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Autonomic Nervous System. Anatomical Division: Sympathetic (spinal cord: thoraco-lumbar) Parasympathetic (spinal cord: cranio-sacral) Functional Classification: Adrenergic Neurons ganglia - acetylcholine post-ganglionic neurotransmitter - norepinephrine Cholinergic Neurons

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autonomic nervous system
Autonomic Nervous System

Anatomical Division:

Sympathetic (spinal cord: thoraco-lumbar)

Parasympathetic (spinal cord: cranio-sacral)

Functional Classification:

Adrenergic Neurons

ganglia - acetylcholine

post-ganglionic neurotransmitter - norepinephrine

Cholinergic Neurons

ganglia - acetylcholine

post-ganglionic neurotransmitter – acetylcholine

Nitrergic Neurons

post-ganglionic neurotransmitter – NO

fundamentals of integrated systems outline for adrenergic cholinergic pharmacology
Fundamentals of Integrated Systems Outline for adrenergic & cholinergic pharmacology

Overview:

- anatomy of autonomic nervous system & transmitters

- functional significance of sympathetic vs. parasympathetic

- adrenergic vs. cholinergic synapse

Adrenergic receptors:

- subtypes (pharmacological evidence)

- pharmacological effects of agonists & antagonists*

Cholinergic receptors:

- subtypes (pharmacological evidence)

- effects of atropine*

Nitrergic neurons, vasodilation, diabetes & Viagra®*

Journal Club; Furchott & Zawadzki, Nature 288: 373, 1980*

* test questions

key points
key points
  • Significance of reflex
  • Rationale for specific pharmacological agonists & antagonists
      • note: potential for effect of an antagonist only if the susceptible system is activated
          • consider propanolol as an example
significance of the autonomic nervous system
Significance of the Autonomic Nervous System

Involuntary regulation

- respiration

- circulation

- GI

- GU

- temperature

- endocrine & exocrine glands

Note: potential for dominance of voluntary control

slide5

Endocrine vs. Nervous Systems

40+ hormones

a) tissue specificity based on chemical structure of hormone &

receptor expression

b) plasma t½ life reflects rate of hormone elimination

c) feedback based on plasma hormone concentration

d) presence/absence of stimulus or counter regulation

2 primary peripheral neurotransmitters (NE & ACh) – actually about 15 total (ex. NO)

a) tissue specificity due to site-specific release

b) local mechanisms for termination of transmitter action**

-neuronal recapture via active transport (cocaine),

then re-storage or metabolism (MAO inhibitors)

-post-junctional metabolism (cholinesterase inhibitors)

c) feedback based on synaptic transmitter concentration**

c) reflex: feedback based on physiological effect**

d) presence/absence of stimulus or counter regulation***

Drugs affecting the nervous system

- analogous to hormones (no site specific release)

- rationale for development of selective agonists & antagonists for pharmacological therapy

sympathetic nervous system
Sympathetic Nervous System

Stress-induced activation:

physiological responses to norepinephrine & epinephrine

- conserve temperature

- elevate blood glucose & FFA

- redistribute blood to brain

- accelerate heart rate & force of contraction

- dilate skeletal muscle blood vessels

- dilate bronchi & pupils

- CNS activation (purposeful responses)

parasympathetic nervous system
Parasympathetic Nervous System

Regulation in a stress-free environment

Physiological responses to post-ganglionic acetylcholine

Inhibitory- hyperpolarize:

slows heart

Stimulatory- depolarize:

stimulates digestive processes

stimulates urination

protects retina from excessive light

(constriction of pupil)

slide11

note:

dual innervation;

parasympathetic at rest;

sympathetic with stress

sympathetic adrenergic nervous system cardiovascular system
Sympathetic/Adrenergic Nervous System & Cardiovascular System:

agonists & relevant receptors:

NE for α1 (vasculature) & β1 (heart)

Epi for α1 (most vasculature) & β1 (heart) & β2(bronchioles,

skeletal muscle vasculature*, muscle tremor, glycogenolysis)

Isoproterenol for β1 & β2

*skeletal muscle vasculature also expresses α1, but effects of β2 predominate

slide14

↑ heart (β1): Epi=NE=Iso

↓ sk mus arteriole (β2): Epi=Iso>>NE

↑ vasoconstriction (α1): Epi~NE>>>Iso

NE for α1 & β1

Iso for β1 & β2

Note:

- equal direct effects of NE, Epi & Isoon heart

-recognize that pulse rate for

NE would = Epi & Iso

in presence of atropine

agonists therapy of asthma rationale for selective agonists
-agonists & therapy of asthma(rationale for selective agonists)

Side Effects

heart blood pressure glycogenolysis tremor*

(direct/reflex) (heart/resistance)

Epi (1 & 1 & 2))

Isoproterenol (1 & 2))

Terbutaline (2)

* tolerance develops

epinephrine allergic reactions itching swelling difficulty breathing fainting
Epinephrine & Allergic Reactions(itching, swelling, difficulty breathing, fainting)

i) vasoconstriction (1) & cardiac stimulation (1) =↑ CNS perfusion

ii) bronchiolar dilation (2) & reduced bronchiolar

secretions (1) = improved ventilation

iii) reduced histamine release (2) = ↓ itching & vascular permeability (swelling/edema)

note: advantage vs. norepinephrine

propanolol
propanolol

Therapeutic uses:

- hypertension-  cardiac output & renin release

(little effect in normotensive)

- symptomatic panic- heart rate & tremor

Side effects:

- CNS (sedation, insomnia, nightmares)

- decreased exercise tolerance

- contraindication in asthma

i)

ii)

- metabolic consequence in Type 1 diabetes

i)

adrenoceptors
-adrenoceptors

2- adrenoceptor

pre-junctional/pre-synaptic/nerve terminal

1- adrenoceptor:

post-junctional/post-synaptic

1 adrenoceptor agonists
1-adrenoceptor agonists

Phenylephrine

mechanism: selective α1-agonist

use: nasal decongestant

(inhalant)

toxicity:

hypertension in predisposed

urinary retention in BPH

slide22

Selective 1-adrenoceptor antagonist

phentolamine (non-selective  antagonist) vs. prazosin (selective α1):

Understanding the rationale for selective α1:

- neuronal release

- NE effect

- net response

non selective vs selective 1 antagonists
non-selective vs. selective α1-antagonists

NE release post-junctional

antagonism response

(@ receptor) (contraction)

control

phentolamine

(non-selective)

prazosin

(selective)

adrenoceptor antagonists
-adrenoceptor antagonists

phentolamine (non-selective  antagonist)vs. prazosin (selective α1):

significance of selective post-junctional antagonism

i) therapeutic effect (hypertension & BPH)

ii) side effect of selective α1

a) (think perfusion)

b) (think reflex)

c) rationale for bed-time administration

indirectly mixed acting sympathomimetics toxicity predictable unpredictable side effects
Indirectly & Mixed Acting Sympathomimetics & Toxicitypredictable & unpredictable side effects

Amphetamine

orally active

indirect acting

Ephedrine

mixed (indirect +  & )

Cocaine

blocks neuronal uptake of released NE

“Fen-Phen”

fenfluramine-phentermine

(serotonin agonist-amphetamine like analog)

fibrosis of heart valves - $$$

monoamine oxidase inhibitors mechanism of action the cheese effect
monoamine oxidase inhibitors:mechanism of action & the “cheese effect”
  • Mechanism of action
    • Rapid and irreversible inhibition of MAO-A in a few days
    • Increased intra-neuronal NE reduces gradient for neuronal re-uptake of released NE
    • Increased synaptic concentrations of NE
    • However, clinical effect as anti-depressant requires few weeks
    • Due to adaptations in CNS receptors ? (Murphy in Psychopharmacology 1987)
  • Cheese effect
    • Inhibit intestinal MAO-A with oral administration
    • Ingest foods with tyramine (cheese, red wine)
    • tyramine is not inactivated (not deaminated by MAO-A) & absorbed
    • Indirectly acting sympathomimetic
    • Consequence?
peripheral cholinergic ach receptors
Peripheral Cholinergic (Ach) Receptors

Muscarinic receptors: (blocked by atropine)

post-ganglionic sites:

cardiac & smooth muscle &

epithelium of glands

Nicotinic receptors:

autonomic ganglia

(blocked by hexamethonium)

skeletal muscle endplate

(blocked by tobocurarine)

cholinergic receptor sub types
Cholinergic Receptor Sub-types

Muscaranic:

- 5 sub-types

- G-protein coupled to activate phospholipase C

(smooth muscle contraction & glandular secretion)

or inhibit adenylate cyclase (heart)

Nicotinic:

- as many as 11 sub-types

- ligand-activated ion channels increasing sodium &

calcium permeability

slide33

Endogenous cholinergic transmitter at all sites

Cholinergic antagonist at ganglia

Cholinergic agonist for ganglia & skeletal muscle

Cholinergic antagonist at skeletal muscle)

nicotinic receptor pharmacology

slide34

focus: muscarinic

receptor

pharmacology

Cholinergic agonist at post-ganglionic sites other than

skeletal muscle)

Selective muscaranic antagonist

slide37

Therapeutic uses of muscarinic antagonists

GI ulcers

opthalmology

excessive respiratory secretions

(anesthesia)

excessive bradycardia

(acute MI)

Parkinson’s disease

motion sickness

**bladder instability

(enuresis; urge incontinence)

experimental information questions for test
experimental information & questions for test

Atropine:

- no effect on blood pressure at rest

ACh:

- vasodilation

- competition by atropine

why was atropine ineffective when given alone?

response to very high doses of Ach + atropine = ?

slide40
experimental design:i.v. drug administration in anesthetized dog - record mean blood pressureexperimental findings:
test question in vivo experimental demonstration of
Test Question: In Vivo experimental demonstration of:

1) absence of significant cholinergic innervation to the

arterioles (resistance vessels)

2) presence of functional cholinergic (muscarinic) receptors

in resistance blood vessels

3) competitive antagonism by atropine

4) mechanism of vasodilation

5) ACh-induced ganglionic transmission & Epi release

slide42

Experimental analysis of

the effect of Ach ± atropine

on B.P.

mechanism of ach induced vasodilation
Mechanism of ACh-induced vasodilation

- indirect effect via endothelium

- ACh via muscaranic receptor on endothelial cells

- increased endothelial NO synthesis from arginine

- NO-induced smooth muscle relaxation

-  cyclic GMP   protein kinase 

 Ca++ &  Ca++ sensitivity of

cross bridge formation

(Ann Med 35:21,2003 & J Cell Physiol 184:409,2002)

slide45

Rationale for sildenafil (Viagra®) use in erectile dysfunction of diabetes?

neurological?

vascular?

cholinergic neurotransmission release
Cholinergic Neurotransmission:Release

Acetylcholine release

- action potential-induced quantal

release (all or none) of vesicles

- inhibited by botulinum toxin (motor neuron)

(proteolysis of proteins necessary for ACh quantal release)

- inhibited by tetanus toxin (spinal cord neuron)

(retrograde migration through nerve to spinal cord to block

transmitter release from inhibitory neurons- spastic paraylsis

of skeletal muscles “lock jaw”

adrenergic vs cholinergic synapse
adrenergic vs cholinergic synapse

differ qualitatively with respect to termination of

neurotransmitter action

uses toxicity of cholinesterase inhibitors
Uses & Toxicity of Cholinesterase Inhibitors

Uses: Glaucoma

Myasthenia gravis

**Insecticide (low human/bird toxicity due to rapid inactivation)

Chemical warfare compounds

Toxicity: muscarinic (visual, respiratory, S.L.U.D.)

nicotinic (respiratory paralysis)

therapeutic uses of cholinomimetics
Therapeutic uses of cholinomimetics

bethanecol

stimulate micturition (give s.c.)

potentially lethal side effect- hypotension

(atropine!!)

pilocarpine

glaucoma (intra-ocular)

test review
Test Review

endogenous regulation including CVS reflexes

I

bronchioles

heart

skeletal muscle perfusion & tremor

cutaneous & visceral vascular resistance

bladder

detrussor

neck

GI motility

vision

salivary secretion

corpus cavernosum

II

effects of NE, Iso, propanaolol, prazosin, cocaine, amphetamine,

sildenafil, atropine, tyramine/MAO-A inhibition

test review cont d in vivo experimental demonstration of
Test Review cont’d: In Vivo experimental demonstration of:

1) absence of significant cholinergic innervation to the

arterioles (resistance vessels)

2) presence of functional cholinergic (muscarinic) receptors

in resistance blood vessels

3) competitive antagonism by atropine

4) ACh-induced ganglionic transmission

5) Mechanism of Ach-induced vasodilation & experimental

evidence for EDRF