AUTONOMIC NERVOUS SYSTEM

•System autonomous from voluntary or conscious control e.g. digestion, secretion of juices, pH, temperature control, endocrine secretions, metabolism. •Inervation of visceral and vascular smooth muscles of heart, exocrine and endocrine glands. •Two types of efferents from CNS i.e. autonomic efferents and somato motor efferents. •Afferent neurons convey impulses from peripheral organs to CNS for integration e.g. via vagus nerve which convey impulses from viscera. •Efferent neurons are divided into parasympathetic (cholinergic), sympathetic (adrenergic) and enteric system.

Basic Anatomy of ANS• Two divisions: PSN and SNS• Two neuron patterns: preganglionic neurons (cell bodies

in CNS), post ganglionic (cell bodies in autonomic ganglia)

• PSN is connected to the CNS via Cranial nerves III, VII, IX, X and the Sacral outflow

• PSN ganglia usually lie close to or within the target organ.

• Sympathetic outflow leaves CNS in thoracic and lumbar spinal roots.

• Sympathetic ganglia form two paravertebral chains plus some prevertebral or midline ganglia.

• Enteric system – controls gastric motility and secretion but receives inputs from ANS.

PHYSIOLOGY OF ANS• Most of the time PSN and SNS exert opposite

effects. Net effect depends on predominant system. SNS is associated with flight and fright while PSN is associated with repose.

• Some organs are innerverted by only one system e.g. spleen, sweat glands, most blood vessels and hair follicles – adrenergic. Ciliary muscles of the iris, adrenal medulla, exocrine glands of stomach and pancrease – cholinergic.

• Cerebral circulation is not regulated by either PSN, SNS – but by chemical environment and perfusion pressure in the capillaries.

NEURO TRANSMISSION IN ANS

• MAIN neurotransmitters – Ach, NA• NANC – ATP, VIP, neuropeptide, nitric oxide,

substance p, 5HT, gabba, Dopamine (principle of co- transmission)

• Above may also be neuromodulators• Other neuro modulators – enkephalins,

adenosine, prostaglandins, somatostatin, TRH, GRH, CCK, ATP.

• Neuro modulators can act presynaptically as neurotransmitters in some circumstances.

• Neuromediators e.g. cyclic Amp, cyclic GMP, the so called second messengers.

Neuro chemical transmission in ANS

• Precussors – depolarization Ca2+ - Synthesis – storage into vesicles – post synaptic activity – termination of action.

• Drug /Chemical intervention can occur at any of the above steps.

Cholinergic Transmission

• Transmitter – Ach – (CNS, ANS)• Cholinergic neurons release Ach and are located

as follows:-• Post ganglionic parasympathetic nerve ending • Post ganglionic SNS to sweat glands and hair

follicles. • Preganglionic neurons to autonomic ganglia and

supra renal medulla. • Somato motor nerves to skeletal muscles • In the CNS. • Cilia in respiratory tract and fallopian tubes• SAN

Synthesis, Storage release of Acetycholine • Precussor – choline (vit B group)• Taken into neurons by active transport system –

Na+ choline co transporter. • Acetyl group donated to choline by Acetyl CoA.

(via choline acetyl transferase. • Storage of Ach into vesicles • Release of Ach due to depolarization and influx

of Ca2+. (exocytosis)• Post synaptic action• Termination of action by acetyl cholinesterase in

the synaptic cleft. • Cholinesterase enzymes are of two types, true

cholinesterase (Ach) and pseudo cholinesterase (Butyrl cholinesterase ( Buche).

Effects of drugs on cholinergic transmission

• Inhibition of choline uptake by inhibiting Na+ choline co transporter – Hemicholinium

• Blocks storage of Ach in synaptic vesicles by preventing active transport of Ach – Vesamicol.

• Blocks release of Ach by exocytosis – Botulinium (from botulinium) and tetanus toxin (clostridium).

• Stimulate release of Ach from the vesicles and its depletion – black widow spider toxin.

• Blocks effects of Ach at receptors: • 1) Non depolarizing neuromuscular blockers –

tubocurarine • 2) Depolarizing neuromuscular blockers -

suxamethonium• Prevents degradation of Ach by cholinesterase i.e

anticholinesterases – neostigmine, pyridostigmine.• Tetrodoxin and saxitoxin-prevent nervous impulse

conduction.

Receptors of Acetylcholine

• Muscarinic – effects produced by Ach correspond to those of poisonous mushroom, Amanita muscara.

• Nicotinic – effects produced by Ach on these receptors found at autonomic ganglia and neuromuscular junction (NMJ) correspond to those of nicotine.

Muscarinic Receptors

• Stimulated by muscarine and blocked by atropine.

• Found in autonomic effector cells of the heart, blood vessels, eye, smooth muscles and glands of git, respiratory, urinary tract, sweat glands, CNS, and autonomic ganglia.

• Muscarinic receptor sub types M1 – M5 (M1, M2, M3 major sub types)

• M1 (neural) M2 (cardiac), M3 (glandular) M4 and M5 (CNS) – may be involved in regulating release of other neuro transmitters.

Nicotinic receptors • Nm (N1) (Neuro muscular junction) and Nn (N2)

found in autonomic ganglia, suprarenal medulla and CNS.

• Main mechanism of action on activation is by opening of cationic channels (Na+, K+, Ca2+ (N2) and depolarization.

• Antagonists: N1 (d-tubocurarine, α bungarotoxin)

• - N2 (Hexamethonium &trimethaphan)

• Main effect of activation of N1 receptors is contraction of skeletal muscle.

• Main effect of activation of N2 receptors is transmission of impulse in autonomic ganglia and release of catecholamine.

• Agonists: N1, N2 – Ach, nicotine.

Pharmacological effects produced on activation of muscarinic receptors

• M1 – mediates gastric secretion, relaxes lower esophageal sphincter on vagal stimulation. May play a role in learning, memory and motor functions.

• M2 – Mediate vagal bradycardia

• M3 – Visceral smooth muscle contraction, glandular secretions and vasodilation via release of EDRF (NO)

Cholinergic drugs • Also called cholinomimetics (effects equivalent to those

of Ach) or parasympathomimetics (effects same as PSN stimulation)

Classification • Direct acting cholinergic receptor agonist e.g choline

esters Ach, bethanecol, carbachol, methacholine • Plant alkaloids: muscarine, nicotine, pilocarpine,

arecoline. • Indirect acting cholinergic receptor agonists: • Reversible cholinesterase inhibitors. Neostigmine,

physostigmine, pyridostigmine, edrophonium, donepezil, carbamate insecticides e.g carbaryl (Sevin) propoxur (Baygon).

• Irreversible cholinesterase inhibitors - organophosphates (malathion, diazinon isoflurophate, echothiophate )

• Drugs that increase Ach release: cisapride, metochlorpropamide

• Other cholinergic receptor agonists: sildenafil.

Summary of pharmacological effects of Acetylcholine

Muscarinic effects:

a) Heart – – Bradycardia via M2 receptors– AVN and His purkinje – conduction decreases

(i.e increase PR interval)

– Force of atrial and ventricular contractions decreases.

Summary of pharmacological effects of Acetylcholine (Continued)

b) Blood vesselsMost blood vessels are not affected by cholinergic system. • Vasodilation of some blood vessels(penile and salivary) by

inhibiting release of noradrenaline. • Vasodilation is also caused via M3 receptors which when

activated release EDRF (NO)• Ach stimulates M3 receptors on cavernosal vessels, releasing

NO and causing vasodilation and penile erection. c) Smooth muscles • Ach acts via M3 receptors, causing contraction of smooth

muscles of most organs: • Increases in git tone and peristalysis. Relaxation of

sphincters and evacuation of bowel. • Ureter: Contraction of detrusor muscles and relaxation of

sphincter muscles – voiding of urine. • Bronchi – Broncho constriction. Contra indicated in

asthmatics.

Summary of pharmacological effects of Acetylcholine (Continued)

d) Glands • Increased secretion via M3 and M2 receptors leading to

sweating, salivation, lacrimation, tracheo bronchial and gastric secretions.

• Effect on secretions from intestine, and pancrease is not marked except for HCL

• Secretion of milk and bile not affected. e) Eye • Miosis due to contraction of circular muscle of iris. • Contraction of ciliary muscle causes spasm of

accommodation, increased outflow of aqueous humour and reduction in intraocular tension – useful in glaucoma.

Pharmacological effects continued

CNS • I.V Ach, no crossing BBB, no effect. • Direct injection of Ach into brain or

administration of cholinergic agonists that enter the brain may cause tremors, hypothermia, increased locomotor activity - all via M1 receptors.

• Selective M1 agonists are being developed to treat dementia because they improve cognition.

Nicotinic effects of acetylcholine

Nicotinic effects of acetylcholine• Stimulates sympathetic and parasympathetic

ganglia. • At high doses, stimulate sympathetic ganglia

leading to NA release (tachycardia and BP increase)

• Contraction of skeletal muscles by interacting with nicotinic receptors at motor end plate.

• High doses intra arterially – twitching and fasciculation. I.V no effect because of rapid hydrolysis of Ach.

Reversible cholinesterase inhibitors (anticholinesterases)

Reversible cholinesterase inhibitors (anticholinesterases)• Form weak bonds with cholinesterase. • Inhibit degradation of Ach at all cholinergic synapses; leading to its

accumulation. • Lipid soluble agents e.g physostigmine can cross BBB causing marked

CNS effects but with less effect on NMJ. They also cause muscarinic and ganglion stimulant effects.

• Lipid insoluble agents e.g neostigmine, edrophonium and pyridostigmine have marked effect on skeletal muscle and ganglia but less effect on muscarinic sites and CNS.

• Duration of action vary – Edrophinium short acting – Physostigmine, pyridostigmine, prostigmine, ambenonium –medium

acting. – Demecarium – long acting.

Summary of pharmacological actions of anticholinesterases• Stimulate ganglia via muscarinic receptors. • High doses block nicotinic receptors and prevent neuro muscular

transmission.

CVS• Bradycardia and Hypotension (muscarinic)• Ganglia - HR increase, BP increase, higher doses

cause a decrease in heart rate and blood pressure.• Medullary centre – stimulation followed by depression. • Overall effect is complex and depends on agent and

dose. Skeletal muscle • Twitching and fasciculation due to increase in

concentration of Ach. • Higher doses – persistent depolarization and NMJ

blockade leading to weakness and paralysis. Glands• Increase secretions – git, respiratory, urinary, eye. • (Homework, pharmacokinetics of reversible ACHE)

Irreversible cholinesterase inhibitors• Mainly organo phosphates, DFP, (dyflos),

Echothiophate ( therapeutically useful agents), insecticides which include parathion, malathion, diazinon, dimethoate and war gases e.g. tabun, soman, sarin.

• Highly lipid soluble and are absorbed from all sites in the body(skin, mucous membrane,CNS.)

• They form strong covalent bonds with esteratic site of cholinesterase – long duration of action.

• Effects of organophosphate poisoning are due to excessive Ach at muscarinic and nicotinic receptors (see handout).mgt-supportive,atropine.pralidoxime.

• Management of organophosphate poisoning is by supportive, atropine and pralidoxime.

Therapeutic uses of cholinergic agonists.

• Ach not useful because of non selective action. • Methacholine – paroxysmal supraventricular

tachycardia (not used any more). • Bethanecol – post operative or post partum

urinary retention and management of gastroesophageal reflux.

• Pilocarpine – eye drops for glaucoma. • Physostigmine eye drops for glaucoma• Metocholorpropamide (plasil) - blocks DA

receptors in CTZ, cholinomimetic, therefore used in nausea and vomiting.

• Cisapride – 5HT4 agonist with cholinomimetic action which was used in nausea and vomiting. Has been discontinued.

Therapeutic uses of agonists (continued)

• Sildenafil is a phosphodiesterase inhibitor, preventing degradation of cyclic GMP. Increase cyclic GMP in corpus cavernosum of the penis causes vasodilation.

• Sildenafil potentiates vasodilator action of Ach, increasing penile blood flow and can therefore be used in male erectile dysfunction.

• Mysthenia gravis (MG) - neostigmine and pyridostigmine are used.

• Drugs contraindicated in myasthenia gravis include: aminoglycosides, quinine, quinidine

• Edrophonium I.V is used for diagnosis of MG.

Therapeutic uses continued

• Overdose with neuromuscular blocking drugs e.g. tubocurarine (edrophonium 10mg I.V).

• Poisoning with atropine, tricyclic antidepressants (TCA) and antipsychotic agents – (physostigmine is used).

• Alzheimer's disease – due to degeneration of cholinergic neurons in CNS and loss of memory. Treated by:

• physostigmine• Donepezil, tacrine ,rivastigmine, galantamine

(centrally acting anticholinesterases)• Choline – to enhance synthesis and release of

Ach• Nootropic agents e.g Piracetam

Contraindications to cholinergic agonists

• Bronchial asthma

• Peptic ulcer

• Myocardial infarction – causes coronary insufficiency, hypotension and conduction block.

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