Neurophysiology 3 - Intro to ANS PDF

Intro to the ANS: Video 1 Nervous System Overview Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy < Spinal cord Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Gan...

Intro to the ANS: Video 1 Nervous System Overview Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy < Spinal cord Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Ganglion Video 3: Parasympathetic Nervous System Anatomy < Brainstem nuclei or sacral spinal cord Myelinated preganglionic neurons Ganglia: Terminal Non-myelinated postganglionic neurons Target Video 4: Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Video 5: Actions of the ANS Video 6: Applied Pharmacology of the ANS CNS PNS – Motor (efferent) Brain cranial nerves cranial nerves Somatic NS skeletal muscle Spinal Cord spinal nerves NS Overview Autonomic NS - cardiac cells, smooth muscle, glands Parasympathetic (rest & digest) Sympathetic (flight or flight) spinal nerves PNS – Sensory (afferent) Special Sensory Somatic Sensory Visceral Sensory Hearing, equilibrium, sight, smell, taste Touch, pain, pressure, vibration, temp, proprioception (ex CN V pain from face) Internal environment (ex Stretch, temp, chemical stimuli) Somatic Sensory Touch, pain, pressure, vibration, temp, proprioception (ex pain from toe) Visceral Sensory Visceral pain Sensory: Neuroanatomy/MSK Review Cranial nerves Match the following cranial nerves with the correct sensory inputs Facial Somatic: Face Glossopharyngeal Special sensory: anterior tongue Trigeminal Visceral: chemoreceptor and baroreceptor info (aorta); sensory info from cardiac, pulmonary and GI systems Vagus Visceral: chemoreceptor and baroreceptor info (carotid bodies) Nervous System: Motor Brain Somatic NS - skeletal muscle Cranial nerves: voluntary (or reflex) actions (head/neck) Autonomic NS – smooth muscle, cardiac cells, glands Spinal Cord Somatic NS - skeletal muscle Autonomic NS – smooth muscle, cardiac cells, glands Spinal nerves: voluntary (or reflex) actions (below head/neck) Parasympathetic Cranial nerves: involuntary actions (upper/middle body) Parasympathetic Spinal nerves (pelvic splanchnic: involuntary actions (lower body) Sympathetic Spinal nerves (some form various splanchnic nerves) involuntary actions (whole body) Somatic Motor: Neuroanatomy/MSK Review - Cranial nerves Which one or more of the cranial nerves listed innervate skeletal muscles in the head/neck region? For any that you select, which areas or muscles? ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Accessory Abducens Oculomotor Facial Glossopharyngeal Hypoglossal Trigeminal Trochlear Vagus Autonomic NS Motor Innervation Dual innervation of heart, smooth muscle, glands ▪ Exceptions: Blood vessels = Sympathetic ▪ Parasympathetic very limited influence outside of GI and reproductive organs Skin = sympathetic ▪ Sweat glands (FYI eccrine) and arrector pili Cardiac cells ▪ Nodal (rate) = Sympathetic and Parasympathetic ▪ Muscle (contractility) = Sympathetic Parasympathetic very limited Intro to Sympathetic System Overview of efferent outflow < < ▪ Spinal cord ▪ Myelinated preganglionic neurons ▪ Ganglia: Paravertebral, Prevertebral ▪ Non-myelinated postganglionic neurons Target Ganglion Sympathetic Nervous System Input from brain Pre-ganglionic neurons < Paravertebral ganglia (sympathetic trunk) Target Tissues T1-L2/3 < < Prevertebral ganglia < < Sensory info from body Cell bodies in the spinal cord, levels T1-L2/3 Receive input from brain OR sensory input from body Exit to synapse on paraOR pre- vertebral (aka collateral) ganglia Post-ganglionic neurons Cell bodies in ganglia Receive input from preganglionic neurons Exit and travel to target tissue Sympathetic Nervous System Preganglionic neurons exit spinal cord and enter the sympathetic trunk T1-L2/3 < < Prevertebral < < Splanchnic N. 3 options: 1) Synapse on a paravertebral ganglion at a different spinal level < Paravertebral (sympathetic trunk) Target Tissues 2) Synapse on a paravertebral ganglion at the same spinal level 3) Pass through & synapse on a prevertebral ganglion (via a splanchnic nerve) Basic SNS Anatomy Solid lines = efferents from spinal cord to 1st ganglion ▪ preganglionic fibre Dotted lines = efferents from ganglion to target organ ▪ postganglionic fibre Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 Test Yourself Before moving onto the next presentation, make sure you are confident in answering the questions on the following slides ▪ All answers are directly in this ppt presentation Test Yourself What 3 general types of cells/structures are innervated by efferents in the ANS? ▪ How does this contrast to what is innervated by efferents in the somatic nervous system? Fill in the blanks: ▪ Parasympathetic motor output comes from either the ____ or ___ ___, while all sympathetic motor output comes from the ___ ___. Test Yourself Draw the general schematic of ANS efferent transmission using the 4 structures listed below. Then answer the corresponding questions with respect to the SNS. ▪ 1) Presynaptic neuron Where does it exit from? Where specifically are the cell bodies found (ie what spinal levels)? ▪ 2) Ganglion What are the two types of ganglia? ▪ Which one is closer to the spinal cord? ▪ 3) Postsynaptic neuron ▪ 4) Target tissue Test Yourself With respect to SNS transmission: ▪ Outline the 3 options for preganglionic neurons after they enter the sympathetic trunk. Include the following for each option: Do they synapse in the trunk? ▪ If so: Where (same or different spinal level)? What is the name of the ganglion? ▪ If not: What type of nerve do they form once they exit? What is the name of the ganglion on which this type of nerve synapses? Neuroanatomy/MSK review questions and answers Reminder: These questions won’t be tested as part of this lecture, but they are a review of MSK and neuroanatomy, so they are testable on the final Question Recap: Cranial nerves - sensory Match the following cranial nerves with the correct sensory inputs Facial Somatic: Face Glossopharyngeal Special sensory: anterior tongue Trigeminal Visceral: chemoreceptor and baroreceptor info (aorta); sensory info from cardiac, pulmonary and GI systems Vagus Visceral: chemoreceptor and baroreceptor info (carotid bodies) Answer: Cranial nerves - sensory Match the following cranial nerves with the correct sensory inputs Facial Special sensory: anterior tongue Glossopharyngeal Visceral: chemoreceptor and baroreceptor info (carotid bodies) Trigeminal Somatic: Face Vagus Visceral: chemoreceptor and baroreceptor info (aorta); sensory info from cardiac, pulmonary and GI systems Question Recap: Cranial nerves – somatic motor Which one or more of the cranial nerves listed innervate skeletal muscles in the head/neck region? For any that you select, which areas or muscles? ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Accessory Abducens Oculomotor Facial Glossopharyngeal Hypoglossal Trigeminal Trochlear Vagus Answer: Cranial nerves – somatic motor Somatic motor innervation to structures in head/neck: ▪ Accessory = Sternocleidomastoid, trapezius ▪ Abducens, oculomotor, trochlear = eye: extraocular muscles Abducens: lateral rectus Trochlear: superior oblique Oculomotor: the rest, plus levator palpabrae superioris ▪ Facial = muscles of facial expression ▪ Glossopharyngeal = stylopharyngeus ▪ Hypoglossal = tongue ▪ Trigeminal =muscles of mastication ▪ Vagus = most of palate/pharynx, plus larynx Intro to the ANS: Video 2 Sympathetic Nervous System Anatomy Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy < Spinal cord Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Video 3: Parasympathetic Nervous System Anatomy < Brainstem nuclei or sacral spinal cord Myelinated preganglionic neurons Ganglia: Terminal Non-myelinated postganglionic neurons Target Video 4: Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Video 5: Actions of the ANS Video 6: Applied Pharmacology of the ANS Ganglion Basic SNS Anatomy Solid lines = efferents from spinal cord to 1st ganglion ▪ pre-gangionic fibre Dotted lines = efferents from gangion to target organ ▪ post-ganglionic fibre Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 Sympathetic Review + Details: Preganglionic Review - Preganglionic neurons exit spinal cord and enter the sympathetic trunk, after which they have 3 options: Synapse on a paravertebral ganglion at a different (1) or same (2) spinal level Pass through (3) & synapse on a prevertebral ganglion (via a splanchnic nerve) Details – Common features of all 3 options Preganglionc neurons have their cell bodies in the intermediolateral horn of the spinal cord, levels T1-L2/3 (see next slide) Preganglionic neurons are myelinated and enter the sympathetic trunk through a connector call the white rami communicans Details: Intermediolateral horn/column Intermediolateral horn ▪ Contains sympathetic preganglionic cell bodies ▪ Gray matter found in lamina VII of the thoracic and upper lumbar spinal cord Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 5-11 SNS – Motor Option 1 Option 1 Cell body found where? ▪ Upper thoracic (T1-2) preganglionic neuron exits spinal cord spinal and enters sympathetic trunk via a white rami communicans (white = myelinated) Axon travels in trunk and synapses at a paravertebral ganglion at a different spinal level ▪ Post-ganglionic neuron exits trunk via a gray (nonmyelinated) rami communicans and joins spinal nerve to travel to target Spinal nerve Anatomy and Physiology, 2nd ed. p. 594, fig. 15.3 SNS – Motor Option 1 Option 1: More details ▪ The sympathetic trunk extends above/below T1-L2 Facilitates innervation of: ▪ Skin and blood vessels ▪ Head/neck/thoracic structures Important paravertebral ganglia include: ▪ superior cervical ▪ Middle cervical ▪ Inferior cervical Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 SNS – Motor Option 1 Option 1: More details ▪ Superior cervical ganglion (C1 – C4) Supplies structures in head/neck ▪ ex: eye, various glands, skin, blood vessels Postganglionic fibers travel along blood vessels and often join fibers of parasympathetic cranial nerves ▪ Examples: join CN III to pupil, CN VII and CN IX to various glands Join CN IX Join CN VII Join CN III SNS – Motor Option 1 Option 1: More details on cervical ganglia ▪ Middle cervical ganglion (C5-C6) and Inferior cervical ganglion (C7-C8) Supply thoracic region ▪ heart, trachea, bronchi, bronchioles, skin and blood vessels Inferior cervical ganglion often fuses with fibres from the first thoracic ganglion to form a stellate ganglion Note: Heart and lungs also receive input from option 2 (synapse at same spinal level, see next slide). This creates weblike cardiac and pulmonary plexuses. SNS – Motor Option 2 Option 2: ▪ T1-L2 level preganglionic neuron exits spinal cord and enters sympathetic trunk via a white rami communicans Axon synapses at a paravertebral ganglion at same spinal level ▪ Post-ganglionic neuron exits trunk via a gray rami communicans and joins spinal nerve to travel to target Gray ramus communicans Spinal nerve Anatomy and Physiology, 2nd ed. p. 594, fig. 15.3 SNS Motor Option 2 Option 2: More details ▪ Model is typical of sympathetic inputs to skin, blood vessels at that spinal level Remember: Above and below T1/L2 covered by option 1 ▪ Also some of the inputs to the heart and lungs (along with option 1) Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 SNS – Motor Option 3 Option 3: ▪ T5-L2 level preganglionic neuron exits spinal cord and enters sympathetic trunk via a white rami communicans Axon passes through paravertebral ganglion (may or may not travel first) without synapsing ▪ Axon exits and helps form splanchnic nerve (does not use gray rami communicans: not joining spinal nerve) Splanchnic nerve synapses at a prevertebral ganglion, postganglionic neuron travels to target Anatomy and Physiology, 2nd ed. p. 594, fig. 15.3 SNS-Motor Option 3 details: ▪ Greater splanchnic nerve (T5-T9) to celiac ganglion Abdominal organs (stomach, spleen, liver, start of SI…) ▪ Lesser splanchnic nerve (T10-T11) to superior mesenteric ganglion, aorticorenal ganglia SI to proximal colon, kidney ▪ Least splanchnic nerve (T12) to renal plexus/ganglia Kidney ▪ Lumbar and sacral splanchnic nerves (L1 – L2/3) to inferior mesenteric ganglion Distal colon to bladder, rectum, genitalia (plexuses to pelvic and lower abdominal organs) General idea: Great, Lesser, Lumber/Sacral splanchnic = upper to lower body, respectively. Least = kidney (with aorticorenal and renal ganglia). Basic SNS Anatomy – “Option 3” The “pretty diagram version” It’s easy to see the preganglionic splanchnic nerves and the ganglia Moore’s Clinically-Oriented Anatomy, p. 1241, fig. 5.88 Basic SNS Anatomy A more realistic picture Splanchnic nerves and prevertebral ganglia look all jumbled together Moore’s Clinically-Oriented Anatomy, p. 1242, fig. 5.89 Test Yourself Before moving onto the next presentation, make sure you are confident in answering the questions on the following slides ▪ All answers are directly in this ppt presentation Test yourself For options 1,2 and 3 of sympathetic outflow from the spinal cord, where do pregangionlic fibers go first? Once they get there: ▪ For options 1 and 2, the fibers ______ in the trunk. Postganglionic fibers then exit via a ____ _____ ____ to join a ___ ____ and travel to their target. ▪ For option 3, the fibers pass through the trunk and form a ____ nerve that synapses on a ______ ganglion. Postganglionic fibers then travel to their target Test yourself Regarding sympathetic innervation to the heart and lungs: ▪ 1) Preganglionic fibers synapse on paravertebral ganglia at ________ spinal levels Choose the correct option to fill in the blank ▪ Same ▪ Different ▪ Same or different ▪ 2) The paravertebral ganglia involved include (choose all that apply): Superior cervical Middle cervical Inferior cervical/stellate Test yourself Regarding sympathetic innervation to the skin and blood vessels: ▪ 1) Preganglionic fibers synapse on paravertebral ganglia at ________ spinal levels Choose the correct option to fill in the blank ▪ Same ▪ Different ▪ Same or different ▪ 2) The paravertebral ganglia involved include (choose all that apply): Superior cervical Middle cervical Inferior cervical/stellate Test yourself Match the splanchnic nerve with the correct ganglion and target (one target will have 2 correct ganglia) Splanchnic Nerve Ganglion Target Great Inferior mesenteric Kidney Lesser Superior mesenteric Distal colon Least Celiac Proximal SI Lumbar/sacral Renal Stomach Intro to the ANS: Video 3 Parasympathetic Nervous System Anatomy Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy Brainstem nuclei or sacral spinal cord Myelinated preganglionic neurons Ganglia: Terminal Non-myelinated postganglionic neurons Ganglion < Video 3: Parasympathetic Nervous System Anatomy < Spinal cord Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Target Video 4: Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Video 5: Actions of the ANS Video 6: Applied Pharmacology of the ANS Nervous System: Motor Brain Somatic NS - skeletal muscle Cranial nerves: voluntary (or reflex) actions (head/neck) Autonomic NS – smooth muscle, cardiac cells, glands Spinal Cord Somatic NS - skeletal muscle Autonomic NS – smooth muscle, cardiac cells, glands Spinal nerves: voluntary (or reflex) actions (below head/neck) Parasympathetic Cranial nerves: involuntary actions (upper/middle body) Parasympathetic Spinal nerves (pelvic splanchnic: involuntary actions (lower body) Sympathetic Spinal nerves (some form various splanchnic nerves) involuntary actions (whole body) Comparing the SNS and PaNS Sympathetic nervous system ▪ Myelinated pre-gangionic fibers: shorter Neuronal cell bodies: T1 – L2 (intermediolateral horn) Synapse on ganglia inside or outside of sympathetic trunk ▪ Ganglia: paravertebral or prevertebral ▪ Non-myelinated post-ganglionic fibres: longer Ganglion Post: Nonmyelinated < ▪ Myelinated pre-ganglionic fibres: longer < Parasympathetic nervous system Pre: Myelinated Neuronal cell bodies: brainstem or sacral spinal levels (interomediolateral horn) Target Synapse on ganglia outside of sympathetic trunk ▪ Ganglia: “terminal” ganglia (near or on target) ▪ Non-myelinated post-ganglionic fibres: shorter Comparing the SNS and PaNS PaNS = “craniosacral” Cranial nerves - nuclei in brainstem: where? Spinal nerves = Pelvic splanchnic nerves - nuclei in sacral spinal cord Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 20-1 Optional Neuroanatomy Review: Cranial Nerve Nuclei Locations Divide into groups of 4 in numerical order ▪ Label as midbrain, pons, medulla (in order from superior to inferior brainstem) ▪ Add in exceptions Not in brainstem: Found in retina Not in brainstem: Found in olfactory bulb I, II, III, IV: Midbrain On the border of pons & medulla, found in both Trigeminal, found in all 3 parts of brainstem (MB, pons, medulla) V, VI, VII, VIII: Pons IX, X, XI, XII: Medulla Parasympathetic motor: Cranial ▪ Oculomotor: CN III Midbrain: Edinger-Westphal nucleus → ciliary ganglion ▪ Post ganglionic fibers (short ciliary nerves) innervate pupil (constriction) and lens (accommodation) ▪ Facial: CN VII Pons: superior salivatory nucleus → ▪ sphenopalatine ganglion Post ganglionic fibers innervate lacrimal and nasal glands (secretions) ▪ submandibular ganglion Post ganglionic fibers innervate sublingual, submaxillary salivary glands (secretions) Parasympathetic motor: Cranial ▪ Glossopharyngeal: CN IX Medulla (inferior salivatory nucleus) → otic ganglion ▪ Post ganglionic fibers innervate parotid salivary glands (secretion) ▪ Vagus: CN X Medulla (dorsal motor nucleus) → terminal ganglia on/near organs ▪ Post ganglionic fibers supply plexuses in the thoracic and abdominal cavities, all the way to the distal colon More details next slide Parasympathetic motor: Cranial Vagus ▪ Responsible for most parasympathetic output ▪ Leaves through jugular foramen, descends alongside the carotid arteries ▪ Longest course of any cranial nerve From brainstem to distal colon Moore’s Clinically-Oriented Anatomy, p. 2410, fig. 10.16 Putting it Together: Pupil PaNS to pupil: constriction ▪ Preganglionic CN III (oculomotor) → ciliary ganglion synapse → postganglionic (short ciliary) SNS to pupil: dilation ▪ Preganglionic SNS → superior cervical ganglion synapse, then through ciliary ganglion → postganglionic (long ciliary) Long ciliary nerve SNS accompanies PaNS from ciliary ganglion to pupil Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 5-11 Putting it Together: Salivary Glands PaNS to salivary glands (dominant) ▪ More secretions, more watery, more digestive enzymes ▪ CN VII: submaxillary ganglion ▪ CN IX: otic ganglion SNS to salivary glands ▪ Less secretions, more “mucous-y” ▪ Superior cervical ganglion ▪ SNS fibers eventually join PaNS (CNVI, IX) Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 5-11 Parasympathetic motor: Sacral Cell bodies found in S2-4 levels of spinal cord (intermediolateral horn) Efferents form pelvic splanchnic nerves to supply: ▪ the rectum ▪ bladder ▪ male and female reproductive organs Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 20-5 Test Yourself Before moving onto the next presentation, make sure you are confident in answering the questions on the following slides ▪ All answers are directly in this ppt presentation Test yourself Label the following as “S” for sympathetic or “P” for parasympathetic or “SP” for both ▪ Shorter preganglionic than postganglionic fibers ▪ Non-myelinated postganglionic fibers ▪ Preganglionic cell bodies in spinal cord or brainstem ▪ Postganglionic cell bodies in ganglia Test yourself Match each cranial nerve with the correct brainstem location, nucleus, ganglion and target. ▪ Some cranial nerves will have > 1 correct answer. Nerve Brainstem Nucleus Ganglion Target Facial Midbrain Dorsal motor Ciliary Abdominal and thoracic cavities Glossopharyngeal Pons EdingerWestphal Otic Medulla Oculomotor Inferior salivatory Vagus Superior salivatory Lacrimal/nasal glands Sphenopalatine Submandibular “Terminal” Parotid gland Pupil Sub- lingual/maxillary glands Test yourself All smooth muscle, cardiac cells, and glands with parasympathetic innervation are supplied by cranial nerves except what 3 general areas of the body? ▪ The parasympathetic innervation to these 3 areas is via which nerves? Where are the cell bodies of their preganglionic fibers found? Intro to the ANS: Video 4 Messengers of the ANS Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy Brainstem nuclei or sacral spinal cord Myelinated preganglionic neurons Ganglia: Terminal Non-myelinated postganglionic neurons Ganglion < Video 3: Parasympathetic Nervous System Anatomy < Spinal cord Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Target Video 4: Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Video 5: Actions of the ANS Video 6: Applied Pharmacology of the ANS Messengers of ANS How do preganglionic neurons “talk” to postganglionic neurons? ▪ Release acetylcholine (ACH) to act on cholinergic receptors Both sympathetic and parasympathetic systems How do postganglionic neurons “talk” to their target tissues? ▪ Release norepinephrine (NE) to act on adrenergic receptors Sympathetic system only ▪ Release the neurotransmitter acetylcholine (ACH) to act on cholinergic receptors Predominantly parasympathetic system, some sympathetic system NE is similar to epinephrine (E), AKA noradrenaline and adrenaline. ANS – Neurotransmitters and Receptors Preganglionic cell body Ganglia NT at ganglia Receptor at NT at Receptor at ganglia tissue tissue Symp T1-L2 spinal cord Paraor prevertebral ACH Cholinergic: NE* N (Nicotinic) Adrenergic**: alpha or beta Para- Brainstem symp or S1-4 spinal cord Terminal ACH Cholinergic: ACH N Cholinergic: M (Muscarinic) * Exceptions 1) Adrenal medulla is a specialized sympathetic ganglion that releases mostly E (some NE) directly into blood stream to reach target tissues 2) ACH release (ie cholinergic sympathetic innervation) in skin: - sweat glands (FYI - eccrine) - blood vessels: both adrenergic and cholinergic sympathetic innervation - adrenergic tonically active, cholinergic responds to increase in body temp ** Exception: ACH acts on cholinergic M receptors at sweat glands & skin blood vessels Nervous System Overview Somatic and ANS neurotransmitters and receptors Sp. Cd. Somatic Nervous System ACH N Skeletal muscle Sp. Cd. Sp. Cd. Somatic Nervous System ANS Sympathetic ACH N ACH N Skeletal muscle α,β NE Smooth muscle, cardiac cells, most glands Sp. Cd. Sp. Cd. Somatic Nervous System ANS Skeletal muscle Sympathetic ACH N ACH → E, NE Ad. M. (ACH) N ACH N N α,β NE Smooth muscle, cardiac cells, most glands (ACH) (M Ex: Sweat glands) Sp. Cd. Sp. Cd. Somatic Nervous System ANS Skeletal muscle Sympathetic α,β NE Smooth ACH N ACH → E, NE Ad. M. N muscle, cardiac cells, most glands (ACH) (M (ACH) N Brainstem or Sp. Cd. ACH N ANS Parasympathetic ACH N Ex: Sweat glands) ACH M Smooth muscle, cardiac cells, glands Sp. Cd. Sp. Cd. Somatic Nervous System ANS Skeletal muscle Sympathetic α,β NE Smooth ACH N ACH → E, NE Ad. M. N muscle, cardiac cells, most glands (ACH) (M (ACH) N Brainstem or Sp. Cd. ACH N ANS Parasympathetic ACH N Ex: Sweat glands) ACH M Smooth muscle, cardiac cells, glands Neurotransmitters Norepinephrine/epinephrine (NE/E) – Quick review: ▪ Released in ANS, sympathetic system only Act on alpha/beta receptors at target tissues ▪ Stored in vesicles until a depolarization causes release via exocytosis NE and E (and dopamine) = catecholamines https://en.wikipedia.org/wiki/Catecholamine Catecholamine Synthesis Tyrosine L-Dopa Dopamine (DA) Outside vesicle Tyr → L-Dopa: Hydroxylation L-Dopa → DA: Decarboxylation Inside vesicle DA → NE: hydroxylation NE E Adrenal medulla: NE → E: methylation (involves moving in and out of vesicle) https://en.wikipedia.org/wiki/File:Biosynthese_Adrenalin.png Catecholamine Synthesis: NE https://med.libretexts.org Catecholamine Synthesis: E Adrenal Medulla https://med.libretexts.org Catecholamine Degradation 50 – 80% of secreted norepinephrine is taken up again into the presynaptic terminal for degradation ▪ Note: does not apply to epinephrine E is secreted into bloodstream by adrenal medulla (chromaffin cells), not nerve endings NE and E ▪ Can be broken down by monoamine oxidase (MAO) Found in neuronal cells, often near synapses in presynaptic terminals FYI: degradation product = dihydromandelic acid ▪ Can be broken down by catechol-O-methyl-transferase (COMT) Widely distributed throughout tissues, often post-synaptic FYI: degradation product = metanephrine After release, NE can: ▪ Act on a post-synaptic alpha or beta receptor to cause a cellular response Tyrosine Dopamine VMAT NE NE NE α or β Post-synaptic receptor Cellular response After release, NE can: ▪ Be transported into the presynaptic terminal for reuptake into a vesicle or degradation by MAO Tyrosine Dopamine VMAT NE Degradation: MAO NE NE α or β Post-synaptic receptor Cellular response After release, NE can: Tyrosine ▪ Be transported into the postsynaptic terminal for degradation by COMT Dopamine VMAT NE Degradation: MAO NE NE α or β Degradation: COMT Post-synaptic receptor Cellular response After release, NE can: Tyrosine ▪ Act on a pre-synaptic alpha2 receptor to turn off further release Dopamine VMAT NE Degradation: MAO (-) NE NE α2 Presynaptic receptor α or β Degradation: COMT Post-synaptic receptor Cellular response After release, NE can: ▪ Act on a postsynaptic alpha or beta receptor to cause a cellular response ▪ Be transported into the presynaptic terminal for reuptake into vesicle or degradation by MAO ▪ Be transported into the postsynaptic terminal for degradation by COMT ▪ Act on a pre-synaptic alpha2 receptor to turn off further release Tyrosine Dopamine VMAT NE Degradation: MAO (-) NE NE α2 Presynaptic receptor α or β Degradation: COMT Post-synaptic receptor Cellular response Neurotransmitters Acetylcholine (ACH) – quick review ▪ Released in somatic nervous system: Acts on N receptors at neuromuscular junctions ▪ Released in ANS: Acts on N receptors at ganglia in both SNS and PaNS Acts on M receptors at target tissues, predominantly in PaNS ▪ SNS exception: sympathetic cholinergic innervation to skin (sweat glands, blood vessels) Acetylcholine Synthesis Acetylcholine is synthesized in presynaptic nerve terminals then stored in vesicles prior to release Acetyl-CoA + Choline ----------------> Acetylcholine Enzyme: choline acetyltransferase med.libretexts.org Acetylcholine Degradation After secretion into synapse, ACH is degraded to acetate and choline by acetylcholinesterase* ▪ Choline is taken back up into the presynaptic terminal for reuse * * Soluble and membranebound forms exist at the synapse med.libretexts.org Basic cholinergic synapse Acetylcholinesterase is widely distributed in connective tissue throughout the body and in the synapse of cholinergic terminals Katzung & Vanderah, Basic and Clinical Pharmacology, 15th ed., fig. 6-3 Receptors of the ANS Neurotransmitter NE, E Receptor α1, α2, β1, β2 ACH M Start of Signaling Cascade Various Gproteins Tissue Response Fight/flight or rest digest activities: cardiac cells, smooth muscle cells, glands N Opening of Na+ channel Ganglionic transmission or skeletal muscle contraction Major Types of Receptors Receptor Type Neurotransmitter G-protein Signaling pathway Nicotinic Acetylcholine N/A Ionotropic receptor → sodium channel opening 1 adrenergic NE slightly > E Gq Activates PLC → IP3, DAG → increased calcium 2 adrenergic NE slightly > E Gi Inhibits AC→ decreased cAMP 1 adrenergic E slightly > NE Gs Stimulates AC → increased cAMP 2 adrenergic (3 adrenergic) E > NE* Gs Stimulates AC → increased cAMP M1 muscarinic (M3 muscarinic) Acetylcholine Gq Activates PLC → IP3, DAG → increased calcium (M2 muscarinic) Acetylcholine Gi Inhibits AC → decreased cAMP * Significant: NE does not bind beta 2 as well as E does PLC = Phospholipase C; AC = Adenylate cyclase Test Yourself Before moving onto the next presentation, make sure you are confident in answering the questions on the following slides ▪ All answers are directly in this ppt presentation Test yourself List - ACH - NE Choose from the list on the left to fill in the blanks regarding the PaNS (Some options will not be used, some will be used more than once) - Alpha - Beta -N -M - Somatic - Sympathetic - Ganglia - Target tissues ▪ Preganglionic nerves release the neurotransmitter ___ to “talk” to postganglionic nerves at the level of the ___. Here, this NT acts on cholinergic ___ receptors. ▪ Postganglionic nerves use the neurotransmitter ___ to “talk” to ___. This same NT can activate two types of cholinergic receptors: ▪ 1) The cholinergic receptor found at skeletal muscle neuromuscular junctions in the ___ nervous system is ____. ▪ 2) The cholinergic receptor found in postganglionic target tissues is ___. Test yourself List - ACH - NE -E Choose from the list on the left to fill in the blanks regarding the SNS (Some options will not be used, some will be used more than once) - Salivary - Sweat ▪ Preganglionic nerves use the neurotransmitter ___ to “talk” to postganglionic nerves at the level of the ___. Here, this NT acts on cholinergic ___ receptors. ▪ Postganglionic nerves mainly use the neurotransmitter ___ to “talk” to ___. The adrenergic receptors found here are either ___ or ___. - Ganglia - Target tissues ▪ Sometimes sympathetic postganglionic nerves are cholinergic in nature. One example is: - Alpha - Beta -N -M Sympathetic cholinergic fibers to ___ glands, which release the NT ___ to act on ___ receptors Test yourself Categorize each of the following neurotransmitters as being made in either the cytoplasm or vesicles ▪ ACH ▪ Dopamine ▪ NE What enzyme metabolizes ACH? ▪ True or false: This enzyme can be found in its soluble form in the vicinity of cholinergic synapses Where are the two enzymes that metabolize NE? ▪ Where is each one predominantly found? Choose the main location for each enzyme: presynaptic neuron, postsynaptic neuron Intro to the ANS: Video 5 Actions of the ANS Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy Brainstem nuclei or sacral spinal cord Myelinated preganglionic neurons Ganglia: Terminal Non-myelinated postganglionic neurons Ganglion < Video 3: Parasympathetic Nervous System Anatomy < Spinal cord Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Target Video 4: Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Video 5: Actions of the ANS Video 6: Applied Pharmacology of the ANS Determining ANS Responses Sympathetic - Ask: what happens during Mostly “fight or flight”? dual Parasympathetic = opposite to sympathetic innervation Sympathetics What would happen if you were confronted by a monster (or a BMS exam that you forgot about …☺ )? ▪ Heart: fast and pounding = increased rate and contractility Note: Parasympathetics have little effect on contractility ▪ Bronchioles: “gulping air” when scared or running Relaxed to maximize the amount of air entering your lungs Determining Sympathetic Responses When dealing with an eminent threat, you are not sitting down to eat and digest a meal ▪ GI functions decrease Motility decreased, sphincters closed Glands: digestive secretions minimal Blood flow to GI minimal ▪ Bladder muscle relaxed, sphincter contracted You are likely “holding everything in” while dealing with your situation FYI: Being so scared you “pee your pants” is a sympathetic over-ride situation Note: Intestinal glands are less controlled by the ANS, more by food in gut lumen Determining Sympathetic Responses You will need energy to deal with your imminent threat: ▪ Glycogenolysis (liver, muscle) Purpose? ▪ Lipolysis (adipose) Purpose? PaNS has an opposite but minimal direct effect Note: The SNS and PaNS also control glucose and fat metabolism through their actions on glucagon and insulin release: - Increased glucagon release/decreased insulin release = sympathetic Rationale? - Increased insulin release/decreased glucagon release = parasympathetic Determining Sympathetic Responses The hairs on your skin stand up and your eyes go “wide with fear” ▪ Arrector pili: contract Dual innervation exception: no opposing parasympathetic effect ▪ Pupils: dilate Note, eyes also have: - lacrimal glands (tears) - ciliary muscle (controls lens shape) Predominantly under PaNS control You start sweating ▪ Dual innervation exception: sweat glands are innervated by sympathetic cholinergic fibers only Determining Sympathetic Responses You need to redistribute blood flow to get oxygen and nutrients to tissues that need them most when fighting or fleeing Skeletal and cardiac muscle = most: Vasodilation Skin = least: Vasoconstriction Different sympathetic actions in different tissues due to the presence of α (constriction) vs β (dilation) receptors. Dual innervation exception: Very little parasympathetic innervation of vasculature outside of the GI and reproductive systems, although all blood vessels have M-receptors. Organ Sympathetic Stimulation Parasympathetic Stimulation Heart - Increased rate & contractility (β1) - Mostly decreased rate (M) (minimal effect on contractility) Blood vessels - Vasoconstriction: skin, most vasculature (α1) - Vasodilation: skeletal. muscle., coronary arteries. liver (β2) - Vasodilation: GI/reproductive (M) (Other vessels have M-receptors, no significant PaNS innervation) Lung - Bronchial muscle relaxation (β2) - Bronchial muscle contraction (M) GI tract - Decreased motility (β2) - Sphincter contraction (α1) - Increased motility (M) - Sphincter relaxation (M) Bladder - Relaxation of detrusor muscle (β2) - Contraction of sphincter (α1) - Contraction of detrusor mus. (M) - Relaxation of sphincter (M) Pancreas - Inhibition of insulin (α2) and stimulation of glucagon release (β2) - Stimulation of insulin, inhibition of glucagon release (M) Liver - Glycogenolysis (α1) (Glycogenesis minimal – M) Adipose - Lipolysis (β3) (Lipogenesis minimal – M) Eye - Dilation of pupil (mydriasis) (α1) (Ciliary muscle relaxation minimal) (Lacrimal gland effects minimal) - Constriction of pupil (miosis) (M) - Contraction of ciliary muscle (M) - Increased lacrimal secretions (M) GI glands - (Less profuse, viscous secretions: minimal) (α1) - Profuse, watery secretions (M) Skin - Increased secretions from sweat gland (M) - Contraction of arrector pili (α1) Autonomic Nervous System Actions – an Overview Boron & Boulpaep, Medical Physiology: A Cellular and Molecular Approach, 2005: fig. 14-4 General Considerations Parasympathetic and sympathetic nervous systems can both cause specific, localized responses ▪ Day-to-day function, as well as reflexes (next slide) SNS can also be diffusely activated ▪ Mass discharge to accomplish the “fight or flight” response Arterial pressure, heart rate, and perfusion to skeletal muscle, heart, brain increase Decreased blood flow through the GI tract, skin, kidneys Hyperglycemia, increased general cellular metabolism, and increased coagulation Autonomic Nervous System Reflexes Major reflexes include: ▪ Baroreceptor reflex GI reflexes also stimulated by sight/taste/ smell of food (CN’s II/VI,IX,X/I, respectively) Afferent – baroreceptors: CNs IX and X Efferent – parasympathetic or sympathetic → CN X or thoracic plexus ▪ GI reflex mediated by food in gut Afferent – visceral receptors: CN X Efferent – parasympathetic → CN X ▪ Micturition (urination) reflex Afferents & efferents at the level of the sacral spinal cord ▪ Efferents cause: Parasympathetic activation (contract bladder) Sympathetic and somatic inhibition (open sphincters) Nucleus tractus solitarius (medulla) receives the sensory input Test Yourself Before moving onto the next presentation, make sure you are confident in answering the questions on the following slides ▪ All answers are directly in this ppt presentation Test yourself ANS has dual innervation (PaNS and SNS) to smooth muscle, cardiac cells and glands, with the following exceptions (SNS only): ▪ Blood vessels (outside of the _____ and _____ systems, which also have PaNS innervation) ▪ Skin: blood vessels, _____ glands, ______ muscles Indicate if the following are predominantly controlled by the parasympathetic or sympathetic nervous system: ▪ Glucose metabolism ▪ Lacrimal gland secretions ▪ Salivary gland secretions ▪ Heart contractility Test yourself Match the actions below with the correct division of the ANS and the correct associated receptor ▪ Divisions: PaNS, SNS ▪ Receptors: α1, α2, β1, β2, M ▪ Actions: Decreased heart rate Relaxation of bronchioles Insulin release Glycogenolysis Profuse sweating Profuse salivation Vasodilation: Skeletal muscle Vasoconstriction: Most vasculature (incl. skin) Contraction of GI sphincters Pupillary constriction Intro to the ANS: Video 6 Intro to ANS Pharmacology Dr. Heisel BMS100 Outline Video 1: Nervous system overview Intro to Sympathetics Video 2: Sympathetic Nervous System Anatomy Brainstem nuclei or sacral spinal cord Myelinated preganglionic neurons Ganglia: Terminal Non-myelinated postganglionic neurons Ganglion < Video 3: Parasympathetic Nervous System Anatomy < Spinal cord: Intermediolateral horn Myelinated preganglionic neurons Ganglia: Paravertebral, Prevertebral Non-myelinated postganglionic neurons Target Video 4: Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Video 5: Actions of the ANS Video 6: Applied Pharmacology of the ANS Application: Pharmacology If the mechanism of a drug is activation of alpha, beta or M receptors, knowing the physiological responses of those receptors allows you to: ▪ Determine theoretical therapeutic uses ▪ Potential adverse effects For example… Application: Pharmacology Therapeutic use: ▪ If a patient has urinary retention from an underactive bladder, a drug that activates M receptors could help* Leads to contraction of bladder wall and opening of sphincter (FYI: bethanecol) Adverse effects: ▪ Often occur due to: * Still need to memorize which drugs are tested and approved for which specific conditions The intended action being too strong ▪ Ex: incontinence (involuntary urination) Unintended but predictable drug actions ▪ Ex: M-receptor stimulation can also increase gut motility, leading to diarrhea Intro to Sympathetic Pharmacology SNS: Adrenergics Directly acting: Act at the receptor Indirect acting: Act outside receptors Direct Adrenergic Effects Agonist – binds and activates a receptor (or enzyme) ▪ Variation – a partial agonist binds but only partially activates a receptor (ie causes a “lesser” response) Antagonist – binds and inactivates a receptor (or enzyme) Biological response ▪ Can be reversible – it will eventually “let go” of the receptor or enzyme ▪ Can be irreversible – it stays bound, and the receptor or enzyme (usually enzyme) is rendered useless Agonist Partial Agonist Antagonist Receptor Selectivity Alpha and beta receptors have different affinities for different agonists and antagonists ▪ A non-selective beta-agonist is one that binds both beta 1 and 2 receptors with high affinity (but has minimal activity at alpha receptors) FYI: isoproterenol = selective beta-agonist with negligible alpha affinity ▪ A selective beta-1 agonist binds beta-1 receptors with high affinity, but has minimal activity at beta-2 (and alpha) receptors ▪ The same principles are true for antagonists FYI: metoprolol is a selective beta-1 antagonist, meaning it blocks beta-1 well but not beta 2 Indirect adrenergic effects Let’s look at how could we increase or decrease adrenergic activation of the catecholamine transmission via indirect effects Indirect Effects on Adrenergic Transmission: Presynaptic How could you block storage of NT in the vesicle? ▪ What would the effect be: increase or decrease in catecholamine transmission? What would happen if you facilitated non-vesiclemediated “leakage” of NT from the presynaptic terminal: ▪ Increase or decrease in catecholamine transmission? Tyrosine Dopamine VMAT Degradation: MAO NE NE (-) NE α2 NE FYI: - Resperpine blocks VMATs - Amphetamine, tyramine facilitate “leakage” of NT Indirect Effects of Adrenergic Transmission: Presynaptic What would the effect be of each of the following: an increase or decrease in catecholamine transmission? ▪ Inhibition of reuptake at the presynaptic terminal ▪ Inhibition of NT degradation ▪ Inhibition of NT release due to auto-receptor activation Tyrosine Dopamine VMAT Degradation: MAO NE NE (-) NE NE α2 FYI: - Reuptake inhibitors include cocaine and venlafaxine (Effexor®) - MAO inhibitors include tranylcypromine - Clonidine can activate autoreceptors Intro to Parasympathetic Pharmacology PaNS: Cholinergic Classifications ▪ Indirect acting: Act outside receptors ▪ Directly acting: Act at the receptor Receptor agonists and antagonists Remember: Overall, blood vessels have M-receptors even though very few have PaNS innervation ▪ M-receptor agonists can therefore cause vasodilation, as they active these receptors even in the absence of parasympathetic innervation ▪ Cholinomimetics: cause cholinergic responses ▪ Anticholinergics: inhibit cholinergic responses Cholinergics can therefore be categorized as: - direct or indirect (ie whether or not they act on the receptor) Plus - cholinomimetic or anticholinergic (ie whether they cause or inhibit cholinergic responses) Apply your knowledge The rest of the slides are for you to work through on your own to practice applying what you have learned ▪ The answers are included after each set of questions The purpose of these slides is application, so it is very important to try to work through them prior to viewing the answers ▪ Reminder: FYI = non-testable (but typically very interesting and clinically applicable!) information You do NOT need to memorize any drug names, as you will NOT be tested on drug names in BMS! ▪ You could be tested on what type of drug mechanism would produce what type of physiological response Apply your knowledge Categorize A-D as direct or indirect PLUS cholinomimetic or anticholinergic A: Prevents ACH degradation (ex neostigmine) ▪ Example drug names are FYI only B: Blocks ACH release (ex Botulinum toxin) C: Binds, activates M receptors (ex pilocarpine) X D: Binds, blocks M receptors (ex atropine) X A ▪ Indirect, does not act at receptor ▪ Cholinomimetic By blocking the acetylcholinesterase enzyme, more ACH is available to act (as less is degraded) B ▪ Indirect, does not act at receptor ▪ Anticholinergic Less ACH released to act C ▪ Direct action at receptor ▪ Agonist: activates receptor D ▪ Direct action at receptor ▪ Antagonist: blocks receptor Apply your knowledge: anticholinergics Based on the previous slide, what indirect drug mechanism would result in decreased cholinergic activity? ▪ A localized intramuscular injection of this type of drug (FYI: BoTox®) would result in less activation of ___ receptors in skeletal muscles (fill in the blank) The resulting muscle relaxation has numerous potential uses, including (FYI): ▪ Reducing wrinkles (ex cosmetic) ▪ Reducing spasticity (ex of calf muscles in cerebral palsy) ▪ Prophylaxis against migraines Apply your knowledge: anticholinergics Block of ACH release from presynaptic terminals Based on the previous slide, what indirect drug mechanism would result in decreased cholinergic activity? ▪ A localized intramuscular injection of this type of drug (FYI: BoTox®) would result in less activation of ___ receptors in skeletal muscle (fill in the blank) Receptor = N The resulting muscle relaxation has numerous potential uses, including (FYI): ▪ Reducing wrinkles (ex cosmetic) ▪ Reducing spasticity (ex of calf muscles in cerebral palsy) ▪ Prophylaxis against migraines Apply your knowledge: cholinergics Myasthenia gravis (MG) is an autoimmune disease ▪ Antibodies block N-receptors at the neuromuscular junctions of skeletal muscle cells This prevents ACH stimulation of muscle contraction, and leads to intermittent muscle paralysis Autoantibodies Y What indirect drug mechanism would allow ACH to last longer after release into the synaptic cleft, thus making it more likely to diffuse further and find an unblocked receptor? Y Y Hint: this type of drug is an “anticholinesterase” - Do not confuse this with an “anticholinergic” Which one of these increases and which one decreases ACH responses? MG Answers Indirect mechanism = blocking degradation of ACH via inhibition of the acetylcholinesterase enzyme ▪ This is an “anticholinesterase” mechanism anticholinesterase against Enzyme that breaks choline ester bonds Inhibits the enzyme that breaks the bond between acetyl and choline groups, thus preventing degradation ACH and increasing ACH responses = cholinomimetic anticholinergic against Molecule that promotes the actions of acetylcholine Inhibits the molecule that promotes ACH actions, thus decreasing ACH responses Apply your knowledge: adrenergics Consider the two hallmark symptoms of anaphylactic shock: ▪ Vasodilation leading to a rapid drop in blood pressure ▪ Bronchoconstriction leading to difficulties breathing To treat anaphylactic shock, what type of agonist would be most useful: ▪ Alpha 1 and 2 agonist ▪ Beta 1 and 2 agonist ▪ Alpha 1 and beta 2 agonist Based on your answer, what is the better choice of treatment: NE or E? (review slide to follow if needed) REVIEW from ANS ppt presentation 5 Receptor Type Neurotransmitter G-protein Signaling pathway Nicotinic Acetylcholine N/A Ionotropic receptor → sodium channel opening 1 adrenergic NE slightly > E Gq Activates PLC → IP3, DAG → increased calcium 2 adrenergic NE slightly > E Gi Inhibits AC→ decreased cAMP 1 adrenergic E slightly > NE Gs Stimulates AC → increased cAMP 2 adrenergic (3 adrenergic) E > NE* Gs Stimulates AC → increased cAMP M1 muscarinic (M3 muscarinic) Acetylcholine Gq Activates PLC → IP3, DAG → increased calcium (M2 muscarinic) Acetylcholine Gi Inhibits AC → decreased cAMP * Significant: NE does not bind beta 2 as well as E does PLC = Phospholipase C; AC = Adenylate cyclase For anaphylactic shock, you want something that will: ▪ Activate alpha 1 receptors Causes vasoconstriction in skin and most vascular beds, thus quickly counteracting any drop on blood pressure ▪ Activate beta 2 receptors Causes bronchodilation, thus alleviating the breathing difficulties Therefore, the best choice is: ▪ Alpha 1 and beta 2 agonist FYI - This is why people with allergies carry an EpiPen®! (Epi = epinephrine) E better than NE ▪ Both E and NE cause significant alpha 1 vasoconstriction and therefore help with blood pressure, but E has the strongest beta 2 effect for bronchodilation (see note at bottom of review table on previous slide) Apply your knowledge: adrenergics Use the following two tables to answer the questions on the subsequent slides ▪ The first table is the ANS actions table, copied and pasted from PPT 5 You should be able to answer the questions without this table, but it is included here as a reference if needed ▪ The second table adds various pharmaceutical agonists and antagonists to your previous receptor table (in brackets) The names of these pharmaceuticals are FYI only in BMS Organ Sympathetic Stimulation Parasympathetic Stimulation Heart - Increased rate & contractility (β1) - Mostly decreased rate (M) (minimal effect on contractility) Blood vessels - Vasoconstriction: skin, most vasculature (α1) - Vasodilation: skeletal. muscle., coronary arteries. liver (β2) - Vasodilation: GI/reproductive (M) (Other vessels have M-receptors, no significant PaNS innervation) Lung - Bronchial muscle relaxation (β2) - Bronchial muscle contraction (M) GI tract - Decreased motility (β2) - Sphincter contraction (α1) - Increased motility (M) - Sphincter relaxation (M) Bladder - Relaxation of detrusor muscle (β2) - Contraction of sphincter (α1) - Contraction of detrusor mus. (M) - Relaxation of sphincter (M) Pancreas - Inhibition of insulin (α2) and stimulation of glucagon release (β2) - Stimulation of insulin, inhibition of glucagon release (M) Liver - Glycogenolysis (α1) (Glycogenesis minimal – M) Adipose - Lipolysis (β3) (Lipogenesis minimal – M) Eye - Dilation of pupil (mydriasis) (α1) (Ciliary muscle relaxation minimal) (Lacrimal gland effects minimal) - Constriction of pupil (miosis) (M) - Contraction of ciliary muscle (M) - Increased lacrimal secretions (M) GI glands - (Less profuse, viscous secretions: minimal) (α1) - Profuse, watery secretions (M) Skin - Increased secretions from sweat gland (M) - Contraction of arrector pili (α1) Receptors Agonists and Antagonists Receptor Type Agonist Antagonist GSignaling pathway protein Nicotinic Acetylcholine (Curare) N/A Ionotropic receptor → sodium channel 1 adrenergic NE slightly > E (Phentolamine, (Phenylephrine) Prazosin) Gq Activates PLC → IP3, DAG → increased calcium 2 adrenergic NE slightly > E (Clonidine) (Phentolamine) Gi Inhibits AC→ decreased cAMP 1 adrenergic E > NE* (Isoproterenol) (Metoprolol Propanolol) Gs Stimulates AC → increased cAMP 2 adrenergic (3 adrenergic) E > NE (Isoproterenol, Albuterol) (Propanolol) Gs Stimulates AC → increased cAMP M1 muscarinic (M3 muscarinic) Acetylcholine (Atropine) Gq Activates PLC → IP3, DAG → increased calcium (M2 muscarinic) Acetylcholine (Atropine) Gi Inhibits AC → decreased cAMP * Significant: NE does not bind beta 2 as well as E does Apply your knowledge: adrenergics Vasoconstriction in mucous membranes leads to decreased mucous production ▪ Use the table to pick the pharmaceutical receptor agonist you would choose as a decongestant. Justify your choice. FYI: This drug is administered orally or as a spray for decongestion ▪ What do you think this drug can used for if administered by IV in an emergent situation? To answer, fill in the blank and justify your choice. Can be used to _____ blood pressure (increase or decrease?) Apply your knowledge: adrenergics Vasoconstriction in mucous membranes leads to decreased mucous production ▪ Use the table to pick the pharmaceutical receptor agonist you would choose as a decongestant. Justify your choice. Phenylephrine, as it is an alpha 1 agonist and therefore causes vasoconstriction FYI: This drug is administered orally or as a spray for decongestion ▪ What do you think this drug can be used for if administered by IV in an emergent situation? To answer, fill in the blank and justify your choice. Can be used to _____ blood pressure (increase or decrease?) Increase: alpha 1 receptors cause vasoconstriction in most vascular beds, which leads to an increase in blood pressure Apply your knowledge: adrenergics Some selective beta 1 agonists are used to increase cardiac output in internal medicine/intensive care settings ▪ By what mechanism do they increase cardiac output? Which type of beta agonist would increase blood pressure the most, and why: ▪ Non-selective beta agonist (ie works well at both beta 1 and 2 receptors) (FYI isoproterenol) ▪ Selective beta 1 agonist (ie works well at beta 1 but not beta 2 receptors) (FYI dobutamine) Apply your knowledge: adrenergics Some selective beta 1 agonists are used to increase cardiac output in internal medicine/intensive care settings ▪ By what mechanism do they increase cardiac output? Beta1 activation leads to increased heart rate and contractility Which type of beta agonist would increase blood pressure the most, and why: ▪ Non-selective beta agonist (ie works well at both beta 1 and 2 receptors) (FYI isoproterenol) ▪ Selective beta 1 agonist (ie works well at beta 1 but not beta 2 receptors) (FYI dobutamine) Dobutamine (selective for beta 1) is more likely to increase blood pressure. Beta 1: increases cardiac output, leading to increased blood pressure Beta 2: causes vasodilation in certain tissues A beta 1 selective agonist will therefore not cause beta 2 vasodilation, which means the vessels will be more constricted overall, contributing to a greater increase in blood pressure Apply your knowledge: adrenergics An agonist with which of the following types of receptor specificities do you think would be a main choice for asthma inhalers? Why did you make that choice? Beta-1 selective agonist Beta-2 selective agonist Non-selective beta agonist ▪ Find the corresponding drug in the table Apply your knowledge: adrenergics An agonist with which of the following types of receptor specificities do you think would be a main choice for asthma inhalers? Why did you make that choice? Beta-1 selective agonist Increased heart rate and contractility Beta-2 selective agonist Bronchodilation Non-selective beta 1 & 2 agonist Both heart and lung effects Beta 2 selective: It will bronchodilate via beta 2 without unwanted heart effects via beta 1 ▪ Find the corresponding drug in the table. Example from table = albuterol (note: not isoproterenol, as this drug acts well on beta 1 receptors as well) FYI – salbutamol is another common inhaled medication in this drug class Apply your knowledge: antiadrenergics Antiadrenergics ▪ Alpha adrenergic antagonists help lower blood pressure by what mechanism? ▪ Beta adrenergic antagonists help lower blood pressure by decreasing heart ___ and ___. Anti-adrenergics therefore lend themselves to treatment of ____tension. (Fill in the blank: hypo or hyper) Apply your knowledge: antiadrenergics Antiadrenergics Alpha antagonists: Vasodilation (via block of vasoconstriction) by blocking alpha 1 effects ▪ Alpha adrenergic antagonists help lower blood pressure by what mechanism? ▪ Beta adrenergic antagonists help lower blood pressure by decreasing heart ___ and ___. Beta antagonists: Decreased heart rate & contractility by blocking beta 1 effects Anti-adrenergics therefore lend themselves to treatment of ____tension. (Fill in the blank: hypo or hyper) Treatment of hypertension: Less blood being pumped out due to decreased heart rate and contractility (beta-blocking effect), and/or vasodilation (alpha-blocking effect), can help reduce blood pressure The End ☺