Pharmacology Cholinergic Agonists

Neurotransmission:
Synthesis: Choline has a positive charge, so cannot pass through the membrane, and thus it
is transported into the cytoplasm by an energy dependent carrier system that cotransports
sodium, and can be inhibited by hemicholinium. Uptake is the rate-limiting step in Ach
synthesis. Choline acetyl transferase catalyzes the reaction of choline with acetyl coenzyme
Storage: Ach is packaged and stored into presynaptic vesicles by an active transport process
coupled to the efflux of protons. The vesicle also contains ATP and proteoglycan.
Release: When an action potential arrives at a nerve terminal, voltage-sensitive calcium
channels open, causing release of vesicles. This release can be blocked by botulinum toxin.
The toxin in black widow spider venom causes all the Ach to empty.
Binding: Ach binds to either of two post-synaptic receptors on the target cell, to presynaptic
receptors, etc. The postsynaptic cholinergic receptors are divided into two classes:
muscarinic and nicotinic.
Degradation: The signal at the postjunctional effector site is rapidly terminated, because
AChE cleaves Ach to choline and acetate in the synaptic cleft.
Recyling: Choline may be recaptured by a sodium-coupled, high-affinity uptake system that
transports the molecule back into the neuron.
Cholinergic Receptors (Cholinoceptors)
Muscarinic:
Muscarinic receptors are G protein-coupled receptors. These receptors, in addition to
binding Ach, also recognize muscarine, an alkaloid that is present in certain poisonous
mushrooms. There are 5 subclasses of muscarinic receptors, although only M1, M2, and M3
have been functionally characterized.
Location: These receptors are found on ganglia of the peripheral nervous system and on the
autonomic effector organs, such as the heart, smooth muscle, brain and exocrine glands.
M1 gastric parietal cells, M2 cardiac cells, M3 bladder, exocrine, and smooth muscle.
Mechanism of signal transduction: M1 and M3 are Gq coupled, which activates
phospholipase C. This leads to the hydrolysis of phosphatidylinositol-(4,5)-bisphosphate to
yield diacylglycerol and inositol (1,4,5)-trisphosphate. Both IP3 and diacylglycerol are second
messengers. IP3 causes an increase in intracellular Ca2+, which can then affect enzymes or
cause hyperpolarization, secretion or contraction. Diacylglycerol activates protein kinase C.
This enzyme phosphorylates numerous proteins within the cell.
In contrast, M2 in cardiac muscle is Gi, which inhibits adenylyl cyclase and increases K+
conductance. The heart responds with a decrease in rate and force of contraction.
Muscarinic agonists and antagonists: There are efforts to make selective drugs. E.G.
Pirenzepine is a tricyclic anticholinergic drug, which has greater selectivity for inhibiting M1.
Darifenacin is a competitive muscarinic M3 agonist.
Nicotinic:
The nicotinic receptor consists of 5 subunits and functions as a ligand-gated ion channel.
Binding of two Ach molecules elicits a conformational change that allows the entry of
sodium ions, resulting in depolarization of the effector cell. Nicotine at low concentration
stimulates the receptor, and at high concentrations blocks the receptor. Nicotinic receptors
located in the CNS, adrenal medulla, autonomic ganglia, and the NMJ. Nm NMJ, Nn all
others. Ganglionic receptors blocked by hexamethonium, whereas NMJ blocked by
tubocurarine.

Direct Acting Cholinergic Agonists
Acetylcholine: Acetylcholine is a quaternary ammonium compound that cannot penetrate
membranes. Although it is a neurotransmitter of parasympathetic and somatic nervers as
well as autonomic ganglia, it lacks therapeutic importance because of its multiplicity of
actions and its rapid inactivation by the cholinesterases.
Decrease in heart rate and cardiac output Mimics vagal stimulation.
Decrease in blood pressure. ACh activates M3 receptors on endothelial cells. This
results in production of nitric oxide from arginine. NO then diffuses to vascular
smooth muscle cells to stimulate protein kinase G production, leading to
hyperpolarization and smooth muscle relaxation via phosphodisterase-3 inhibition.
Atropine blocks this.
Other actions Ach increases salivary secretions and stimulates intestinal secretions
and motility. Enhances Bronchiolar secretions. In the genitourinary tract, increases
tone of detrusor urinae muscles causing expulsion of urine. In the eye, Ach is
involved in ciliary muscle contraction for near vision and in the constriction of the
papillae sphincter muscle, causing miosis.

Bethanechol: Bethanechol is an unsubstituted carbamoyl ester structurally related to ACh. It
is not hydrolyzed by AChE, although it is inactivated by other esterases. It lacks nicotine
actions. Major actions on smooth musculature of bladder and GI tract.
Actions: Bethanechol directly stimulates muscarinic receptors, causing increased
intestinal motility and tone. It also stimulates the detrusor muscle of the bladder,
whereas the trigone and sphincter are relaxed.
Therapeutic applications: Bethanechol is used to stimulate the atonic bladder,
particularly in postoperative, nonobstructive urinary retention.
Adverse effects: Bethanechol causes the effects of generalized cholinergic
stimulation. These include sweating, salivation, flushing, decreased blood pressure,
nausea, abdominal pain, diarrhea, and bronchospasm. Atropine sulphate may be
administered to overcome severe cardiovascular or bronchoconstrictor responses.

Carbachol: Muscarinic and nicotinic. Poor substrate for AChE.
Actions: Carbachol affects CV and GI systems. Can cause release of E from adrenal
medulla. Instilled in the eye, causes miosis and accommodation.
Therapeutic uses: Rarely used, because of nonselectivity and long duration of action.
Sometimes used as miotic agent to treat glaucoma.

Pilocarpine: Far less potent than ACh or derivatives, but is uncharged and will penetrate
CNS. Muscarinic agonist.
Applied to the eye, produces rapid miosis and contraction of the ciliary muscle. One
of the most potent stimulators of secretions such as sweat, tears and saliva.
Sjogrens syndrome, which is characterized by dry mouth and lack of tears, is treated
with oral pilocarpine tablets.
Pilocarpine is used to treat glaucoma and is the drug of choice in the emergency
lowering of intraocular pressure. Opens trabecular meshwork around Schlemms
canal.
Can enter brain and cause CNS disturbances. Poisoning with this agent is
characterized by exaggerated PS effects, including profuse sweating and salivation.
Similar to consumption of Inocybe mushrooms. Atropine used to combat pilocarpine.

Indirect Acting Cholinergic Agonists (AChE inhibitors)
AChE is an enzyme that specifically cleaves ACh to acetate and choline. Can provoke
response at all cholinoceptors in the body.
Edrophonium: Edrophonium is the prototype short-acting AChE inhibitor. Edrophonium
binds reversibly to the active center of AChE, preventing hydrolysis of ACh. Rapidly
eliminated renally. Used in diagnosis of MG. Care must be taken not to cause a cholinergic
crisis (atropine is the antidote).
Physostigmine:
Actions: Physostigmine has a wide range of effects. Duration is 2-4 hours. Can enter
CNS.
Therapeutic uses: Increases intestinal and bladder motility, which serve as its
therapeutic action. Placed topically in the eye, causes miosis and spasm of
accommodation, as well as lowering of intraocular pressure.
Adverse effects: May lead to convulsions when high doses used. Bradycardia and a
fall in cardiac output. May result in paralysis of skeletal muscle.

Neostigmine:
Unlike physostigmine, neostigmine has a quaternary nitrogen. Therefore, it is more
polar, is absorbed poorly from GI tract, and does not enter CNS.
Therapeutically used to stimulate bladder and GI tract, as an antidote to
tubocurarine. Used to treat MG.
Adverse effects include salivation, flushing, decreased blood pressure, nausea,
abdominal pain, diarrhea, and bronchospasm.

Pyridostigmine and ambenonium: Other cholinesterase inhibitors that are used chronically
to manage MG.
Tacrine, donepezil, rivastigmine and galantamine: Patients with Alzheimer disease have
deficiency of cholinergic neurons in CNS.
Indirect Acting Cholinergic Agonists (Anticholinesterases
irreversible)
Many of these drugs are extremely toxic, and many were developed by the military as nerve
agents. Related compounds, such as parathion, are used as insecticides.
Echothiophate:
An organophosphate that covalently binds to AChE. Once this occurs, the enzyme is
permanently inactivated.
Actions include generalized cholinergic stimulation, paralysis of motor function, and
convulsions. Echothiophate produces intense miosis. Intraocular pressure falls.
An ophthalmic solution is applied topically.
Toxicology: Pralidoxime used. Atropine also, and diazepam.
Cholinergic Antagonists