3 Lecture Outline Homeostasis Divisions of the ANS Cellular Organization of the ANS Pathways of the...
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Transcript of 3 Lecture Outline Homeostasis Divisions of the ANS Cellular Organization of the ANS Pathways of the...
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Lecture Outline
• Homeostasis
• Divisions of the ANS
• Cellular Organization of the ANS
• Pathways of the ANS
• Pharmacology of Autonomic Function
• Clinical Correlations
Autonomic Nervous System (ANS)• Involuntary or visceral nervous system• Regulates the activity of:
– Cardiac Muscle (Heart)– Smooth Muscle ( In Hollow Organs)
• Blood Vessels• Digestive System• Bronchioles• Sphincters
– Glands• Adrenal• Digestive glands
Negative Feedback Control System
Controlled variable
Effector Sensor
Comparator Set point
+
-
Sensory Input
Autonomic Control Centers
Autonomic Outflow-Sympathetic and Parasympathetic Divisions dual innervation of viscera-
• Somatic efferents • • • • Sympathetic efferents • • • • Parasympathetic efferents
ACh
ACh
ACh ACh
NA
nAChR
mAChR(M1-5)
nAChR
nAChR
Alpha/beta R
CNS PNS
Cellular Organization
Cellular Organization • First Order Neurons
ACh
ACh
ACh
CNS PNS
• Cell bodies in CNS • Axons in PNS • Myelinated • Cholinergic
Cellular Organization • Second Order Neurons of ANS Divisions
ACh
NA
nAChR
nAChR
• Cell bodies in ganglia • Nicotinic ACh receptors • Axons in PNS • Unmyelinated
CNS PNS
• Sympathetic: adrenergic • Parasympathetic: cholinergic
Cellular Organization • Target Cells and Receptors
• Somatic efferents: Striated muscle • Nicotinic ACh receptors
• Autonomic efferents: • Smooth muscle • Cardiac muscle • Glands
• Receptors: • Sympathetic innervation:
Adrenergic receptors • Parasympathetic innervation:
Muscarinic ACh receptors
Sympathetic Pathways
Eye Salivary glands
Bronchial tree
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Cervical Thoracic
Lumbar
Sacral
Prevertebral ganglia
Paravertebral ganglia
Sympathetic Pathways
Eye Salivary glands
Bronchial tree
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Cervical Thoracic
Lumbar
Sacral
Sympathetic Pathways
Prevertebral ganglia
Paravertebral ganglia
Eye Salivary glands
Bronchial tree
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Cervical Thoracic
Lumbar
Sacral
Sympathetic Pathways
Prevertebral ganglia
Paravertebral ganglia
Table below gives you an overview of the CNS origin, the paravertebral orprevertebral ganglia involved, and the targets of sympathetic efferents:
a1 a2 b1 b2 b3
↑cAMP ↑cAMP ↑cAMP↑IP3 /DAG ↓ cAMP
↑ I K+
↓ I Ca2+ ↑ PKA ↑ PKA ↑Ca2+
↑ PKC ↑ PKA
Adrenergic Receptors
ISO>A>NA NA>AResponsiveness-NA>A>ISO
* ISO - isoproterenol
RECEPTOR SUBTYPE TISSUE EFFECTS
α1 Vascular smooth muscle
Genitourinary smooth muscleIntestinal smooth muscleHeartLiver
Contraction
ContractionRelaxation↑ Inotropy and excitabilityGlycogenolysis and gluconeogenesis
α2 Pancreatic β-cellsPlateletsNerve (pre-synaptic) Vascular smooth muscle
↓ Insulin secretionAggregation↓ Norepinephrine releaseContraction
β1 HeartHeartRenal juxtaglomerular cells
↑ Chronotropy and inotropy↑ AV-node conduction velocity↑ Renin secretion
β2 Smooth muscleLiver
Skeletal muscle
RelaxationGlycogenolysis and gluconeogenesisGlycogenolysis and K+ uptake Vasculature*
β3 Adipose Lipolysis
Physiological effects of Adrenergic Receptor activation
The overall effect of the catecholamines is to increase glucose production
Eye Salivary glands
Bronchial tree
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Cervical Thoracic
Lumbar
Sacral
CN III CN VII CN IX CN X
Distinct parasympathetic ganglia
Terminal parasympathetic ganglia embedded in organ walls
Parasympathetic Pathways
Distinct Parasympathetic Ganglia
Ciliary ganglion
Pterygopalatine ganglion
Otic ganglion
Submandibular ganglion
Pic
ture
: co
pyr
igh
ted
ma
teria
l, w
ith p
erm
issi
on
Eye Salivary glands
Bronchial tree
Heart Liver GI tract Adrenal medulla
Urinary bladder
Sex organs
Cervical Thoracic
Lumbar
Sacral
CN III CN VII CN IX CN X
Distinct parasympathetic ganglia
Terminal parasympathetic ganglia embedded in organ walls
Parasympathetic Pathways
Eye Salivary glands
Bronchial tree
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Cervical Thoracic
Lumbar
Sacral
CN III CN VII CN IX CN X
Distinct parasympathetic ganglia
Terminal parasympathetic ganglia embedded in organ walls
Parasympathetic Pathways
CNS origin, either distinct parasympathetic ganglia or terminal ganglia, and their target organs are presented in the table below:
The nerve fibers that innervate the adrenal medulla are best described as•Adrenergic sympathetic•Cholinergic sympathetic•Adrenergic parasympatheticCholinergic parasympathetic
Which of the following is caused by activity in the sympathetic system?•Decreased heart rate•Cutaneous vasoconstriction•Increased gastric secretion•Constriction of the pupil•Erection of the penis
Sweat glands are innervated by•Parasympathetic cholinergic postganglionic fibers•Sympathetic cholinergic postganglionic fibers•Sympathetic adrenergic postganglionic fibers•Parasympathetic cholinergic preganglionic fibersSympathetic cholinergic preganglionic fibers
The high ratio of postganglionic to preganglionic fibers in the sympathetic system has the physiologic result that•Convergence of stimuli occurs•Synaptic transmission is slow, leading to a delay in response•Stimulation of the sympathetic nervous system leads to widespread effects•Stimulation of the sympathetic nervous system leads to very localized, discrete effects•Sympathetic effects are very weak
You administer a muscarinic blocker to your patient. This drug is most effective at blocking•The somatic neuromuscular junction•The parasympathetic ganglia•The sympathetic ganglia•The parasympathetic neuroeffector junctionThe sympathetic neuroeffector junction
M1 M2 M3 M4 M5
Muscarinic Receptors
CNS. Autonomic Ganglia. Parietal Cell
CNS.CNS.
Smooth Muscle contraction. GI Glands Secrn
Bronchial Secrn
Sweat Vasodilation*.
Cardiac; SA & AV node.
Autonomic Ganglia.
Physiological effects of Muscarinic Receptor activation
Overview
Sympathetic
Parasympathetic
CNS origin thoraco-lumbar cranio-sacral Preganglionic fiber short
myelinated cholinergic
long myelinated cholinergic
Receptor on postganglionic
nicotinic
nicotinic
Postganglionic fiber long unmyelinated noradrenergic (*)
short unmyelinated cholinergic
Divergence high low Receptor on target adrenergic (*)
muscarinic
(*) Sympathetic innervation of sweat glands: cholinergic (!) postganglionic fibers and muscarinic (!) acetylcholine receptors
Responses of Effector Organsto Autonomic Nerve Impulses
• Autonomic Control of the Pupil
Adrenergic Impulses
Cholinergic Impulses
Responses Responses Effector Organs Rec. type
Contraction (mydriasis)
Dilator muscle of pupil
α1
Contraction (miosis)
Constrictor muscle of pupil
M
Horner’s SyndromeUnilateral miosis (small pupil), commonly associated with ptosis (drooping of the upper eyelid) and facial anhydrosis (loss of sweating).Horner's syndrome is due to underactivity of the ipsilateral sympathetic outflow, which can be caused by (1) central lesions that involve the hypothalamospinalpathway (transection of the cervical spinal cord), (2) preganglionic lesions(compression of the sympathetic chain by a lung tumor), (3) postganglionic lesions at the level of the internal carotid artery (tumor in the cavernous sinus).
35
Responses of Effector Organsto Autonomic Nerve Impulses
• Autonomic Control of Accommodation
Adrenergic Impulses
Cholinergic Impulses
Responses Responses Effector Organs Rec. type
Relaxation (β2) Contraction (near vision)
Ciliary muscle
36
Responses of Effector Organsto Autonomic Nerve Impulses
• Autonomic Control of Cardiac Function
Adrenergic Impulses
Cholinergic Impulses
Responses Responses Effector Organs Rec. type
Increase in heart rate
Decrease in heart rate(M2)
SA Node β1
β2
Increase in contractility
Decrease in Contractility(M2)
Atria, Ventricles β1
β2
37
Responses of Effector Organsto Autonomic Nerve Impulses
• Autonomic Control of the Airways
Adrenergic Impulses
Cholinergic Impulses
Responses Responses Effector Organs Rec. type
Relaxation Contraction Tracheal and bronchial muscles
β2
38
Responses of Effector Organsto Autonomic Nerve Impulses
• Autonomic Control of the Urinary Bladder
Adrenergic Impulses
Cholinergic Impulses
Responses Responses Effector Organs Rec. type
Relaxation
Contraction
Detrusor muscle β2
Contraction
Relaxation
Trigone and sphincter muscle
α1
Autonomic Control of Reproductive Organs
41
Pharmacological Influence on Autonomic Function
Drug Receptor Function Medical use
Atenolol
1 adrenergic Antagonist Hypertension
Salbutamol 2 adrenergic Agonist Asthma (bronchodilator)
Atropine muscarinic Antagonist Mydriatic; Reduction of drooling in Parkinson’s disease
M1 M2 M3 M4 M5
Muscarinic Receptors
CNS. Autonomic Ganglia. Parietal Cell
CNS.CNS.
Smooth Muscle contraction. GI Glands Secrn
Bronchial Secrn
Sweat Vasodilation*.
Cardiac; SA & AV node.
Autonomic Ganglia.
Physiological effects of Muscarinic Receptor activation
A middle aged woman was carried to the district hospital in Murewa in a semiconscious state. Her husband reported that when he returned home from work he had found his 45 year old wife, Sibongile lying on the bed moaning,unable to move and barely conscious. On the bed there was vomitus and a wet patch. He said that when he had left in the morning she had been well but he had noticed that since the day before she seemed to have been upset aboutsomething and had barely talked to him; but he couldn’t think of a reason why. Asked if his wife took any medications, he said no. But then his neighbour who had accompanied him said that he had noticed there was a “Ketokil” tin in the bedroom and there was an empty cup near it. He explained that Ketokil was the stuff they used to kill weeds.On examination, the physician noted that the patient had labored respiration (8 breaths per minute) and that she seemed to be drooling. Her pulse rate was 45 bpm. Auscultation of the thorax revealed rhonchi and auscultation of the abdomen showed increased abdominal sounds. Meanwhile the hospital pharmacist reported that the active ingredient of Ketokil was parathion.1. What symptoms do you expect following intoxication with organophosphates?
2. How do you explain these symptoms from a biochemical-physiological view point?
3. What kind of therapeutic intervention do you suggest? Justify your ideas.
•Parasympathetic Vasodilation: •Endothelium Derived Relaxing Factor; NO(nitric oxide)
ACh activates Muscarinic (M3) rec. to initiate NO production via eNOS. NO freely diffusable and produces smooth muscle relaxation / vasodilation.
Muscarinic Receptor Agonists
Which clinical conditions would they benefit?
Eye:
Muscarinic agonists
Contract circular muscle
Miosis Outflow of aqueous humor
↓ intraocular pressureBenefits glaucoma
GIT Bladder, urinary tract
Contract smooth muscle
↑ Motility
Restore GIT and UT motility after anesthesia/surgery
Salivary glands
↑ Salivation Benefits xerostomia
Muscarinic Receptor Agonists - Parasympathomimetics
Methacholine Carbachol Bethanechol Pilocarpine
Derivatives of ACh
Acetylcholine is NOT used clinically – very short t1/2
Differ in pharmacokinetic properties, resistance to ChEsterase and their affinity to both Nm and Muscarinic rec.
Methacholine: used in diagnosis of asthma
Carbachol: affinity for Nm rec resistant to ChE used topically – as a miotic agent to treat glaucoma
Asthmatics are more sensitive to the bronchial secreting actions of methacholine
Bethanechol: Selective for Muscarinic receptors
Uses: to ↑ GIT and urinary tract motility
Pilocarpine:Uses topically as a miotic in glaucoma
as a sialogogue to ↑ saliva secretion
Muscarinic Receptor Antagonists “Parasympatholytics”
Mode of Action
Bind to muscarinic receptors and prevent Ach from exerting its effects Competitive antagonists
Prototype: ATROPINE (Plant alkaloid from Atropa belladonna)
Actions: Pupil dilation Tachycardia ↓ secretions (salivary, bronchial, GIT)
Clinical Uses of Atropine:
1. To produce mydriasis for ophthalmological examination (applied topically) 2. To reverse sinus bradycardia caused by excessive vagal tone 3. To inhibit excessive salivation and mucus secretion during anesthesia and surgery 4. To counteract the effects of muscarine poisoning AND poisoning with anticholinesterases
RECEPTOR SUBTYPE TISSUE EFFECTS
α1 Vascular smooth muscle
Genitourinary smooth muscleIntestinal smooth muscleHeartLiver
Contraction
ContractionRelaxation↑ Inotropy and excitabilityGlycogenolysis and gluconeogenesis
α2 Pancreatic β-cellsPlateletsNerve (pre-synaptic) Vascular smooth muscle
↓ Insulin secretionAggregation↓ Norepinephrine releaseContraction
β1 HeartHeartRenal juxtaglomerular cells
↑ Chronotropy and inotropy↑ AV-node conduction velocity↑ Renin secretion
β2 Smooth muscleLiver
Skeletal muscle
RelaxationGlycogenolysis and gluconeogenesisGlycogenolysis and K+ uptake Vasculature*
β3 Adipose Lipolysis
Physiological effects of Adrenergic Receptor activation
Epinephrine & Norepinephrine Affinities for a and b adrenoceptors
Epinephrine;-higher affinity for b adrenoceptors has a predominant ‘b’ effect. At higher concentrations it has an effect on a1 adrenoceptors. At high doses effective at treating anaphylaxis and used for vasoconstriction in cojunction with local anaesthetic.
Norepinephrine: Has affinity for a1 and b1 adrenoceptors. Little affinity for b2 adrenoceptors.
1a Adrenergic receptor agonists & antagonists: Clinical Uses
Major physiological response following a1 receptor activation is increased peripheral resistance & genitourinary smooth muscle contraction.
a1 Agonists Methoxamine: Limited use except for hypotension from circulatory shock. Side effects: Reflex vagal sinus bradycardia Phenylephrine: Used as nasal decongestant. Side efffects: Hypertension
a1 Antagonists
Prazosin: Used for treatment of hypertension and Benign Prostatic Hypertrophy Side effects: Postural orthostatic/ hypotension related to 1st dose phenomena. Tamsulosin: Used for Benign Prostatic Hypertension. More selective for genitourinary smooth muscle receptor subtype (a1A). Less postural / orthostatic hypotension
Major physiological response following a2 rec. activation is reduced NE release
2a Adrenergic receptor agonists & antagonists: Clinical Uses
a2 Agonists
Clonidine: Used for treatment of hypertension (decreased peripheral sympathetic outflow) and opioid withdrawal. Side Effects: Bradycardia & hypotension.
a2 Antagonists
Yohimbine: Previously used for male impotence. Side Effects: bradycardia and hypertension
Stimulation of β1-adrenergic receptors causes an increase in heart rate and the force of contraction, resulting in increased cardiac output. Stimulation of β2-adrenergic receptors causes relaxation of vascular, bronchial, and gastrointestinal smooth muscle.
Non Selective b Adrenergic Receptor Agonists: Clinical Uses
Non selective b receptor agonists: Isoproterenol: Emergency arrhythmias & bronchospasm. More selective agonists now available. Side effects: Hypertension, palpitations, tremor
Selective b1 receptor agonists: Dobutamine: Has prominent inotropic effects resulting in increased contractility and cardiac output. Short half life due to COMT metabolism. Used in the ACUTE management of heart failure.
Selective b2 receptor agonists
Albuterol: Used as ‘asthma reliever’. Rapid action (15 min) relative short duration (4-6 hours). Salmeterol: Long-acting beta agonists (LABA’s). Have lipophilic side chains that resist degradation. Enhance duration (12-24-hours), used for prevention of bronchoconstriction.
Used for treatment of Asthma. Pulmonary drug delivery enhances selectivity of β2-adrenoceptors agonists, avoids cardiac (b1) and skeletal (b2) side effects.
β-Adrenergic Antagonists: Clinical Uses
Propranolol: Clinically used for Hypertension, angina. Side effects include sedation (central effect) and dyspnoea. Timolol: As an ocular formulation used in the treatment of glaucoma. MOA unknown but thought to be through reduced production of aqueous humor.
Most significant effect these compounds have to reduce the chronotropic and inotropic actions of endogenous catecholamines at cardiac β1-receptors, resulting in decreased heart rate and myocardial contractility. Blockade of b1 receptors in kidney to reduce renin secretion also clinically relevant in reducing fluid overload and vasomotor tone. Are first line drugs used in treatment of hypertension. Blockade of b2 receptors is clinically undesirable.
Non-selctive b adrenoceptor antagonists
β1-Selective Adrenergic Antagonists: Clinical Uses
Esmolol Clinically used in emergency b receptor blockade as in a thyroid storm (Half-life ~ 4 minutes). Atenolol: Clinically used in treatment of hypertension and angina, improves life expectancy in patients with HF#.
Side Effects: Similar to Propanolol but much less severe.
Partial b1 Agonists: Clinical Uses*
As a partial agonist they are effective at reducing the effect of endogenous NE at b1 receptors. This leads to smaller decreases in resting heart rate & blood pressure (compared to b1 receptor antagonists). Acebutolol Clinically used for treatment of hypertension in patients with bradycardia or low cardiac reserve.
* Partial agonists are effectively weak ‘antagonists’
# Clinical benefit in HF through volume reduction (↓afterload) via ↓ renin production. Contraindicated in severe HF
Catecholamine Metabolism: MAO & COMT
Mono Amine Oxidase (MAO): Mitochondrial enzyme. Isoforms; MAO A & MAO B MAO A: Serotonin > NE > Dopamine & tyramine MAO B: Dopamine > serotonin>NE Catechol-O-methyl transferase (COMT): Cytosolic enzyme expressed primarily in liver
Inhibitors of Re-Uptake: Cocaine: Inhibits NET. Tricyclic Antidepressants (TCA’s) inhibit NET. Imipramine: Used for treating mild depression. Side effects Postural hypotension & tachycardia Inhibitors of Storage: Reserpine blocks VMAT Tyramine transported via VMAT & displaces
vesicular NE.
Inhibitors of Metabolism: MAO Inhibitors used for treatment of mild depression. Phenelzine: Non selective MAO Inhibitor. Implicated in elevated tyramine leading to hypertensive crisis Selegiline: Selective MAO B Inhibitor. Safer with respect to dietary restriction also useful for Parkinson’s
Drugs Affecting Storage Reuptake & Storage
Inhibitors of Re-uptake and Storage Amphetamines (i) Displaces endogenous
catecholamines from storage vesicles
(ii) blocks NET (iii) a weak inhibitor of MAO Methylphenidate: Used for ADHD Pseudoephidrine: Used for nasal
decongestion