Autonomic Nervous System Anatomical Division: Sympathetic (spinal cord: thoraco-lumbar) Parasympathetic (spinal cord: cranio-sacral) Functional Classification:

Autonomic Nervous SystemAnatomical Division:

Sympathetic (spinal cord: thoraco-lumbar)Parasympathetic (spinal cord: cranio-sacral)

Functional Classification:Adrenergic Neurons

ganglia - acetylcholinepost-ganglionic neurotransmitter - norepinephrine

Cholinergic Neuronsganglia - acetylcholinepost-ganglionic neurotransmitter – acetylcholine

Nitrergic Neurons

post-ganglionic neurotransmitter – NO

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

• 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

Involuntary regulation- respiration- circulation- GI- GU - temperature- endocrine & exocrine glands

Note: potential for dominance of voluntary control

Endocrine vs. Nervous Systems

40+ hormonesa) tissue specificity based on chemical structure of hormone &

receptor expressionb) plasma t ½ life reflects rate of hormone eliminationc) feedback based on plasma hormone concentrationd) 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 releaseb) 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

note: dual innervation

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

Regulation in a stress-free environment

Physiological responses to post-ganglionic acetylcholine

Inhibitory- hyperpolarize:slows heart

Stimulatory- depolarize:stimulates digestive processesstimulates urinationprotects retina from excessive light

(constriction of pupil)

note: dual innervation;parasympathetic at rest;sympathetic with stress

adrenergic vs. cholinergic dominance of major organ systems at rest

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

Note:

- equal direct effects of NE, Epi & Iso on heart

-recognize that pulse rate for NE would = Epi & Iso

in presence of atropine

↑ 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

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

Epi (1 & 1 & 2))

Isoproterenol (1 & 2))

Terbutaline (2)

Side Effects heart blood pressure glycogenolysis tremor*(direct/reflex) (heart/resistance)

* tolerance develops

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

non-selective blocker

propanololTherapeutic 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 diabetesi)

-adrenoceptors

2- adrenoceptor

pre-junctional/pre-synaptic/nerve terminal

1- adrenoceptor:

post-junctional/post-synaptic

Note: pre-junctional α2 & post-junctional α1

1-adrenoceptor agonists

Phenylephrine

mechanism: selective α1-agonist

use: nasal decongestant(inhalant)

toxicity:hypertension in predisposedurinary retention in BPH

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 α1-antagonists

NE release post-junctional

antagonismresponse

(@ receptor) (contraction)

control

phentolamine(non-selective)

prazosin(selective)

-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

Amphetamine orally activeindirect acting

Ephedrinemixed (indirect + & )

Cocaineblocks neuronal uptake of released NE

“Fen-Phen” fenfluramine-phentermine(serotonin agonist-amphetamine like analog)fibrosis of heart valves - $$$

MAO-A inhibitors, anti-depressant effect & “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?

Cholinergic Physiology & Pharmacology

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

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

nicotinic receptor pharmacology

Cholinergic agonist for ganglia & skeletal muscle

Cholinergic antagonist at ganglia

Cholinergic antagonist at skeletal muscle)

Endogenous cholinergic transmitter at all sites

focus: muscarinicreceptorpharmacology

Cholinergic agonist at post-ganglionic sites other thanskeletal muscle)

Selective muscaranic antagonist

Understanding the effects of atropine (muscaranic antaginist)

Therapeutic uses of muscarinic antagonists

GI ulcersopthalmologyexcessive respiratory secretions

(anesthesia) excessive bradycardia

(acute MI)Parkinson’s diseasemotion sickness**bladder instability

(enuresis; urge incontinence)

Common Side Effects of a muscarinic antagonist when used for incontinence

1)

2)

3)

4)

5)

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 = ?

experimental design:i.v. drug administration in anesthetized dog

- record mean blood pressure

experimental findings:

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 atropine4) mechanism of vasodilation5) ACh-induced ganglionic transmission & Epi release

Experimental analysis of

the effect of Ach ± atropine on B.P.

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)

ACh (exogenous)- (evidence against significance of endogenous functional cholinergic innervation; i.e. EFS→CC dilation & lack of atropine effect)) M3 receptors on vascular endothelium PLC IP3 Ca++ release NO in endothelium NO from nitrergic neurons

diffusion to vascular smooth muscle cyclic GMP * GMP smooth muscle relaxation * - phosphodiesterase-5 & site of sildenafil (Viagra®) action in corpus cavernosum - mechanisms for tissue & drug specificity - site specific NO release - isozyme tissue localization - sildenafil isozyme specificity - sildenafil effect only when ↑ c-GMP (in response to sexual stimulation & NO release)

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

neurological?

vascular?

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

differ qualitatively with respect to termination of neurotransmitter action

Uses & Toxicity of Cholinesterase Inhibitors

Uses: GlaucomaMyasthenia 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

bethanecolstimulate micturition (give s.c.)potentially lethal side effect- hypotension

(atropine!!)

pilocarpineglaucoma (intra-ocular)

Test Review

bronchiolesheartskeletal muscle perfusion & tremorcutaneous & visceral vascular resistancebladder

detrussorneck

GI motilityvisionsalivary secretioncorpus cavernosum

endogenous regulation including CVS reflexesI

IIeffects of NE, Iso, propanaolol, prazosin, cocaine, amphetamine,sildenafil, atropine, tyramine/MAO-A inhibition

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 atropine4) ACh-induced ganglionic transmission5) Mechanism of Ach-induced vasodilation & experimental

evidence for EDRF