autonomic nervous system anatomical division: sympathetic (spinal cord: thoraco-lumbar)...
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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
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)
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
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
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 - $$$
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
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
Therapeutic uses of muscarinic antagonists
GI ulcersopthalmologyexcessive respiratory secretions
(anesthesia) excessive bradycardia
(acute MI)Parkinson’s diseasemotion sickness**bladder instability
(enuresis; urge incontinence)
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
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)
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
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