Seminar 11 Pharmacology of Autonomic Nervous System PDF

PHARMACOLOGY OF AUTONOMIC NERVOUS SYSTEM 3° MEDICINE Academic year: 2024/25 Professor: Vittoria Carrabs PhD 1. Agonist and antagonist definitions The ability of a drug to initiate a cellular effect is called efficacy (also known as intrinsic activity) Drugs th...

PHARMACOLOGY OF AUTONOMIC NERVOUS SYSTEM 3° MEDICINE Academic year: 2024/25 Professor: Vittoria Carrabs PhD 1. Agonist and antagonist definitions The ability of a drug to initiate a cellular effect is called efficacy (also known as intrinsic activity) Drugs that have both receptor affinity and efficacy are called agonists, whereas drugs that have receptor affinity but lack efficacy are called antagonists. Antagonists have common components sufficient for receptor affinity, but only agonists have the structure required for efficacy. 1. Agonist and antagonist definitions There are three types of agonists: Full agonists can produce the maximal response obtainable in a tissue and therefore have maximal efficacy. Partial agonists submaximal response. In the presence of a full agonist, a partial agonist will act like an antagonist because it will prevent the full agonist from binding to the receptor and exerting a maximal response. Inverse agonists inverse agonist decreases the rate of signal transduction. 1. Agonist and antagonist definitions There are three types of agonists: Full agonists can produce the maximal response obtainable in a tissue and therefore have maximal efficacy. Partial agonists submaximal response. In the presence of a full agonist, a partial agonist will act like an antagonist because it will prevent the full agonist from binding to the receptor and exerting a maximal response. Inverse agonists inverse agonist decreases the rate of signal transduction. Do you remember any example of inverse agonist currently used? 1. Agonist and antagonist definitions Antagonists can prevent the action of agonists and inverse agonists by occupying binding sites on the receptor. Competitive antagonists bind to the same site as the agonist on the receptor but are reversibly bound. Noncompetitive antagonists block the agonist site irreversibly, usually by forming a covalent bond. aspirine + AchE 1. Agonist and antagonist definitions Somatic Nervous System Voluntarily responds to external stimuli Autonomic Nervous System Involuntarily regulates internal body functions Cholinergic system  Muscarinic Receptors Nicotinic Receptors M1 SNC stimulation Stimulation of gastric digestive Nm In the skeletal neuromuscular glands secretion junction Its antagonists more specific are M3 Vasodilation tubocurare and 𝛼-bungarotoxina Secretion stimulation Contraction of digestive system Nn Expressed in the SNC, autonomic and bladder ganglia Bronchoconstriction Ocular fibers contraction: ciliary and circular muscle M2 Cardiac inhibition Muscarinic Agonists 1. Direct Action Pilocarpine, Cevimeline, Bethanecol 2. Indirect action (inhibitors of Acetylcholinesterese) Muscarinic and nicotinic activation Therapeutic applications: Reduce tachycardia Treatment of glaucoma (agonists cause miosis and reduce eye pressure) Treatment of urinary retention and paralytic ileus (temporary absence of normal muscular contractions of the intestines) – agonists stimulate non-vascular smooth muscle contraction Muscarinic Antagonists (parasimpatolytcs) Muscarinic receptor antagonists (parasympatholytic drugs) are Compound competitive antagonists of muscarinic receptors Atropine At high doses are able to block nicotine receptors Glycopyrronium Hyoscine (scopolamine) Therapeutic applications: Ipratropium Treatment of bradycardia after myocardial infarction In pre-anesthesia (protection of vagal manifestations: bradycardia on Tropicamide Cyclopentolate induction) Darifenacin As an antispasmodic in gastrointestinal hypertonia or urinary hypertonia. Solifenacin Antidote to acetylcholinesterase inhibitors. Tolterodine Adrenergic System 𝛼1 Vasoconstriction Relaxation of GI smooth muscle Salivary secretion Hepatic glycogenolysis 𝛼2 Inhibition of transmitter release (NA and Ach from autonomic nerves) Platelet agregation Vascular smooth muscle contraction Reduction of insulin release β1 Increased cardiac rate and force β2 Bronchodilation Vasodilation Relaxation of visceral smooth muscle Hepatic glycogenolysis Muscle tremor β3 Lipolysis and thermogenesis, bladder detrusor muscle relaxation Classification of sympathomimetics Classification of sympathomimetics Direct action Indirect action No selective Selective Increasing release: Tyramine (no therapeutic use) Adrenaline (𝛼, β1, β2) 𝛼1:Phenilephrine Inhibition of uptake: ATC, cocaine Noradrenaline (𝛼, β1) 𝛼2: Clonidine Inhibition of degradation: IMAO Isoprenaline (β) β1: Dobutamine Dopamine (α1 and β1) β2 -agonists Mixed action Ephedrine, amphetamine, Pseudoephedrine Pharmacological effects - Treatment of bradycardia or cardiac arrest (positive inotropic and chronotropic effects) - To prevent or control local bleeding (vasoconstriction) - Anaphylactic shock (avoid cardiorespiratory arrest and bronchospasm) - Nasal and ocular decongestant - To prolong local anesthesia - Severe hypotension Adrenergic Antagonists α-adrenoceptor antagonists are: β-adrenoceptor antagonists are: Non-selective between subtypes (e.g. phenoxybenzamine , phentolamine ) Non-selective between β1 and β2 -adrenoreceptors: α1 -selective Propranolol, alprenolol, oxprenolol, timolol (e.g. prazosin , doxazosin , terazosin, ergot β1-selective: derivatives ) Atenolol, metoprolol, bisoprolol, nevibolol α2 -selective (e.g. yohimbine , idazoxan ) Mixed. Labetalol and Carvedilol (𝛼1-antagonist/β-antagonist) Pharmacological effects α action: for example, prazosin (α1): treatment of high blood pressure or heart failure. β action: for example, atenolol (ß1, cardioselective), propranolol (ß1 and ß2). Reduction in strength and heart rate (ß1 blockade) / bronchoconstriction (ß2 blockade – undesirable effect) Therapeutic application: Treatment of hypertension, tachycardias or arrhythmias Objectives: 1. To investigate and demonstrate the pharmacological properties of drugs affecting the autonomous nervous system, heart, or blood vessels. To study the “in vivo” HR and BP variations in an anaesthetized animal. 2. To understand the uses in practice of drugs that interact at the adrenergic receptors as well as toxicities that could occur as a result of these interactions. CVS Rat Cardiovascular System To simplify the pharmacological effects and their interpretation, a denervated and unmedicated rat (pithed rat) is chosen. As the nerve connection to the brain is severed, the reflexes associated with carotid artery baroreceptors are suppressed and the interpretation of pharmacological effects is simplified. Tutorial RatCVs https://youtu.b e/rFdQfFinLL0?f eature=shared http://spider.science.strath.ac.uk/sipbs/software_sims.htm CVS Rat Cardiovascular System The following graphic shows an example of the plots you will see on your computer screen for: Arterial blood pressure: ABP = arterial blood pressure (mmHg) Left ventricular pressure: LVP = Left ventricular pressure Venous blood pressure: VBP = Venous blood pressure Cardiac contraction force: Con HF = Heart contraction force Heart rate: HR = Heart rate (beats/min) CVS Rat Cardiovascular System Drug list and affinity for receptors Drug R muscarinic R nicotinic R 𝛼-AR R β1-AR R β2-AR Acetylcholine Agonist Adrenaline Agonist Noradrenaline Agonist Phenylephrine Agonist 𝛼-1 Salbutamol Agonist Atropine Antagonist Phentolamine Antagonist Prazosin Antagonist 𝛼-1 Propranolol Antagonist ADRENALINE Exercise 1 Simulate the curve dose-response of Isoprenaline (0.2, 1, 5, 20 μg/kg). Simulate the same curve dose response in presence of propanolol (2mg/kg) 0.2 1 5 20 HR ABP HR ABP HR ABP HR ABP Isoprenaline 378 111 374 69 548 63 631 79 Propanolol + 351 90 372 80 351 76 63 45 Isoprenaline Rational Exercise 2 Administer two doses (2 and 5 µg/kg) of noradrenaline (NA) and measure its response on blood pressure, in the absence and presence of the antagonist, of which a single dose (1 mg/kg) will be administered. Record the results in the table STEPS Start The Virtual Rat simulation software (RATCVS). Then return to the Chart tab and select the pitted rat model from the lower Preparation menu. Press Start to start the experiment. After a few seconds of stabilization of the measurements, inject 2 μg/kg of NA (Standard Drugs menu) and observe the variation in the animal's blood pressure. Note the result. Now administer the dose of 5 µg/kg NA. Repeat the experiment, but now in the presence of the antagonist. New experiment by administering 1 mg/kg of antagonist (Standard Drugs) and 5 seconds later inject 2 μg/kg of NA. Record the result in the presence of the antagonist. Then administer 5 μg/kg of NA. Record the result in the table. Finally, administer a high dose of noradrenaline (100 μg/kg), to observe the effect produced Exercise 2 Administer two doses (2 and 5 µg/kg) of noradrenaline (NA) and measure its response on blood pressure, in the absence and presence of the antagonist, of which a single dose (1 mg/kg) will be administered. Record the results in the table ABP with 2 μg/kg of ABP with 5 μg/kg of NA NA NA ABP: 107 ABP : 96 Antagonist + NA proponol ABP : 125 ABP : 70.49 Exercise 3 We will administer three doses of noradrenaline (50, 200 and 500 µg/kg) and measure its response on heart rate, in the absence and presence of the antagonist, of which a single dose (10 mg/kg) will be administered. STEPS In the Chart tab, select the pithed rat model from the Preparation bottom menu. Press Start to start the experiment. After a few seconds of stabilization of the measurements, inject 5 0 μg/kg of NA (Standard Drugs menu) and observe the variation in the animal's heart rate. Then administer the 200 µg/kg dose, allow the effect to occur and add the 500 µg/kg NA (Standard Drugs) dose. Write the results in the table. Repeat the experiment again first administering 10 mg/kg of antagonist (Standard Drugs) and 5 seconds later inject 50 μg/kg of NA. Record the results. Then add the 200 μg/kg NA dose, record the results, then add the 500 μg/kg NA dose and record the results again. Exercise 3 We will administer three doses of noradrenaline (50, 200 and 500 µg/kg) and measure its response on heart rate, in the absence and presence of the antagonist, of which a single dose (10 mg/kg) will be administered. HR with 50 μg/kg of HR with 200 μg/kg of NA NA NA 480 475 Antagonist+ NA 367 351 Exercise 4 We will administer three doses of acetylcholine (1, 10 and 100 µg/kg) and measure its response on heart rate and blood pressure, first in the absence of the antagonist, then in the presence of the antagonist, of which a single dose (1 mg/kg) will be administered. STEPS In the Chart tab and select in the lower menu Preparation the pithed rat model. Press Start to start the experiment. After a few seconds of stabilization of the measurements, inject 1 μg/kg of ACh (Standard Drugs menu) and observe the effects. Record the results. Then administer the 10 µg/kg dose, allow the effect to take place and add the 100 µg/kg dose of ACh (Standard Drugs menu). Record the results in the table. Repeat the experiment again (File: New rat), first administering 1 mg/kg of antagonist (Standard Drugs) and 5 seconds later inject 1 μg/kg of ACh. Record the results. Then add the 10 μg/kg dose of ACh, record the results, then add the 100 μg/kg dose of ACh and record the results again. Exercise 4 We will administer three doses of acetylcholine (1, 10 and 100 µg/kg) and measure its response on heart rate and blood pressure, first in the absence of the antagonist, then in the presence of the antagonist, of which a single dose (1 mg/kg) will be administered. 1 µg/kg 10 µg/kg 100 µg/kg ABP HR ABP HR ABP HR Ach 97 356 72 322 38 257 Antagonist + Ach 72 351 68 351 64.4 237.2