pharmacy, University of Nizwa
Cholinergic Agonist
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-14
October 25, 2011

2. Cholinergic Neuron
Preganglionic fibers terminating in the adrenal medulla, autonomic ganglia (parasympathetic and sympathetic), and postganglionic fibers of parasympathetic division use acetylcholine (ACh) as a neurotransmitter
Cholinergic neurons innervate the muscles of the somatic system
Important role in the CNS

3. Peripheral Nervous System

4. Neurotransmission at Cholinergic Neurons
Six steps in the normal cholinergic transmission process:
1. Synthesis of the ACh
2. Storage of the ACh
3. Release of the ACh by a nerve action potential
4. Binding to receptor
5. Degradation of ACh
6. Recycling of choline

5. Synthesis and Storage of ACh

6. Neurotransmission at Cholinergic Neurons
1. Synthesis of the ACh
Choline is transported from the extra-cellular fluid into the cytoplasm of the cholinergic neuron
an energy-dependent carrier system that cotransports sodium
can be inhibited by the drug hemicholinium.
Uptake of choline is the rate-limiting step in ACh synthesis
Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form ACh in cytosol
2. Storage of the ACh
Packaged into presynaptic vesicles by an active transport
Mature vesicle contains not only ACh but also ATP and proteoglycan

7. Neurotransmission at Cholinergic Neurons
3. Release of the ACh
Propagation of action potential at the nerve ending increases intracellular calcium concentration
Elevated calcium levels promote the fusion of vesicles with the cell membrane and release ACh into the synaptic space
This release can be blocked by botulinum toxin
Black widow spider venom facilitates ACh release
4. Binding to receptor
ACh binds
postsynaptic receptors on the target cell
presynaptic receptors in the neuron that released the ACh
Postsynaptic cholinergic receptors on surface of effector organs are divided into 2 classes, muscarinic and nicotinic
Binding to a receptor leads to a biologic response

8. Neurotransmission at Cholinergic Neurons
5. Degradation of ACh
Acetylcholinesterase (AChE) cleaves ACh to choline and acetate in the synaptic cleft
6. Recycling of choline
Choline is taken up by the neuron, where it is acetylated into ACh that is stored until released by a subsequent action potential

9. Cholinergic Receptors (Cholinoceptors)
Two families of cholinoceptors:
1. Muscarinic receptors
Affinity towards ACh
High affinity towards muscarine, low affinity towards nicotine
Five subclasses: M1, M2, M3, M4 and M5
2. Nicotinic receptors
High affinity towards nicotine, low affinity towards muscarine

10. Muscarinic Receptors 1. Locations
Found on ganglia and on the autonomic effector organs, such as heart, smooth muscle, brain, and exocrine glands
M1 receptors found on gastric parietal cells
M2 receptors on cardiac cells and smooth muscle
M3 receptors on bladder, exocrine glands, and smooth muscle
2. Mechanism of ACh signal transduction
When activated, receptor undergoes a conformational change and interacts with a G protein, which in turn transmits the signal to initiate different molecular events
3. Muscarinic agonists and antagonists
Attempts are currently underway to develop muscarinic agonists and antagonists

11. Nicotinic Receptors
Located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction
The nicotinic receptors of autonomic ganglia differ from those of the neuromuscular junction. For example, ganglionic receptors are selectively blocked by hexamethonium, whereas neuromuscular junction receptors are specifically blocked by tubocurarine

12. Direct-acting Cholinergic Agonists
Cholinergic agonists mimic the effects of ACh by binding directly to cholinoceptors
These agents may be broadly classified into two groups:
choline esters, include ACh and synthetic esters of choline, such as carbachol and bethanechol
Naturally occurring alkaloids, such as pilocarpine
All of the direct-acting cholinergic drugs have longer durations of action than ACh

13. Acetylcholine (ACh)
ACh is a quaternary ammonium compound that cannot penetrate membranes
ACh has both muscarinic and nicotinic activity
Its actions include:
Decrease in heart rate and cardiac output
Causes vasodilation and lowering of blood pressure
Increases salivary secretion and stimulates intestinal secretions
Involved in stimulating ciliary muscle contraction for near vision

14. Bethanechol
Structurally related to ACh, in which the acetate is replaced by carbamate and the choline is methylated. Hence, it is not hydrolyzed by AChE
Actions: Directly stimulates muscarinic receptors, causing increased intestinal motility
Adverse effects: Causes the effects of generalized cholinergic stimulation. These include sweating, salivation, decreased blood pressure, nausea, abdominal pain, and diarrhea

15. Carbachol Carbachol has both muscarinic as well as nicotinic actions
It has effects on both the cardiovascular system and the GI system

16. Pilocarpine
Pilocarpine is stable to hydrolysis by AChE. It exhibits muscarinic activity
Actions: Applied topically to the cornea, pilocarpine produces a rapid miosis and contraction of the ciliary muscle
Therapeutic use in glaucoma: Drug of choice in the emergency lowering of glaucoma
Adverse effects: Can enter the brain and cause CNS disturbances. It stimulates sweating and salivation

17. Indirect-Acting Cholinergic Agonists: Anticholinesterases (Reversible)
AChE is an enzyme that specifically cleaves ACh to acetate and choline and, thus, terminates its actions
Located both pre- and postsynaptically in the nerve terminal
Inhibitors of AChE indirectly provide a cholinergic action. This results in the accumulation of ACh in synaptic space

18. Physostigmine Physostigmine is a substrate for AChE
Actions: Acts on both muscarinic and nicotinic receptors. Its duration of action is about 2 to 4 hours. It stimulates the cholinergic sites in the CNS
Therapeutic uses: Increases intestinal & bladder motility. Placed topically in the eye, it produces miosis, as well as a lowering of intraocular pressure. It is also used in the treatment of overdoses of drugs with anticholinergic actions, such as atropine
Adverse effects: Effects on CNS may lead to convulsions when high doses are used. Bradycardia may also occur

19. Neostigmine Neostigmine reversibly inhibits AChE.
Unlike physostigmine, it has a quaternary nitrogen; hence, it is more polar and does not enter the CNS
Neostigmine has a moderate duration of action, usually 30 minutes to 2 hours
Actions: Used to stimulate the bladder and GI tract. Also, used in symptomatic treatment of myasthenia gravis, an autoimmune disease at neuromuscular junctions
Adverse effects: Generalized cholinergic stimulation, such as salivation, decreased blood pressure, nausea, abdominal pain, and diarrhea

20. Pyridostigmine
Pyridostigmine is a AChE inhibitor that is used in the chronic management of myasthenia gravis
Its durations of action is 3 to 6 hrs
Adverse effects: Similar to that of neostigmine

21. Edrophonium
The actions of edrophonium are similar to those of neostigmine, except that it is more rapidly absorbed and has a short duration of action of 10 to 20 minutes
Edrophonium is a quaternary amine and is used in the diagnosis of myasthenia gravis
Intravenous injection of edrophonium leads to a rapid increase in muscle strength
Care must be taken, because excess drug may provoke a cholinergic crisis. Atropine is the antidote