Download 44. a. Classify cholinergic receptors and subtypes, agonists and

44. a. Classify cholinergic receptors and subtypes, agonists and antagonists
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The cholinergic drugs act on receptors that are activated by
acet ylcholine.
Neurotransmission in cholinergic neurons involves sequential six steps :
1. Synthesis
2. Storage
3. Release
4. Binding of acetylcholine
to a receptor
5. Degradation of the neurotransmitter in the synaptic gap
6. Recycling of choline
Cholinergic Receptors (Cholinoceptors)
-The postsynaptic cholinergic receptors on
the surface of the effector organs are divided
into two classes
1- Muscarinic
2- Nicotinic
-Binding to a receptor leads to a biologic
response within the cell .
-The two families of cholinoceptors, can be
distinguished from each other on the basis of
their different affinities for agents that mi mic
the action of acet ylcholine . (cholinomimetic
agents or parasympathomimetics).
Nicotinic receptors
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In addition to binding acetylcholine, also recognize nicotine and show
only a weak affinity for muscarin e.
The nicotinic receptor is composed of five s ubunits, and it functions as
a ligand-gated ion channel .
Binding of two acet ylcholine molecules elicits a conformational change
that allows the entry of sodium ions, resulting in the depolarization of
the effector cell.
Nicotine (or acetylcholine) initia lly stimulates and then blocks the
receptor.
Nicotinic receptors are located in the CNS, adrenal medulla, autonomic
ganglia, and the neuromuscular junction.
Those at the neuromuscular junction are sometimes designated N M and
the others N N .
Ganglionic receptors are selectively blocked by hexamethonium.
Neuromuscular junction receptors are specifically blocked by
tubocurarine.
Muscarinic receptors
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These receptors, in addition to bindin g acetylcholine, also recognize
muscarine and show only a weak affinit y for nicotine.
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Binding studies and specific inhibitors, as well as cDNA
characterization, have distinguished five subclasses of muscarinic
receptors: M 1 , M 2 , M 3 , M 4 , and M 5 .
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By gene cloning, only M 1 , M 2 and M 3 , receptors have been functionally
characterized.
Locations of muscarinic receptors:
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All five subt ypes have been found on neurons.
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M 1 receptors are also found on gastric parietal cells.
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M 2 receptors on cardiac cells and smooth mus cle.
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M 3 receptors on the bladder, exocrine glands, and smooth muscle.
Cholinergic Agonists
1.Direct-Acting Cholinergic Agonists
2.Indirect-Acting Cholinergic Agonsists:
Anticholinesterases (Reversible)
3.Indirect-Acting Cholinergic Agonsists:
Anticholinesterases (Irreversible)
Cholinergic Antagonist
1. Antimuscarinic Agents
2. Ganglionic Blockers
3. Neuromuscular Blocking Drugs
Direct-Acting Cholinergic Agonists
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Mimic the effects of acetylcholine by binding directly to
cholinoceptors.
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Classified into two groups:
1. Choline esters, which include acetylcholine and synthetic esters of
choline, such as carbachol and bethanechol.
2. Naturally occurring alkaloids, such as pilocarpine.
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All of the direct acting cholinergic drugs have longer durations of action
than acetylcholine.
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Pilocarpine and bethanechol preferentially bind to mu scarinic receptors .
Indirect-Acting Cholinergic Agonsists: Anticholinesterases (Reversible)
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Acetylcholinesterase is an enzyme that specifically cleaves
acet ylcholine to acetate and choline and , thus, terminates its actions.
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Inhibitors of acet ylcholineste rase indirectly provide a cholinergic action
by prolonging the lifetime of acetylcholine produced endogenously at
the cholinergic nerve endings.
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Resulting in the accumulation of acetylcholine in the synaptic space
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These drugs can thus provoke a response a t all cholinoceptors in the
body, including both mus carinic and nicotinic receptors.
Indirect-Acting Cholinergic Agonsists: Anticholinesterases (Irreversible)
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A number of synthetic organophosphate compounds have the capacity to
bind covalently to acetylch olinesterase.
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The result is a long-lasting increase in acetylcholine at all sites where it
is released.
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Many of these drugs are extremely toxic and were developed by the
military as nerve agents.
The Cholinergic Antagonists
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Bind to cholinoceptors, but they do not trigger the usual receptor mediated intracellu lar effects.
Antimuscarinic Agents
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These agents selectively block muscarinic synapses of the
parasympathetic nerves .
The effects of parasympathetic innervation are thus interrupted, and the
actions of sympathetic stimulation are left unopposed.
For example, atropine and scopolamine cause inhibition of all
muscarinic functions and i n addition, block the few exceptional
sympathetic neurons that are cholinergic, such as those innerva ting
salivary and sweat glands.
Antimuscarinic drugs do not block nicotinic rece ptors, thus have little
or no action at skeletal neuromuscular junctions or autonomic ganglia.
Ganglionic Blockers
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Show a preference for the nicotinic r eceptors of the sympathetic and
parasympathetic ganglia.
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Some also block the ion channels of the autonomic ganglia.
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These drugs block the entire output of the autonomic nervous system at
the nicotinic receptor.
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Except for nicotine, the other drugs mentioned above in these category
are competitive antagonists.
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The responses observed are complex and unpredictable, therefore,
ganglionic blockade is rarely used therapeutically.
Neuromuscular Blocking Drugs
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These drugs block cholinergic transmission between motor nerve
endings and the nicotinic rece ptors on the neuromuscular end plate of
skeletal muscle.
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These neuromuscular blockers are structural analogs of acetylcholine,
and act either as antagonists (nondepolarizing type) or agonists
(depolarizing type) at the receptors on the end plate of the
neuromuscular junction.
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They are clinically useful during surgery for producing complete muscle
relaxation.
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Agents are also useful in facilitating intubation as well.
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A second group, the central muscle relaxants, are used to control spastic
muscle tone. These drugs include:
1.
Diazepam, which binds at γ-aminobutyric acid (GABA) receptors
2. Dantrolene, which acts directly on muscles by interfering with the
release of calcium from the sarcoplasmic reticulum .
3. Baclofen, which probably acts at GABA receptors in the CNS.