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3 Lecture Outline Homeostasis Divisions of the ANS Cellular Organization of the ANS Pathways of the ANS Pharmacology of Autonomic Function Clinical.

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Presentation on theme: "3 Lecture Outline Homeostasis Divisions of the ANS Cellular Organization of the ANS Pathways of the ANS Pharmacology of Autonomic Function Clinical."— Presentation transcript:

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3 3 Lecture Outline Homeostasis Divisions of the ANS Cellular Organization of the ANS Pathways of the ANS Pharmacology of Autonomic Function Clinical Correlations

4 Role of the Autonomic Division in Homeostasis

5 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

6 6 Negative Feedback Control System Controlled variable Effector Sensor Comparator Set point + -

7 7 Sympathetic and Parasympathetic Divisions Enteric division: largely self-contained control of the GI system recognize that most organs innervated receive motor information from both divisions of the autonomic (visceral) motor system. Although the enteric division of the autonomic nervous system contains both afferents and efferents, it does not work completely independently, but can be modulated by efferent fibers of the sympathetic and parasympathetic divisions of the autonomic nervous system.

8 8 Somatic efferents Sympathetic efferents Parasympathetic efferents ACh NA nAChR mAChR nAChR AR CNS PNS Cellular Organization

9 9 First Order Neurons ACh CNS PNS Cell bodies in CNS Axons in PNS Myelinated Cholinergic

10 10 Cellular Organization Second Order Neurons of ANS Divisions ACh NA nAChR Cell bodies in ganglia Nicotinic ACh receptors Axons in PNS Unmyelinated CNS PNS Sympathetic: adrenergic Parasympathetic: cholinergic

11 11 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

12 12 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

13 13 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

14 14 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

15 Table below gives you an overview of the CNS origin, the paravertebral or prevertebral ganglia involved, and the targets of sympathetic efferents:

16 16 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

17 17 Distinct Parasympathetic Ganglia Ciliary ganglion Pterygopalatine ganglion Otic ganglion Submandibular ganglion Picture: copyrighted material, with permission

18 18 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

19 19 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

20 CNS origin, either distinct parasympathetic ganglia or terminal ganglia, and their target organs are presented in the table below:

21 21 Overview (*) Sympathetic innervation of sweat glands: cholinergic (!) postganglionic fibers and muscarinic (!) acetylcholine receptors

22 22 Responses of Effector Organs to Autonomic Nerve Impulses Autonomic Control of the Pupil Adrenergic Impulses Cholinergic Impulses Responses Effector Organs Rec. type Contraction (mydriasis) Dilator muscle of pupil α1α1 Contraction (miosis) Constrictor muscle of pupil M

23 23 Responses of Effector Organs to Autonomic Nerve Impulses Autonomic Control of Accommodation Adrenergic Impulses Cholinergic Impulses Responses Effector Organs Rec. type Contraction (near vision) Ciliary muscle

24 24 Responses of Effector Organs to Autonomic Nerve Impulses Autonomic Control of Cardiac Function Adrenergic Impulses Cholinergic Impulses Responses Effector Organs Rec. type Increase in heart rate Decrease in heart rate SA Node β1β2β1β2 Increase in contractility Decrease in contractility Atria, Ventricles β1β2β1β2

25 25 Responses of Effector Organs to Autonomic Nerve Impulses Autonomic Control of the Airways Adrenergic Impulses Cholinergic Impulses Responses Effector Organs Rec. type RelaxationContraction Tracheal and bronchial muscles β2β2

26 26 Responses of Effector Organs to Autonomic Nerve Impulses Autonomic Control of the Urinary Bladder Adrenergic Impulses Cholinergic Impulses Responses Effector Organs Rec. type Relaxation Contraction Detrusor muscleβ2β2 Contraction Relaxation Trigone and sphincter muscle α1α1

27 27 Pharmacological Influence on Autonomic Function

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29 Parasympathetic Neurotransmitters Pre-ganglionic –Acetylcholine (nicotinic) –Enkephalin, Substance P, GnRH – Post-ganglionic –Acetylcholine (muscarinic) –VIP –

30 Sympathetic Neurotransmitters Preganglionic –Acetylcholine (nicotinic) –Enkephalin, Substance P, GnRH – Postganglionic –Norepinephrine {alpha (  ), beta (  )} –Neuropeptide Y, ATP –

31 Cholinergic Pharmacology NOTE: Also Muscarinic receptors in CNS

32 Cholinergic Pharmacology

33 Nicotinic Receptors Located in CNS Autonomic Ganglia and NMJ CNS and Ganglionic receptors (Nn) distinct from NMJ Nicotinic receptors (Nm). Consists of 5 subunits: Combination of (2   ). Ach binds to the two  subunits Requires 2 Ach molecules for channel opening Ach binding / dissociation kinetics are rapid + action of Ach Esterase makes effects of Ach at Nicotinic receptor brief (10ms). Fast EPSP. Shows ‘desensitization’ to high levels / prolonged activation of Ach binding site.

34 K+K+ Na+ More Na + entry Than K + leaving Causes depolarisation Nicotinic Receptor: Ion channel selective for Na+ & K+ Na+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+ K+K+

35 Muscarinic Receptors G-Protein coupled Receptors Muscarinic Receptors M1 / M5M3M2 / M4 ↑IP3 / DAG ↓cAMP ↑IP3 / DAG ↑K+ channel open. ↑ Ca2+ ↑PKC ↑ Ca2+ ↑PKC

36 M1M2M3M4M5 Muscarinic Receptors CNS. Autonomic Ganglia. Parietal Cell CNS. Smooth Muscle contraction. GI Glands Secr n Bronchial Secr n Sweat Vasodilation*. Cardiac; SA & AV node. Autonomic Ganglia. Physiological effects of Muscarinic Receptor activation

37 * Parasympathetic Vasodilation: Endothelium Derived Relaxing Factor; NO ACh activates Muscarinic (M3) rec. to initiate NO production via eNOS. NO freely diffusable and produces smooth muscle relaxation / vasodilation.

38 Muscarinic Receptor Agonists Which clinical conditions would they benefit? Eye: Muscarinic agonists Contract circular muscle MiosisOutflow 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

39 Muscarinic Receptor Agonists 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

40 Bethanechol:Selective for Muscarinic receptors Uses:to ↑ GIT and urinary tract motility Pilocarpine: Usestopically as a miotic in glaucoma as a sialogogue to ↑ saliva secretion

41 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)

42 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

43 Storage & Release of Acetylcholine Acetyl CoA (from glycolysis) Choline (re-uptake, plasma stores & phosphloipids) Rate limited by Choline re-uptake Vesicular Storage via Ach – H+ antiport Ca 2+ dependent vesicle release ACh interacts with presynaptic and postsynaptic nicotinic & muscarinic receptors AChE = ACh Esterase, rapidly degrades ACh to choline + acetate

44 Drugs Affecting Storage & Release Hemicholinium: Prevents Choline re-uptake Vesamicol: Prevents vesicular storage of ACh no clinical use Botulinum Toxin: degrades synaptobrevin (SNARE) and prevents vesicle fusion / exocytosis Clinically in cases with increased skeletal muscle tone, LES tone, focal dystonia’s. AChE Inhibitors: Elevate synaptic conc n of Ach therefore enhancing the postsynaptic effects of ACh. (parasympathomimetics)

45 Anticholinesterase Drug Types A: Simple alcohols: Short duration of ation; Useful for diagnosing Myasthenia gravis and Eaton Lambert B: Carbamic Acid dervivatives: Longer duration of action; useful for treating MG; reversal of neuromuscular blockers Neostigmine and Physostigmine. C: Organophosphates: Irreversible, toxic, commonly used in flea / tick medications

46 Adrenergic Pharmacology NOTE: Also Adrenergic receptors in CNS

47 11 22 11 22 33 ↑ cAMP ↑ IP3 /DAG ↓ cAMP ↑ I K + ↓ I Ca 2+ ↑ PKA ↑ Ca 2+ ↑ PKC ↑ PKA Adrenergic Receptors

48 RECEPTOR SUBTYPETISSUEEFFECTS α1α1 Vascular smooth muscle Genitourinary smooth muscle Intestinal smooth muscle Heart Liver Contraction Contraction Relaxation ↑ Inotropy and excitability Glycogenolysis and gluconeogenesis α2α2 Pancreatic β-cells Platelets Nerve (pre-synaptic) Vascular smooth muscle ↓ Insulin secretion Aggregation ↓ Norepinephrine release Contraction β1β1 Heart Heart Renal juxtaglomerular cells ↑ Chronotropy and inotropy ↑ AV-node conduction velocity ↑ Renin secretion β2β2 Smooth muscle Liver Skeletal muscle Relaxation Glycogenolysis and gluconeogenesis Glycogenolysis and K + uptake Vasculature* β3β3 AdiposeLipolysis Physiological effects of Adrenergic Receptor activation

49 Epinephrine & Norepinephrine Affinities for  and  adrenoceptors Epinephrine;- higher affinity for  adrenoceptors has a predominant ‘  ’ effect. At higher concentrations it has an effect on  1 adrenoceptors. At high doses effective at treating anaphylaxis and used for vasoconstriction in cojunction with local anaesthetic. Norepinephrine: Has affinity for  1 and  1 adrenoceptors. Little affinity for  2 adrenoceptors.

50  Adrenergic receptor agonists & antagonists: Clinical Uses Major physiological response following  1 receptor activation is increased peripheral resistance & genitourinary smooth muscle contraction.  1 Agonists Methoxamine: Limited use except for hypotension from circulatory shock. Side effects: Reflex vagal sinus bradycardia Phenylephrine: Used as nasal decongestant. Side efffects: Hypertension  1 Antagonists Prazosin: Used for treatment of hypertension and Benign Prostatic Hypertrophy Side effects: Postural orthostatic/ hypotension related to 1 st dose phenomena. Tamsulosin: Used for Benign Prostatic Hypertension. More selective for genitourinary smooth muscle receptor subtype (  1A). Less postural / orthostatic hypotension

51 Major physiological response following  2 rec. activation is reduced NE release  Adrenergic receptor agonists & antagonists: Clinical Uses  2 Agonists Clonidine: Used for treatment of hypertension (decreased peripheral sympathetic outflow) and opioid withdrawal. Side Effects: Bradycardia & hypotension.  2 Antagonists Yohimbine: Previously used for male impotence. Side Effects: bradycardia and hypertension

52 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  Adrenergic Receptor Agonists: Clinical Uses Non selective  receptor agonists: Isoproterenol: Emergency arrhythmias & bronchospasm. More selective agonists now available. Side effects: Hypertension, palpitations, tremor

53 Selective  1 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  2 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 (  1) and skeletal (  2) side effects.

54 β-Adrenergic Antagonists: Clinical Uses Propranolol: Clinically used for Hypertension, angina. Side effects include sedation (central effect) and dyspnea. 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  1 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  2 receptors is clinically undesirable. Non-selctive  adrenoceptor antagonists

55 β1-Selective Adrenergic Antagonists: Clinical Uses EsmololClinically used in emergency  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  1 Agonists: Clinical Uses* As a partial agonist they are effective at reducing the effect of endogenous NE at  1 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

56 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

57 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

58 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


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