introduction to the autonomic nervous system

Introduction to the Autonomic Nervous System

Ed Bilsky, Ph.D.Department of PharmacologyUniversity of New England

Phone 283-0170, x2707

E-mail: [email protected]

Autonomic Nervous System

• A largely autonomous system that monitors and controls internal body functions to maintain homeostasis and meet the organisms demands– cardiac output– blood volume and pressure– digestive processes

• Contains both afferent and efferent components, along with integrating centers

• Drugs which modify the function of the autonomic nervous system can be used therapeutically for many disease states


• There are two efferent divisions that act antagonistically to each other– allows for a greater degree of control over various

processes than one system would allow

• Sympathetic branch (fight or flight)– increased cardiac output– redirection of blood flow from GI system and skin to skeletal

muscle

• Parasympathetic branch (rest and maintenance)– decreased cardiac output– increased GI motility and secretions

Divisions of the ANS use a two neuron system:

Preganglionic neuron:– cell bodies in the spinal cord– nerves terminate in ganglion

Postganglionic neuron:– cell bodies in the ganglion– nerves terminate on effector organs including smooth

muscle and cardiac muscle

Ganglion: aggregation of nerve cells in the peripheral nervous system


Preganglionic Cell Locations

Sympathetic:– thoracic spinal cord– lumbar spinal cord

Parasympathetic:– cranial nerves (CN III, VII, IX, X)– sacral spinal cord


Two primary neurotransmitters in the ANS:

Acetylcholine:– preganglionic cells of the parasympathetic and

sympathetic branches– postganglionic cells of the parasympathetic branch– some postganglionic cells of the sympathetic

branch

Norepinephrine:– most postganglionic cells of the sympathetic

branch

Neurotransmitters of the ANS

Ach

Ach

Neurotransmitters of the ANS

NE

NE

Ach

Ach

Ach

Ach

cranialparasympathetic

nerves

visceraleffectors

visceraleffectors

visceraleffectors

visceraleffectororgans

sympathetic(thoracolumbar)

nerves

sacralparasympathetic

nerves

• There are numerous other substances found in cholinergic and noradrenergic neurons, as well as other neurons of the ANS

• These substances may modulate the actions of the primary neurotransmitters or have functions of their own

Examples:– Substance P– CGRP– serotonin– VIP– CCK

Neuromodulators of the ANS

Adrenergic Cholinergic

2 1 2Muscarinic

M1 M2 M3

Nicotinic

NN NM

Primary Receptors of the ANS

3

Cholinergic Receptors

Receptor Primary Locations Main Biochemical Effects

M1 sympathetic post-ganglionic neurons, formation of IP3 and DAG -->

CNS neurons increased intracellular Ca2+

M2 myocardium, smooth muscle inhibition of adenylyl cyclase

open K+ channels

M3 vessels (smooth muscle/endothelial), formation of IP3 and DAG -->

exocrine glands increased intracellular Ca2+

NN postganglionic neurons increased Na+ conductance -->

depolarization of neuron

NM neuromuscular junction increased Na+ conductance -->

initiation of muscle contraction

Adrenergic Receptors

Receptor Primary Locations Main Biochemical Effects

1 smooth muscle formation of IP3 and DAG -->

increased intracellular Ca2+

2 presynaptic nerve terminals inhibition of adenylyl cyclase -->

platelets, lipocytes, smooth muscle decreased cAMP

1 cardiac muscle, lipocytes, CNS stimulation of adenylyl cyclase -->

presynaptic ANS nerve terminals increased cAMP

2 smooth muscle, cardiac muscle stimulation of adenylyl cyclase -->

increased cAMP

3 lipocytes stimulation of adenylyl cyclase -->

increased cAMP

Neurotransmission

Four Major Steps:

1. Synthesis and Storage of the neurotransmitter in the presynaptic neuron

2. Release of the neurotransmitter into the synaptic cleft

3. Interaction of the neurotransmitter with receptors on the post-synaptic cell

4. Termination of the synaptic actions of the neurotransmitter

Synthesis and Storage

Acetylcholine example:

• The precursor choline is transported into cholinergic nerve terminals

– hemicholinums can block the transporter --> decreased synthesis of ACh

• Once synthesized, acetylcholine is transported into vesicles for storage

– vesamicol can block the vesicular transporter, decreasing stores of releasable ACh

• Because of the ubiquitous nature of acetylcholine, these drugs are not used in clinical pharmacology

Release of Neurotransmitter

Release

Acetycholine example:

• Botulinum toxins are among the most potent pharmacological agents known

• The various botulinum toxins are produced by distinct strains of Clostridium botulinum

• The light chain of the protein exerts a metalloprotease effect that cleaves proteins involved in exocytosis

– SNAP-25– syntaxin– VAMP-1 and 2

Clinical Correlate

• Intramuscular injections of botulinum toxin type A are the most effective treatment for focal dystonia and may be used in a limited form in patients with segmental or generalized dystonia

• Treatment is necessary every 3 to 5 months in most patients, and this therapy has been used safely in some patients for more than 15 years

– some patients develop resistance to the clinical response, and antibodies to the A toxin may develop

– if the dose is limited to less than 300 U per procedure and the treatment is given no more frequently than every 3 months, the risk of immunoresistance is minimized

Interaction of Neurotransmitters with Receptors

Ligand-gatedchannel

G-proteinregulated

Na+

Agonist

EffectorOpioid receptor

G protein complex

ACh

Termination of Neurotransmitter Effect

Enzymatic breakdown of neurotransmitter:

Acetylcholinesterase

• Acetylcholinesterase (AChE) is one of only a few enzymes that have obtained near catalytic perfection

– the rate of hydrolysis is close to the rate of diffusion to the active site

– a single enzyme can hydrolyze 14,000 ACh molecules/second

• Blockade of acetylcholinesterase will rapidly increase synaptic levels of acetylcholine

– neostigmine-reversible inhibitor– sarin, malathion-irreversible

inhibitors

Termination of Neurotransmitter EffectReuptake of neurotransmitter:

Reuptake of Catecholamines

• Dopamine and norepinephrine are inactivated primarily via reuptake

– specific transporters that transport the catecholamines back into the presynaptic terminal

• The effects of cocaine and amphetamine are mediated in part through the dopamine transporter

Cholinomimetic Drugs

Ed Bilsky, Ph.D.Department of PharmacologyUniversity of New England

Phone 283-0170, x2707

E-mail: [email protected]

Drugs that Increase Cholinergic Activity

Cholinergic agonists– muscarinic agonists (pilocarpine)– nicotinic agonists (nicotine)

Inhibitors of acetylcholinesterase– reversible inhibitors (neostigmine)– irreversible inhibitors (nerve gas, insecticides)

Direct Acting Cholinomimetics

Structure:

• Major differences exist between drugs in this class

• The choline esters have quaternary structures that possess positive charges (e.g., bethanechol)– water soluble

• Other agents do not have have a charge (e.g., pilocarpine)

• There is a strong stereoselective binding requirement for the muscarinic receptor– (S)-bethanechol >> (R)-bethanechol


Pharmacokinetics:

• The quaternary amines are poorly absorbed and poorly distributed into the CNS compared to the tertiary amines– bethanechol versus pilocarpine

• Some of these compounds are more resistant to cholinesterases than others– bethanechol >> acetylcholine

• Modification of the structure can influence the affinity of the drug for muscarinic and nicotinic receptors– bethanechol versus acetylcholine


Pharmacodynamics:

• Muscarinic receptors are coupled to G-proteins that activate phospholipase C (M1 and M3) or inhibit adenylyl cylase (M2)– increased production of IP3 and DAG, decreased levels of

cAMP

• These second messengers produce a number of intracellular effects– increase intracellular Ca2+ levels and activation of protein

kinase C– opening of K+ channels --> hyperpolarization of the cell

• Activation of nicotinic receptors produces an influx of Na+ ions and depolarization of the cell --> action potential

Organ System Effects

Cardiovascular system:

• Primary effects of muscarinic agonists are a decrease in peripheral resistance and changes in heart rate

• Direct effects of the heart include:– increased K+ current in atrial muscle, SA and AV nodes– decreased Ca2+ current in cardiac cells– a reduction in hyperpolarization-activated current that

underlies diastolic depolarization

• net effect is to slow the pace maker cells and decrease atrial contractility– the ventricles are less densely innervated than the atrial

tissue


Cardiovascular system (continued):

• The direct effects of muscarinic agonists on the heart are usually opposed by reflex sympathetic discharge– elicited by the fall in blood pressure

• Muscarinic agonists can produce marked vasodilation– generation of EDRF from endothelial cells (NO main

contributor)

Respiratory system:

• Muscarinic agonists produce smooth muscle contraction and stimulate secretion in the bronchial tree– can aggravate symptoms associated with asthma


Genitourinary tract:

• Stimulation of muscarinic receptors increases tone of the detrusor muscle and relaxes the trigone and sphincter muscles of the bladder– promotes voiding of urine

• No major effects on uterine contractility


Eye:

• muscarinic stimulation leads to contraction of the smooth muscle of the iris sphincter and of the cilliary muscle– responsible for miosis and accomodation, respectively

• Both effects promote the outflow of aqueous humor– decreases intraoccular pressure

Miscellaneous secretory glands:

• muscarinic agonists stimulate the secretory activity of sweat, lacrimal and nasopharyngeal glands


CNS effects:

• The CNS contains both muscarinic and nicotinic receptors

• Nicotine has important effects on the brainstem and cortex– stimulant type effects, addiction liability– high doses can cause tremor and convulsions

• Muscarinic receptors play a role in movement, cognition, learning and memory, and vestibular function– potential therapeutic applications to CNS diseases, though

side-effects limit the clinical use of these agents


PNS effects:

• Activation of nicotinic receptors produces action potentials in post-ganglionic nerves of the ANS

• The activation of both branches of the ANS results in complex effects on the organism– cardiovascular effects are primarily sympathomimetic– GI and genitourinary effects primarily parasympathomimetic

Neuromuscular junction:

• nicotine receptors initiate muscle action potentials– fasciculations to strong contractions of an entire muscle

possible– can produce depolarization blockade

Indirect Acting Cholinomimetics

Structure:• Three major classes of compounds

– simple alcohols bearing quaternary ammonium group– carbamic acid esters of alcohols bearing quaternary or tertiary

ammonium groups– organic derivatives of phosphoric acid (organophosphates)

Pharmacokinetics:

• The quaternary derivatives are poorly absorbed and poorly distributed into the CNS compared to the tertiary amines– physostigmine > neostigmine

• Differences in insecticide absorption and metabolism can affect the safety of these products– malathion metabolized quickly in mammals and birds, not insects

Indirect Acting Cholinomimetics

Pharmacodynamics:

• The affinity of the drug to acetycholinesterase determines the duration of action– edrophonium and related quaternary alcohols interact weakly

(electrostatic and hydrogen bonds) --> 2-10 min interaction– carbamate esters (e.g., neostigmine) form covalent bonds -->

30 min to 6 hr interactions– organophospahtes can form very strong covalent bonds that

are basically irreversible --> hundreds of hours

• An aging process can strengthen the organophosphate bonds making treatment of nerve gas poisoning very difficult to manage


Cardiovascular system:

• These drugs exert negative chronotropic, inotropic and dromotropic effects on the heart --> decreased CO

• Limited effects on the vasculature

• Net effect of moderate doses is modest bradycardia and a fall in CO, with only minimal effects on blood pressure– higher doses produce marked bradycardia and hypotension

Respiratory, GI and GU systems:

• Similar to effects produced by direct acting agents


Neuromuscular junction:

• Low (therapeutic) doses prolong and intensify the effects of physiologically released acetylcholine

• Higher doses can lead to muscle fibrillation and fasiculations of an entire motor unit

Therapeutic Applications: Myasthenia Gravis

• Myasthenia gravis is an autoimmune disorder that attacks the nicotinic ACh receptors at the neuromuscular junction– leads to profound muscle weakness

• Acetylcholinesterase inhibitors increase the amount of acetylcholine in the neuromuscular junction– neostigmine is frequently used for this disorder

• If muscarinic side-effects are prominent, anticholinergics can be administered (e.g., atropine)– tolerance usually occurs to the muscarinic side-effects

Why are the direct acting cholinomimetics not used for myasthenia gravis?

Therapeutic Applications: Reversal of NMB

• By increasing levels of acetylcholine in the NMJ, the compounds are able to facilitate recovery from competitive neuromuscular blockade– restores neuromuscular transmission

• Edrophonium has a more rapid onset of action than neostigmine, and shorter duration of action

• Neostigmine is preferable to other agents when >90% twitch depression is to be antagonized

• Constriction of the ciliary body promotes aqueous humor outflow --> decreased intraoccular pressure

• Direct and indirect cholinomimetics can be used to treat glaucoma– pilocarpine is the most commonly used agent– typically formulated as eye drops

Therapeutic Applications: Glaucoma

• The smooth muscle of the GI and GU systems can show depressed activity in certain states– post-operative ileus– congenital megacolon

• Bethanechol and neostigmine are the most widely used agents– increases secretion and motility in the G.I. tract – can be given orally or by injection

Therapeutic Applications: Atonic GI/GU

These agents can not be used if there is a mechanical obstruction of the GI or urinary tract

• Physostigmine is rarely used for reversing the effects of anticholinergic poisoning– has many side-effects of its own that are difficult

to control

• The use of edrophonium for treating supraventricular tachyarrhythmias has been discontinued– newer agents that act at adenosine receptors and

calcium channels have replaced its use in this condition

Therapeutic Applications: Other Uses

Anticholinergics

Neuromuscular receptor antagonists– Tubocurarine (nicotinic antagonist)

Ganglionic receptor antagonists– hexamethonium

Muscarinic receptor antagonists– atropine and scopolamine (belladonna alkaloids)– pirenzepine

Structure:

• Atropine is the prototypic drug in this class– found in Atropa belladonna (deadly nightshade) and Datura

stramonium (Jimson Weed)– tertiary amine structure allows passage across the BBB

• Other drug classes possess anticholinergic activity by virtue of their similar chemical structures– many antihistamines, antipsychotics and antidepressants

• Anticholinergics that are quaternary amines have been developed for limiting CNS effects– ipratropium for asthma– propantheline for GI use

Anticholinergics

Pharmacokinetics:

• The quaternary amines are poorly absorbed from the GI tract and poorly distributed into the CNS compared to the tertiary amines– atropine >> propantheline

• Metabolism is drug specific– atropine has a relatively short half-life, with the majority of

the drug being eliminated in the urine unchanged, some metabolism in the urine (hydrolysis and conjugation)

Anticholinergics

Pharmacodynamics:

• Atropine produces reversible blockade of muscarinic receptors– very selective for muscarinic receptors

– does not differentiate between M1, M2 and M3 receptors

• Other anticholinergics possess subtype selective profiles– pirenzepine M1 > M2 > M3

Anticholinergics

CNS:

• Clinical doses of atropine typically produce minimal CNS effects– scopolamine has greater CNS effects (sedation, amnesia)– higher doses of these agents can produce hallucinations

• Blockade of muscarinic receptors has been used to treat tremors associated with Parkinson’s disease– newer agents have replaced anticholinergics as a primary treatment,

sometimes used as an adjunct

• Vestibular disturbances, especially motion sickness, appears to be mediated by CNS muscarinic receptors– scopolamine can be given orally or by transdermal patch


Eye:

• Tertiary anticholinergics produced marked mydriasis due to unopposed sympathetic activity

• Decreased contraction of the ciliary muscle produces cycloplegia and a loss of accommodation

• These effects are useful for certain ophthalmology procedures– contraindicated in patients with glaucoma

Cardiovascular effects:

• Moderate doses have pronounced effects on the SA node to increase heart rate– low doses can cause bradycardia due to presynaptic muscarinic

receptor blockade


Respiratory system:

• Blockade of muscarinic receptors in the bronchial tree produces bronchodilation and decreased secretions

• Older class of agents used for treating asthma– largely replaced in the treatment of asthma by beta-2

agonists

• Ipratropium is sometimes used in asthma and COPD as an inhalational drug– decreased systemic distribution compared to atropine

• Anticholinergics can decrease secretions during intubation procedure and during the delivery of volatile anesthetics


GI effects:

• Decreases secretions and motility in the GI system– dry mouth and constipation are frequent side-effects

• infrequently used for treating peptic ulcer and diarrhea– better agents available that have produce less side-effects– selective M1 blockers are being developed (pirenzepine)

• Decreases spasms of the bladder and ureters is useful in treating some inflammatory conditions where incontinence is a problem (M3 antagonists)

Sweat glands:

• thermoregulatory sweating is inhibited by atropine– sympathetic nervous system effect

• Large doses of atropine may increase body temperature in adults– infants and children are much more sensitive to this effect


• A number of insecticides and nerve gasses can produce cholinergic toxicity

• Many of the signs and symptoms can be reversed by administering atropine

• There are several compounds that can hydrolyze the phosphoryalted acetylcholinesterase and reverse organic phosphate poisoning – need to be administered soon after the exposure– pralidoxine (PAM) “regenerates” the acetycholinesterase

• Atropine can be used to treat certain types of mushroom poisoning (Inocybe genus and others)

Cholinergic poisoning

• High doses of belladonna alkaloids can produce their own toxic syndrome– dry as a bone, blind as a bat, red as a beet, mad as a hatter

• Typically associated with accidental poisoning in people seeking the hallucinogenic actions of the drug– long-lasting agitation and delerium

• Overdose is typically treated symptomatically due to problems with the antidotes (physostigmine)– temperature control and diazepam for seizures

Anticholinergic poisoning

• The lack of specificity with these agents limits their clinical use– hexamethonium and others are used in preclinical research

• The specific response elicited depends on the predominant ANS innervation– cycloplegia and loss of accommodation and usually dilation of

the pupil– cardiovascular effects include significant hypotension– marked decrease in GI activity and loss of sexual function

• These compounds (e.g., trimethaphan) were once used to treat malignant hyperthermia– replaced by other drugs (e.g., nitroprusside)

Ganglion Blocking Agents

introduction to the autonomic nervous system

Documents

neuron system

gi system

preganglionic cells

camp1cardiac muscle

autonomous system

aggregation of nerve

spinal cordnerves

cell bodies