Lesson 29: Parasympathetic Nervous System:

Parasympathetic Nervous System

A division of the autonomic nervous system that conserves energy by slowing the heart rate and increasing intestinal and gland activity.

Neurotransmitter at postganglionic parasympathetic nerve terminal

Acetylcholine (ACh) is released at the postganglionic parasympathetic nerve terminal.

G-protein receptor stimulation associated with bradycardia

Muscarinic receptor stimulation is associated with bradycardia.

Preganglionic neuron's origin in the parasympathetic division

The preganglionic neuron's origin is in the cranio-sacral region.

Ganglia location in the parasympathetic system

Most ganglia of the parasympathetic system are located near—or even within—the target effector.

Ratio of preganglionic to postganglionic fibers in many organs

There is a 3:1 ratio of preganglionic fibers to postganglionic fibers.

Effects of the parasympathetic system

The effects of the parasympathetic system tend to be more discrete and localized.

Primary transmitter of all preganglionic neurons

All preganglionic neurons (sympathetic and parasympathetic) synthesize and release acetylcholine (ACh) as their primary transmitter.

Receptors at autonomic ganglia

The receptors at autonomic ganglia are cholinergic: nicotinic.

Primary neurotransmitter of parasympathetic postganglionic neurons

Parasympathetic postganglionic neurons synthesize and release acetylcholine (ACh) as their primary neurotransmitter.

Receptors that bind acetylcholine in parasympathetic system

Muscarinic receptors bind acetylcholine in the parasympathetic system.

Effects of parasympathetic division stimulation on pupil diameter

Stimulation of the parasympathetic division causes miosis (constriction of pupils).

Effects of parasympathetic stimulation on heart rate

Parasympathetic stimulation leads to a decrease in heart rate.

Effects of parasympathetic stimulation on blood pressure

Parasympathetic stimulation leads to a decrease in blood pressure.

Effects of parasympathetic stimulation on gastrointestinal activity

Parasympathetic stimulation stimulates gastrointestinal activity.

Effects of parasympathetic stimulation on insulin release

Parasympathetic stimulation increases insulin release, leading to lower blood glucose concentration.

G-protein receptor stimulation causing bronchoconstriction

Muscarinic receptor stimulation causes bronchoconstriction.

Types of Cholinergic Receptors

ACh possesses both muscarinic and nicotinic receptors.

Nicotinic receptors

Nicotinic receptors are found in autonomic ganglia, skeletal muscle neuromuscular junction, adrenal medulla, and CNS.

Function of nicotinic receptors

Nicotinic receptors increase cellular permeability to Na+ ions, leading to depolarization and excitation.

Nicotinic muscular receptors (NM)

Nicotinic muscular receptors are found in the neuromuscular junction and lead to depolarization and skeletal muscle contractions.

Mydriasis

Mydriasis refers to the dilation of the pupils.

Miosis

Miosis refers to the constriction of the pupils.

Nicotinic neuronal receptors

A type of acetylcholine receptor that is found in the nervous system.

Muscarinic receptors

A type of acetylcholine receptor that is G protein-coupled and mediates various physiological responses.

M1, M3, M5 receptors

Muscarinic receptors that activate Gq protein.

M2, M4 receptors

Muscarinic receptors that activate Gi protein and inhibit adenylyl cyclase.

M3 receptors in vascular endothelium

Non-innervated muscarinic receptors that release nitric oxide, activating guanylyl cyclase and causing vasodilation.

Acetylcholine

A quaternary amine and the prototype for directly acting cholinergic agonists.

Pharmacological effects of Acetylcholine on the cardiovascular system

Produces a rapid fall in blood pressure; brief duration, mainly mediated by the release of endothelial Nitric Oxide, leading to vasodilation.

Effects of Acetylcholine on heart rate

Lowers heart rate and speed of conduction of electrical impulses in the heart.

Effects of Acetylcholine on the eye

Causes miosis, loss of accommodation, and reduces intraocular pressure.

Effects of Acetylcholine on smooth muscle

Increases contraction of the urinary bladder and uterus.

Effects of Acetylcholine on bronchiolar smooth muscle

Causes constriction of bronchiolar smooth muscle.

Intra-arterial injection of Acetylcholine

Leads to excitation and convulsions.

Cholinergic agonists

Also known as parasympathomimetics, they produce acetylcholine-like effects on effector cells.

Direct-acting cholinergic agonists

Activate cholinergic receptors on effector cells.

Indirect-acting choline esters (Cholinesterase inhibitors)

Lead to accumulation of acetylcholine in synaptic junctions, increasing cholinergic action.

Direct-acting parasympathomimetics

Include choline esters like Bethanechol and natural alkaloids like Pilocarpine.

Bethanechol

A direct-acting parasympathomimetic that selectively stimulates muscarinic receptors and is resistant to hydrolysis by AChE.

Indications for Bethanechol

Used for GI paralytic ileus and urinary retention associated with bladder muscle atony.

Pilocarpine

A muscarinic receptor agonist used in ophthalmic solutions to treat glaucoma and increase tear production.

Adverse effects of parasympathomimetics

Include bronchoconstriction, bradycardia, miosis, salivation, sweating, vomiting, diarrhea, urinary incontinence, neuromuscular effects, CNS effects at high doses, and uterine contraction.

Pharmacological effect of Bethanechol

Includes urinary retention, increases GI and bladder contractions, mydriasis, and bronchodilation.

Cholinesterase inhibitors (anticholinesterase)

Substances that inhibit the enzyme acetylcholinesterase (AChE), preventing the breakdown of acetylcholine (ACh).

Irreversible Cholinesterase Inhibitors

Inhibitors that form a stable enzyme-inhibitor complex with AChE, requiring new enzyme synthesis for recovery.

Organophosphate compounds

A type of irreversible cholinesterase inhibitor that interacts with AChE at the esteratic site and causes phosphorylation.

Reversible cholinesterase inhibitors

Inhibitors that temporarily bind to AChE, allowing for the hydrolysis of ACh to resume after the inhibitor is removed.

Physostigmine

An alkaloid from Physostigma venonosum that combines reversibly with AChE to inhibit the hydrolysis of ACh.

Neostigmine

A reversible cholinesterase inhibitor that prolongs the action of ACh and can reactivate the enzyme to hydrolyze ACh.

Pyridostigmine

A reversible cholinesterase inhibitor used therapeutically for conditions like myasthenia gravis.

Edrophonium

A reversible cholinesterase inhibitor used to reverse neuromuscular blockade.

Therapeutic uses of Physostigmine

Used primarily for the treatment of glaucoma.

Therapeutic uses of Neostigmine and Pyridostigmine

Used for the treatment of myasthenia gravis.

Contraindications for Reversible Cholinesterase Inhibitors

Include impaction with obstruction and pregnancy.

Toxicology of Neostigmine

Can cause skeletal muscle weakness, nausea, vomiting, colic, diarrhea, pupil constriction, dyspnea, bradycardia, hypotension, and respiratory paralysis.

Antagonist: Atropine

A competitive antagonist used against cholinergic effects caused by irreversible cholinesterase inhibitors.

Organophosphorous compounds poisoning

Causes cholinomimetic effects such as profuse salivation, vomiting, hypermotility of GIT, defecation, urination, bradycardia, hypotension, severe bronchoconstriction, and muscle paralysis.

Antidote for Organophosphate poisoning

Atropine is used as a competitive antagonist to AChE reactivators like Pralidoxime.

Clinical significance of cholinergic agonists

Includes their role in treating various medical conditions related to the cholinergic system.

Cholinergic antagonists

Inhibits actions of acetylcholine by blocking cholinergic receptors.

Anti-muscarinic

Antagonize muscarinic receptors.

Ganglionic blockers

Antagonize the NN receptor.

Neuromuscular blockers

Antagonize NM receptors.

Antimuscarinic agents (Parasympatholytics)

Inhibits muscarinic actions of acetylcholine and related cholinergic agonists.

Atropine

Prototype antimuscarinic agent, an alkaloid extracted from Atropa belladona.

Scopolamine

An alkaloid extracted from Datura stramonium, also known as l-hyoscine.

Mechanism of action of antimuscarinic agents

Competitive antagonism that prevents ACh binding to these receptors.

Vagolytic effect

Requires large dose to block cholinergic effect, allowing sympathetic action to dominate.

Salivary and sweat glands

Susceptible to small doses of atropine.

Atropine - Pharmacologic effects (Cardiovascular system)

Causes tachycardia, increases cardiac output and blood pressure.

Atropine - Pharmacologic effects (Gastrointestinal tract)

Relaxes GIT, relieves intestinal spasm and hypermotility, decreases secretions.

Atropine - Pharmacologic effects (Urinary system)

Relaxes smooth muscle of the urinary bladder, causing urinary retention.

Atropine - Pharmacologic effects (Bronchioles)

Decreases secretions and causes bronchodilation.

Atropine - Pharmacologic effects (Ocular effect)

Causes mydriasis and cycloplegia (paralysis of the ciliary muscle).

Antimuscarinic drugs - contraindicated in

Increased intraocular pressure.

Atropine - Pharmacologic effects (Sweat glands)

Causes anhidrotic effect through cholinergic mechanism.

Atropine - Pharmacologic effects (CNS)

Minimal effects, but excess dose can lead to hallucinations, excitement, depression, and coma.

Species sensitivity to atropine

Rabbits are resistant due to atropinase enzyme from the liver.

Therapeutic uses of antimuscarinic agents

Includes antidote for cholinergic agonists, prevention of motion sickness, antispasmodic, and antisecretory agent.

Glycopyrrolate (Robinul-V®)

Preanesthetic use in veterinary medicine; potent antimuscarinic with longer duration of action than atropine.

Homatropine

Ester of mandelic acid used for mydriasis and cycloplegia.

Ipratropium

Used for bronchodilation and available as a nasal spray.

Scopolamine butylbromide (Buscopan®)

Smooth muscle relaxant that does not cross the blood-brain barrier.

Antidote for cholinergic drug poisoning

C. Atropine.

Therapeutic role of glycopyrrolate in horses

Used as a preanesthetic agent.