Cholinergic System Flashcards
Cholinergic System
1) CNS
2) All Autonomic Ganglia (Nn)
(Sympathetic and Parasympathetic)
3) Parasympathetic Postganglionic Effector (M)
4) Skeletal Muscle Neuromuscular Junction (NMJ)/Motor End Plate (Nm)
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Nicotinic
1) @ Parasympathetic and Sympathetic Ganglia (Nn),
2) @ (Sympathetic) Adrenal Medulla (Nn),
3) @ (Somatic) Skeletal Muscle (Nm)
Muscarinic
1) @ Parasympathetic Effector
2) @ Sympathetic Thermoregulatory Sweat Glands
Muscarinic Receptors
G Protein coupled
_Responses are Slower than Nicotinic Responses.
Responses may be Excitatory or Inhibitory
Responses not necessarily linked to changes in Ion permeability.
M1:
_Mainly Neural,
_Mainly Excitatory
M2:
@ Heart
_Inhibitory
M3:
@ Smooth Muscle
@ Glands
Nicotinic Receptor Subtypes
Ligand-Gated Ion Channels;
_Rapid Response!
Activation Results in
1) Rapid Increase in Permeability to Na+ and K+
2) Depolarization
3) Excitation
Nm @ Motor end-plate
Nn @ Ganglia
_Nn = Nicotinic (neuron) _Nm = Nicotinic (muscle)
Muscarinic Stimulation
Eye: 1) Sphincter muscle (Iris): Contraction (Miosis) (Constricted Pupils) (M3, M2) 2) Ciliary muscle (Accommodation): Contraction for Near Vision (M3, M2)
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Heart: (M2) 1) SA Node: Decreased Heart Rate (Vagal Arrest) 2) Decreased Contractility
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Blood Vessels: (M3)
1) Dilation via Nitric Oxide
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Lung: Makes Difficult to Breathe! 1) Tracheal and Bronchial Muscle: Contraction (M2 = M3) 2) Bronchial Glands: Increased Secretion (M2, M3)
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ GI Tract: ==> Diarrhea 1) Smooth Muscle (except sphincters): (M2 = M3) Increased Motility and Tone ==> Diarrhea 2) Sphincters: (M3, M2) Relaxed ==> Diarrhea 3) Mucosa: (M3, M2) Increased Secretion
________________
Gall Bladder and Ducts:
_Contraction
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Urinary Bladder: ==> Urinary Incontinence 1) Detrusor: (M3 than M2) Contraction 2) Trigone and Sphincter: (M3 than M2) Relaxation
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Skin:
1) Thermoregulatory Sweat Glands:
_Increased Secretion (M3, M2)
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ Glands: 1) Salivary Glands: Profuse, Watery Secretion (M3) 2) Lacrimal Glands: Secretion (M3, M2) 3) Nasopharyngeal Glands: Secretion (M3, M2)
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Pancreatic Acini:
_Secretion (M3, M2)
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Male Sex Organs:
1) Erectile Tissue:
_Erection (M3)
Termination of Action of ACh
Recall that Esters and Amides are the 2 groups that undergo Hydrolysis.
_ACh is an Ester.
Rapid Hydrolysis By Esterases: 1) Acetylcholinesterase _Located @ Nerve Endings, _@ NMJ _@ CNS
2) Pseudocholinesterase:
_@ Plasma
Will Break down ACh in blood, so cannot give ACh as drug.
Cholinomimetics
3 Types:
1) Choline Esters
2) Cholinomimetic Alkaloids
3) Anticholinesterases
Direct Acting:
_Are Cholinergic Agonists, with affinity and intrinsic activity
_Act Directly @ the ACh Receptor
_Are, therefore, Selective.
_Include Choline Esters and Cholinomimetic Alkaloids.
Indirect Acting: _Anticholinesterases _Do NOT act at ACh Receptor. _Thus, Lack Selectivity. _Inhibit Action of Cholinesterases: Inhibiting ACh Hydrolysis _Thus, Increases ACh Concentration by Decreasing its Breakdown
Choline Esters
Direct Acting.
Cholinergic Agonists.
Selective.
Have Quaternary Amines.
1) Acetylcholine
_Both Muscarinic and Nicotinic
2) Bethanechol:
_Relatively Selective for Smooth Muscle @ GI and @ Bladder
_Used for Constipation when there is LACK OF TONE.
_Only use when certain there is NO OBSTRUCTION; otherwise, will result in PERFORATION.
3) Methacholine: _Predominantly Muscarinic _Particular affinity for Heart _Used only for Bronchial Challenge Test. _Slows Heart Rate (May cause arrhythmias and heart blocks.)
Bronchial Challenge Test: tests for bronchial hyperreactivity, a hallmark of Asthma.
Alkaloids
Naturally occurring, Nitrogen-containing substances.
_Are Bases.
_May be Tertiary or Quaternary Amines.
1) Pilocarpine:
_Tertiary Amine (Lipid-soluble)
_Mostly Muscarinic action.
_*Sweat and *Salivary Glands are Very Sensitive to Pilocarpine.
_Used for Xerostomia (oral)
_Used for Glaucoma (not first line) (eye drops)
2) Muscarine:
_Mushroom (Amanita muscaria)
_Poisoning is treated with Atropine.
3) Nicotine:
_Ganglion stimulant
_From Tobacco. Well absorbed.
_Highly toxic.
Anticholinesterases
Cholinesterase Inhibitors
Indirect Acting. Lack Selectivity.
1) Inhibit or Inactivate Cholinesterases (Acetylcholinesterase and Pseudocholinesterase),
2) Preventing Breakdown of ACh,
3) Resulting in ACh Accumulation,
4) Increasing Cholinergic Stimulation.
Truly Reversible, Truly Competitive:
- -Bind to cholinesterase, preventing ACh binding to it.
- -Then, detaches itself from enzyme.
Reversible False Substrates:
- -Bind and are Hydrolyzed by cholinesterase
- -Hydrolyzed pieces Detach from enzyme.
Irreversible: Organophosphates.
–Permanently binds to cholinesterase by forming a Phosphate Bond.
Reversible Anticholinesterases
I) Edrophonium: _Truly Competitive _Truly Reversible _Binds to cholinesterase, preventing ACh binding to it; then, detaches itself from enzyme. _Short-Acting (5-10 min) _(Diagnostic for Myasthenia Gravis)
II) -Stigmines:
_False Substrates
_Hydrolyzed by Enzyme
(1) Physostigmine:
Tertiary Amine:
Lipid-Soluble; Enters CNS.
Treats Antimuscarinic Toxicity
(2) Neostigmine: Quaternary Amine: Ionized; Cannot enter CNS. Treats Antimuscarinic Toxicity Treats Atony in Post-operative Ileus
(3) Centrally Acting:
-Used to Treat Alzheimer’s
-Lipid-Soluble; Enter CNS.
(Not quaternary)
-Patch administration.
*Donepezil,
*Rivastigmine,
*Galantamine
*Tacrine
Irreversible Anticholinesterases
Echothiophate:
_Long-Acting
_Miotic (Eye)
Organophosphate Insecticides and Nerve Gases: _Very Lipid-Soluble!! _May be absorbed through intact skin! *Malathion (insecticide) *Sarin (Nerve Gas)
Mechanism of Action:
1) Bind to esteratic site and Phosphorylate
2) Over time, the Phosphate Bond becomes very stable
==> Irreversible (Aging)
*Oximes: e.g. *Pralidoxime
_Can be given if Aging has not yet occurred.
_Must be given quickly or it will not help.
Effects of Anticholinesterases
Muscarinic: _Salivation _Lacrimation _Urination _Defecation (SLUD) _Pupillary Constriction _Bradycardia, Decreased Cardiac Output _Bronchoconstriction, Increased Bronchial Secretions _Increased Gastric Contractions, Increased Gastric Secretions _Increased GI Motility
Nicotinic: _Stimulation, Followed by Paralysis of NMJ, Ganglia _Diaphragm Paralysis (STOPPED BREATHING)
CNS:
_Stimulation, Followed by Depression
Treatment of Anticholinesterase Toxicity
1) Decontamination!
_Otherwise will continue to poison themselves and poison others.
2) Atropine parenterally
3) Maintain Respiration if necessary
_Ventilator
4) For Organophosphate Poisoning:
*Oximes: e.g. *Pralidoxime
_Pralidoxime regenerates the cholinesterase.
_Can be given if Aging has not yet occurred.
_Must be given quickly or it will not help.
5) Benzodiazepines for Seizures
6) **Pyridostigmine:
_Reversible inhibitor of Cholinesterase
(Thus, is itself an Anticholinesterase)
_Dissipates within hours, allowing enough time for clearance of the organophosphate agent from the body
_Protects the cholinesterase enzyme by reversibly binding to it, preventing organophosphate binding.
_Limited to Peripheral Nervous System b/c does not readily enter CNS
_One-time dose is fine
_Repeated doses causes Gulf War Syndrome:
Muscle Aches and Weakness, Diarrhea, Fatigue, Cognitive Problems.
Pesticides = Main Source of Anticholinesterase Poisoning @ Home and @ Agriculture
_Must be Treated Promptly!!
_Dominant Initial Signs:
Miosis, Salivation, Bronchial Constriction, Vomiting, Diarrhea
_CNS involvement:
(Cognitive Disturbances, Convulsions, Coma)
-Usually Follows Rapidly, Accompanied by Peripheral Nicotinic Effects,
especially Depolarizing Neuromuscular Blockade.
Cholinesterase Inhibitors used in Agriculture can cause Slowly or Rapidly developing symptoms, which may Persist for Days.
Cholinesterase inhibitors used in Chemical Warfare agents induce effects Rapidly.
Therapeutic Uses of Cholinomimetics @ Muscarinic Sites
1) GI Tract and GU Tract:
_Treat Atony
e.g. post-operative ileus *Neostigmine
e.g. urinary retention *Bethanechol
2) Eye:
_Glaucoma. Not first line.
(Contracts the Ciliary muscle, facilitating drainage of aqueous humor)
3) Reverse the Action of Non-Depolarizing Muscle Blockers
(with Atropine)
4) Myasthenia Gravis:
_Neostigmine
5) Alzheimer’s:
_Must enter CNS.
Donepezil, Rivastigmine, Galantamine, Tacrine
6) Poisoning by Antimuscarinics, such as Atropine
