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INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM. Subdivisions of the Peripheral Nervous System Somatic nervous system (voluntary) Autonomic nervous system (involuntary). Somatic nervous system. innervation of skeletal muscles (movement) CNS control (corticospinal or pyramidal tracts).

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introduction to the autonomic nervous system
INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM

Subdivisions of the

Peripheral Nervous System

  • Somatic nervous system
    • (voluntary)
  • Autonomic nervous system
    • (involuntary)
somatic nervous system
Somatic nervous system
  • innervation of skeletal muscles (movement)
  • CNS control (corticospinal or pyramidal tracts)
somatic nervous system3
Somatic nervous system
  • somatic innervations consist of a single neuron (final common motor neuron) arising in spinal cord and extending via the ventral root to the skeletal muscles
  • releases acetylcholine (ACh)
autonomic nervous system
Autonomic nervous system
  • Functional considerations:
    • mediates control of vegetative or involuntary functions
    • innervation of cardiac muscle, vascular and nonvascular smooth muscle and exocrine glands
    • functions in these systems often occur without conscious control
autonomic nervous system5
Autonomic nervous system
  • Anatomical considerations:
    • In contrast to somatic efferents, autonomic innervations consist of 2 sequential neurons
    • These sequential neurons are the preganglionic and postganglionic neurons which synapse at autonomic ganglia
autonomic nervous system6
Autonomic nervous system
  • Anatomical considerations:
    • The autonomic nervous system consists of two divisions:
      • sympathetic
      • parasympathetic
slide7

Somatic

MotorFiber

Skeletal

Muscle

Ach

Ganglion

Sympathetic

Smooth Muscle

Cardiac Cells

Gland Cells

Postganglionic Fiber;

Adrenergic

Ach

NE

Ganglion

Sympathetic

Sweat

Glands

Ach

Ach

Preganglionic Fiber; Cholinergic

Postganglionic Fiber; Cholinergic

Sympathetic

EPI/NE

Ach

Smooth Muscle

Cardiac Cells

Gland Cells

Adrenal Gland

Para-

sympathetic

Ganglion

Ach

Ach

sympathetic nervous system
Sympathetic nervous system
  • preganglionic neurons exit the spinal cord at the thoraco-lumbar level to synapse with postganglionic nerves at para-vertebral ganglia (22 pairs on each side of spinal cord) or prevertebral ganglia (celiac, mesenteric) in the abdomen.
sympathetic nervous system9
Sympathetic nervous system
  • The adrenal medulla is considered to be a modified sympathetic ganglion; the medulla is embryonically and anatomically homologous to the sympathetic ganglia
sympathetic nervous system10
Sympathetic nervous system
  • Sympathetic innervations usually consist of one short preganglionic fiber synapsing with several (one or more) long postganglionic fibers in the sympathetic ganglia
sympathetic nervous system11
Sympathetic nervous system
  • there is a greater ramification of sympathetic fibers compared to the parasympathetic system (the ratio of pre to postganglionic fibers  1:20)
  • diffuseaction; “fight or flight” responses (i.e., stress)
sympathetic nervous system12
Sympathetic nervous system
  • this system is normally active with the degree of activity varying from moment to moment and organ to organ
  • this system constantly adjusts to a changing environment, especially during rage or fright
sympathetic nervous system13
Sympathetic nervous system

Typical sympathetic responses include:

  • increase in heart rate
  • shift in blood flow to muscles
  • increase in blood glucose levels
  • dilation of the pupils
parasympathetic nervous system
Parasympathetic nervous system
  • preganglionic neurons originate in the cranial nerves of the brain stem and the sacral portion of the spinal cord
  • these neurons synapse with post-ganglionic neurons in ganglia very close or in the organs innervated
parasympathetic nervous system15
Parasympathetic nervous system
  • Parasympathetic innervations typically consist of one longpreganglionic fiber synapsing with one shortpost-ganglionic fiber in the parasympathetic ganglia.
parasympathetic nervous system16
Parasympathetic nervous system
  • this system is more circumscribed than the sympathetic system, although a 1:1 ratio of pre to postganglionic fibers is not always the case
  • discreteaction; conservation and restoration of energy, localized control of discrete functions
  • essentialforlife
parasympathetic nervous system17
Parasympathetic nervous system

Typical parasympathetic responses include:

  • slowing the heart rate
  • lowering blood pressure
  • protecting the retina from light
  • emptying the bladder
physiological antagonism
Physiological antagonism
  • The sympathetic and parasympathetic systems usually do not function independently; i.e., they are physiologicalantagonists.
physiological antagonism19
Physiological antagonism
  • Often when one system inhibits a process, the other system will augment the level of activity so that the total response depends on the influence of both systems, although this is not always the case.
  • The integration of these system regulates functions below the level of consciousness.
neurochemical classification of peripheral nervous system
Neurochemical classification of Peripheral Nervous System

Acetylcholine (ACh or Cholinergic) synapses include:

  • Allpreganglionic fibers outside CNS (sympathetic & parasympathetic)
  • Allparasympatheticpostganglionic nerve endings (ACh is the transmitter)
    • Exception: sympathetic postganglionic nerve endings of sweat glands
  • somatic motor neurons innervating skeletal muscle
neurochemical classification of peripheral nervous system21
Neurochemical classification of Peripheral Nervous System
  • Noradrenergic (NE) synapses:
    • all postganglionic sympathetic fibers (except those to sweat glands)
    • adrenal medulla (norepinephrine & epinephrine)
acetylcholine
Acetylcholine

Chemistry

  • acetylcholine is synthesized from acetyl co-enzyme A and choline using the enzyme choline acetyl transferase
  • the major means of inactivation of acetylcholine is degradation in the synapse using the enzyme acetylcholine esterase
acetylcholine23
Acetylcholine
  • Acetylcholine (Cholinergic) Receptors
    • Muscarinic
    • Nicotinic
acetylcholine24
Acetylcholine
  • Muscarinic receptors
    • postganglionic parasympathetic fibers innervating heart, smooth muscle and exocrine glands
    • exception: postganglionic sympathetic fibers innervating sweat glands
    • blocked by antimuscarinic agents (e.g., atropine)
acetylcholine25
Acetylcholine
  • Nicotinic receptors
    • classically a biphasic response is observed with stimulation at low doses and inhibition at high doses
    • sympathetic and parasympathetic auto-nomic ganglia and the adrenal medulla
    • effects blocked with ganglionic blockers (e.g., trimethaphan, hexamethonium)
acetylcholine26
Acetylcholine
  • Nicotinicreceptors
    • neuromuscular junction of skeletal muscle
    • effects blocked with neuromuscular blockers (e.g., curare)
norepinephrine
Norepinephrine

Chemistry

  • norepinephrine is ultimately synthesized from tyrosine using the enzyme tyrosine hydroxylase which converts tyrosine to DOPA
  • aromatic L-amino acid decarboxylase converts DOPA to dopamine
  • dopamine b-hydroxylase converts dopamine to norepinephrine
norepinephrine28
Norepinephrine
  • Phenylethanolamine N-methyl-transferase converts norepinephrine to epinephrine
  • the major means of inactivation of norepinephrine is reuptake back into the presynaptic neuron from which it was released
norepinephrine29
Norepinephrine

Norepinephrine (noradrenergic) receptors:

  • a1 (alpha 1)
  • vascular smooth muscle, genitourinary smooth muscle, liver (contraction)
  • intestinal smooth muscle (hyperpolarization and relaxation)
  • heart (increased contractile force, arrhythmias)
norepinephrine30
Norepinephrine

Norepinephrine (noradrenergic) receptors:

  • a2(alpha 2)
  • pancreatic islets (b cells, decreased insulin secretion)
  • platelets (aggregation)
  • vascular smooth muscle (contraction)
norepinephrine31
Norepinephrine

Norepinephrine (noradrenergic) receptors

  • b1 (beta 1)
  • heart (increased force and rate of contraction, AV nodal conduction velocity)
  • juxtaglomerular cells (increased renin secretion)
norepinephrine32
Norepinephrine

Norepinephrine (noradrenergic) receptors

  • b2 (beta 2)
  • smooth muscle [vascular, bronchial, gastrointestinal, genitourinary] (relaxation)
  • skeletal muscle (glycogenolysis; uptake of K+)
  • liver (glycogenolysis; gluconeogenesis)
potential ways to affect autonomic neurotransmission
Potential ways to affect autonomic neurotransmission
  • Synthesis
    • availability of precursors for the NT
    • availability of synthesis enzymes
potential ways to affect autonomic neurotransmission34
Potential ways to affect autonomic neurotransmission
  • Storage (vesicles)
    • protects the NT from degradation
    • provides for the quantal release of the NT
potential ways to affect autonomic neurotransmission35
Potential ways to affect autonomic neurotransmission
  • Release (Ca2+ dependent exocytosis)
    • agents could interfere with or enhance the release of the NT
potential ways to affect autonomic neurotransmission36
Potential ways to affect autonomic neurotransmission
  • Receptor activation
    • Agonist- high affinity and high intrinsic activity
    • Antagonist - high affinity but NOintrinsic activity
potential ways to affect autonomic neurotransmission37
Potential ways to affect autonomic neurotransmission
  • Termination of NT effect
    • Acetylcholine - metabolism in synaptic cleft via acetylcholine esterase
    • Norepinephrine - reuptake into presynaptic neuron
slide38

Summary---KEY POINTS:

  • The ANS is a rapid homeostatic and ‘autonomous’ nervous system.
  • The ANS is composed of 2 divisions with different anatomical and pharmacological organization.
  • Sympathetic and parasympathetic efferents are disynaptic.
  • Parasympathetic activation stimulates muscarinic cholinergic receptors. Sympathetic activation stimulates adrenergic receptors;
  • Afferent input to the brainstem and brain are required for ANS coordination throughout the body.
slide39

Where in the autonomic nervous system isnorepinephrine stored?

  • Preganglionic sympathetic nerve endings
  • Postganglionic sympathetic nerve endings
  • Preganglionic parasympathetic nerve endings
  • Postganglionic parasympathetic nerve endings
  • Increased parasympathetic activity results in
  • decreased salivary secretion.
  • increased cardiac contractility.
  • decreased gastric motility and tone.
  • increased bronchiolar smooth muscle contraction.

.

cholinoceptive sites receptor subtypes
Cholinoceptive Sites: Receptor Subtypes
  • Muscarinic: M 1 (nerves)

M 2 (cardiovascular)

M 3 (glandular)

all blocked by atropine

  • Nicotinic: NM (skeletal muscle)

blocked by curare

NN (nerves)

blocked by hexamethonium

sites of dominance in the ans
SITES OF DOMINANCE IN THE ANS

Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics

1The vast majority of blood vessels do not receive parasympathetic innervation

cholinoceptor activating drugs
Cholinoceptor activating drugs:
  • DEFINITION:

Drugs that produce effects similar to those observed during the stimulation of postganglionic parasympathetic fibers, i.e., drugs which exert their effects largely via stimulation of peripheral muscarinic receptors.

  • Called cholinergic agonists; muscarinic agonists, parasympathomimetics
classifications of cholinergics
Classifications of Cholinergics
  • Direct-acting – Act on the receptors to activate a tissue response
  • Indirect-acting – Inhibit the action of the enzyme cholinesterase by forming a chemical complex, thus allowing acetylcholine to persist and attach to the receptor (cholinesterase inhibitor or an anticholinesterase drug)
    • Reversible – bind the cholinesterase for minutes to hours
    • Irreversible
slide48

Cholinomimetics (cholinergics)

Direct-acting Indirect-acting

Muscarinic Nicotinic

Organophosphates

(very long-acting)

Choline esters Alkaloids

Carbamates

(intermediate, long-acting)

parasympatimimetics

Edrophonium (short-acting)

acetylcholine and its metabolites
ACETYLCHOLINE AND ITS METABOLITES

Acetylcholine

Choline

Acetate

actions of acetylcholine considerations
Actions of acetylcholine: Considerations
  • Rapid hydrolysis in plasma by cholinesterase
  • Penetration to nicotinic sites is poor
  • Does not penetrate the CNS
actions of cholinergics
Actions of Cholinergics
  • Stimulate bladder and GI tone
  • Constrict pupils of the eyes (miosis)
  • Increase neuromuscular transmission
  • Increased salivary, GI, and bronchial glandular secretions
pilocarpine
Pilocarpine

-Origin of the Drug

-South American Shrub

- Pilocarpus jaborandi

-Isolated in 1875

-Chemical Structure

+

- Cholinergic Parasympathomimetic agent

actions
Actions

Eye

  • Myosis
  • Accommodation
  • Reduce Intraocular Pressure

Increased Secretion M-R activation

slide56

MajorPartsoftheEye

Sclera

Ciliarybody

Choroid

Retina

Cornea

Iris

Pupil

OpticNerve

AnteriorSegment

Lens

CanalofSchlemm

PosteriorSegment

(containsvitreoushumor)

Marieb Fig16-6

slide57

Eye Fluid Production and Pressure

Cornea

Anteriorchamberangle

Iris

Trabecularmeshwork

Schlemm’scanal

(out)

Pupil

Posteriorchamber

Ciliarybody

(in)

Lens

Vitreous

Zonule

Cassel, Billig, Randall Fig 8-2

intraocular pressure iop
Intraocular Pressure (IOP)
  • Eye is like a balloon
  • “Normal Pressure” (16 - 21)mm Hg
  • Continuous replacement of aqueous humor
slide60

- Types of Glaucoma

1) Closed-Angle Glaucoma

2) Open-Angle Glaucoma

- Effects of Glaucoma

1) Tunnel Vision

2) Blindness

types of glaucoma
Types of Glaucoma

Closed-Angle Glaucoma

Open-AngleGlaucoma

Blocked drainage of aqueous

Blocked drainage of aqueous

Anterior chamber open

Anterior Chamber

angle closure

Blockage at trabecular

meshwork

Cassel, Billig, Randall Fig 8-4

Cassel, Billig, Randall Fig 8-3

slide63

Cause of Blindness

- Cupping of Optic Nerve

Cassel, Billig, Randall

slide64

Reaction Mechanism

- Pilocarpine binds to muscarinic receptor

- Activates receptor binds G-protein

- Removal of GDP and addition of GTP to G-protein

- Dissociation of G-protein from muscarinic receptor

- Separation of G-protein into alpha and beta-gamma

subunits

- Alpha subunit interacts with and activates Phospholipase C -

Phosphatidyl inositol biphosphate (PIP) complex

- Phospholipase breaks down PIP into inositol

1,4,5-triphosphate (IP3)and diacylglycerol (both 2o)

- IP3 interacts with ER membrane which releases Ca2+

slide65

Muscle Action

- Ca2+ binds to calmodulin forming a complex

- This complex binds to caldesmon

- When caldesmon is bound by Ca2+/calmodulin complex

this allows myosin-actin interactions to occur

-The muscle (pupil)contracts

Marieb Fig 16-7

slide66

The End Result

- Contraction of pupil and stimulation of ciliary muscle

- Tension on scleral spur opening trabecular meshwork

- Increased out flow, lowering of pressure

uses for direct acting cholinergics
Uses for Direct-Acting Cholinergics
  • Treatment of glaucoma – contricts the pupil thus opening the canal of Schlemm allowing drainage of aqueous humor and decreasing intraocular pressure (Pilocarpine)
  • To increase urination – Brethanechol chloride (Urecholine) increases tone of the detrusor urinae muscle.
toxic effects
Toxic Effects
  • S – Salivation
  • L – Lacrimation
  • U – Urinary incontinence
  • D – Diarrhea
  • G – GI cramps
  • E – Emesis
indirect acting cholinergics
Indirect-acting Cholinergics
  • Cholinesterase breaks down acetylcholine
  • A small amount of cholinesterase breaks down a large amount of acetylcholine
  • A cholinesterase inhibitor binds the cholinesterase allowing acetylcholine to activate the muscarinic and nicotinic cholinergic receptors permitting skeletal muscle stimulation and increasing the force of muscular contraction
pharmacokinetics
Pharmacokinetics:
  • Most are readily absorbed from the GI tract, SC, and mucous membranes; distribution varies among drugs; metabolized by enzymes in the plasma; excreted in the urine.
uses for indirect acting cholinergics
Uses for Indirect-acting Cholinergics
  • Reversible inhibitors
    • Diagnosing myasthenia gravis – Tensilon (short-acting)
    • Increasing muscle tone and strength in clients with myasthenia gravis (Neostigmine, pyridostigmine bromide, ambenonium chloride)
    • Muscarinic antagonist poisoning
slide72

Additional effects include increased GI motility, bradycardia, miosis, bronchial constriction, and increased micturitionUse with caution in patients with bradycardia, asthma, peptic ulcers or hyperthyroidismContraindicated in patients with intestinal or urinary obstruction

uses for indirect acting cholinergics73
Uses for Indirect-acting Cholinergics
  • Irreversible inhibitors – cholinesterase has to regenerate before drug effect diminishes (days to weeks)
    • Pupillary constriction
    • Manufacture organophosphate insecticides
  • Pralidoxime (Protopam) is the antidote
cholinoceptor blocking drugs overview
Cholinoceptor blocking drugs: Overview
  • Definition and classification
    • Alkaloids
    • Quaternary and non-quaternary synthetics
  • Sites of action
  • Prototypes: atropine; scopolamine
  • Therapeutic uses
  • Toxicity
  • Contraindications
cholinergic receptor antagonists cholinoceptor blocking drugs
Cholinergic Receptor Antagonists Cholinoceptor blocking drugs
  • DEFINITION:

Drugs which occupy muscarinic receptors and prevent the muscarinic actions of endogenous acetylcholine or other muscarinic agonists.

Often referred to as anticholinergics or antimuscarinics

naturally occurring compounds
Naturally occurring compounds

(Belladonna alkaloids)

plantdrug

Atropa belladonna atropine scopolamine

Dautura stramonium atropine

Hyosacyamus niger scopolamine

synthetic semisynthetic compounds
Synthetic/semisynthetic compounds
  • Non-quaternary compounds

Dicyclomine (generic, Bentyl)

Homatropine (Isopto Homatropine)

Tropicamide (Nydriacyl)

prototypes atropine scopolamine
Prototypes: Atropine & scopolamine
  • The actions of these drugs upon peripheral tissue/organ activity are similar to that which would occur following reduction of activity in postganglionic, parasympathetic and postganglionic cholinergic sympathetic nerves.
  • Both drugs also block CNS muscarinic receptors
quaternary vs non quaternary antimuscarinics
Quaternary vs Non-quaternary antimuscarinics
  • Absorption. Quaternary compounds are less well absorbed and lack CNS actions
  • Nicotinic actions. Quaternary compounds can block nicotinic receptors and may have ganglion or neuromuscular blocking action
cardiovascular system effects
Cardiovascular system effects
  • Heart: low dose bradycardia high dose tachycardia
  • Vascular
    • no (direct) effect
    • block hypotensive effect of muscarinic agonists
extravascular smooth muscle
Extravascular smooth muscle
  • Eye:
    • mydriasis (dilation of iris sphincter)
    • cycloplegia (relaxation of ciliary muscle)
  • Bronchial: dilation
  • GIT: decreased tone, motility (antispasmodic effect)
  • Urinary: relaxation of detrusor, ureter; constriction of sphincter
  • Glands decrease in all secretions
central nervous system
Central nervous system
  • Action at respiratory center
    • therapeutic dose: faster deeper breathing
    • larger doses: depression of respiration
  • Cerebral centers:
    • low doses: sedation
    • high doses: restlessness, amnesia, delirium
    • higher doses: stupor; coma
  • Note: with therapeutic doses, atropine generally has less CNS sedative effects
tissue organ specificity of antimuscarinics
Tissue organ specificity of antimuscarinics

Order of appearance of physiological effects with increasing dosage:

  •  Salivary, bronchial, sweat secretions
  •  Micturition
  • Tachycardia, mydriasis, cycloplegia
  •  Intestinal motility
  •  Gastric secretion
therapeutic uses of antimuscarinics
Therapeutic uses of antimuscarinics
  • Respiratory disorders:
    • Ipratropium (Atrovent). Inhalational drug to reverse bronchial constriction and secretion
    • Asthma, emphysema, chronic bronchitis (COPD).
therapeutic uses of antimuscarinics86
Therapeutic uses of antimuscarinics
  • Ophthalmology
    • production of mydriasis and cycloplegia of long or short duration
    • routine examination: short duration; minimal cycloplegia.
    • many appear in combinations with alpha adrenergic drugs
therapeutic uses of antimuscarinics88
Therapeutic uses of antimuscarinics
  • Gastroenterology: Peptic ulcer treatment.
    • Can reduce basal and nocturnal acid secretion (other drugs are better, e.g., H2 antagonists)
    • Inhibit gastrointestinal motility
    • Reduce pain and prolong actions of antacids
    • Drugs:

atropine, dicyclomine, propantheline

therapeutic uses of antimuscarinics89
Therapeutic uses of antimuscarinics
  • Gastroenterology: Irritable bowel syndrome
    • Reduce motility for reduction of pain, constipation, or diarrhea
    • Drugs:atropine, dicyclomine, propantheline
therapeutic uses of antimuscarinics90
Therapeutic uses of antimuscarinics
  • Urologic disorders
    • Increase bladder capacity
    • Decrease bladder pressure
    • Drugs: dicyclomine, oxybutynin
therapeutic uses of antimuscarinics91
Therapeutic uses of antimuscarinics
  • Motion sickness
    • Scopolamine is useful in preventive treatment via CNS action in vestibular nuclei and reticular formation
  • Muscarine poisoning
    • poisoning with muscarinic mushrooms (Inocybe) or cholinesterase inhibitors
    • Drugs: Belladonna alkaloids or synthetics (propantheline)
sources of belladonna poisoning
Sources of Belladonna Poisoning:
  • Nonprescription drugs
  • Plants of the Solanaceae family
  • Antiparkinsonian drugs
classic symptoms of belladonna poisoning
Classic symptoms of belladonna poisoning:
  • Hot as a hare
  • Dry as a bone
  • Red as a beet
  • Blind as a bat
  • Mad as a hatter
  • Bloated as a toad
contraindications for antimuscarinics
Contraindications for Antimuscarinics
  • Glaucoma
  • Prostatic hypertrophy
  • Toxicity more severe in children
toxicity
Toxicity

Xerostoma constipationUrinary retention hyperthermiaMydriasis headacheBlurred vision DizzinessFlushing, dry skin ExcitementHeart palpitation Mental confusion, memory loss, hallucinations

drugs with anticholinergic side effects
Drugs with anticholinergic side-effects
  • Antihistamines
  • Monoamine oxidase inhibitors
  • Antipsychotics
  • Lithium
  • Tricyclic Antidepressants
  • Antiparkinsonian drugs