Transcript Slide 1

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
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+ hormones
a) tissue specificity based on chemical structure of hormone &
receptor expression
b) plasma t ½ 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
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 processes
stimulates urination
protects 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
↑ heart (β1): Epi=NE=Iso
↓ sk mus arteriole (β2): Epi=Iso>>NE
↑ vasoconstriction (α1): Epi~NE>>>Iso
Note:
- equal direct effects of NE, Epi & Iso on
heart
-recognize that pulse rate for
NE would = Epi & Iso
in presence of atropine
NE for α1 & β1
Iso for β1 & β2
-agonists & therapy of
asthma
(rationale for selective agonists)
Side Effects
heart
blood pressure
(direct/reflex)
(heart/resistance)
Epi (1 & 1 & 2))
Isoproterenol (1 & 2))
Terbutaline (2)
* tolerance develops
glycogenolysis
tremor*
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
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
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 predisposed
urinary 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
antagonism
response
(@ receptor)
control
phentolamine
(non-selective)
prazosin
(selective)
(contraction)
-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 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 - $$$
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
Endogenous cholinergic transmitter at all sites
Cholinergic antagonist at ganglia
Cholinergic agonist for ganglia & skeletal muscle
nicotinic receptor pharmacology
Cholinergic antagonist at skeletal muscle)
focus: muscarinic
receptor
pharmacology
Cholinergic agonist at post-ganglionic sites other than
skeletal muscle)
Selective muscaranic antagonist
Understanding the effects of atropine (muscaranic antaginist)
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)
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 atropine
4) mechanism of vasodilation
5) 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: 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
bethanecol
stimulate micturition (give s.c.)
potentially lethal side effect- hypotension
(atropine!!)
pilocarpine
glaucoma (intra-ocular)
Test Review
I
endogenous regulation
including CVS reflexes
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:
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