Autonomic Nervous System - lecture-notes.tiu.edu.iq

Autonomic Nervous SystemAsmaa A.

The nervous system is divided into central nervous system (CNS:brain and spinal cord) and peripheral nervous system (PNS). PNScan be further divided into somatic nervous system and autonomicnervous system (ANS).

In the sympathetic system, the preganglionic fibres are short andpostganglionic fibres are long. On the other hand, the parasympatheticpreganglionic fibres are long and postganglionic fibres are short.

Most of the visceral organs have dual nerve supply, i.e. they are suppliedby both divisions of the ANS, but effects of one system predominate. Theciliary muscle, pancreatic and gastric glands receive onlyparasympathetic supply; sweat glands, hair follicles, spleen and most ofthe blood vessels have only sympathetic supply. Their stimulationusually produces opposite effect on the innervating organ.

CHOLINERGIC SYSTEM

Cholinergic Transmission

Acetylcholine (ACh) is the main neurotransmitter in thecholinergic system. The neurons that synthesize, store andrelease ACh are called cholinergic neurons.

1.preganglionic fibres of both sympathetic and parasympathetic system; 2.postganglionic fibres of parasympathetic system.3.Sympathetic postganglionic fibres supplying the sweat glands.4.nerve fibres supplying the adrenal medulla; 5. motor nerve6.postganglionic fibres of sympathetic system that release NA.

Synthesis of Acetycholine

Choline enters the cholinergic neuron by carrier-mediatedtransport, where it reacts with acetyl-CoA with the help of cholineacetyltransferase (ChAT) to form ACh.

The ACh is then stored in storage vesicles. It is released into thesynaptic cleft, when an action potential reaches the nerveterminals. The released ACh interacts with cholinergic receptors oneffector cell and activates them. In the synaptic cleft, the ACh israpidly hydrolysed by acetylcholinesterase (AChE) enzyme.

Cholinesterases

Acetylcholine is rapidly hydrolysed to choline and acetic acid bythe enzyme cholinesterase. There are two types of cholinesterases:

1. True cholinesterase or AChE: It is found in cholinergic neurons,ganglia, RBCs and neuromuscular junction (NMJ). It rapidlyhydrolyses ACh and a choline ester, methacholine.

2. Pseudocholinesterase or butyrylcholinesterase: It is found inplasma, liver and glial cells. Pseudocholinesterase can act on a widevariety of esters including ACh, but it does not hydrolysemethacholine

Cholinergic Receptors

They are divided broadly into two types—muscarinic andnicotinic. Muscarinic receptors are further divided into fivedifferent subtypes: M1–M5. All muscarinic receptors are G-protein-coupled receptors and regulate the production ofintracellular second messengers.

Nicotinic receptors are divided into two subtypes—NN and NM.Activation of these receptors directly opens the ion channels and causesdepolarization of the membrane.

Note: No clinically important agents interact solely with M4 and M5 receptors

CHOLINERGIC AGENTS (CHOLINOMIMETICS, PARASYMPATHOMIMETICS)

Acetylcholine is a quaternary ammonium compound and israpidly hydrolysed by cholinesterases. Hence, it has notherapeutic application. It has to be given intravenously to studyits pharmacological actions. Even when given intravenously, alarge amount of the drug is destroyed by pseudocholinesterase inthe blood.

Choline Esters

Choline esters include acetylcholine, carbachol and bethanechol.

Acetylcholine

Acetylcholine produces muscarinic and nicotinic effects by interacting withrespective receptors on the effector cells .

Muscarinic actions

1. Cardiovascular system

a. Heart: The effects of ACh are similar to those following vagal stimulation.ACh, by stimulating M2 receptors of the heart, opens K+ channels resulting inhyperpolarization. Therefore, S–A and A–V nodal activity is reduced .

b. Blood vessels: Acetylcholine stimulates the M3 receptorsof vascular endothelial cells, which release endothelium-dependent relaxing factor (EDRF; NO), leading tovasodilatation and a fall in blood pressure (BP)

2. Smooth muscles

a. Gastrointestinal tract

b. Urinary bladder

c. Bronchi

3. Exocrine glands: All parasympathomimetic agents stimulate salivarysecretion. They also increase lacrimal, sweat, bronchial, gastric andother gastrointestinal (GI) secretions.

4.Eye:Acetylcholine does not produce any effect on topicaladministration because of its poor penetration through tissues.

Nicotinic actions

To elicit nicotinic actions, larger doses of ACh are required:

1. Autonomic ganglia: Higher doses of ACh produce dangerous muscariniceffects, especially on the heart. Hence, prior administration of atropine isnecessary to elicit nicotinic actions.

Higher doses of ACh stimulate both sympathetic as well as parasympatheticganglia,causing tachycardia and a rise in BP.

2. Skeletal muscles: At high concentration, ACh initially producestwitching, fasciculation followed by prolonged depolarization of NMJand paralysis.

3. CNS: Intravenously administered ACh does not cause any centraleffects because of its poor penetration through the blood–brain barrier(BBB).

Anticholinesterases

They inhibit the enzyme cholinesterases, which is responsible for hydrolysis ofacetylcholine. Thus, ACh is not metabolized, gets accumulated at muscarinicand nicotinic sites, and produces cholinergic effects. Hence, anticholinesterasesare called indirectly acting cholinergic drugs.

Reversible Anticholinesterases

1. Physostigmine

2. Neostigmine

3. Pyridostigmine

4. Edrophonium

5. Rivastigmine

6. Donepezil

Mechanism of action: ACh is rapidly hydrolysed by both true and pseudocholinesterases.Reversible anticholinesterases inhibit both true and pseudocholinesterases reversibly—thus, Ach gets accumulated and produces cholinergic effects.

Therapeutic Uses of Reversible Anticholinesterases

1. Eye.

a. Glaucoma.

b. To reverse pupillary dilatation after refraction testing.

c. Miotics are used alternatively with mydriatics to break adhesions between iris and lens.

2. Myasthenia gravis.

3. Belladonna poisoning.

4. Curare poisoning and reversal of nondepolarising neuromuscular blockade.

5. Postoperative urinary retention and paralytic ileus.

6. Alzheimer’s disease.

Adverse Effects of Anticholinesterases

They are due to overstimulation of both muscarinic and nicotinicreceptors—increased sweating, salivation, nausea, vomiting, abdominalcramps, bradycardia, diarrhoea, tremors and hypotension

Actions of some cholinergic agonists

Comparative Aspects of Physostigmine and Neostigmine

Irreversible Anticholinesterases

All organophosphorous (OP) compounds except echothiophatehave no therapeutic applications. Echothiophate is rarely used inresistant cases of glaucoma.

Organophosphorous (OP) compounds used as agricultureinsecticides have only toxicological importance. Common OPcompounds are parathion, malathion, dyflos, etc. Theyirreversibly inhibit cholinesterases and cause accumulation ofACh at muscarinic and nicotinic sites.