Pharmacology of the Autonomic Nervous System PDF

Pharmacology of the autonomic Pharmacology and Therapeutics II Nuno Coelho nervous system Integrated master – Veterinary Medicine 3rd year; 2024-2025  for teaching purposes only...

Pharmacology of the autonomic Pharmacology and Therapeutics II Nuno Coelho nervous system Integrated master – Veterinary Medicine 3rd year; 2024-2025  for teaching purposes only 1) INTRODUCTION 2) Brief revision of what is the autonomic nervous system Summary (ANS) 3) Pharmacological modulation of the sympathethic system 4) Pharmacological modulation of the parasympathethic system 5) Conclusion  for teaching purposes only Clinical case o14 years old mare is being treated for a corneal ulcer with antibiotic and atropine (ophtalmic solutions) oNow is agitated (in the day before was ok), trying to roll, not eating and not drinking, tachycardia. The eye with the córnea ulcer is dilated (mydriatic). you give an antiinflammatory (flunixin meglumine), a nasogastric tube was passed (a moderate amount of gas) and also some gas in cecum oyou asked to see the medication – you realize they switch the frequency of the antibiotic and atropin, so they are give atropine more frequently than they should. oWhat happened?  for teaching purposes only Clinical case – What is happening? o this as a colic probably because of overadministration of atropine o Atropine can be absorbed sistematically from eye o atropine is anticholinergic – block Ach effects at muscarinic receptor; is parassympatholytic o the result is an increase in sympathetic tone increased heart rate, decreased GI motility and secretions and urine retention  for teaching purposes only 1) Introduction Do. you still remember what is the autonomic nervous system? drugs that target the ANS are present in almost all the future classes  for teaching purposes only 1) Introduction. Do you still remember what is the autonomic nervous system? critical role in regulating processes to maintain physiological homeostasis and responding to acute stressors (mostly involuntary) E.g. regulation of cardiac function (heart rate, contractility), blood flow, GI motility and digestion, urogenital processes, reproduction 2) Autonomic nervous system for teaching purposes only  2) Autonomic nervous system Sympathethic activation for critical emergencies or the famous “fight-or-flight” response S activation promotes increased heart rate and cardiac contractility, vascular vasoconstriction in skin and viscera with shunting of blood flow to skeletal muscles, hepatic glycogenolysis, bronchiolar and pupillary dilation, and contraction of the spleen for teaching purposes only  2) Autonomic nervous system Parasympathethic activation initiating and sustaining energy conservation and homeostasis during periods of relative physiological quiescence = “rest and digest” In general, increasing the level of activity of PS reduces heart rate, stimulates gastrointestinal secretions and peristalsis, contracts the body of the urinary bladder, and modulates immune function for teaching purposes only  Physiological responses of selected organs and effector tissues produced by activation of efferent S (sympathetic stimulation) and PS (parasympathetic stimulation) nerves In many instances physiological responses produced by activation of PS or S nerves to a target tissue/ organ that receives dual ANS innervation may be: functionally antagonistic - e.g.: heart in some cases, S and PS may have similar responses – e.g. salivary glands for teaching purposes only for teaching purposes only 2) Autonomic nervous system Use of neurotransmitters for conveying information between nerve cells and from postganglionic neurons and target cells The principal transmitters are acetylcholine (ACh) and norepinephrine (NE) aka noradrenaline (NA) Many organs and tissues are innervated by both S and PS – dual innervation; examples?  2) Autonomic nervous system Presynaptic terminals, which release neurotransmitters in response to nerve activity, can be influenced by various substances, including neurotransmitters themselves There are several processes involved in the synthesis, storage and release of transmitters Almost all these processes can be modulated by drugs Ecco Pharmacology 1, Uptake of precursors; 2, synthesis of transmitter; 3, uptake/transport of transmitter into vesicles; 4, degradation of surplus transmitter; 5, depolarisation by propagated action potential; 6, influx of Ca2+ in response to depolarisation; 7, release of transmitter by exocytosis; 8, diffusion to postsynaptic membrane; 9, interaction with postsynaptic receptors; 10, inactivation of transmitter; 11, reuptake of transmitter or degradation products by nerve terminals; 12, uptake and release of transmitter by non-neuronal cells; 13, interaction with presynaptic receptors for teaching purposes only  for teaching purposes only 2) Autonomic nervous system Central neural circuits play a crucial role in generating and modulating the activity of peripheral S and PS nerves in response to various stimuli – axonal conduction is typically not influenced by drugs targeting ANS Drugs that target ANS act mainly on receptors and neurotransmitters – Donc, we need to learn a bit more about this Cholinergic neurons Adrenergic neurons vesicles for Ach storage and other substances (as ATP) catecholamines (NE, E and dopamine) comes from tyrosine ChAT (choline acetyltransferase) synthesizes Ach from dopamine β-hydroxylase converts dopamine to NE in acetyl-CoA and cholin postganglionic S neurons Acetylcholinesterase (AchE) – inactivation of Ach  for teaching purposes only 2) Autonomic nervous system Central neural circuits play a crucial role in generating and modulating the activity of peripheral S and PS nerves in response to various stimuli – axonal conduction is typically not influenced by drugs targeting ANS Drugs that target ANS act mainly on receptors and neurotransmitters – Donc, we need to learn a bit more about this Drugs targeting autonomic nervous system act in several ways: interaction with receptors modulate neurotransmitter release modulate neurotransmitter breakdown modulate neurotransmitter reuptake from synaptic cleft  2) Autonomic nervous system Adrenergic receptors (adrenoceptors α and β) expressed at target sites innervated by S nerves α1 and α2 (with subtypes) β: 1, 2 and 3 G-protein coupled receptors A fundamental mechanism underpinning the capability of the ANS to produce various types of physiological response profiles arises from the fact that specific adrenergic or cholinergic receptors couple primarily to specific G proteins for teaching purposes only  2) Autonomic nervous system Cholinergic receptors nicotinic (N): in postganglionic neurons and chromaffin cells of adrenal medulla (NN) and in neuromuscular junctions (NM) ligand-gated ion channels, with 5 subunits homologous around central pore muscarinic (M): at target sites (organs/tissues); 5 subtypes (M1 → M5) G-protein coupled receptors for teaching purposes only  2) Autonomic nervous system Because there are several types of G proteins (Gs, Gi, and Gq), each associated with different signaling pathways, the activation of these proteins leads to a variety of physiological and pharmacological effects in the body. for teaching purposes only for teaching purposes only  2) Autonomic nervous system for teaching purposes only Mechanism of action of receptors coupled to Gq (α1; M1, M3, M5) Mechanism of action of receptors coupled to Gs (β) Neurotransmitter binding leads to Gq activation, triggering Gs activation: ↑ adenylate cyclase that ↑ cAMP leading the second messenger cascade that ↑ PLC , and then IP3, DAG and ↑ Ca2+ to PKA formation → triggering a cellular response 2) Autonomic nervous system for teaching purposes only Mechanism of action of receptors coupled to Gi (α2; M2 and M4) Gi activation: ↓ adenylate cyclase that ↓ cAMP with inhibitory effects  DEB DANA “The job of the autonomic nervous system is to ensure the survival in moments of danger and to thrive in times of safety. Survival requires threat detection and the activation of a survival response. Thriving demands the opposite: the inhibition of a survival response so that social engagement can happen” for teaching purposes only  3) Pharmacological modulation of sympathethic Modulation of sympathethic system 2.1 Adrenergic Sympathomimetic drugs: mimic receptor pharmacological and physiological actions of agonists endogenous cathecolamines, activating adrenergic receptors 2.2 Sympatholytics: antagonists of adrenoceptors Adrenergic that inhibit its activation by NE receptor antagonists for teaching purposes only  3) Pharmacological modulation of sympathethic In 1896, Oliver and Schafer discovered that intravenous injection of extracts of adrenal gland in anaesthetized cats caused a rise in arterial pressure - Adrenaline (epinephrine) was identified as the active principle! for teaching purposes only 3.1) Adrenergic agonists for teaching purposes only antidepressant tricyclic direct-acting: bind directly and activate adrenoceptors indirect-acting: promote the increasing levels of endogenous catecholamines in synapses (release stored CL, decrease CL metabolism or inhibit their reuptake) 3.1) Adrenergic agonists for teaching purposes only Indirect sympathomimetics mode of action 1) promoting the release of cathecolamines, as NE 2) inhibiting reuptake of NE 3) Reducing metabolism by inhibiting breakdown by monoamine oxidase (MAO) or cathecol O- methyltransferase (COMT) 3.1) Adrenergic agonists smooth muscle contraction sympathomimetic drugs exert their effect by initiating its binding to adrenergic receptors they can act on α or β adrenergic receptors myriad of pharmacological (and physiological) responses for teaching purposes only for teaching purposes only 3.1) Adrenergic agonists for teaching purposes only Receptor selectivity is variable, depending on the affinity for the subtypes of receptors of the agonist prolonged exposure to agonists → desensitization of adrenergic receptors 3.1) Adrenergic agonists: cardiovascular responses β2 Receptors (via Gs protein): Increase cAMP, leading to smooth muscle relaxation and vasodilation α1 Receptors (via Gq protein): Increase intracellular Ca²⁺, causing smooth muscle contraction and vasoconstriction α2-Adrenergic Receptors (Gi protein): Decrease cAMP, promoting smooth muscle contraction and vasoconstriction catecholamines can fine tune vascular tone by either promoting relaxation or contraction of smooth muscle, depending on the specific adrenergic receptor they activate for teaching purposes only 3.1) Adrenergic agonists: cardiovascular responses stimulating β-receptors augment all heart functions including: systolic force (positive inotropic effect) velocity of myocyte shortening sinoatrial rate (positive chronotropic effect), conduction velocity (dromotropic effect) excitability (bathmotropic effect) for teaching purposes only  for teaching purposes only 3.1) Adrenergic agonists: cardiovascular responses potent and selective α1 agonist; topical and injectable Phenylephrine - produces arterial VC, ↑ peripheral vascular resistance (↑ blood pressure) and venoconstriction (PE) - applications; topical vasoconstrictor (not very used); nephrosplenic entrapment horse - colic (splenic contraction due venoconstriction leads to size reduction that helps) α1, α2 and β1 agonist NE VC and venocostriction (α-mediated effect) positive inotropic (increased cardiac contractility) and chronotropic (increased heart rate) (cardiac β1-mediated effect) potent α (1, 2) and β (1,2) agonist; injectable (adrilan) VC (α1) and reduces blood flow in some vascular beds (visceral); in arterial vasculature of skeletal muscle VD can occur (β2) E potent positive inotropic and chronotropic (β1), leading to increase in cardiac output Applications: addition to local anesthetics ; hypotension; Bronchial asthma and bronchospasms; anafilactic reactions potent β (1,2) agonist; not very used in vet - VD and increase in blood flow in regions with high expression of β2 and reduced peripheral vascular resistance (↓ in BP); Isoproterenol NOT VC (no affinity for α-receptors) - potent cardiac stimulant (β1-mediated effect): positive inotropy and chronotropy  3.1) Adrenergic agonists: cardiovascular responses Adrenergic agonists drugs that regulate arterial blood pressure DA1 agonist - IV low dose (0.5 – 2 µg/kg/min): VD in some vascular beds (renal, splanchnic) dopamine - IV moderate doses (2-10µg/kg/min) with adrenergic agonism: activate cardiac β1 (positive inotropic and chronotropic) - IV high doses (10-20µg/kg/min) activates α1 – VC and increased peripheral resistance α1, β1, β2(-) agonist at lower doses (0,1 mg/kg) with transient increase in MAP, ↑cardiac output and stroke volume (β1 effect in the ephedrine heart and β2 in vascularity with higher doses (0,25 mg/kg) – more sustained ↑ in blood pressure, cardiac parameters and ↑ systemic vascular resistance (α1 receptors activation involved): effective treatment for hypotension (e.g. associated with anesthesia) and decongestant β1 (+), but also β2 and α1 (-) agonists β1 activation: increases cardiac contractions and stroke volume dobutamine indicated to treat conditions with low cardiac output: congestive heart failure, dilated cardiomyopathy because of modest α agonist effect – less effective for hypotension (particularly surgery-induced) for teaching purposes only  3.1) Adrenergic agonists: urinary incontinence Adrenergic receptors are expressed at numerous sites in the urinary tract: ureters (β2 receptors) and detrusor muscle of the bladder body (β2 and β3 receptors) bladder base (α1 receptors) and internal urethral sphincter (α1 receptors) Stimulation of sympathetic nerves innervating these sites or activation of these receptors secondary to administration of sympathomimetics produces smooth muscle relaxation of the bladder body via β2-adrenergic receptors (and β3), and smooth muscle contraction at the bladder base and the internal urethral sphincter by activation of α1-adrenergic receptor Urethral sphincter incompetence - daily dose of phenylpropanolamine (sympathomimetic) results in an increase in urethral pressure values and improved urinary continence in most affected dogs – Uristop, Propalin, Uriphex (syrup or oral solution for dogs) for teaching purposes only 3.1) Adrenergic agonists: respiratory system Clinical case: 15 years old mare, with cough and abdominal effort; with bronchovesicular sounds and expiratory wheezes at auscultation What can we do? for teaching purposes only 3.1) Adrenergic agonists: respiratory system Clinical case: 15 years old mare, with cough and abdominal effort; with bronchovesicular sounds and expiratory wheezes at auscultation) β2 agonist to activate those receptors in bronchial smooth muscle relaxation bronchodilation example: albuterol - selective β2 agonist (aerosolized, as a short-acting drug – 1 to 2 hours) for teaching purposes only  for teaching purposes only 3.1) Adrenergic agonists: respiratory system Other drugs functioning as bronchodilators and adrenergic agonists E and isoproterenol are also bronchodilators terbutaline β₂ agonist commonly used in small animals (airway constriciton in dogs and cats parenteral or oral administration Clenbuterol β₂ agonist may be prepared as a syrup – oral administration longer duration of action (12 hours, vs 1-2 in albuterol) for horses (withdrawal time of 28d for meat), but not for food-producing animals – residues of the drug are toxic 3.2) Adrenergic antagonists Adrenergic receptor antagonists demonstrate selectivity and specificity for the various adrenergic receptors, and drugs are classified based on their antagonism of α- or β-adrenergic receptors, or mixed for teaching purposes only  3.2) Adrenergic antagonists: alpha antagonists These drugs are predominantly competitive antagonists at α-adrenergic receptors, with the exception of phenoxybenzamine which irreversibly binds to the α-adrenergic receptor cardiovascular: dilation of arterial and venous vessels, ↓ blood pressure due to ↓ in peripheral vascular resistance; Effects noncardiovascular may inhibit the α1-mediated contraction of urethral smooth muscle, decreasing resistance to urine flow protrusion of 3rd eyelid miosis nasal stuffiness reversing sedation (when α2 agonists were used to sedate) for teaching purposes only  3.2) Adrenergic antagonists: alpha antagonists Langfitt, 2017 Nonselective α1- α2 antagonists - irreversible (covalent) binding to adrenergic receptors - more substantial antagonistic effects of α1 Phenoxybenzamine - indication: manage symptons of catecholamine excess in pheochromocytoma; may also help dealing with urethral spams – smooth muscle relaxant phentolamine Few clinical indication in veterinary medicine, not commonly used - Also nonselective α-adrenergic receptor antagonists; acepromazine, chlorpromazine, phenothiazine and promazine tranquilizers - although their use as tranquilizers, may decrease peripheral vascular resistance (attention) for teaching purposes only  3.2) Adrenergic antagonists: alpha antagonists Selective α1 antagonists - competitive antagonist, in particular for α1 Prazosin Oral tablets indication: ↓ resistance urine flow (urethra) in dogs with functional obstruction, urethral spasm, hyperplasia prostatic, facilitate voiding Tamsulosin - second generation antagonist, in particular for α1 - higher affinity for α1A and α1D receptors than for the α1B subtype - third generation antagonist, very selective for α11A May promote hypotension silodosin - decrease intraurethral pressure, with less effects on blood (specially the less recent drugs as prazosin) pressure for teaching purposes only  3.2) Adrenergic antagonists: alpha antagonists Selective α2 antagonists tolazoline antagonists that are used, in veterinary, to reverse the sedative effects of α2-adrenergic agonists such Yohimbine as medetomidine, dexmedetomidine atipamezole (e.g. Atipam, antisedan) for teaching purposes only  3.2) Adrenergic antagonists: beta antagonists Beta antagonists also called Beta-blockers β-adrenergic receptor antagonists are structurally similar to catecholamines and competitively reduce receptor occupancy by catecholamines and other β-adrenergic agonists cardiac diseases: used widely in human medicine because of their efficacy in the treatment of hypertension, ischemic heart disease, congestive heart failure, and certain cardiac arrhythmias; less in vet Ocular disease – timolol to ↓ intraocular pressure by decreasing aqueous humor production for teaching purposes only 3.2) Adrenergic antagonists: beta antagonists Beta antagonists also called Beta-blockers (BB) for teaching purposes only  3.2) Adrenergic antagonists: beta antagonists for teaching purposes only Beta antagonists also called Beta-blockers – MAIN EFFECTS Cardiovascular effects: Eye: reduce slows atrioventricular intraocular conduction: negative pressure (topical inotropic and administration) chronotropic effects, by ↓ aqueous which may lead to humor reduction in cardiac production output (glaucoma) ↓ blood pressure in hypertension ↓ vascular resistance ↓ renin release Pulmonary effects Metabolic effects block β2 – bronchoconstriction – attention in inhibit lipolysis and glycogenolysis asthma or chronic obstructive pulmonary diseases hypoglycemia  4) Cholinergic pharmacology Parasympathomimetic agents: compounds with an Ach-like effect on effector cells innervated by postganglionic neurons of the PS direct-acting: activate cholinergic receptors located on effector cells indirect-acting: cholinesterase inhibitors – allow endogenous Ach to accumulate and intensity/prolong its action for teaching purposes only  41) Direct-acting parasympathomimetic agonists parasympathomimetic agonists choline esters like Ach and other synthetic esters methacholine, carbachol, bethanecol are primary choline derivatives muscarine, pilocarpine, and arecoline are primary cholinomimetic alkaloids pharmacological effects: mediated by activation of cholinergic receptors these agonists show nonuniform susceptibility to metabolism by cholinesterases, differential relative affinity for muscarinic and nicotinic receptors, and specificity in target organ effects (e.g. bethanecol and carbachol less effective on the cardiovascular system) for teaching purposes only  4.1) Direct-acting parasympathomimetic agonists Ach is the prototypical cholinergic agonist but not used therapeutically: Effects of Ach: 1) N and M receptors located in numerous sites – no cardiovascular: ↓ blood pressure (↓ peripheral resistance) and heart rate (effect potentiated by selective therapeutic effect could be seen high doses 2) very short duration of action – inactivation by nonvascular smooth muscle: contraction of smooth muscle of urinary bladder, uterus and bronchioles cholinesterases GI system: GI motility and secretions ↑ CNS: no BBB crossing for teaching purposes only  4.1) Direct-acting parasympathomimetic agonists Clinical uses in veterinary medicine Choline Esters: Methacholine, Carbachol, and Bethanecol similar effects to Ach, but with variations relative to organ-selectivity (methacholine with cardiovascular effects as Ach, carbachol and bethanecol more on GI and urinary bladder; last longer than Ach few clinical uses bethanecol used to promote bladder contraction in paraplegic cats and dogs; PO tablets carbachol: ophthalmic solution Miostat®, administered at the end of cataract surgery for miosis Cholinomimetic Alkaloids: Pilocarpine, Muscarine, and Arecoline activity exerted more on muscarinic receptors (minimal nicotinic effects Pilocarpine: stimulating secretions from exocrine glands (salivary, mucous, gastric, and digestive pancreatic) Clinical uses Pilorcapine: ophtalmic solution (1-4%) that causes constriction of the pupils (miosis) and ↓ intraocular pressure; USE: glaucoma and neurogenic keratoconjunctivits sicca) for teaching purposes only  4.2) Cholinesterase inhibitors Cholinesterase inhibitors (anticholinesterase agents) inactivate or inhibit acetylcholinesterase (AChE), increasing the level of synaptic ACh, and intensifying the activity of endogenous Ach Parasympathomimetic (muscarinic) effects Physostigmine, neostigmine, and edrophonium produce a reversible inhibition of cholinesterase organophosphate compounds produce an irreversible inhibition! for teaching purposes only 4.2) Cholinesterase inhibitors for teaching purposes only  4.2) Cholinesterase inhibitors these cholinesterase inhibitors interact, reversibly, with the anionic and esteratic sites of the enzyme, thereby preventing ACh from affixing to the enzyme EFFECTS: GI: physostigmine and neostigmine cause contraction of smooth muscle, ↑ motility and peristalsis of the gut eye: physostigmine causes pupillary constriction skeletal muscle: neostigmine stimulate nicotinic receptors on skeletal muscle fibers Adverse Side Effects of cholinergic drugs: may include bradycardia, hypotension, heart block, lacrimation, diarrhea, vomiting, increased intestinal activity, intestinal rupture, and increased bronchial secretions for teaching purposes only  for teaching purposes only 4.2) Cholinesterase inhibitors CLINICAL USES: can be used to reverse the effects of non-depolarizing neuromuscular blocking drugs in voluntary muscles Edrophonium can be used also to make a diagnosis for myasthenia gravis myasthenia gravis in dogs (rare in cats), with oral administration, specially: o pyridostigmine bromide; longer duration and less adverse GI effects; 0.5-3 mg/kg PO, BID or TID for dogs o neostigmine bromide: treat urine retention and GI atony; also used as antidote for neuromuscular blocking agents  4.3) Muscarinic receptor antagonists Muscarinic antagonists, also known as antimuscarinic medications, are a class of drugs that block the activation of muscarinic receptors of the parasympathetic nervous system atropine, the prototypical muscarinic blocking agent is an alkaloid extracted from Atropa belladonna (deadly nightshade) other antimuscarinic agents: propantheline, glycopyrrolate, tropicamide and butylscopolamine for teaching purposes only  4.3) Muscarinic receptor antagonists MECHANISM OF ACTION Muscarinic receptor antagonists interact with muscarinic receptors of effector cells and, by occupying these sites, prevent ACh from binding to the receptor Physiological responses to parasympathetic nerve impulses are attenuated for teaching purposes only  4.3) Muscarinic/cholinergic receptor antagonists Places of action of anticholinergic drugs https://www.lecturio.com/pt/concepts/farmacos-anticolinergicos/ for teaching purposes only 4.3) Muscarinic receptor antagonists Pharmacological effects (atropine): CVS: ↑ in heart rate and intranodal conduction velocity; cardiac output may increase, but arterial BP = or slightly increases GI: relaxation of GI smooth muscle USE: treatment of intestinal spams and hypermotility; act from stomach to colon Decreased salivation and intestinal and gastric secretions Respiratory system: decrease airway secretions and promotes bronchodilation Eyes: mydriasis and cycloplegia; contraindicated with glaucoma Urinary tract: relaxation of smooth muscle of urinary tract; spasmolytic effect for teaching purposes only 4.3) Muscarinic receptor antagonists remember the clinical case less important in veterinary medicine, the sweat production for teaching purposes only 4.3) Muscarinic receptor antagonists Clinical uses - atropine and - antispasmodics or spasmolytics to - atropine is used to facilitate control smooth muscle spasm propantheline used for ophthalmoscopic examination of bradyarrhythmias internal ocular structures - used to decrease or abolish GI hypermotility and depress associated with effects on – 1% ophthalmic solution, due to hypertonicity of uterus, urinary cardiac output and blood effect as mydriatic and cycloplegic; bladder, ureter, bile duct, and pressure - treatment of iridocyclitis in bronchioles veterinary - propantheline with - N-butylscopolamine bromide - tropicamide (Mydriacyl )can also indicated for spasmodic colic in similar actions to atropine, be used for diagnosis ophthalmic horses and bronchodilator but can be used PO and for chronic settings for teaching purposes only Thank you ! for teaching purposes only  References Riviere, J. E., & Papich, M. G. (Eds.). (2018). Veterinary pharmacology and therapeutics. John Wiley & Sons. Ritter, J. M., Flower, R., Henderson, G., Loke, Y. K., MacEwan, D., & Rang, H. P. (2020).Rang and Dale's Pharmacology. Philadelphia, PA: Elsevier. Lüllmann, H., Mohr, K., Hein, L., & Bieger, D. (2018). Color atlas of pharmacology. New York: ThiemeTillement, J. P. Allerton, F. (2020). BSAVA: Small Animal Formulary (Ed. 10). British Small Animal Veterinary Association