Introduction to Autonomics - Jose Emilio Abad Santos PDF

Introduction to Autonomics Module 03: Wound Healing and Repair Josef S. Soller, MD-MBA, DPCOM |Asynchronous TABLE OF CONTENTS I. AUTONOMIC DRUGS........................................................................ 1 ○ Presynaptic nerve terminals ● A lot of these drugs will have side effects aff...

Introduction to Autonomics Module 03: Wound Healing and Repair Josef S. Soller, MD-MBA, DPCOM |Asynchronous TABLE OF CONTENTS I. AUTONOMIC DRUGS........................................................................ 1 ○ Presynaptic nerve terminals ● A lot of these drugs will have side effects affecting different organs of the body II. REVIEW OF THE AUTONOMIC NERVOUS SYSTEM (ANS)................... 1 A. ANATOMY OF THE ANS................................................................ 1 B. ANS SYNAPSES............................................................................. 3 III. CHOLINERGIC AND ADRENERGIC TRANSMISSION........................... 4 A. FIVE KEY FEATURES OF NEUROTRANSMITTER FUNCTION........... 4 B. CHOLINERGIC TRANSMISSION..................................................... 4 C. ADRENERGIC TRANSMISSION...................................................... 6 D. COTRANSMITTERS IN CHOLINERGIC AND ADRENERGIC TRANSMISSION................................................................................ 9 E. NONADRENERGIC NONCHOLINERGIC (NANC) NEURONS............ 9 IV. FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY.............. 10 V. PHARMACOLOGIC MODIFICATION OF AUTONOMIC ACTION.......... 10 SUMMARY OF TERMS........................................................................11 QUESTIONS....................................................................................... 11 ANSWER KEY..................................................................................... 12 RATIONALE........................................................................................12 LEARNING OBJECTIVES 1. Discuss the structure and functions of the Autonomic Nervous System 2. Enumerate the process of autonomic transmission and the drugs that affect this process II. REVIEW OF THE AUTONOMIC NERVOUS SYSTEM (ANS) ● Functional divisions of the nervous system: Autonomic Nervous System (ANS) and Somatic Nervous System (SNS) ○ ANS: Control and integration of visceral functions ▸ Cardiac Output ▸ Blood Flow Distribution ▸ Digestion ○ SNS: Conscious control (e.g., movement, respiration, posture) ▸ Voluntary part of the nervous system ▸ Skeletal Muscles – E.g., muscles that aid in respiration and posture: intercostals and diaphragm ● New evidence ○ ANS: The vagus nerve influences immune functions and some CNS functions (e.g., seizures) ○ Autonomic nerves: Influence cancer development and progression A. ANATOMY OF THE ANS Figure 1. Outline of Autonomic Pharmacology I. AUTONOMIC DRUGS ● Drugs that mimic or block actions of chemical transmitters to selectively modify autonomic functions ○ Act like they are the neurotransmitters ○ Mimic: Some of them act like they are the same as neurotransmitters causing mimetic activity ○ Block: Can inhibit the function of those processes ● Effector tissues: ○ Cardiac muscle ○ Smooth muscle ○ Vascular endothelium→ affects blood pressure ○ Exocrine organs (e.g., salivary glands, lacrimal glands) YL6:03.05 Figure 2. Autonomic nervous system and effector organs ● Sympathetic Autonomic Nervous System ○ Fight-or-Flight ○ “Adrenaline rush” ○ Most of the nerves arise from the thoracolumbar division ● Parasympathetic Autonomic Nervous System ○ Rest-and-digest ○ Nerves arise from the brainstem and sacral vertebrae area (craniosacral division) ● No ANS nerves arise from the cervical part of the spinal cord ● Examples of ANS effector organs: TG13: Abad Santos, Ahalajal, Alba, Bernardo, Binobo, Cai, Dy, Gamboa, Pacis, Rejuso, Tan CG05: Abangan, David, Del Corro, Layug, Mendoza, J., Mendoza, R., Ng, Santiago, Santos, Tseng, Uy, Villavicencio 1 ○ Heart: Has both sympathetic and parasympathetic stimulation ○ Digestive tract: mostly parasympathetic ▸ Celiac ganglion: contributes to sympathetic stimulation Table 1. Summary of differences between PNS and CNS Sympathetic (SANS) Parasympathetic (PANS) Fight-or-Flight Rest-and-Digest Thoracolumbar division (T1-T12; L1-L5) Craniosacral division: CN III, VII, IX, X (Remember 1973); S1-S5 Short pre-ganglionic fibers → Nicotinic receptors Long pre-ganglionic fibers → Nicotinic receptors GI Tract Decreased motility Increased motility Liver ↑ Glycogen to glucose Glucose synthesis conversion Kidneys Decreased urine Increased urine Urinary bladder Contraction of sphincter Relaxation of sphincter Sweat glands Increased sweating No change Penis Ejaculation (Shoot) Erection (Point) Long post-ganglionic fibers → Short post-ganglionic fibers Adrenergic receptors → Nicotinic receptors Ganglia: Paravertebral chains along the spinal cord + along anterior aspect of abdominal aorta Ganglia: Most located in the organs EXCEPT: Ciliary, pterygopalatine, submandibular, otic ganglia RECEPTORS ● Nicotinic receptors ○ Acetylcholine (ACh) is the neurotransmitter that binds to receptors ● Muscarinic receptors ○ ACh is also used as the neurotransmitter ● Adrenergic receptors ○ Different neurotransmitters: epinephrine, norepinephrine, dopamine Table 3. Summary of Sympathetic and Parasympathetic Effector Organs Sympathetic (SANS) Take Note! ● The pre-ganglionic fibers for SANS and PANS are BOTH NICOTINIC receptors ● The difference is with their post- ganglionic fibers, where SANS has ADRENERGIC receptors and PANS has MUSCARINIC receptors ● The SANS pre-ganglionic fiber is shorter with longer post-ganglionic fibers → Ganglia are farther from effector organs ● The PANS post-ganglionic fiber is shorter → Ganglia are closer to effector organ Table 2. Comparison of Different Effects of the SNS and PNS on the Body Structure Sympathetic Parasympathetic Eyes/Pupils Dilatation/Mydriasis Constriction/Miosis Nasal mucosa Mucosal reduction Mucosal increase Salivary glands Salivary reduction Salivary increase Heart rate Tachycardia Bradycardia Arteries Constriction Dilatation Lungs Bronchial dilation Bronchial constriction YL6:03.05 Figure 3. Anatomy of the Autonomic Nervous System (ANS) Introduction to Autonomics Parasympathetic (PANS) Ganglia are farther from its effector organs Ganglia are closer to its effector organs Short pre-ganglionic fibers Long pre-ganglionic fibers Long post-ganglionic fibers Short post-ganglionic fibers Effector Organs ● Sweat glands ● Cardiac and smooth muscle ● Gland cells ● Nerve terminals ● Renal vascular smooth muscle Effector Organs ● Cardiac and smooth muscle ● Gland cells ● Nerve terminals ● Pre-ganglionic Receptors ○ Neurotransmitter used is ACh ○ Receptors are all nicotinic ● Post-ganglionic Receptors ○ Sympathetic ▸ Receptors are adrenergic alpha or beta ▸ Neurotransmitters are norepinephrine or dopamine ▸ Exception: Sweat glands – Receptors are muscarinic – Neurotransmitters are ACh ○ Parasympathetic ▸ Receptors are muscarinic 2 ▸ Neurotransmitters ACh ● Has serotonin (5-HT) receptors aside from acetylcholine (ACh) and norepinephrine (NE) receptors Anatomy of PANS: PLANSMA PANS (Parasympathetic Nervous System) Long pre-ganglionic fibers Acetylcholine (as a pre-ganglionic neurotransmitter) Nicotinic (receptor) Short post-ganglionic fibers Muscarinic (receptor) Acetylcholine (as a post-ganglionic neurotransmitter) Anatomy of SANS: SSANLANED SANS (Sympathetic Nervous System) Short pre-ganglionic fibers Acetylcholine (as a pre-ganglionic neurotransmitter) Nicotinic (receptor) Long post-ganglionic fibers Adrenergic (receptor) NorEpinephrine and Dopamine (as a post-ganglionic neurotransmitter) Figure 5. Modulatory role and sensory inputs of the ENS NEUROTRANSMITTERS ENTERIC NERVOUS SYSTEM ● Important system that exists in the digestive tract ● Large and highly organized collection of neurons in the walls of the gastrointestinal tract ○ From the esophagus to the distal colon ○ Found in the Myenteric Plexus (Auerbach’s Plexus) and the Submucosal Plexus (Meissner’s Plexus) ○ Semi-autonomous ● 3rd division of the autonomic nervous system ○ Integrates the signals from the sympathetic and parasympathetic nervous systems ● Controls motor, secretory, and sensory activities in the gut ○ Necessary for synchronization of impulses → forward propulsion (peristalsis) and relaxation of sphincters ▸ With propulsion, sphincters will relax ▸ Without propulsion, sphincters will constrict ● Acetylcholine (ACh) ○ In the preganglionic fibers of SANS and PANS ○ Primary transmitter at: ▸ ANS ganglia ▸ Somatic neuromuscular junction ▸ Parasympathetic postganglionic nerve endings ○ Major neuron-to-neuron transmitter in the ENS ● Norepinephrine (NE) ○ In the postganglionic fibers of SANS ○ Primary transmitter at most sympathetic postganglionic nerve endings ● Serotonin (5-HT) ○ Important transmitter/cotransmitter at excitatory neuron-to-neuron junctions in the ENS B. ANS SYNAPSES ● Different from other synapses such as in the somatic nervous system as the release of postganglionic fibers are found in varicosities ○ Varicosities: widened/dilated areas where neurotransmitters are released ● Target effector has many areas of varicosities ○ Covers more smooth muscles that contracts in coordination with each other ● Wider junctions between the ANS and effector cells compared to the somatic nervous system ○ Results in a slower effect in the ANS Figure 4. Intrinsic nerve plexuses (ENS) ● Has a modulatory role as it receives sensory inputs ○ From the wall of the gut ○ Stretch receptors ○ Sympathetic and parasympathetic fibers ○ Chemical and mechanical information from the mucosa YL6:03.05 Introduction to Autonomics 3 ● Nicotinic Receptors ○ Two types of nicotinic receptors ▸ NN - for neurons ▸ NM - for muscle (somatic nervous system) Adrenoreceptors ● Alpha1, Alpha2, Beta1, Beta2, Beta3 Dopamine receptors ● Beta-agonist drugs (e.g., Salbutamol) are used for asthma ● Beta-blockers are used for hypertension Take Note! Figure 6. Postganglionic varicosity ● Adrenoreceptors and dopamine receptors will be discussed further in future lectures Active Recall Box Figure 7. Autonomic efferent pathway TYPES OF RECEPTORS 1. What kind of receptors can be found in the Enteric Nervous System? A. Acetylcholine receptors B. Serotonin receptors C. Norepinephrine receptors D. All of the above E. None of the above 2. T/F: Autonomic drugs act only like hormones 3. Sympathetic ANS: Fight-or-Flight; Parasympathetic ANS: __ 4. The ___ is the only effector organ of the sympathetic nervous system whose neurotransmitters are acetylcholine and receptors are muscarinic. Answers: 1D, 2F, 3 Rest-and-Digest, 4 Sweat gland Rationale: 2F: Autonomic drugs act like neurotransmitters. III. CHOLINERGIC AND ADRENERGIC TRANSMISSION Figure 8. Major Autonomic Receptor Types Take Note! ● Refer to Table 6 in Master Tables for better readability Cholinoreceptors ● Muscarinic Receptors ○ M1, M4, M5 can be found in CNS neurons ○ M2 can be found in the heart ○ How do they differ as to mode of action? ▸ When acetylcholine binds to M1, M3, M5, there is a secondary messenger system that will form IP3 and DAG ▸ Calcium concentration also increases ○ M2 and M4 open calcium channels ▸ Done by inhibition of cAMP YL6:03.05 Introduction to Autonomics ● Cholinergic = acetylcholine ○ Almost all efferent fibers leaving CNS ○ Most parasympathetic postganglionic and some sympathetic postganglionic fibers ● Adrenergic/Noradrenergic = norepinephrine ○ Most postganglionic sympathetic fibers ○ Dopamine ○ Adrenal medulla (embryologically similar to postganglionic sympathetic neurons) = combination of norepinephrine and epinephrine A. FIVE KEY FEATURES OF NEUROTRANSMITTER FUNCTION ● Synthesis ○ Formation of neurotransmitter ● Storage ○ Store into vesicles ● Release ○ Released because of depolarization that happens in this area ● Receptor effects ○ Bind to receptors ○ Cholinergics, anticholinergics, and adrenergic drugs ● Termination of Action ○ Can also inhibit the one that destroys the neurotransmitter 4 B. CHOLINERGIC TRANSMISSION SYNTHESIS ● Acetylcholine (ACh) = Acetyl + Choline ○ Choline enters the encircled area via a symporter with sodium using the sodium-dependent choline transporter (CHT) ○ Acetyl CoA comes from the mitochondrion in order to combine with choline ● Enzyme: Choline acetyltransferase (ChAT) ● Inhibitor: Hemicholinium (drug used in animal research) Figure 10. Storage of Acetylcholine RELEASE Figure 9. Synthesis of Acetylcholine STORAGE ● Acetylcholine formed is transported into vesicles ○ Via Vesicle-associated transporter (VAT) ○ Driven by proton efflux ▸ Proton leaves the vesicle so that ACh can enter ○ “Quanta” of ACh Molecules (1,000-50,000) ● Most (+) ACh = bound to (-) vesicular proteoglycan (VPG) ● Inhibitor: Vesamicol ○ Experimental drug use for adenocarcinoma YL6:03.05 Introduction to Autonomics ● SNARES ○ Concentrate vesicles on the inner surface of the nerve terminal ○ Surface protein found on the outside of vesicles ○ Types of SNARES: ▸ VAMPS (v-SNAREs, Synaptobrevin, Synaptotagmin) ▸ SNAPS (t-SNAREs, Syntaxin, and SNAP-25) ● Process: ○ Depolarization ▸ Depolarization from the axon reaches the end ▸ Leads to change of membrane charge ○ Activates calcium channels ▸ Calcium enters ○ Calcium interacts with VAMP synaptogamin ○ Fusion of vesicle with the terminal membrane ○ Release of ACh ● Inhibitor: Botulinum Toxin ○ Causes paralysis ○ Instead of ACh binding to neurotransmitter, ACh is prevented from being available in the synapse ○ Produced by Clostridium botulinum ○ Clinical syndrome: Botulism ○ Botulism may occur through: ▸ Ingestion of contaminated food ▸ Colonization of infant GI tract ▸ Wound infection ○ Botulism symptoms: ▸ Blurred vision, slurred speech, nausea, vomiting, and muscle weakness ○ Pharmaceutical companies concentrated the toxin and made it a drug for cosmetics ○ Botox 5 ▸ Not only for cosmetic purpose to look younger through muscle paralysis, but also for hyperhidrosis – E.g., people with sweaty armpits or palms will take this injection to get rid of this ○ Botox Cosmetic ▸ For the lines on the face ▸ Glabellar lines, lateral canthal lines Figure 12. Termination of action Cholinergic Transmission: HVB (Hepa Virus B) DAI Figure 11. Release of Acetylcholine RECEPTOR EFFECTS ● This is when cholinergics and anticholinergics act ● Cholinoreceptors: ○ M1-M5 ○ NM and NN ● Pharmacologic Correlates: ○ Cholinomimetic (Cholinergic): Direct-Acting and Indirect-Acting ▸ Indirect-acting: don’t necessarily act on the receptor ○ Anticholinergics: Antimuscarinic and Antinicotinic ○ Mimics or blocks the receptor ● Recall: Cholinoreceptors ○ M1, M3, M5 - forms IP3 and DAG, increased intracellular calcium ○ M2, M4 - open potassium channels ○ NN - for neurons ○ NM - for somatic or skeletal muscles Hemicholinium: Synthesis Vesamicol: Storage Botulinum Toxin: Release Direct Cholinergics (+) and Anticholinergics (-): Receptor Effects Indirect Cholinergics (-): Termination of Action (03.09, 2026) C. ADRENERGIC TRANSMISSION ● Same flow as cholinergic transmission, but with different enzymes and drugs TERMINATION OF ACTION ● Breakdown of ACh by acetylcholinesterase into choline and acetate ● Inhibitors: indirect cholinergics ○ Blocks acetylcholinesterase, so nothing breaks down ACh ○ With more ACh available to bind, this leads to more action YL6:03.05 Introduction to Autonomics 6 SYNTHESIS Figure 13. Synthesis in adrenergic transmission ● Synthesis of dopamine, epinephrine, or norepinephrine from tyrosine ● Rate limiting step: step catalyzed by tyrosine hydroxylase ○ Tyrosine hydroxylase: enzyme that turns tyrosine to dopa ▸ Dopa is then turned to dopamine which is stored inside ▸ Dopamine can be turned into norepinephrine and epinephrine ● Metyrosine ○ Inhibits tyrosine hydroxylase ○ Previously used for hypertension in pheochromocytoma ▸ Pheochromocytoma: tumor in the adrenal medulla causing hypertension, causing over release of norepinephrine and epinephrine ○ However, there are newer drugs that are more effective Figure 14. Pathway on Conversion of Tyrosine to Dopa STORAGE Figure 15. Storage in adrenergic transmission ● Vesicular Monoamine Transporter (VMAT) ○ If in cholinergic transmission, there is VAT, in adrenergic transmission there is VMAT ○ High-affinity antiporter in storage vesicle YL6:03.05 Introduction to Autonomics 7 ● Reserpine and related drugs (tetrabenazine, deutetrabenazine) ○ Inhibitor for VMAT ○ Cause depletion of the stores ○ Previously used for hypertension, but it’s not in the guidelines anymore because it also affects different parts of the body ○ According to MIMS, it is used for chronic psychosis ▸ Newer drugs are available for the treatment of chronic psychosis RELEASE – Equivalent of acetylcholinesterase (breaks down norepinephrine) ○ Tyramine ▸ Stimulant ▸ Derivative of tyrosine ▸ Found in foods such as fish sauces, liver, beer, red wine ○ Ephedrine ▸ Stimulant ▸ Related to pseudoephedrine, which is found in decongestants ▸ Bronchodilator for people with asthma ▸ For postural hypertension or orthostatic hypotension ▸ When given, norepinephrine will be released causing an increase in blood pressure ▸ Not the drug of choice of the mentioned indications Inhibitors ● Bretylium ○ Given for arrhythmia, which is caused by too much sympathetic nervous stimulation ○ Inhibits the release of norepinephrine ○ Not a drug of choice anymore ● Guanethidine ○ Former antihypertensive drug ○ Not part of the guidelines anymore because of numerous side effects Sympathomimetics and Inhibitors: MR. TAE BG Metyrosine (for synthesis, inhibitor) Reserpine (for storage, inhibitor) Tyramine (for release, sympathomimetic) Amphetamine (for release, sympathomimetic) Ephedrine (for release, sympathomimetic) Bretylium (for release, inhibitor) Guanethidine (for release, inhibitor) Figure 16. Release in adrenergic transmission ● Same mechanism (cholinergic) ● Mediated by binding of Ca2+ to VAMP causing fusion of vesicle with the membrane, causing the release of neurotransmitters like norepinephrine ○ Release of norepinephrine with ATP. dopamine-β-hydroxylase, and peptide co-transmitters (03.09, 2026) Sympathomimetics ● Capable of releasing stored transmitters (e.g., tyramine, amphetamine, ephedrine) ○ Poor agonists of receptors ○ Taken up by norepinephrine transporter (NET), transported by VMAT, displace NE ▸ NET: allows entry of sympathomimetics ▸ They replace/push out norepinephrine in the vesicle, causing the release of norepinephrine ○ Amphetamine ▸ Stimulant ▸ Brand name: Adderall – For the treatment of ADHD – Drug that is abused ▸ Inhibit monoamine oxidase (MAO) YL6:03.05 Introduction to Autonomics RECEPTOR EFFECTS ● Adrenoreceptor ○ Receptors that respond to catecholamines like norepinephrine ▸ α-adrenoreceptors (α1, α2) – Alpha agonists and alpha blockers ▸ β-adrenoreceptors (β1, β2, β3) – Beta agonists and beta blockers ▸ Dopamine-adrenoreceptors – D1 (DA1), D2 (DA2), D3, D4, D5 ● Based on agonist and antagonist selectivity ● Major Adrenoreceptors and Dopamine Receptors (Katzung, 2017) (Table 6, Appendix) TERMINATION OF ACTION Via Diffusion ● Diffuse into the synapse and will not bind with adrenoreceptors anymore Via Norepinephrine Transport (NET) ● Reuptakes norepinephrine back into the vesicles ● Uptake 1 or reuptake 1 ● Partially responsible for termination of synaptic activity 8 Inhibitors ● Cocaine and Tricyclic Antidepressants ● Make norepinephrine more available in the synapse ● Effect: Increases sympathetic nervous activity such as increased blood pressure [Clinical Correlation] Diagnosis of Pheochromocytoma (Catecholamine Metabolism) ● Epinephrine, norepinephrine, and dopamine are further degraded by enzymes such as catechol-Omethyltransferase (COMT) and MAO producing 3Methoxy-4-hydroxymandelic acids (VMA) and metanephrines ● Recall: Inhibiting MAO makes neurotransmitters more available for binding ● The VMA and other metanephrines can be checked in a 24-hour urine sample to estimate catecholamine turnover ○ Too high → production of norepinephrine by the body is also high ● Patients being tested for pheochromocytoma can be confined, during which their urine can be extracted via foley catheter Figure 18. Metabolism of adrenergic neurotransmitters by COMT and MAO D. COTRANSMITTERS IN CHOLINERGIC AND ADRENERGIC TRANSMISSION ● Some neurotransmitters don’t act as primary transmitters, but as cotransmitters in both cholinergic and adrenergic transmission ● Can be found on the same vesicle or different vesicle ● Their actions can be supplementary or modulatory ○ Primarily possibly for feedback inhibition Take Note! ● There is no need to memorize Figure 23 in Appendix ● It was shown to stress that some neurotransmitters do not act as primary neurotransmitters but as cotransmitters (E.g., ATP, CCK, Serotonin) E. NONADRENERGIC NONCHOLINERGIC (NANC) NEURONS Figure 17. Termination of action (Adrenergic Transmission) ● E.g., Enteric nervous system (ENS) in the gut ○ Small intestine neurotransmitters: ▸ NO ▸ Calcitonin gene-related peptide ▸ CCK ▸ Enkephalins ▸ Gastrin-releasing peptide ▸ 5-HTSerotonin ▸ NeuropeptideY ▸ Somatostatin ▸ SubstanceP ▸ VIP ○ “Sensory-efferent” or “sensory-local effector” SEROTONIN ● 5-HT serotonin ● Neurotransmitter in the brain ○ Affects mood and behavior ○ Some drugs given for depression and anxiety are selective serotonin reuptake inhibitors (SSRIs) ▸ Makes serotonin more available for binding YL6:03.05 Introduction to Autonomics 9 ● Other functions ○ Intestinal motility ○ Temperature regulation ○ Hemostasis: Platelet aggregation & vasoconstriction ● GI Tract: small intestines ○ Intense rhythmic contractions ▸ Direct and indirect effects (ganglia) ○ Stimulates vomiting via 5-HT3 receptors on vagal afferents and central receptors ○ Antiemetics ▸ Particular drug in anesthetics and surgery ▸ 5-HT3 receptor antagonists ▸ Main effect is to prevent 5-HT3 stimulation – Prevents nausea and vomiting ▪ Ondansetron ▪ Metoclopramide (Brand name: Placil) ○ SANS and PANS affect the activity of the heart ultimately affecting mean arterial pressure and blood pressure (See FIgure 20) ● Presynaptic regulation ○ Autoreceptors and heteroreceptors: act as receptors for negative feedback ● Postsynaptic regulation ○ At the synapse itself ○ Upregulation and downregulation of receptors ▸ Increase or decrease the number of receptors ○ Modulation by transmitters acting on different postsynaptic receptors ▸ When a neurotransmitter binds to an adjacent postsynaptic receptor, it can prevent the activity of other neurotransmitters binding to the main post-synaptic receptors Figure 20. Integration of cardiovascular function, where both PANS and SANS affect the activity of the heart, ultimately affecting blood pressure V. PHARMACOLOGIC MODIFICATION OF AUTONOMIC ACTION ● See Figure 24 in Appendix for the steps in autonomic transmission and effects of some drugs ● Table 4 shows the drugs and their actions, as highlighted by the lecturer Table 4. Cholinergic and adrenergic drugs and their actions CHOLINERGIC TRANSMISSION Figure 19. Serotonin receptors Drug IV. FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY ● Mostly regulated by negative feedback ○ Important in the responses of the ANS to the administration of autonomic drugs ● Central Integration ○ Autonomic nervous system works hand in hand with the midbrain, medulla, PANS, SANS, and the endocrine system ○ Sensory input from the higher CNS centers ▸ I.e., Cerebral Cortex ○ PANS: trophotropic ▸ Leads to growth ▸ “Rest and Digestion” ○ SANS: ergotropic ▸ Leads to energy expenditure ● Integration of Cardiovascular Function ○ Autonomic activity is integrated with cardiovascular function YL6:03.05 Introduction to Autonomics Action Hemicholinium Block uptake of choline and slow ACh synthesis Vesamicol Prevents storage, depletes Botulinum Toxin Prevents ACh release Cholinergic Drugs ● Nicotine ● Bethanechol ● Bind and activate receptors ● Nicotine: Binds in nicotinic receptors; opens ion channel in postsynaptic membrane ● Bethanechol: Binds and activates muscarinic receptors Anticholinergic Drugs ● Tubocurarine ● Atropine ● Receptor blockage 10 ● Tubocurarine: Prevent activation of nicotinic receptors ● Atropine: Binds muscarinic receptors; prevents activation ● Inhibits enzymes ● Prolongs and intensifies transmitter action after release Neostigmine ADRENERGIC TRANSMISSION Drug Action ● Inhibits tyrosine hydroxylase ● Blocks synthesis of catecholamines Metyrosine Reserpine, Tetrabenazine Prevents storage, deletes Stimulants ● Tyranime ● Amphetamine ● Ephedrine Promote transmitter release Inhibitors ● Bretylium ● Guanethidine Displaces noradrenaline from storage vesicles and Inhibits its release Adrenergic blockers and agonists ● Timolol ● Propranolol Prevents activation of betareceptors Tricyclic antidepressants (TCAs), Cocaine, SNRI antidepressants ● Inhibit uptake ● Increase transmitter effect on postsynaptic receptors ● People who take cocaine can die from heart attack Figure 22. Overview of adrenergics [Example] Autonomics in the Eyes ● Net effect of parasympathetic nervous system in the eyes: miosis → pupillary constriction happens ○ Miosis: contraction of the pupillary constrictor muscle ● PANS and muscarinic cholinomimetics ● Atropine: anticholinergic drug ○ Eye drop given to patients for examination of the retina ○ Effect: Dilates patient’s pupils ○ Mimic autonomic nervous system activity or block it ▸ In this case, you want to block parasympathetic activity ● Alpha-receptor stimulation ○ Brimonidine: Alpha-agonist for glaucoma (e.g., Alphagan) ○ Effect: Decreases rate of aqueous production ○ Given for glaucoma since there is increased pressure in the eyes which can impinge parts of the eye ● Beta-receptor stimulation ○ Timolol: Beta-blockers for glaucoma ○ Effect: Decrease aqueous production ○ Blocking beta stimulation with beta-blockers → symptoms of glaucoma is alleviated/prevented Active Recall Box Figure 21. Overview of Cholinergics and Anticholinergics 5. The following are the five key features of neurotransmitter function, EXCEPT: A. Receptor effects B. Synthesis C. Termination of Action D. Relapse E. Storage 6. T/F: All neurotransmitters act as primary neurotransmitters. 7. Enumerate the steps of cholinergic transmission 8. Which of the following sympathomimetics are stimulants? A. Amphetamine B. Tyramine D. Ephedrine D. AOTA Answers: 5D, 6F, 7 Synthesis, Storage, Release, Receptor Effects, Termination of Action, 8 AOTA YL6:03.05 Introduction to Autonomics 11 Rationale: 6F: Some neurotransmitters act as cotransmitters for both cholinergic and adrenergic transmission. QUICK REVIEW SUMMARY OF TERMS Table 5. Cholinergic vs. adrenergic drugs CHOLINERGIC ADRENERGIC Synthesis Hemicholinium Metyrosine Storage Vesamicol Reserpine Release Botulinum Toxin Bretylium, Guanethidine Receptor Effects Cholinergics and Anticholinergics Adrenergic Receptor Agonists and Antagonists Termination of Action Indirect cholinergics Cocaine, TCAs C. Release : Vesamicol D. Termination of Action : Indirect Cholinergics 7. Which muscarinic receptors bind to ACh that forms IP3 and DAG? A. M1, M2, M3 B. M1, M3, M4 C. M2, M4, M5 D. M1, M3, M5 E. M2, M3, M4 8. The following are true of sympathomimetics except: A. Capable of releasing stored transmitters B. Absorb norepinephrine into the vesicle, eventually causing its release C. Poor agonists of receptors D. NOTA 9. The following are true about serotonin and its receptors, EXCEPT: A. Affects mood and affect B. Causes intense rhythmic contractions in the small intestines C. 5-HT3 receptors inhibit vomiting D. A & B E. NOTA 10. T/F: Metyrosine is an adrenergic drug that promotes transmitter release. QUESTIONS 1. All of the following are under the ANS, EXCEPT: A. Cardiac output B. Blood flow distribution C. Digestion D. Voluntary part of nervous system 2. The pre-ganglionic fibers for SANS and PANS are both nicotinic receptors. Their post-ganglionic fibers are both muscarinic receptors. A. Only statement 1 is true B. Only statement 2 is true C. Both statements are true D. Both statements are false 3. Which of the following is/are involved in binding muscarinic receptors? A. Nicotine B. Atropine C. Bethanechol D. A and B E. B and C 4. The anatomy of the parasympathetic nervous system consists of short pre-ganglionic fibers with acetylcholine as a neurotransmitter. The post-ganglionic fiber of the sympathetic nervous system is long, with norepinephrine and dopamine as a post-ganglionic neurotransmitters. A. Only statement 1 is true B. Only statement 2 is true C. Both statements are true D. Both statements are false 5. Which neurotransmitter is the primary transmitter at the sympathetic postganglionic nerve endings? A. Norepinephrine B. Acetylcholine C. Epinephrine D. Serotonin 6. Which of the following is paired correctly? A. Storage : Hemicholinium B. Synthesis : Botulinum Toxin YL6:03.05 Introduction to Autonomics ANSWER KEY 1D, 2A, 3E, 4B, 5A, 6D, 7D, 8B, 9D, 10F RATIONALE 1. D. Voluntary part of nervous system. This is part of the Somatic nervous system. 2. A. Only statement 1 is true. The pre-ganglionic fibers for SANS and PANS are both NICOTINIC receptors. The difference is with their post- ganglionic fibers, where SANS has ADRENERGIC receptors and PANS has MUSCARINIC receptors. 3. E. B and C. Atropine and Bethanechol bind to muscarinic receptors, but they have opposite effects. The former prevents the activation of the receptors while the latter activates the receptors. Nicotine binds in nicotinic receptors. 4. B. Only statement 2 is true. Recall the mnemonics PLANSMA and SSANLANED. Statement 1 is false because PANS has long pre-ganglionic fibers with acetylcholine as a neurotransmitter. 5. A. Norepinephrine. NE is the primary transmitter at most sympathetic postganglionic nerve endings. Ach is the primary transmitter at the ANS ganglia, Somatic neuromuscular junction, and Parasympathetic postganglionic nerve endings. 5-HT is important at the excitatory neuron-to-neuron junctions in the ENS. 6. D. Termination of Action : Indirect Cholinergics. The process of cholinergic transmission is matched with its inhibitor. Storage is inhibited by vesamicol, synthesis by hemicholinium, and release by botulinum toxin. Thus, D is the correct answer. Termination of action is inhibited by indirect cholinergics. 7. D. M1, M3, M5. When acetylcholine binds to M1, M3, M5, there is a secondary messenger system that will form IP3 and DAG. 12 8. B. Absorb norepinephrine into the vesicle, eventually causing its release. Sympathomimetics replace or push out norepinephrine in the vesicle, causing its release. 9. D. A & B. Serotonin affects mood and BEHAVIOR. 5-HT3 receptors STIMULATE vomiting. 10. F. Metyrosine is an adrenergic drug that inhibits tyrosine hydroxylase and blocks the synthesis of catecholamines. REFERENCES REQUIRED ● 💻 Soller, J.S., MD-MBA, DPCOM (2020, August 13). Introduction to Autonomics [Video]. https://www.youtube.com/watch?v=kqdNU8MVDJ4&ab_channel=Jo sefSoller SUPPLEMENTARY 📖 Katzung, B. (2017). Basic and Clinical Pharmacology 14th Edition. McGraw-Hill Education/Medical. ● 📄 ASMPH 2026. 03.09: Introduction to Autonomic Drugs by Soller, J.S., MD-MBA, DPCOM ● Concerns and Feedback form: http://bit.ly/YL6CFF2027 How’s My Transing? form: https://bit.ly/2027YL6HMT Mid-Semester Evaluation form: https://bit.ly/2027YL6MidSem End-of-Semester Evaluation form: https://bit.ly/2027YL6EndofSem Errata Points Trackers: https://bit.ly/YL62027EPT YL6 TransMap: https://bit.ly/2027YL6TransMap YL6:03.05 Introduction to Autonomics 13 APPENDIX Figure 23. Transmitter substances found in Autonomic Nervous System, Enteric Nervous System, and nonadrenergic, noncholinergic neurons YL6:03.05 Introduction to Autonomics 14 Figure 24. Steps in Autonomic Transmission and Effects of Some Drugs YL6:03.05 Introduction to Autonomics 15 MASTER TABLES Table 6. Major Autonomic Receptor Types (Katzung, 2017) (03.09, 2026) Receptor Name Typical Locations Result of Ligand Binding Cholinoreceptors Muscarinic M1 CNS neurons, sympathetic postganglionic neurons, some presynaptic sites Formation of IP3 and DAG, increased intracellular calcium Muscarinic M2 Myocardium, smooth muscle, some presynaptic sites, CNS neurons Opening of potassium channels, inhibition of adenylyl cyclase Muscarinic M3 Exocrine glands, vessels (smooth muscle, endothelium); CNS neurons Like M1 receptor-ligand binding Muscarinic M4 CNS neurons; possibly vagal nerve endings Like M2 receptor-ligand binding Muscarinic M5 Vascular endothelium, especially cerebral vessels; CNS neurons Like M1 receptor-ligand binding Nicotinic NN Postganglionic neurons, some presynaptic cholinergic terminals; pentameric receptors typically contains α- and β-type subunits only Opening of Na+, K+ channels, depolarization Nicotinic NM Skeletal muscle neuromuscular endplates; receptors typically contain two α1- and β1-type subunits in addition to gamma and delta subunits Opening of Na+, K+ channels, depolarization Adrenoreceptors Alpha1 Postsynaptic effector cells, especially smooth muscle Formation of IP3 and DAG, increased intracellular calcium Alpha2 Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of adenylyl cyclase, decreased cAMP Beta1 Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic adrenergic and cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body epithelium Stimulation of adenylyl cyclase, increased cAMP Beta2 Postsynaptic effector cells, especially smooth muscle and cardiac muscle Stimulation of adenylyl cyclase, increased cAMP, activates cardiac G1 under some conditions Beta3 Stimulation of adenylyl cyclase, increased cAMP Dopamine Receptors D1(DA1), DS Brain, effector tissues, especially smooth muscle of the renal vascular bed Stimulation of adenylyl cyclase, increased cAMP D2(DA2) Brain, effector tissues, especially smooth muscle, presynaptic nerve terminals Inhibition of adenylyl cyclase, increased potassium conductance D3 Brain Inhibition of adenylyl cyclase D4 Brain, cardiovascular system Inhibition of adenylyl cyclase YL6:MM.LL [Lecture Title] 16