They are not well absorbed by the GI tract because they are hydrolyzed by stomach acid and GI tract, and only acetylcholine is broken down by acetylcholinesterase
Muscarinic Agonists: Muscarine & Oxotremorine
They are parasympathomimetic - slows the heart down, decreased rate and force of contraction, causes NO release to dilate blood vessels, complicated reflexes. Dilation of blood vessels might cause high heart rate (baroreceptor reflex)
Vasodilation requires to have endothelial cell layer in order for tissue relaxation.
Required for vasodilation: Endothelial Derived Relaxing Factor (EDRF = NO, Nitric Oxide, not Nitrous Oxide)
NO causes activation of guanylyl cyclase which produces cGMP. cGMP causes muscle excitation
1st response, non-damaged vessel
2nd response, endothelia damaged
Muscarine Receptor Effects
Contracts the sphincter muscle of iris - Miosis (pin point pupils).
Contracts ciliary muscle - accommodation for near vision - myopia.
Cholinergic effects allow aqueous humour to leave the eye, lowers intraocular pressure - useful for glaucoma
Muscarinic Effects on Respiratory System, GI Tract and Bladder
Respiratory Tract: Contraction of bronchiole smooth muscle and increases secretion, can exacerbate asthma
GI Tract: Increased saliva, stomach acid secretion, motility and peristalsis.
Bladder: Stimulation of detrussor muscle and relaxation of trigone and internal sphincter.
Nicotinic Agonists stimulate sympathetic, parasympathetic divisions and neuromuscular transmissions.
Emesis - cause people to throw up
Comas - high levels can lead to comas
Insecticide - used to keep insects from eating the plant
Lobeline - nicotine substitute.
Nicotinic Effects on Ganglion
Stimulates both branches of the Autonomic Nervous System
Sympathetic stimulation causes hypertension and cardiac stimulation, causes vasoconstriction and stimulation of the heart.
Stimulates the GI tract - to increase secretion and motility
Nicotinic Effects on Skeletal Muscle Effects
Nicotine will cause the skeletal muscle cells to be more easily depolarized.
Depolarization and Excitation - muscle fibres twitching, can range from disorganized (random muscle twitches) to strong contraction of whole muscle.
Flaccid Paralysis - due to Nicotine Effects
Flaccid paralysis - depolarization of a muscle for a long period of time, will cause the Na+ channels which generate action potentials, inactivate or desensitize. Nicotine can produce a depolarizing block
Muscle can't contact, and it's paralysis because even though signals are sent, no action potentials are possible.
Anticholinesterases and Examples of Anticholinesterases
Facilitate the presence of ACh to indirectly cause nAChR and mAChR stimulation.
Memory Enhancers in Alzheimer's
3 Groups of Anticholinesterases
Reversible, used therapeutically: Edrophonium
Carbamic esters of alcohols with quaternary and tertiary ammonium groups: Neostigmine
Nerve Gases/Insecticides: Malathion/Soman
The molecular mechanisms of each group is different
Characteristics of Anticholinesterases
Well absorbed from skin, gut, lung and eyes (conjunctiva)
Similar effects to directly acting cholinergic agonists, because it results in the accumulation of ACh at the synapses
Respiration - bronchiole constriction and increased secretion
Increased gut motility and bladder stimulation
Heart - bradycardia, decreased cardiac output.
Effects of Anticholinesterase on Vasculature
Effects on vasculature system is balanced because Acetylcholinesterase results in more ACh everywhere, and ACh will have parasympathetic effects on the target tissue but will also stimulate the autonomic ganglia, although heart rate slows down, there will still be a vasoconstriction. Cancelling effects.
Effects of Anticholinesterase on Neuromuscular Transmission
Increased strength of contraction, muscle twitches better
Higher concentrations cause muscle fasciculations
Highest concentrations cause polarizing neuromuscular blockade followed by a phase of non-depolarizing block.
Anticholinesterase effects are stronger than direct cholinergic agonists
Effects of Nerve Gas
Fluid in lungs increases and bronchioconstriction
Blockade of respiratory muscle contraction (respiratory muscle is a voluntary muscle, it will block)
You will drown in your own lung fluid and you won't be able to breathe.
Atropine oppose Actions of Anticholinesterases
Atropine - used to limit the effects of nerve gases (similar to epi-pen but it is an antidote for nerve gases)
E.g. Atropine can be used to prevent the parasympathomimetic effects of the nerve gas. Used in chemical warfare, if nerve gas is expected.
Therapeutic Effects of Cholinomimetics: Glaucoma
Anticholinesterases or muscarinic agonists can be used for Glaucoma - which is a condition of high intraocular pressure.
Cholinergic contraction of ciliary body allows outflow of aqueous humour.
Therapeutic Effects of Cholinomimetics: Urinary Retention
Postoperative Ileus - after surgery, activating all the sympathetic outflow to the gut.
Cholinomimetics will cause a jump start to the GI tract, and cause urinary flow again.
Therapeutic Effects of Cholinomimetics: Neuromuscular Junction
Myasthenia Gravis - autoimmune disease, antibodies produced which destroy nAChR at neuromuscular junction. Symptoms look similar to neuromuscular block produced by D-tubocurarine.
Cholinomimetics can be used to increase concentration of ACh for more agonist to act at receptors.
Neuromuscular Blockers: Succinylcholine
Therapeutic uses - used during surgery.
Paralyzing agent during surgery so that while someone is doing surgery, muscle reflexes don't cause any problems
Neuromuscular Blockers: D-Tubocurarine
First neuromuscular blocker - D-Tubocurarine, used by South American endogenous population.
They used blow darts to paralyze animals, they would then eat the animal, but Tubocurarine didn't paralyze the hunter.
Tubocurarine is not well absorbed from GI tract.
Found in snake venom.
Very similar to D-Tubocurarine, not absorbed by the GI tract.
α-Bungarotoxin - is a protein and is hydrolyzed in snake venom drinks when served with alcohol.
Ganglion Blocker: Hexamethonium
Blocks both parasympathetic and sympathetic sides of the autonomic ganglia.
Blocks EPSP's generated by nicotinic effect
Belladonna - "Beautiful Woman" - in 19th century girls would put Belladonna in their eyes, to dilate their pupils.
It is still used today in opthamology.
Causes near vision focusing
Inhibits lacrymal secretion
Treatments with Atropine: Parkinson's Disease
Parkinson's is a condition where there is an excess of cholinergic activity and a lack of dopaminergic in the striatum.
Anti-muscarinic drugs can be used to control tremor associated with Parkinson's
Treatments with Atropine: Vestibular Disturbances
Motion sickness, involve cholinergic effects, treated with Scopolamine
Atropine Side Effect
Pupillary Constrictor muscle is under muscarinic and parasympathetic tone.
In presence of atropine, muscarinic effect is blocked and unopposed sympathetic effect dilates pupils.
Weakening of ciliary muscle, can only focus on near sightedness.
Atropine Effects on Cardiovascular System
Heart is under parasympathetic tone.
Rate, force of contraction and AV conduction are increased by blockers such as Atropine. This causes cardiac activity to rise.
Atropine Effects on Respiratory System
Slight bronchodilation and decreased secretion of mucous due to blocking of parasympathetic tone.
Ipratropium - useful in Chronic Obstructive Pulmonary Diseases (COPD), it
Atropine Effects on GI Tract
Muscarinic Antagonists decrease secretion and motility, decreased salivary secretion.
M1 selective antagonists such as Pirenzepine was once used in treatment of ulcer.
Used to treat COPD - blocks the muscarinic receptors in the bronchial muscles of the lung, to cause bronchiodilation which allows for greater airflow.
Blocks Muscarinic receptors and inhibits gastric secretion to treat gastric ulcers
Treats Vestibular Disturbance
Reduces sympathetic tone in blood vessels and parasympathetic tone in heart.
Paralytic Surgery - used to paralyzed for surgery to prevent reflex muscle movements
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