Autonomic Nervous System

The autonomic nervous system controls smooth muscle, visceral organs, and glands

v  Smooth muscles (Spindle shape) are present in iris of the eyes, wall of hollow internal structures (blood vessels, lungs, stomach, intestines, gallbladder, urinary bladder & uterus.

v  Skeletal or striated muscle (Cylindrical in shape)

The autonomic nervous system is divided into 3 groups

Ø  Parasympathetic nervous system

Ø  Sympathetic nervous system

Ø  Enteric nervous system

Parasympathetic nervous system (Cholinergic ) Cranio [3,7,9]-sacral	Sympathetic nervous system (Adrenergic) Thoracic-lumber
Slow heart beat	Increase heart beat
Gall bladder contract	Gall bladder relax
Urinary bladder contraction muscular wall Relaxation of sphincter	Urinary bladder Relaxation of muscular wall Contraction of sphincter
Iris, radial muscle  : no known effect Iris, circular muscle : constriction of pupil Ciliary muscles of eye :contraction	Iris, radial muscle: contraction→ dilation of pupil Iris, circular muscle : no known effect Ciliary muscles of eye : relaxation
Ø  Stimulate secretion (tears, bile, digestive enzymes & insulin) Ø  No known effect	Ø  Inhibit secretion Ø  Increase sweating
Muscles in bronchi constrict	Muscles in bronchi dilates
Peristalsis fast	Peristalsis slow

Parasympathetic nervous system

Acetylcholine (ACh) synthesis:

v  Requires choline, which enters the neuron via carrier-mediated transport system

v  Hemicholinium blocks choline uptake (rate limiting step in Ach synthesis)

v  Requires acetylation of choline, utilising acetyl coenzyme A as source of acetyl groups, and involves choline acetyl transferase, a cytosolic enzyme found only in cholinergic neurons.

v  ACh is packaged into synaptic vesicles at high concentration by carrier-mediated transport.

v  Active transport of ACh into synaptic vesicles is effected by another carrier which is blocked by vesamicol

v  Two toxins are interfere with cholinergic transmission by affecting release: botulinus toxin inhibits release, while black widow spider toxin induces massive release & depletion

v  ACh is hydrolysed by the enzyme cholinesterase & choline is recycled

v  There are two major types of cholinesterases: acetylcholinesterase (AChE) and pseudocholinesterase (pseudo-ChE). AChE (also known as true, specific, or erythrocyte cholinesterase) is found at a number of sites in the body, the most important being the cholinergic neuroeffector junction. & Pseudo-ChE (also known as butyryl-, plasma, and

Nonspecific cholinesterase) has a widespread distribution, with enzyme especially abundant in the liver, where it is synthesized, and in the plasma. In spite of the abundance of pseudo-ChE, its physiological function has not been definitively identified. It does, however, play an important role in the metabolism of such clinically important compounds as succinylcholine, procaine, and numerous other esters.

v  ACh release occurs by Ca²⁺-mediated exocytosis. At the neuromuscular junction, one presynaptic nerve impulse releases 100-500 vesicles.

v  At the neuromuscular junction, ACh acts on nicotinic receptors to open cation channels, producing a rapid depolarisation (endplate potential), which normally initiates an action potential in the muscle fibre. Transmission at other 'fast' cholinergic synapses (e.g. ganglionic) is similar.

v  At 'fast' cholinergic synapses, ACh is hydrolysed within about 1 ms by acetylcholinesterase, so a presynaptic action potential produces only one postsynaptic action potential.

v  There is no reuptake system in cholinergic nerve terminals to reduce the concentration of ACh in a synaptic cleft, unlike the reuptake systems for other neurotransmitters such as dopamine, serotonin, and norepinephrine

v  Transmission mediated by muscarinic receptors is much slower in its time course, and synaptic structures are less clearly defined. In many situations, ACh functions as a modulator rather than as a direct transmitter.

         

Effects on various organs

1. Cardiovascular effects

Low doses of muscarinic agonists given intravenously relax arterial smooth muscle and produce a fall in blood pressure. These responses result from the stimulation of muscarinic receptors on vascular endothelial cells. Activation of these receptors causes the endothelial

cells to synthesize and release nitric oxide. Nitric oxide can diffuse into neighboring vascular smooth muscle cells, where it activates soluble guanylyl cyclase, thereby increasing the synthesis of cyclic guanosine monophosphate (cGMP) and relaxing the muscle fibers.

2. Eye

Open-angle glaucoma, a chronic condition in which the porosity of the trabecular meshwork is insufficient to permit the movement of fluid into the canal of Schlemm, Open-angle glaucoma can be effectively treated with cholinomimetics such as pilocarpine and carbachol, because contraction of the ciliary muscle stretches the trabecular network, increasing its porosity and permeability to the outflow of fluid. This beneficial effect, however, comes at the price of a spasm of accommodation and miosis, which seriously disturb vision. Cholinomimetics, therefore, have been replaced by β-blockers and carbonic anhydrase inhibitors, both of which decrease the formation of aqueous humor without affecting vision.

Contraction of the iris sphincter (miosis) by cholinomimetic stimulation is less important than contraction of the ciliary muscle for treating angle-closure glaucoma, but it may be essential as emergency therapy for acute-angle glaucoma to reduce intraocular pressure prior to surgery (iridectomy). Contraction of the iris sphincter by pilocarpine pulls the peripheral iris away

from the trabecular meshwork, thereby opening the path for aqueous outflow.

Angle-closure glaucoma, an emergency condition in which an abnormal position of the peripheral iris blocks the access of fluid to the trabecular meshwork.

            

Parasympathetic nervous system contains two types of receptor

Parasympathetic nervous system
Muscarinic (G-protein )				Nicotinic (Ligand gated)
	M1(neural)	M2(cardiac )	M3(gland)	NM	NN
Transducer mechanism	IP3/DAG -↑ Cytosolic Ca2+ , PLA2 – PG synthesis	K+ channel opening, ↑cAMP	IP3/DAG -↑ Cytosolic Ca2+ , PLA2 – PG synthesis	Opening of cation (Na+, K+) channels	Opening of cation (Na+, K+, Ca2+) channels
Agonist	Oxotremorine	Methacholine	Bethanechol	PTMA (Phenyl trimethyl ammonium )	DMPP (Dimethyl phenyl piperazinium)
Antagonist	Pirenzepine	Tripitramine	Darifenacin	Tubocurarine	Hexamethonium

IP₃/DAG = inositol triphosphate, Diacylglycerol

Acetylcholine receptors

o   Main subdivision is into nicotinic (nAChR) and muscarinic (mAChR) subtypes.

o   mAChRs are G-protein-coupled receptors causing:

§  activation of phospholipase C (hence formation of inositol triphosphate (IP₃)and diacylglycerol (DAG) as second messengers)

§  inhibition of adenylyl cyclase

§  Activation of potassium channels or inhibition of calcium channels.

o   mAChRs mediate acetylcholine effects at postganglionic parasympathetic synapses (mainly heart, smooth muscle, glands), and contribute to ganglionic excitation. They occur in many parts of the CNS.

o   Two further molecular mAChR subtypes, M₄ and M₅, occur mainly in the CNS.

o   All mAChRs are activated by acetylcholine and blocked by atropine. There are also subtype-selective agonists and antagonists.

The Main Effects of The Autonomic Nervous System

Organ	Sympathetic effect	Adrenergic receptor type	Parasympathetic effect	Cholinergic receptor type
Heart
Sinoatrial node	Rate ↑	β1	Rate ↓	M2
Atrial muscle	Force ↑	β1	Force ↓	M2
Atrioventricular node	Automaticity ↑	β1	Conduction velocity ↓ Atrioventricular block	M2 M2
Ventricular muscle	Automaticity ↑ Force ↑	β1	No effect	M2
Blood vessels
Arterioles
Coronary	Constriction	α	No effect	-
Muscle	Dilatation	β2	No effect	-
Viscera, skin, brain	Constriction	α	No effect	-
Erectile tissue	Constriction	α	Dilatation	M3b
Salivary gland	Constriction	α	Dilatation	M3b
Veins	Constriction	α	No effect	-
	Dilatation	β2	No effect	-
Viscera
Bronchi
Smooth muscle	No sympathetic innervation, but dilated by circulating adrenaline (epinephrine)	β2	Constriction	M3
Glands	No effect	-	Secretion	M3
Gastrointestinal tract
Smooth muscle	Motility ↓	α1, α2, β2	Motility ↑	M3
Sphincters	Constriction	α2, β2	Dilatation	M3
Glands	No effect	-	Secretion Gastric acid secretion	M3 M3
Bladder	Relaxation	β2	Contraction	M3
	Sphincter contraction	α1	Sphincter relaxation	M3
Uterus
Pregnant	Contraction	α	Variable	-
Non-pregnant	Relaxation	β2
		α	Erection	M3
Eye
Pupil	Dilatation	α	Constriction	M3
Ciliary muscle	Relaxation (slight)	β	Contraction	M3
Skin
Sweat glands	Secretion (mainly cholinergic via M3 receptors)	-	No effect
Pilomotor	Piloerection	α	No effect	-
Salivary glands	Secretion	α, β	Secretion	M3
Lacrimal glands	No effect	-	Secretion	M3
Kidney	Renin secretion	β1	No effect	-
Liver	Glycogenolysis Gluconeogenesis	α, β2	No effect

Cholinergic drugs
Direct acting (Cholinergic agonist)	Indirect acting (Anticholinesterase drugs)
	Reversible		Irreversible
Acetylcholine	Carbamates	Acridine	Organophospahtes	Carbamates
Methacholine	Physostigmine	Tacrine	Dyflos	Carbaryl
Carbachol	Neostigmine		Echothiophate	Propoxur
Bethanechol	Pyridostigmine		Parathion
Muscarine	Edrophonium		Malathion
Pilocarpine	Rivastigmine		Diazinon
Arecoline	Galantamine

In a functional sense, the indirect cholinomimetic effect of AChE inhibitors is more selective than the effect of directly acting cholinomimetics, because the inhibitors of AChE increase the activation of cholinoreceptors only at active cholinergic synapses. This permits strengthening of the phasic stimulation of synaptically activated cholinoreceptors rather than the persistent activation by directly acting cholinomimetics.

Structure

v  Reversible Indirect acting drugs attach to anionic site of enzyme

v  Irreversible Indirect acting drugs attach to esteric site

Drug	Duration of action		Main site of action	Notes
Edrophonium	Short		NMJ	Used mainly in diagnosis of myasthenia gravis Too short acting for therapeutic use
Neostigmine	Medium		NMJ	Used intravenously to reverse competitive neuromuscular block Used orally in treatment of myasthenia gravis Visceral side effects
Physostigmine	Medium		P	Used as eye drops in treatment of glaucoma
Pyridostigmine	Medium		NMJ	Used orally in treatment of myasthenia gravis Better absorbed than neostigmine and has longer duration of action
Dyflos	Long		P	Highly toxic organophosphate, with very prolonged action Has been used as eye drops for glaucoma
Ecothiopate	Long		P	Used as eye drops in treatment of glaucoma Prolonged action; may cause systemic effects
Parathion	Long		-	Converted to active metabolite by replacement of sulfur by oxygen Used as insecticide but commonly causes poisoning in humans

NMJ = neuromuscular junction, P, postganglionic parasympathetic junction

Medium-duration anticholinesterases 

Neostigmine and pyridostigmine, which are quaternary ammonium compounds of clinical importance, and physostigmine (eserine), a tertiary amine, which occurs naturally in the Calabar bean. These drugs are all carbamyl, as opposed to acetyl, esters, and all possess basic groups that bind to the anionic site. Transfer of the carbamyl group to the serine hydroxyl group of the esteratic site occurs as with ACh, but the carbamylated enzyme is very much slower to hydrolyse, taking minutes rather than microseconds. The anticholinesterase drug is therefore hydrolysed, but at a negligible rate compared with ACh, and the slow recovery of the carbamylated enzyme means that the action of these drugs is quite long-lasting. 

Myasthenia Gravis

Ø  Myasthenia gravis is an autoimmune disease in which antibodies recognize nicotinic cholinoreceptors on skeletal muscle. This decreases the number of functional receptors and consequently decreases the sensitivity of the muscle to ACh. Muscle weakness and rapid fatigue of muscles during use are characteristics of the disease.

Ø  Anticholinesterase agents help to alleviate the weakness by elevating and prolonging the concentration of ACh in the synaptic cleft, producing a greater activation of the remaining nicotinic receptors. By contrast, thymectomy, plasmapheresis, and corticosteroid administration are treatments directed at decreasing the autoimmune response. Anticholinesterase agents play a key role in the diagnosis and therapy of myasthenia gravis, because they increase muscle strength.

Ø  During diagnosis, the patient’s muscle strength is examined before and immediately after the intravenous injection of edrophonium chloride. In myasthenics, an increase in muscle strength is obtained for a few minutes.

Ø  The pronounced weakness that may result from inadequate therapy of myasthenia gravis (myasthenic crisis) can be distinguished from that due to anticholinesterase overdose (cholinergic crisis) by the use of edrophonium. In cholinergic crisis, edrophonium will briefly cause a further weakening of muscles, whereas improvement in muscle strength is seen in the myasthenic patient whose anticholinesterase therapy is inadequate. Means for artificial respiration should be available when patients are being tested for cholinergic crisis.

Ø  Pyridostigmine and neostigmine are the major anticholinesterase agents used in the therapy of myasthenia gravis, but ambenonium can be used when these drugs are unsuitable. When it is feasible, these agents are given orally. Pyridostigmine has a slightly longer duration of action than neostigmine, with smoother dosing, and it causes fewer muscarinic side effects. Ambenonium may act somewhat longer than pyridostigmine, but it produces more side effects and tends to accumulate.

Treatment of Anticholinesterase Poisoning

The first step in treatment of anticholinesterase poisoning should be injection of increasing doses of atropine sulfate to block all adverse effects resulting from stimulation of muscarinic receptors. Since atropine will not alleviate skeletal and respiratory muscle paralysis, mechanical respiratory support may be required. If the poisoning is due to an organophosphate, prompt administration of pralidoxime chloride will result in dephosphorylation of cholinesterases in the periphery and a decrease in the degree of the blockade at the skeletal neuromuscular junction. Since pralidoxime is a quaternary amine, it will not enter the CNS and therefore cannot reactivate central cholinesterases. In addition, pralidoxime is effective only if there has been no aging of the phosphorylated enzyme. Pralidoxime has a greater effect at the skeletal neuromuscular junction than at autonomic effector sites.