Pharmacology: Introduction to Autonomic Nervous System PDF

PHARM20: PHARMACOLOGY INTRODUCTION TO AUTONOMIC NERVOUS SYSTEM Aileen Icban, MD| 19 SEPTEMBER 2023 OUTLINE V. FUNCTIONAL SYMPATHETIC VS PARASYMPATHETIC I....

PHARM20: PHARMACOLOGY INTRODUCTION TO AUTONOMIC NERVOUS SYSTEM Aileen Icban, MD| 19 SEPTEMBER 2023 OUTLINE V. FUNCTIONAL SYMPATHETIC VS PARASYMPATHETIC I. INTRODUCTION: ORGANIZATION OF a. Nervous System AUTONOMIC ACTIVITY b. Sympathetic VS a. Integration of Parasympathetic cardiovascular c. Autonomic VS Somatic function Nervous System b. Presynaptic d. Enteric Nervous regulation System II. CHOLINERGIC TRANSMISSION a. Cholinoreceptors: Muscarinic and Nicotinic receptors III. ADRENERGIC TRANSMISSION a. Adrenoreceptors” Alpha adrenoreceptors & betaadrenoreceptprs IV. DOPAMINE RECEPTORS V. NONADRENERGIC, NONCHO- LINERGIC NEURONS (NANC) Sympa ka S for Short pre, Parasympa long word, long Pre SYMPATHETIC PARASYMPATHETIC Thoracic and lumbar Brain and sacral IMPORTANT Must Know BOOK Old Trans Sites of origin region of the spinal area of the spinal cord (thoracolumbar) cord (craniosacral) INTRODUCTION Long preganglionic NERVOUS SYSTEM Short preganglionic Length of fibers Short Long postganglionic postganglionic Location of Close to the spinal Within or near ganglia cord effector organs Preganglionic Extensive Minimal fiber branching Distribution Wide Limited Type of Diffuse Discrete response AUTONOMIC VS SOMATIC MOTOR SYSTEMS Central nervous system (CNS): Comprises the brain and spinal cord Peripheral Nervous system (PNS): divided into motor neurons and sensory neurons. o Motor neurons further subdivided into: ▪ Somatic Nervous System: controls voluntary movements ▪ Autonomic Nervous System: Controls the involuntary responses. Further subdivided into: Sympathetic: “fight or flight” Parasympathetic: “rest or Difference between sympathetic and parasympathetic digest” based on their preganglionic axon, as well as postganglionic axon. Parasympathetic Nervous System o Preganglionic, myelinated: long ▪ one preganglionic axon would stimulate one receptor ALENCHERIL | BULAON | LORILLA | PATAWARAN | QUIAZON 1  INTRODUCTION TO AUTONOMIC NERVOUS SYSTEM o Post-ganglionic, unmyelinated: short CHOLINERGIC TRANSMISSION o Response: To secrete o Location of ganglia is near the effector organ Sympathetic Nervous System o Preganglionic, myelinated - short ▪ One preganglionic can produce or can stimulate many effector cells o Post-ganglionic, unmyelinated - long ▪ Has diffuse distribution o Location of ganglia is close to the spinal cord AUTONOMIC NERVOUS SYSTEM NEUROTRANSMITTER: Choline from the cytoplasm would enter the neuron by your choline transporter. Entry of choline in the neuron via Na+ Dependent transporter (CHT1) is inhibited by Choline Entry: Hemicholinium. Choline enters the nerve through a special transporter called CHT1, which depends Once on sodium choline it enters, (Na+). will bind with AcetylCoA, forming Choline entry can be blocked by Hemicholinium. Acetylcholine by choline acetyltransferase. Making Acetylcholine: Next step would be the storage of acetylcholine. Inside the Acetylcholine nerve, Cholinewill now be stored + AcetylCoA in the vesicle = Acetylcholine, in by your VAT presence of choline acetyltransferase. (Vesicular Acetylcholine Transporter) which is inhibited by Vesamicol. Storing Acetylcholine: o Inside the vesicle the Ach is also stored together Acetylcholine is stored in vesicles using a transporter called VAT. All preganglionic neuron of both Sympathetic and Vesamicol blocks VAT, withstopping other transmitters acetylcholine(ATP and peptide). storage. Preganglionic Neurons (Sympathetic & Parasympathetic): Release Acetylcholine (ACh). Parasympathetic would release Acetylcholine After storage it will be released. The vesicle also contains ATP and peptides. Trigger for release will be Parasympathetic postganglionic would release an action potential causing depolarization reaching the Parasympathetic Postganglionic Neurons: Release Acetylcholine. Releasing terminal Acetylcholine: will stimulate calcium influx and calcium will now Acetylcholine which will bind to receptor (cholinoceptor). ACh binds to cholinergic receptors (cholinoceptors). An action potential causes calcium to enter the nerve, which helps All Sympathetic postganglionic would release: bind your VAMP (Vesicle Associated Membrane Protein) or vesicles release Acetylcholine by fusing with the cell membrane. Norepinephrine Sympathetic Postganglionic and will bindNorepinephrine, Neurons:Release to an adrenoceptor. binds to adrenergic VAMP helps your thisfusion fusionprotein process. which will cause fusion of the vesicle receptors (adrenoceptors). o Except those that go to the sweat gland which Botulinum and toxinrelease of Ach can block thisand otherbytransmitter. release preventing the vesicles from Exception: Postganglionic neurons to sweat glands release Acetylcholine. fusing. o Release and fusion of the vesicle is inhibited by would release Acetylcholine Sympathetic Peripheral Some of Fibers: the peripheral sympathetic Some secrete Dopamine.fiber would secrete Botulinum toxin. Acetylcholine Action: Dopamine. After release Ach would then bind to the receptors Adrenal Medulla: Secretes Epinephrine. Once released, Acetylcholine binds to muscarinic or nicotinic receptors Adrenal medulla would secrete Epinephrine (cholinoceptor: either muscarinic or nicotinic). Ach will on other cells. Somatic On System: Nervous the Somatic system, motor neuron would release now be degraded Acetylcholinesterase breaks by yourAcetylcholine down acetylcholinesterase intoand into choline choline acetate. Motor Neuronsacetylcholine release Acetylcholine. and will bind to nicotinic receptors. and acetate Some acetylcholine which binds has no effect to presynaptic on the stimulation receptors to reduce itsofown your ACh binds to nicotinic receptors. release. cholinoceptors. o Some Ach will bind to the presynaptic receptor ENTERIC NERVOUS SYSTEM (muscarinic or nicotinic) will inhibit the release of 3rd division of the ANS its receptor. Its effect will be in the GIT, Pancreas, Gallbladder What will happen to acetylcholine if Hemicholinium is “Brain of the GUT” given? Controls the motility exocrine and endocrine secretion and microcirculation of the GIT o Decrease Parasympathetic activity due to Modulated by both Parasympathetic and Sympathetic inhibition of entry of choline affecting the nervous system synthesis What will happen if Vesamicol is given? o Decrease Parasympathetic activity due to inhibition of storage What will happen if Acetylcholinesterase inhibitor is given? o Increase Parasympathetic activity since it will inhibit the breakdown of Ach to choline and acetate. Ach is now viable to the cholinoceptors. ALENCHERIL | BULAON | LORILLA | PATAWARAN | QUIAZON 2  INTRODUCTION TO AUTONOMIC NERVOUS SYSTEM Effect of presence of Botulinum toxin Then acetylcholine binding to M2 and M4 receptor would o Decrease because Botulinum toxin will block the stimulate the Gi, inhibiting your adenylyl cyclase. release of Ach from presynaptic. M1 : Considered a Neural receptor. o Found mainly in the CNS. o Also seen in gastric parietal cells. CHOLINORECEPTORS o M1 found in gastric parietal cells are responsible for the increase in gastric acid secretion by Vagal stimulation. o M1 receptors would lead to decrease in potassium conductance leading to membrane depolarization producing its excitatory effect. o Absence of this kind of Ach mediated effect in the brain is associated with DEMENTIA. M2: Located in the Heart as well as presynaptic terminals of peripheral central neurons. It produces an inhibitory effect. o It would cause potassium hyperpolarization, reducing your heart rate (bradycardia). MUSCARINIC RECEPTORS: o In the heart, main regulatory nervous system will Muscarinic receptors are further subdivided into: be the aprasympathetic o M1, M2, M3, M4, and M5 o Stimulation of M2 receptors in the heart would M1, M3, and M5: will activate Phospholipase C (Excitatory): cause Gi stimulation, inhibition of adenylyl o are associated with the activation of the Gq. cyclase, K conductance, hyperpolarization o Where activation will result in activation of your thereby decreasing the heart rate and force. IP3 and DAG. it will also result in your M3: Salivary, Bronchial (Bronchoconstriction), and Sweat o This produces mainly excitatory M3 Receptor: mobilization of intracellular calcium which will Foundo in glands It caused the stimulation of the glandular and muscles. result in calcium mediated responses like secretion, saliva, bronchial and sweat glands, contraction, secretion and neurotransmission. Helps increase saliva, sweat, contraction of theand visceral smooth muscle, M2 and M4 are associated with the activation of the Gi causes bronchoconstriction (tightening relaxation of vascular smooth muscle. airways). (Inhibitory): ▪ Increase salivary secretion o When Gi is activated, it will inhibit adenylyl ▪ Also causes muscles Bronchial in organs to smooth muscle: contract. bronchoconstriction cyclase, inhibition of the adenyl cyclase would ▪ Increase sweat lead to opening of K channels, hyperpolarization Effect of M3 stimulation: “DUMBELS” leading into reduction of heart rate. o Diarrhea All of the muscarinic receptors are coupled by your G o Urination protein second messenger. o Miosis o Bronchoconstriction o Emesis o Lacrimation o Salivation NICOTINIC RECEPTORS: Second type of cholinoceptors Nicotinic receptors are ligand-gated ion channels which causes the opening of sodium potassium channels which leads to depolarization Two types of nicotinic receptors: o NN: present in the autonomic ganglia and adrenal medulla. ▪ Excitatory ▪ it is responsible for the transmission of cholinergic signals o NM: present in the skeletal neuromuscular Binding of acetylcholine to M1, M3 & M5 would activate junction M1, M3, and M5 your IP3 PLC When Receptors: Pathway, bindrelease of IP3 would to Acetylcholine, cause the it activates a ▪ Excitatory pathway calledrelease IP3 PLC. of your calcium. ▪ Responsible for muscle contraction This pathway releases o calcium, which can alsonervous The parasympathetic cause release systemofhas nitricno oxide. direct effect on the blood vessel/vascular smooth NO helps relax blood vessels, causing vasodilation (wider blood vessels). It is important to know the effects of cholinoreceptor stimulation muscle, but the release of calcium would also and what receptor is stimulated. Parasympathetic Effect onstimulate the endothelial nitric oxide. This Blood Vessels: Ex. Identify the cholinoreceptor that is stimulated: endothelial The parasympathetic nervous system nitric oxide doesn’t stimulates directly your cyclic affect blood vessels, but the calcium releasedGMPcan and wouldNO, stimulate cause vasodilation. causing vasodilation. ▪ Muscle contraction: nm ALENCHERIL | BULAON | LORILLA | PATAWARAN | QUIAZON 3  Introduction to Autonomic Nervous System sodium depolarization and potassium repolarization leading to a response - It is further subdivided into two: NN - Excitatory - Found in the autonomic ganglia and adrenal medulla NM - Excitatory - Found in the skeletal neuromuscular junction Note: Muscarinic Receptors - Knowing the effect of your muscarinic receptors, what would be its adverse effect? ○ Cholinergic agonist: DUMBELS ○ Cholinergic antagonist: Opposite of DUMBELS  Ex. Diarrhea – Constipation  Remember atrophy ADRENERGIC TRANSMISSION - The DOPA will be stored in the vesicle by your vesicular monoamine transporter 2 (VMAT2) ○ This is inhibited by Reserpine - Inside the vesicle, there are other neurotransmitters and not only dopamine ○ This is why when your cholinergic and adrenergic vesicle are exocytosed, other neurotransmitters are also released (Ex. Substance P, ATP) - Action potential causes influx of calcium, stimulating exocytosis of the vesicle - Norepinephrine would bind to the different receptors ○ For sympathetic receptors, we call them adrenoreceptors  Alpha 1  Alpha 2  Beta 1  Beta 2  Beta 3 - When norepinephrine binds to the receptor, it produces the effect ○ The endogenous ligand here is Norepinephrine Note: What would terminate the effect of your Norepinephrine? - Diffusion - Reuptake by your Norepinephrine transporter, which will go back to the cytoplasm of your neuron ○ Drugs that inhibit the reuptake: - Sympathetic nervous system  Cocaine - The main neurotransmitter released is Norepinephrine,  Anti-depressants except your sweat glands  Solriamfetol - Tyrosine will enter the cytoplasm and be converted into ○ Taking these drugs will cause an increase in DOPA (rate-limiting step in NE synthesis), which is catalyzed sympathetic activity or wakefulness by your DOPA dehydroxylase ○ Inhibition of the reuptake Norepinephrine will cause more Norepinephrine to be available in the synapse to bind the receptor, producing an effect Note: Tyrosine Metabolism to produce DOPA - Take note that there are receptors located presynaptically, - According to the discussion of Dr. Aileen Icban (23:16) of the and these adrenoreceptors are your Alpha 2 adrenoceptors recording, tyrosine enters the cytoplasm of the neuron via DOPA dehydroxylase. However, based on Katzung, it should be and they function as autoreceptors because they regulate Tyrosine Hydroxylase the release of your Norepinephrine ADRENERGIC RECEPTOR (ADRENORECEPTOR) - Adrenoreceptor is classified into: ○ Alpha 1 ○ Alpha 2 ○ Beta 1 ○ Beta 2 Bracewell | Naik | Pineda | Rivera | Tanglao | Tiamson 4  Introduction to Autonomic Nervous System Type Tissue Actions Most vascular smooth Contraction muscles (innervated) Contraction (dilates pupil) Pupillary dilator muscle mydriasis Pilomotor smooth muscle Erects hair α1 Prostate Contraction Increases force of Heart contraction Relaxation GIT smooth muscle (hyperpolarization) Adrenoceptors - Vasoconstriction - Increased peripheral resistance - Increase blood pressure α1 - Mydriasis - Increased closure of internal sphincter of the bladder - When alpha 1 receptors are activated, it would cause - Inhibition of norepinephrine release vasoconstriction. α2 - Inhibition of acetylcholine release ○ In the nasal mucosa, if you give topical alpha-1 - Inhibition of insulin release adrenoreceptor like Oxymetazoline or - Tachycardia Phenylephrine which are used as a nasal - Increased lipolysis decongestant  it would cause constriction of the β1 - Increased myocardial contractility vessel in the nasal mucosa  increase total - Increased release of renin peripheral resistance and decrease venous - Vasodilation (skeletal, smooth muscle and capacitance leading to decongestion vascular smooth muscle to the liver)  Nasal Decongestant should not be given - Decreased peripheral resistance beyond 5 days to prevent rebound β2 - Bronchodilation congestion (Rhinitis medicamentosa) - Increased muscle and liver glycogenolysis ○ In the blood pressure, net effect would be increase - Increased release of glucagon in blood pressure. - Relaxed uterine smooth muscle ○ In the Pupillary Dilator muscle  it would cause ALPHA ADRENORECEPTOR contraction causing dilation of the pupil ○ Pilomotor  erects hair ALPHA 1 (STIMULATES GQ) ○ There will be contraction and ejaculation in the - Gq: IP3, DAG and Calcium influx Prostate  promoting urinary continence ○ If there is calcium influx in the body, it would ○ In the heart  it would cause positive inotropic cause contraction and constriction ○ Most of Alpha 1 receptors are located in the vascular smooth muscle. So, if Alpha 1 is present ALPHA 2 (INHIBITORY GI ) in the vascular smooth muscle and are activated, - Located pre-synaptically this would cause vasoconstriction leading to ○ Decrease or inhibit adenylyl cyclase causing hypertension because of increased peripheral decrease in neurotransmitter release resistance ○ Sympatholytic  When Norepinephrine binds to alpha 1,  Even though they are alpha receptor, it would cause vasoconstriction they do not increase or enhance sympathetic stimulation  It decreases the release of Norepinephrine reducing the symptoms. - If stimulated, this would inhibit the release of Norepinephrine ○ Clonidine is used to control hypertension  It binds to Alpha 2 adrenoreceptor, so Alpha 2 will be stimulated thereby inhibiting the release of epinephrine. So, if you give Clonidine, less Norepinephrine will be released leading to less vasoconstriction ○ ↓ release of Norepinephrine= ↓ vasoconstriction Location Effect Postsynaptic CNS neurons Probably multiple Platelets Aggregation Bracewell | Naik | Pineda | Rivera | Tanglao | Tiamson 5  Introduction to Autonomic Nervous System Adrenergic and cholinergic Inhibits transmitter release A α2 nerve terminals P Platelet Aggregation Some vascular smooth muscle Contraction R Regulates the release of Norepinephrine (NE) I Insulin release Fat cells Inhibits lipolysis L Lipolysis inhibition Note: Mnemonics for Alpha 2 (APRIL) Receptor Effect Alpha 1A Predominant alpha 1 present in the vascular smooth muscle; Vasoconstriction Alpha 1 Alpha 1B Cardiac Growth and structure, Behavioral Sensitization and Vulnerability to Addiction (postsynaptically) Alpha 1D Vasoconstriction in the Aorta and coronaries Sympatholytic which inhibits the release of norepinephrine; vasoconstriction precapillary vessels in Alpha 2A skeletal muscle Alpha 2 Alpha 2B Dominant mediator of A2 vasoconstriction (presynaptically) Dominant receptor modulating dopamine neurotransmission; dominant receptor inhibitor hormone Alpha 2C release from adrenal medulla - Also classified based on their affinity and effect of the adrenoreceptor agonist ○ Epinephrine ≥ Norepinephrine >> Isoproterenol for alpha adrenergic receptors ○ Isoproterenol > Epinephrine ≥ Norepinephrine for Beta adrenergic receptor BETA ADRENORECEPTOR leading to increase cardiac output, heart rate, - Beta 1 and 2 (Activate Gs) stroke volume and pulse pressure - Increase in cyclic AMP - Also present in the JG cells of the Kidney wherein it - Most of the response to Beta receptor secretion would be stimulates renin release stimulation ○ Renin promotes water reabsorption and ○ Heart: Beta secretion results to inotropic effect of potassium secretion via stimulation of the heart aldosterone secretion ○ Bronchial smooth muscle: Bronchodilation ○ Renin acts on angiotensinogen producing angiotensin I. The conversion of angiotensin I to II is mediated by the angiotensin converting enzyme. ○ Renin release is also stimulated by baroreceptors when there is hypotension or decreased perfusion. - Beta agonist mimics the effect of your norepinephrine binding to the beta receptor - Adverse effects of Beta 1 agonist: ○ Increase BP ○ Increase HR ○ Increase myocardial demand because of the increase in HR BETA-2 RECEPTOR - Beta 2 is located in respiratory, uterine and vascular smooth muscle which promotes smooth muscle relaxation and bronchodilation - In the skeletal muscle  it promotes potassium uptake - In the liver  it promotes glycogenolysis ○ Beta 2 receptor activation may cause hyperglycemia Other Effects of Beta 2 Receptors Receptor Location Effect Increases force and rate Heart, Juxtaglomerular β1 of contraction cells Increases renin release Respiratory, uterine, and Promotes smooth muscle vascular smooth muscle relaxation β2 Promotes potassium Skeletal muscle uptake Human Liver Activates glycogenolysis β3 Bladder Relaxes detrusor muscle - All Beta receptors stimulate Gs  Positive excitatory BETA-1 RECEPTOR - Beta 1 is located in the heart. - All Beta receptors stimulate Gs  stimulate/ activate ○ Once stimulated, it would cause increase in contraction as well as increase in the rate  Bracewell | Naik | Pineda | Rivera | Tanglao | Tiamson 6  Introduction to Autonomic Nervous System BETA-3 RECEPTOR - Higher dose: Stimulate beta receptor → increase in peripheral - Beta 3 is located in the bladder resistance as well as tachycardia ○ It would relax the detrusor muscle leading to - Very high dose: Stimulate the alpha receptor → vasoconstrictions - Ex. If you have a patient with dengue hemorrhagic fever and then increase bladder capacity you give the patient a fluid resuscitation but the patient does not respond, in some patient we give inotropic dopamine. If your goal DOPAMINE RECEPTORS is to increase renal perfusion you start at low dose. If your goal is to increase the peripheral resistance or increase the heart rate to increase the BP, increase the dose and then at higher dose Dopamine Receptors alpha adrenoreceptor are stimulated. D1 Brain; effectors tissues, Stimulation of adenylyl (DA1), especially smooth muscle cyclase and increase Information from MD 2026: D5 of the renal vascular bed cAMP Dopamine Receptors Brain; effector tissues Inhibition of adenylyl - Low concentration: vascular D1 receptors -> (renal, mesenteric, D2 especially smooth muscle, cyclase; increase coronary bed) (DA2) presynaptic nerve potassium conductance ○ Ex: Dengue patient low urine output. Inhibition of adenylyl ○ You can start the patient with low dose dopamine (5- D3 Brain 10) to increase renal perfusion cyclase ○ But if your goal is to increase the blood pressure Inhibition of adenylyl D4 Brain, cardiovascular system titrate the dose (10-15 or 7.5-10) cyclase - Higher doses: (+) inotropic effect on myocardium acting on B- adrenergic receptors -> DA cause release of NE from nerve terminals -> effects on heart Note: Mnemonic Don Bosco Academy (DBA) - Very high doses: DA activates vascular alpha-1 receptors -> - Low concentration: Stimulate dopamine receptor (particularly in vasoconstriction the renal vasculature) → increasing renal perfusion NON-ADRENERGIC, NON-CHOLINERGIC NEURONS - There are some neurotransmitters of substances that are either classified or they do not have the property of being a sympathetic, so they are termed ad non-adrenergic or non-cholinergic neurons. - Non-adrenergic or non-cholinergic are sometimes used in neuromodulation when they are released, they can either increase the effect of your sympathetic or parasympathetic or can either inhibit sympathetic or parasympathetic. Transmitter Location Function Non-Peptides Fat depolarization/contraction of smooth muscle cells ATP Post ganglionic neurons (e.g. Blood vessels, vas deferens) GABA, 5-hydroxytryptamine Enteric neurons Peristaltic reflex Dopamine Some sympathetic neurons (e.g. kidney) Vasodilation Nitric oxide Pelvic nerves Erection Peptides Facilitates constrictor action of noradrenaline, inhibits Neuropeptide Y Post ganglionic sympathetic neurons noradrenaline release (e.g. blood vessels) Vasoactive intestinal peptide Parasympathetic nerves to salivary glands Vasodilation, co-transmitter with, acetylcholine, (VIP) NANC innervation of airways smooth muscle bronchodilation Gonadotropin-releasing hormone Sympathetic ganglia Slow depolarization, co-transmitter with acetylcholine Substance P Sympathetic ganglia, enteric neurons Slow depolarization, co-transmitter with acetylcholine Calcitonin gene-related peptide Non-myelinated sensory neurons Vasodilation, vascular leakage, neurogenic inflammation FUNCTIONAL ORGANIZATION OF AUTONOMIC ACTIVITY INTEGRATION OF CARDIOVASCULAR FUNCTION - Central organization ○ Midbrain and medulla ○ Endocrine system ○ Parasympathetic: trophotropic ○ Sympathetic: ergotropic - There should be homeostasis. - Most parasympathetic predominates. - How is our autonomic nervous system regulated? ○ It is regulated in the CNS as well as there is hormonal regulation of your sympathetic and parasympathetic nervous system. - In hormonal feedback loop, a change in the mean arterial pressure will stimulate the baroreceptors. Bracewell | Naik | Pineda | Rivera | Tanglao | Tiamson 7  Introduction to Autonomic Nervous System ○ When there is decrease in mean arterial pressure - Presynaptic receptors that respond to the primary baroreceptors would send signals to the transmitter released by the nerve endings. vasomotor center so the integration of - Usually inhibitory except β-receptor on many cardiovascular functions is regulated by your noradrenergic fibers and many cholinergic fibers, especially baroreceptor autonomic as well as your hormonal somatic motor fiber. feedback loop o Example: α2 which are located pre synaptically - In autonomic regulation, a change in the mean arterial pressure and this α2 agonist bind to the alpha two will stimulate the baroreceptors as well receptor, they would inhibit norepinephrine ○ When there is decrease in the mean arterial release pressure, the baroreceptors are stimulated and send signals to the vasomotor center. This HETERORECEPTORS stimulates sympathetic it will secrete - Activated by substances from other nerve terminals that norepinephrine to increase the heart rate, synapses with the nerve endings. contractile force, venous tone and peripheral o Example: Acetylcholine may inhibit the release of vascular resistance, thereby restoring the blood epinephrine or vice versa pressure - There are also substance that may inhibit or stimulate - When there increase in BP, the parasympathetic nervous system other neurotransmitter release. is stimulated to help normalize it. Simultaneously, the hormonal o Example: Prostaglandin would inhibit feedback loop is activated due to decreased perfusion to the norepinephrine & histamine kidneys. ○ When there is decreased perfusion and renal POSTSYNAPTIC REGULATION blood flow, the kidneys secrete renin. ○ Renin facilitates the conversion of angiotensin I to - Modulation by the history of the activity at the primary angiotensin II. receptor.  Angiotensin II is a vasoconstrictor that o Up or down regulate the receptor number. increases peripheral vascular o Example: skeletal muscle nicotinic receptor is resistance, to compensate for the normally restricted to the end plate. Surgical elevated blood pressure. Additionally, denervation results in marked proliferation of angiotensin II stimulates the release of nicotinic cholinergic. aldosterone, which causes sodium o Reserpine: Increased sensitivity of smooth reabsorption and potassium secretion. muscle and cardiac muscle effector. ○ This process increases blood volume, stroke - Modulation by other associated events. volume, heart rate, and cardiac output, thereby o Ganglionic transmission restoring blood pressure. POSTSYNAPTIC REGULATION EXAMPLE - The slow excitatory effect produced by various mediators, PRESYNAPTIC REGULATION including acetylcholine and peptides such as substance P, on - It is usually responsible for negative feedback. many peripheral and central neurons results mainly from a - Two types of presynaptic regulation: decrease in K+ permeability. Conversely, the inhibitory effect of o Autoreceptors and heteroreceptors various opioids is mainly due to increase K+ permeability.  Autoreceptors & Heteroreceptors are - Neuropeptide Y enhance the vasoconstrictor effect of involved in neuromodulation Noradrenaline AUTORECEPTORS - They regulate their own neurotransmission release Process Drug Example Site Action Action Potential Local anesthetics, tetrodotoxin,a Block sodium channels; block Nerve axons Propagation saxitoxinb conduction Cholinergic nerve terminals: Blocks uptake of choline and slows Hemicholinium Transmitter membrane synthesis of acetylcholine Synthesis Adrenergic nerve terminals and Inhibits tyrosine hydroxylase and α-methyltyrosine (metyrosine) adrenal medulla: cytoplasm blocks synthesis of catecholamines Transmitter Vesamicol Cholinergic terminals: vesicles Prevents storage, depletes Storage Reserpine Adrenergic terminals: vesicles Prevents storage, depletes Manyc Nerve terminal membrane receptors Modulates release ω-Conotoxin GVIAd Nerve terminal calcium channels Reduces release Transmitter Botulinum toxin Cholinergic vesicles Prevents release Release Alpha-latrotoxine Cholinergic and adrenergic vesicles Causes explosive release Tyramine, amphetamine Adrenergic nerve terminals Promotes release Transmitter uptake Cocaine, tricyclic antidepressants Inhibit uptake; increase transmitter Adrenergic nerve terminals after release 6-Hydroxydopamine effect of postsynaptic receptors Norepinephrine Binds α receptors; causes activation Phentolamine Binds α receptors; prevents activation Receptors at adrenergic junctions Binds β receptors; activates adenyl Isoproterenol cyclase Receptor Propranolol Binds β receptors; prevents activation Activation or Receptors at nicotinic cholinergic Binds nicotinic receptors; opens ion Blockade Nicotine junctions (autonomic ganglia, channel in post-synaptic membrane neuromuscular end plates) Prevents activation of NN receptors Tubocurarine Neuromuscular end plates Prevents activation of NM receptors Bracewell | Naik | Pineda | Rivera | Tanglao | Tiamson 8